Oxford Textbook of Neurocritical Care Edited by Martin M. Smith, Giuseppe G. Citerio, and W. Andrew I. Kofke Abstract Neurocritical care is a subspecialty of intensive care medicine dedicated to providing comprehensive management for all life-threatening neurological disorders and their complications. Improved understanding of pathophysiology and advances in monitoring and imaging techniques have led to the introduction of more effective and individualized treatment strategies that have translated into improved outcomes for patients. As the knowledge base underpinning the practice of neurocritical care has increased and evidence of outcome benefits has emerged, there has been a commensurate growth in the subspecialty of neurocritical care and in neurointensivists and their specialist teams. The delivery of effective neurocritical care requires an understanding of underlying physiological and pathophysiological processes in addition to interpretation of subtle changes in clinical status and in neuromonitoring and neuroimaging variables. Critically ill neurological patients require meticulous general intensive care support to optimize systemic organ system function and provide an optimal physiological environment for neurological recovery, as well as interventions targeted to their neurological disorders. The management of acute brain injury is particularly complex and requires a coordinated and stepwise approach that includes clinical assessment, monitoring, and multifaceted management strategies targeted to minimize secondary neurological injury. Collaboration and cooperation between clinicians from multiple disciplines is crucial to the effective delivery of care. The Oxford Textbook of Neurocritical Care has gathered together a group of international experts from many disciplines to provide a comprehensive global overview of the specialty. Each chapter highlights advances in specific areas and emphasizes the importance of the meticulous attention to detail that underpins the clinical practice of neurocritical care. Although primarily aimed at those working in neurocritical care, this textbook will also be of interest to those from other disciplines who have regular or occasional contact with patients with acute neurological disease. Less
Bibliographic Information Publisher: Oxford University Press Print Publication Date: Mar 2016 Print ISBN-13: 9780198739555 Published online: Mar 2016 DOI: 10.1093/med/9780198739555.001.0001 Martin M. Smith, editor MBBS, FRCA, FFICM, Consultant and Honorary Professor in Neurocritical Care, The National Hospital for Neurology and Neurosurgery, and National Institute for Health Research, University College London Hospitals; Biomedical Research Centre, London, UK Giuseppe G. Citerio, editor Director of Neuroanaesthesia and Neuro Intensive Care, and Director of Neurocritical Care and Neuroanaesthesia, School of Medicine and Surgery, University Milano-Bicocca, and Department of Anaesthesiology and Critical Care, San Gerardo Hospital, Monza, Italy W. Andrew I. Kofke, editor MD, MBA, FCCM, FNCS, Professor and Director of Neuroscience in Anaesthesiology and Critical Care Program; Co-Director of Neurocritical Care, Department of Anaesthesiology and Critical Care, and Professor in Department of Neurosurgery, University of Pennsylvania, Philadelphia, USA
Foreword Author(s): Graham M. Teasdale and Nino Stocchetti The emergence of intensive care from the dark ages after World War II was the result of a combination of factors. The experience gained in the polio epidemics of the 1940s and 1950s had left a legacy of theoretical and practical knowledge of managing patients with inadequate respiration and airway protection. The frequency that respiratory failure often accompanied a terminal decline made it an obvious target for intervention. General intensive care, for respiratory support irrespective of aetiology, evolved then but in the context of more specialized approaches for specific pathologies, such as acute brain damage. The importance of brain injury as a major cause of death and disability became clear and the pessimistic view that these outcomes were largely inevitable was challenged. But what was not appreciated at the beginning was the complexity of the processes involved, how they are compounded by the interactions between intracranial and extracranial events, with possible benefits of powerful treatments (such as barbiturates or hypothermia) offset by contrary adverse effects. The Oxford Textbook of Neurocritical Care shows just how the specialty has now advanced to meet these challenges. The editors have brought together an impressive group of more than 60 experts in general critical care, respiratory medicine, specialized neurocritical care, neurology, neurosurgery, and radiology. Their work has been well orchestrated, reducing redundancies and overlaps to an unavoidable minimum. The structure of the book properly reflects what intensive care should be about: grounded on physiopathology and mechanisms (part 1 is devoted to basic principles), based on continuous and sophisticated measurements (part 2 covers a range of monitoring modalities), and fine-tuned to specific pathological conditions (part 3), from postoperative care to neuromuscular disorders. The evidentiary basis of practice is reviewed extensively and synthesized clearly. There is an average of 122 citations per chapter, leading to an impressive total of 3789 references. Each topic includes investigations of disease mechanisms, and how these can be modified in experimental models and in patients, together with results from rigorous clinical studies. The quality of tables and figures is excellent, with schematic drawings of anatomical features, down to microscopic details, and clear definitions of terms. Chapters on neuropathophysiology and blood flow regulation are exemplary, with useful schematic illustrations of histology, anatomy, and neurophysiology. This effective educational style is expressed in several topics: for example, when fluid management is addressed, water homeostasis and compartmentalization are carefully described, and illustrated in diagrams. When possible, as in the case of sedation, a practical approach is proposed, with a logical algorithm presenting the various options faced in everyday clinical practice. Inevitably in several areas there are educated opinions rather than strong evidence. This honest admission doesn’t leave the reader in a limbo of uncertainty, but clearly separates what is proven from what is not; options, in these cases, are still presented with clinical wisdom and experience. Brain damage may be fatal, or have lifelong consequences. The social implications of acute brain injury, for survivors and their families, are acknowledged. The last chapter is devoted to outcome and prognosis, with specific data on risk adjustment and prognostic models in different pathologies. Survival rates, and quality of survival, are addressed. Ethical implications are wide, both for grading intensity of care and for withdrawing futile therapies. These issues are covered in a precise chapter which reports legal and ethical implications, and in a further chapter focused on organ donation. Neurointensive care is rapidly evolving and expanding. Several features are changing, new competencies are required, and keeping up to date may appear to favour rapid access to the latest online information. Nevertheless, clinicians still need a clear, comprehensive, and credible source of the core of information upon which the speciality is based. This textbook, in a quickly moving scenario, provides the necessary account of the foundations of neurocritical care. We believe it will be valued by both the diligent student and the more experienced practitioner.
Professor Graham M. Teasdale, DSc Mental Health and Wellbeing, University of Glasgow Gartnavel Royal Hospital Glasgow, United Kingdom Professor Nino Stocchetti Department of Physiopathology and Transplantation Milan University Neuro ICU Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, Italy
Preface Author(s): Martin Smith , Giuseppe Citerio , and W. Andrew Kofke Neurocritical care has evolved rapidly in the last two decades from its initial focus on the management of postoperative neurosurgical patients to a multidisciplinary specialty that provides comprehensive management for all life-threatening disorders of the central nervous system (CNS) and their complications. Managing the complex interaction between the injured brain and systemic organ systems is the cornerstone of neurocritical care which, in parallel with increased understanding of the pathophysiology of CNS disease and advances in monitoring and imaging techniques, has led to the introduction of more effective and individualized treatment strategies that have translated into improved outcomes for critically ill neurological patients. The cornerstone of neurocritical care is the identification of individuals at risk of developing secondary brain injury and the delivery of targeted interventions to provide the optimal conditions to minimize such injury and maximize the chances of good neurological outcome. A major challenge for the neurointensivist is balancing the risks and benefits of various treatment options, being mindful that brain injury and brain-directed therapies can have potentially adverse effects on systemic organ systems and management of failing systemic organ systems can similarly have adverse effects on the injured brain. Thus the delivery of effective neurocritical care requires an understanding of underlying physiological and pathophysiological processes and interpretation of subtle clinical changes in association with neuromonitoring and neuroimaging data. Possibly more than any other branch of intensive care medicine, neurocritical care also requires collaboration and cooperation between clinicians from multiple disciplines. Whilst the neurointensivist and their teams coordinate and direct the management of patients on the neurocritical care unit, input from other disciplines, including neurology, neurosurgery, neuroradiology, trauma, and stroke physicians, is of crucial importance. The Oxford Textbook of Neurocritical Care recognizes the common knowledge base and skills that are required for the management of critically ill neurological patients and has gathered together a group of international experts from multiple disciplines to provide a comprehensive global overview of the specialty. Each chapter of this book highlights advances in the respective areas but also emphasizes the importance of getting the basics right. Management of systemic and cerebral physiology is as important as interventions targeted to a specific neurological pathology or disease state, and this textbook quite rightly emphasizes throughout the importance of doing lots of little things consistently well. In this way, we hope that it will provide a framework for developing the meticulous attention to detail that underlies the clinical practice of neurocritical care.
Although primarily aimed at those working in neurocritical care, we anticipate that this textbook will also be of interest to those from other disciplines who have regular or occasional contact with patients with acute neurological disease. We particularly hope that it will be a useful educational resource for trainees from many disciplines and that it might stimulate their interest in neurocritical care. We would like to thank our colleagues who have contributed to this book, our families for their forbearance during its preparation, and of course our patients from whom we have learned so much. Martin Smith Giuseppe Citerio W. Andrew Kofke
Abbreviations
3D three-dimensional AAN American Academy of Neurology ABI acute brain injury ABP arterial blood pressure ACTH adrenocorticotropic hormone ADC apparent diffusion coefficient ADEM acute disseminated encephalomyelitis ADH antidiuretic hormone AED antiepileptic drug AF atrial fibrillation AHA American Heart Association AIS acute ischaemic stroke AKI acute kidney injury ALI acute lung injury AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANS autonomic nervous system APACHE Acute Physiology And Chronic Health Evaluation AQP aquaporin ARDS acute respiratory distress syndrome ASA American Stroke Association aSAH aneurysmal subarachnoid haemorrhage ASL arterial spin labelling ASPECT Alberta Stroke Pogramme Early CT Score ATLS Advanced Trauma Life Support ATP adenosine triphosphate AVM arteriovenous malformation BAO basilar artery occlusion BBB blood–brain barrier BFV blood flow velocity BI Barthel Index BNP brain natriuretic peptide BOLD blood oxygen level-dependent BP blood pressure BTF Brain Trauma Foundation CBF cerebral blood flow CBV cerebral blood volume CCP critical closing pressure CEA carotid endarterectomy cEEG continuous electroencephalogram CFU colony forming unit
CI confidence interval CIM critical illness myopathy CIP critical illness polyneuropathy CK creatine kinase CMR cerebral metabolic rate CMRO2 cerebral metabolic rate of oxygen CNS central nervous system CO2 carbon dioxide CoCBF cortical cerebral blood flow CPAP continuous positive airway pressure CPP cerebral perfusion pressure CRS-R Coma Recovery Scale—Revised CSF cerebrospinal fluid CSW cerebral salt wasting CT computed tomography CTA computed tomography angiography CTP computed tomography perfusion DAG diacylglycerol DBP diastolic blood pressure DCD donation after cardiac death DCI delayed cerebral ischaemia DCS diffuse correlation spectroscopy DI diabetes insipidus DND donation after neurological death DSA digital subtraction angiography DTI diffusion tensor imaging DWI diffusion-weighted imaging EAAT excitatory amino acid transporter ECF extracellular fluid ECG electrocardiogram ED emergency department EDH extradural haematoma EDHF endothelial-derived hyperpolarization factor EEG electroencephalogram EF ejection fraction EGL endothelal glycocalyx layer EMG electromyogram EP evoked potential EPO erythropoietin EPOR erythropoietin receptor ET endothelin EVD external ventricular drain FFP fresh frozen plasma FLAIR fluid-attenuated inversion recovery fMRI functional magnetic resonance imaging FOUR Full Outline of UnResponsiveness FV flow velocity FVC forced vital capacity GABA gamma-aminobutyric acid GCS Glasgow Coma Scale GH growth hormone GOS Glasgow outcome score GRE gradient-echo HFO high-frequency oscillation HMPAO hexamethylpropyleneamine oxime HPA hypothalamic–pituitary–adrenal
HR heart rate HSP heat shock protein HSV herpes simplex virus IA intra-arterial ICAM intercellular adhesion molecule ICH intracerebral haemorrhage ICP intracranial pressure ICU intensive care unit IHCA in-hospital cardiac arrest IL interleukin IP3 inositol 1,4,5-triphosphate IPC intermittent pneumatic compression ITP intrathoracic pressure ITT intensive insulin therapy LDF laser Doppler flowmetry LEMS Lambert–Eaton myasthenic syndrome LLA lower limit of autoregulation LMWH low-molecular-weight heparin LOS length of stay LV left ventricular MABP mean arterial blood pressure MAC minimal alveolar concentration MAP mean arterial pressure MCS minimally conscious state MD microdialysis MDCT multidetector-row computed tomography MEP maximal expiratory pressure MG myasthenia gravis MIP maximal inspiratory pressure MODS Multiple Organ Dysfunction Score MPM Mortality Prediction Model MRA magnetic resonance angiography MRC Medical Research Council MRI magnetic resonance imaging MRP magnetic resonance perfusion MTT mean transit time MUAP motor unit action potential NCCT non-contrast computed tomography NCCU neurocritical care unit NCSE non-convulsive status epilepticus NCSz non-convulsive seizures NDD neurological determination of death NF-κB nuclear factor kappa B NICU neurointensive care unit NIHSS National Institutes for Health Stroke Scale NIRS near-infrared spectroscopy NMDA N-methyl-D-aspartate NO nitric oxide NSAID non-steroidal anti-inflammatory drug NSE neuron-specific enolase O2 oxygen OEF oxygen extraction fraction OHCA out-of-hospital cardiac arrest OR odds ratio PaCO2 partial pressure of arterial carbon dioxide PAF platelet-activating factor
PaO2 partial pressure of arterial oxygen PCAS post-cardiac arrest syndrome PCI primary percutaneous intervention PCT perfusion computed tomography PCV pressure control ventilation PED periodic epileptiform discharge PEEP positive end-expiratory pressure PET positron emission tomography PKC protein kinase C PLED periodic lateralized epileptiform discharge PP periodic paralysis PRx pressure reactivity index PSH paroxysmal sympathetic hyperactivity PtiO2 brain tissue oxygen tension PTT partial thromboplastin time PVS persistent vegetative state PWI perfusion-weighted imaging qEEG quantitative electroencephalogram QOL quality of life RAA renin–angiotensin–aldosterone ROS reactive oxygen species ROSC return of spontaneous return circulation RR respiratory rate rtPA recombinant tissue plasminogen activator RV right ventricular RWMA regional wall motion abnormality SAH subarachnoid haemorrhage SaO2 arterial oxygen saturation SAPS Severity of Illness And Physiology Score SBP systolic blood pressure SCI spinal cord injury SDH subdural haematoma SE status epilepticus SG specific gravity SIADH syndrome of inappropriate antidiuretic hormone secretion sICH symptomatic intracerebral haemorrhage SjvO2 jugular venous oxygen saturation SOFA Sequential Organ Failure Score SPECT single-photon emission computed tomography SpO2 peripheral oxygen saturation SSEP somatosensory evoked potential STEMI ST-segment elevation myocardial infarction TAI traumatic axonal injury TBI traumatic brain injury TCD transcranial Doppler TDF thermal diffusion flowmetry TIA transient ischaemic attack TNF tumour necrosis factor TOF time-of-flight tPA tissue plasminogen activator TRP transient receptor potential UCNS United Council of Neurological Subspecialties UFH unfractionated heparin UNOS United Network for Organ Sharing UTI urinary tract infection UWS unresponsive wakefulness syndrome
VAP VC VCAM VEGF VILI VTE VZV WFNS WLST
ventilator-associated pneumonia vital capacity vascular cell adhesion protein vascular endothelial growth factor ventilator-induced lung injury venous thromboembolism varicella zoster virus World Federation of Neurological Surgeons withdrawal of life-sustaining therapy
Contributors
Imoigele Aisiku Assistant Professor, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
Craig Anderson Professor of Stroke Medicine and Clinical Neuroscience, The George Institute for Global Health, University of Sydney, Australia, Head of Neurology, Royal Prince Alfred Hospital, Sydney, Australia Jonathan Ball Consultant and Honorary Senior Lecturer in General and Neuro Intensive Care, St George’s Hospital, London, UK Ronny Beer Assistant Professor, Department of Neurology, Neuro-ICU, Medical University of Innsbruck, Innsbruck, Austria Antonio Belli Professor of Trauma Neurosurgery, University of Birmingham, Queen Elizabeth Hospital and NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK Olivier Bodart Research Fellow in Neurology, Coma Science Group, University and University Hospital of Liège, Liège, Belgium Nicolas Bruder Professor, Aix-Marseille Université, CHU Timone, Marseille, France Iole Brunetti Department of Surgical Sciences and Integrated Diagnostics IRCCS AOU San Martino—IST, Genoa, Italy Jayaram Chelluri Critical Care Fellow, University of Pittsburgh, Presbyterian Hospital, Pittsburgh, PA, USA Lakshmi P. Chelluri Professor, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Newton Cho Division of Neurosurgery and Spinal Program, Toronto Western Hospital, Toronto, Canada Chandril Chugh Fellow in Endovascular Surgical Neuroradiology, Texas Stroke Institute, Plano, TX, USA Jan Claassen Associate Professor of Neurology, Columbia University College of Physicians & Surgeons, New York, NY, USA Giuseppe Citerio Professor in Anaesthesia and Critical Care, School of Medicine and Surgery, University of Milano-Bicocca, Italy David W. Crippen Professor, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Barry M. Czeisler Assistant Professor of Neurology, Division of Neurocritical Care, New York University School of Medicine, New York, NY, USA Neha S. Dangayach Assistant Professor, Mount Sinai Hospital, New York, NY, USA Candice Delcourt Clinical Research Fellow, The George Institute for Global Health, University of Sydney, Royal Prince Alfred Hospital, Camperdown, Australia Michael N. Diringer Professor of Neurology, Neurosurgery and Anaesthesiology, Washington University School of Medicine, St. Louis, MO, USA Nazzareno Fagoni Consultant, Department of Anaesthesia, Critical Care and Emergency, Spedali Civili University Hospital, Brescia, Italy Michael G. Fehlings Professor of Neurosurgery, University of Toronto, Toronto, Canada; Medical Director Krembil Neuroscience Center, Toronto Western Hospital, Toronto, Canada Jennifer A. Frontera Associate Professor of Neurology, Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Cleveland, OH, USA Olivia Gosseries Post-Doctoral Researcher, Coma Science Group, University and University Hospital of Liège, Liège, Belgium Raimund Helbok Assistant Professor, Department of Neurology, Neuro-ICU, Medical University of Innsbruck, Innsbruck, Austria J. Claude Hemphill III Professor of Neurology and Neurological Surgery, University of California, San Francisco, CA, USA Hooman Kamel Assistant Professor of Neurology, Weill Cornell Medical College, New York, NY, USA
Matthew A. Kirkman Specialty Trainee in Neurosurgery and Honorary Fellow in Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK W. Andrew Kofke Professor and Director of Neuroscience in Anaesthesiology and Critical Care Program; CoDirector of Neurocritical Care, Department of Anaesthesiology and Critical Care, University of Pennsylvania, Philadelphia, USA Peter Komlosi Department of Radiology, Neuroradiology Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Nicola Latronico Director, University Division of Anesthesia and Critical Care Medicine and School of Speciality in Anesthesia and Critical Care Medicine, University of Brescia at Spedali Civili, Piazzale Ospedali Civili, Brescia, Italy Steven Laureys Director, Coma Science Group, University and University Hospital of Liège, Liège, Belgium Andrea Lavinio Director, Neurosciences and Trauma Critical Care Unit, Consultant, Department of Anaesthesia, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK Stephan A. Mayer Director, Neurocritical Care, Mount Sinai Health System, Professor of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA RajaNandini Muralidharan Division of Neurocritical Care, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA Jerry P. Nolan Honorary Professor of Resuscitation Medicine, University of Bristol, UK, Consultant in Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UK Jan Novy Consultant Neurologist, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Mauro Oddo Staff Physician, Department of Intensive Care Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Paolo Pelosi Dipartimento Scienze Chirurgiche e Diagnostiche Integrate (DISC), Università degli Studi di Genova, AOU IRCCS San Martino IST, Genova, Italy Bettina Pfausler Assistant Professor, Department of Neurology, Neuro-ICU, Innsbruck Medical University, Innsbruck, Austria Derek J. Roberts Surgery and Clinician Investigator Program Resident, Foothills Medical Centre, Alberta, Canada Claudia Robertson Professor, Baylor College of Medicine, Houston, TX, USA Andrea O. Rossetti Director of the Epilepsy Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Daniel Sahlein Assistant Professor of Clinical Radiology, Columbia University Medical Centre, New York, NY, USA Erich Schmutzhard Professor of Neurology and Critical Care Medicine, Department of Neurology, NeuroICU, Medical University Innsbruck, Innsbruck, Austria Sam Shemie Professor, Division of Critical Care, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Canada Ivan Rocha Ferreira da Silva Director, Neurocritical Care Department, Americas Medical City, Rio de Janeiro, Brazil Adikarige Haritha Dulanka Silva Specialist Registrar in Neurosurgery, Queen Elizabeth University Hospital, Birmingham, UK Martin Smith Consultant and Honorary Professor in Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK Luzius A. Steiner Professor and Chairman, Department of Anaesthesia, University Hospital Basel, Basel, Switzerland Pouya Tahsili-Fahadan Neurocritical Care Section, Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA Jeanne Teitelbaum Associate Professor, Neurology, Neurosurgery and Critical Care, Montreal Neurological Institute, McGill University, Montreal, Canada Aurore Thibaut Research Fellow, Coma Science Group, University and University Hospital of Liège, Liège, Belgium Maria Vargas Dipartimento Scienze Chirurgiche e Diagnostiche Integrate (DISC), Università degli Studi di Genova, AOU IRCCS San Martino IST, Genova, Italy Lionel Velly Associate Professor in Anaesthesiology, Centre Hospitalier Universitaire Timone, Marseille, France Bala Venkatesh Professor of Intensive Care, University of Queensland, Brisbane, Australia
Federico Villa San Gerardo Hospital, Monza, Italy Leslie M. Whetstine Associate Professor, Walsh University, North Canton, OH, USA Hayden White Associate Professor and Director, Logan HospitalMeadowbrook, Australia Jefferson R. Wilson Department of Surgery, University of Toronto, Toronto, Canada Max Wintermark Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA Mingxing Xie Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Yanrong Zhang, Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China David A. Zygun Division of Critical Care Medicine, University of Alberta and the University of Alberta Hospital, Alberta, Canada
General principles 1. 2. 3. 4. 5. 6. 7. 8.
1 Introduction to neurocritical care Martin Smith 2 Applied neuropathophysiology and neuropharmacology RajaNandini Muralidharan and W. Andrew Kofke 3 Cerebral blood flow physiology, pharmacology, and pathophysiology Chandril Chugh and W. Andrew Kofke 4 Cardiorespiratory support in critically ill neurological patients Maria Vargas, Iole Brunetti, and Paolo Pelosi 5 Fluid management Jonathan Ball 6 Sedation and analgesia in the neurocritical care unit Mauro Oddo and Luzius A. Steiner 7 Intracranial hypertension Andrea Lavinio 8 Ethical and legal issues in neurocritical care Leslie M. Whetstine, David W. Crippen, and W. Andrew Kofke
Introduction to neurocritical care Chapter: Introduction to neurocritical care Author(s): Martin Smith DOI: 10.1093/med/9780198739555.003.0001 Critical care medicine has evolved rapidly in recent decades as therapeutic and technological advances have led to improved outcomes in a wide variety of life-threatening conditions. This is particularly the case in traumatic, haemorrhagic, and ischaemic brain injury where improved understanding of pathophysiology and advances in monitoring and imaging techniques have led to the introduction of more effective and individualized treatment strategies that have translated into improved outcomes for patients. In parallel, neurocritical care has developed as a subspecialty of intensive care medicine dedicated to the treatment of critically ill neurological patients (1).
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History of neurocritical care
The origins of modern critical care lie in the poliomyelitis epidemics of the 1940s and 1950s when the principles of mechanical ventilation and high-intensity nursing in dedicated wards were established. During the 1970s and 1980s, developments in neuroanaesthesia and neurosurgical techniques allowed more complex operative interventions that required higher levels of care in the early postoperative period. Patients were managed in dedicated areas of neurosurgical wards where a team of skilled nursing staff provided close monitoring to detect neurological deterioration. In association with immediate access to neurosurgical support in the event of such deterioration, the earliest neurosurgical critical care units were established. In the United States, Allan Ropper (neurologist), Sean Kennedy (neuroanaesthetist), and Nicholas Zervas (neurosurgeon) developed the first combined neurological and neurosurgical intensive care unit (ICU) at the Massachusetts General Hospital in Boston, and their collaboration led to the publication of the first textbook of neurocritical care in 1983 (2). Subsequently, neurocritical care has broadened to provide comprehensive management for all life-threatening disorders of the central nervous system (CNS) and their complications. Managing the complex interaction between the injured brain and systemic organ systems is the cornerstone of neurocritical care which has evolved from its original focus on the CNS into a speciality providing all aspects of a critically ill neurological patient’s care. Neurocritical care gained formal recognition by the United Council of Neurological Subspecialties (UCNS) in October 2005 and this led to the accreditation of neurocritical care training programmes and certification of neurointensivists in the United States (3). Although there is no similar recognition in Europe and many other countries, the UCNS neurocritical care curriculum is comprehensive and has broad relevance.
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Principles of neurointensive care Critically ill neurological patients require meticulous general intensive care support as well as interventions targeted to their neurological disorder. The management of acute brain injury (ABI) is particularly complex. In addition to braintargeted therapy, general intensive care principles including optimization of cardiorespiratory variables, glycaemic control, management of pyrexia, and early enteral nutrition are of key importance (Table 1.1). Therapeutic targets in neurocritical care are often different from those on the general ICU. For example, cardiovascular management in the context of ABI is quite different from that after acute myocardial infarction. After ABI, therapeutic efforts are aimed towards providing the optimal conditions to minimize secondary brain injury and optimize neurological outcome. In some cases, brain-directed therapy can have potentially adverse effects on systemic organ systems and vice versa. Table 1.1 Summary of neurocritical care management of patients with acute brain injury
Respiratory
Cardiovascular
ICP and CPP management (for TBI)
Treatment of intracranial hypertension
◆ PaO2 > 13 kPa and PaCO2 4.5–5.0 kPa ◆ Positive end-expiratory pressure (≤15 cmH2O) to maintain oxygenation ◆ Protective ventilatory strategies with low tidal volume as PaCO2 permits ◆ Ventilator care bundle to minimize risk of pneumonia ◆ Mean arterial pressure > 90 mmHg ◆ Euvolaemia ◆ Vasopressors/inotropes ◆ ICP < 20 mmHg and CPP 50–70 mmHg ◆ Sedation/analgesia ◆ 20–30° head-up tilt ◆ Volume expansion plus norepinephrine (noradrenaline) to maintain CPP ◆ Cerebrospinal fluid drainage ◆ Sedation
Miscellaneous
◆ Osmotic therapy (mannitol or hypertonic saline) ◆ CPP optimization ◆ Moderate hyperventilation ◆ Moderate hypothermia ◆ Barbiturates ◆ Decompressive craniectomy
◆ Normoglycaemia ◆ Normothermia ◆ Early enteral nutrition ◆ Thromboembolic prophylaxis ◆ Seizure control
Management protocols have evolved with international consensus and provide guidelines that assist clinicians in delivering optimal care, although many do not focus on the critical care aspects of patient management (4,5,6,7). Recent developments have changed the way in which acute disorders of the CNS are treated. In particular, the critical care management of ABI has undergone extensive revision following evidence that longstanding and established practices are not as efficacious or innocuous as previously believed (8). Traditional therapies such as routine fluid restriction and hyperventilation are no longer recommended, and newer or ‘re-invented’ therapies, such as targeted temperature management and decompressive craniectomy, remain controversial. The sole goal of identifying and treating intracranial hypertension has been superseded by a focus on the prevention of secondary brain insults using a systematic, stepwise approach to maintenance of adequate cerebral perfusion and oxygenation (9). Further, the substantial temporal and regional pathophysiological heterogeneity after ABI means that some interventions may be ineffective, unnecessary, or even harmful in certain patients at certain times, emphasizing the importance of monitorguided individualized therapy.
Neuromonitoring The monitoring of critically ill neurological patients has become increasingly complex. Along with the close monitoring andassessment of cardiac and respiratory variables relevant to all critically ill patients, neurocritical care utilizes a range of neuromonitoring techniques to identify or predict secondary brain insults and guide therapeutic interventions (10,11). Fundamental to neurological monitoring is the serial clinical assessment of neurological status by a trained nurse at the bedside. The Glasgow Coma Scale (GCS) provides a standardized, internationally recognized method for evaluating a patient’s global neurological status by recording best eye opening, motor, and verbal responses to physical and verbal stimuli (see Chapter 26). In association with identification and documentation of localizing signs such as pupil responses and limb weaknesses, the GCS remains the mainstay of clinical assessment 50 years since its first description (12). Clinical assessment is limited in sedated patients or those with decreased conscious level and several techniques are available for global and regional brain monitoring which provide assessment of cerebral perfusion, oxygenation, and metabolic status, and early warning of impending brain hypoxia and ischaemia (13). These techniques are discussed in detail elsewhere in this book (see Chapters 9–12). While intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are crucially important and routinely monitored variables after ABI, they provide no assessment of the adequacy of cerebral perfusion and therefore of the risk of brain ischaemia (9). Multiple studies have demonstrated that secondary brain ischaemic/hypoxic insults may go unnoticed when therapy is guided by ICP/CPP monitoring alone, and that brain hypoxia can occur despite ICP and CPP being within accepted thresholds for normality (14,15). Measurement of ICP and CPP in association with monitors of the adequacy of cerebral perfusion, such as brain tissue oxygenation and biochemistry, provide a more complete picture of the injured brain and its response to treatment (10,13). Therapeutic targets and choice of therapy are therefore best determined by monitoring more than one variable (multimodal monitoring). In current clinical practice this most commonly involves the simultaneous measurement of ICP/CPP and brain tissue oxygen tension, possibly in combination with other modalities such as cerebral blood flow and microdialysis. Multimodal monitoring allows cross validation between different monitoring variables and guides individually tailored, patient-specific management. Apart from being used to guide treatment interventions, multimodal monitoring also gives clinicians confidence to withhold potentially dangerous therapy in those with no evidence of brain
ischaemia/hypoxia or metabolic disturbance (13). Multimodal monitoring generates large and complex datasets, and systems that analyse and present information in a user-friendly format at the bedside are essential to maximize its clinical relevance (see Chapter 13) (16).
Case mix As neurocritical care has evolved, so has its case mix broadened. Although traumatic brain injury (TBI), subarachnoid haemorrhage (SAH), and intracerebral haemorrhage (ICH) continue to make up a large proportion of cases, the admission of patients with other diagnoses, such as acute ischaemic stroke (AIS), neuromuscular disorders, status epilepticus, and CNS infection, is becoming increasingly common. Patients with severe ABI that would previously have been considered unsalvageable are now being admitted to the neurocritical care unit (NCCU) and there is evidence that early aggressive intervention can result in excellent outcomes in some patients (17).
Acute brain injury The intensive care management of severe TBI requires a coordinated and comprehensive approach to treatment, including strategies to prevent secondary brain injury by avoidance of systemic physiological disturbances, such as hypotension, hypoxaemia, hypo- and hyperglycaemia, and hyperthermia, and maintenance of adequate cerebral perfusion and oxygenation. Management protocols have evolved with international consensus, providing evidencebased guidelines that assist clinicians in delivering optimal care (4). Improved diagnostic and monitoring modalities are improving the understanding of the pathophysiology of head injury and allowing the delivery of individualized therapy (9). Less invasive interventions for securing a ruptured aneurysm have allowed treatment of more unstable patients and, as a result, greater numbers of poor-grade SAH patients are being admitted to the NCCU (18). Aggressive cardiopulmonary and neurological resuscitation, early aneurysm control, and advanced monitoring and management in a NCCU delivers good outcomes for such patients despite their substantial co-morbidities and high risk of intracranial and systemic complications (17,18). ICH is the most devastating form of stroke, with high rates of mortality and morbidity, but aggressive treatment, including meticulous blood pressure, fluid balance, and glycaemic control, and management of intracranial complications, is associated with improved outcome (19). Early studies confirmed that patients cared for by dedicated stroke teams in stroke units have better outcomes, and integrated multidisciplinary services for stroke patients are now commonplace (20). An increasing proportion of patients with severe AIS now require admission to an ICU for neurological monitoring and management of post-stroke complications (21).
Neurological disease Neurocritical care is also concerned with the management of primary neurological illness and its consequences. Patients with myasthenia gravis, Guillain–Barré syndrome, encephalopathies, status epilepticus, and CNS infections require treatment of the underlying condition as well as management of ensuing complications such as ventilatory failure and autonomic disturbances (see Chapter 22). Many patients remain dependent on ventilatory support for considerable periods of time, resulting in substantial psychological problems for the patient and their carers.
Systemic complications Brain injury and brain-directed therapies can lead to non-neurological organ system dysfunction and failure, and systemic organ system dysfunction and failure can also adversely affect the injured brain (22,23). Non-neurological organ dysfunction and failure are independent contributors to morbidity and mortality after ABI and therefore represent potentially modifiable risk factors (see Chapter 27). However, their management presents significant challenges because the optimum treatment for the failing systemic organ system may conflict with brain-directed therapies.
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Benefits of neurocritical care units There is accumulating evidence that treatment in a dedicated NCCU is beneficial for patients with neurological disease generally and for those with ABI in particular. In an early study, data collected prospectively by Project Impact,
the national critical care data system of the Society of Critical Care Medicine, from 42 participating ICUs over a 3-year period demonstrated that not being in an NCCU was associated with an increased hospital mortality rate (odds ratio (OR) 3.4) after acute ICH (24). A recent systematic review and meta-analysis including 18 studies and more than 40,000 patients confirmed that the management of critically ill patients with ABI in an NCCU is associated with a lower risk of mortality (OR 0.72) and poor neurological outcome (OR 0.7) when compared to management in a general ICU (25). The potential benefits of neurocritical care are likely to be multifactorial (Box 1.1) (26,27).
Box 1.1 Aspects of neurocritical care that contribute to improved outcome o o
◆ Delivery of individualized, protocol-guided care ◆ Multimodal monitoring-guided treatment strategies ◆ Dedicated, specialist multidisciplinary team including specialist neuroscience critical care nurses and therapists ◆ Supervision of management by dedicated neurointensivists ◆ Rapid access to neurosurgical services ◆ Increased expertise from higher caseload ◆ Awareness of the interplay between the injured brain and systemic organ systems: • improved control of systemic physiology • greater understanding of the causes and treatment of non-neurologic organ system dysfunction and failure. Damian and colleagues used the UK Intensive Care National Audit and Research Centre database to assess mortality in critically ill neurological patients (including more than 10,300 patients with primary ICH) over time and to determine whether the type of ICU in which the patients were treated affected mortality (28). There was a statistically significant decrease in ICH-related mortality between 1996 and 2009, and hospital mortality was lower in patients treated in an NCCU compared to a general ICU even after adjusting for multiple confounders including surgery. There was a greater reduction in mortality over time in patients treated in an NCCU, but a longer ICU and hospital length of stay. A population-based study of more than 4000 patients admitted to four Canadian ICUs over an 11-year period also demonstrated that mortality decreased and outcome in survivors improved over time, and in this study these effects were most pronounced in patients with TBI and SAH (29). Multiple practice modifications, including the introduction of neurointensivists, implementation of a TBI management protocol, and improved management of systemic physiological variables, are likely to have contributed to the improved outcomes identified in this study. However, temporal improvements in outcome can also occur in the absence of a defined change in the model of care. In a study of patients with ICH, mortality was 19% in those admitted to hospital between 2005 and 2009 compared to 62% in those admitted between 1990 to 1994 despite similar baseline characteristics and management in a specialist NCCU in both periods (30). Despite multiple studies examining its impact there is no agreement on what exactly constitutes neurocritical care, and different models of care delivery predominate in different countries. In some, neurocritical care is delivered by neurointensivists in a specialist unit admitting only critically ill neurological patients. This is the most common model in the United States and increasingly in Europe. Neurocritical care can also be provided by neurointensivists in dedicated areas of a mixed ICU, whereas in other centres critically ill neurological patients are managed in a mixed ICU without specialty-specific arrangements. In addition to different care delivery locations, the availability of full-time neurointensivists and protocol-driven care also varies between centres. Thus when examining the evidence of benefits from neurocritical care, it is important that the context of care delivery and who provides it is understood. It is also uncertain whether the potential outcome benefits of neurocritical care apply to all neurological diseases equally, or primarily to ABI (25).
Caseload Specialization attracts a greater caseload and with it increased expertise. Higher caseloads have been associated with improved outcome after TBI (31), SAH (32), ICH (24), and AIS (33). In an Austrian study of 1856 patients with severe TBI, those admitted to large centres treating more than 30 cases per year had lower mortality compared to those admitted to medium (10–30 cases/year) and small (< 10 cases/year) centres (31). Multiple studies have confirmed that mortality after SAH is also significantly reduced in high-volume centres that provide access to specialized multidisciplinary neurocritical care, and the Neurocritical Care Society has recently recommended that all patients should be managed in centres treating more than 60 cases per year (34).
The neurocritical care team The benefits of a multidisciplinary critical care team and the presence of a full-time intensivist are well established in general intensive care (35), and similar findings have recently been confirmed in neurocritical care. In one study, the presence of a full-time neurointensivist was associated with a 51% reduction in NCCU mortality, a 12% shorter length of stay in hospital, and 57% greater odds of being discharged to home or a rehabilitation unit compared to a long-term care facility (36). More recently, the introduction of a multidisciplinary neurocritical care team has been shown to be associated with decreased ICU and hospital lengths of stay and a greater proportion of patients with haemorrhagic and ischaemic stroke being discharged home (37). The presence of a neurocritical care team has been shown to be an independent predictor of decreased hospital mortality (OR 0.7) and is associated with reduced NCCU and hospital lengths of stay without increasing ICU readmission rates (38). The 24/7 provision of experienced neurocritical care staff ensures that the application of individualized therapies aimed at preventing secondary brain injury by optimization of intracranial and systemic physiological variables are applied in a timely and consistent fashion (39). Neurocritical care teams are familiar with the unique aspects of CNS disease processes and the effects of interventions on the injured brain, and integrate all aspects of neurological and medical management into a single care plan (1). Systemic physiological derangements have specific consequences in the context of ABI and require different management strategies than in the general ICU setting (40). Neurocritical care teams have the experience to identify and appropriately manage such derangements and are mindful of the complex interactions between the injured brain and systemic physiological disturbances (26). Neurocritical care nurses require excellent general ICU skills and in addition must be proficient at neurological examination to a greater degree of sophistication and precision than their general ICU counterparts (39). Not only is the neurocritical care nurse the most important bedside neurological monitor, he/she is also in a unique position to make sure that local management protocols are delivered. Acute rehabilitation plays a major role in securing improved long-term neurological outcomes after ABI, and intervention from neurophysiotherapists, including early patient mobilization, is likely to occur more reliably in a specialist than a general unit (41).
Management protocols Most neurocritical care treatments are directed by consensus guidance rather than a clear evidence base (42). Very few specific interventions have been shown to improve outcome in large randomized controlled trials and, with the possible exception of avoidance of hypotension and hypoxaemia (43), most are based on observational studies or analysis of physiology and pathophysiology. There is a focus on preventing or rapidly correcting even minor abnormalities in physiological variables such as arterial blood pressure, arterial blood gases, blood glucose, sodium, and temperature. Given the complex pathophysiology of ABI it is unlikely that any one of these interventions in isolation will affect outcome, but their combination into a management protocol designed to avoid secondary brain injury can have a powerful effect (44,45). Compliance with standard protocols has been shown to be associated with improved outcome (46). A recent study demonstrated that increased adherence to Brain Trauma Foundation guidelines for ICP and CPP management was associated with a pronounced reduction in severe TBI mortality, suggesting a causal relationship (47).
Length of stay and cost-effectiveness Although some early single-centre studies suggested that management in an NCCU was associated with a shorter length of stay and lower resource usage compared to a general ICU (48), most data indicate the contrary (24,28,49). In a population-based study, ICU length of stay increased as outcome improved over time (29). This might be related to more aggressive and longer duration therapy, or be the result of delayed decisions about withdrawal of lifesustaining interventions arising from an increased appreciation of satisfactory outcome after initially severe ABI. In a recent UK study, management of patients with severe TBI in an NCCU was associated with a higher 6-month cost but higher quality of life and lower long-term health and social care costs compared to management in a general ICU, suggesting that management in an NCCU may be cost-effective (50).
Therapeutic nihilism Patients with severe brain injury that would previously have been considered unsalvageable are increasingly being offered treatment, with excellent results in many cases (17). Other patients will have a poor outcome despite maximal
intervention and it is essential that aggressive early treatment is linked to compassionate end-of-life care if a satisfactory degree of clinical improvement does not occur within an appropriate timescale (51). The confidence to withdraw treatment after a failed trial of early maximal intervention means that the usual justification for withholding treatment in the acute phase (survival with a devastating neurological injury) becomes irrelevant. In this way, patients have access to care that might allow them to recover beyond initial expectations. Therapeutic nihilism is a major factor adversely affecting outcome after ABI. Too early an assessment of poor prognosis and subsequent withdrawal of care or do-not-resuscitate orders leads to a self-fulfilling prophecy (52). Tools to predict long-term prognosis in severe ABI are imperfect (53), but those who work regularly with critically ill braininjured patients develop a deeper understanding of the factors that influence recovery, including the effects of brain plasticity and neurological rehabilitation, and apply more robust assessments of outcome as well as more realistic time frames for recovery (54).
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Research There are limited data to guide the majority of interventions during neurocritical care and management guidelines are often developed based on expert consensus (42). Numerous drugs with promising neuroprotective effects in preclinical studies have failed to translate into outcome benefits for patients in large clinical studies, and the effectiveness of many treatment algorithms and physiological interventions that are routinely applied during neurocritical care has not been evaluated in large studies. While there might be reluctance to subject long-standing clinical practices to rigorous investigation, there is an urgent need for well-conducted studies to determine optimal strategies for many neurocritical care interventions. Patient registry or large observational cohorts are important in disease surveillance or to understand the pathophysiology of specific disease states, while adequately designed and well-conducted phase I and II studies are required to assess the safety profile and efficacy of established and novel pharmaceuticals so that only agents with a reasonable chance of success enter phase III. The establishment of the Neurocritical Care Research Network, under the auspices of the Neurocritical Care Society, will facilitate multicentre, international collaboration and patient enrolment into neurocritical care clinical trials (55). In this way it is anticipated that future research will determine which of the many interventions that are currently provided on an empirical basis are of particular benefit and which might possibly be causing harm.
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Applied neuropathophysiology and neuropharmacology Chapter: Applied neuropathophysiology and neuropharmacology Author(s): RajaNandini Muralidharan and W. Andrew Kofke DOI: 10.1093/med/9780198739555.003.0002
Neural function is essential to human existence and the loss of any neural element represents a major loss to the individual. Thus the primary aim of the management of critically ill neurological patients is the preservation of neural function. The brain is the most vulnerable organ in the human body for several reasons. It is has a high energy requirement but very limited ability to store substrate so is dependent on a continued blood supply to deliver oxygen and essential nutrients to support aerobic metabolism. It is also unable to expand physically because of its containment in the rigid skull and therefore has limited ability to compensate for insults such as haemorrhage, oedema, and inflammation. In brain injury, neurons or their supporting elements may be lost in a small, virtually unnoticeable manner or there may be widespread neuronal loss and tissue infarction. Based on the notion that maintenance of some level of neural function is the essence of acceptable survival, it is crucial to consider neural viability and the impact and interactions of primary disease processes and therapeutic interventions on the central nervous system (CNS) during the critical care management of brain injury. Mature neurons cannot proliferate except possibly in a few brain areas or under special circumstances (1), but they can undergo adaptive change in response to injury. However, beyond a certain threshold adaptive mechanisms fail and subsequent neuronal loss translates into loss of function for the individual. In a general sense, brain injury involves one or more of ischaemia, trauma, neuroinflammation, and neuroexcitation, all of which have distinct yet interrelated pathways that ultimately result in neuronal death if unchecked.
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Neurophysiology This section will review the important overarching concepts of neurophysiology and pathophysiology relevant to neurocritical care and the reader is referred elsewhere in this book for detailed discussions of pathology-specific issues.
Cells of the central nervous system Despite the nervous system’s wide distribution and complexity, it contains only two principal categories of cells— neurons and glia. There are an estimated 100 billion neurons and ten times as many glial cells in the nervous system (2), although the actual number and distribution is uncertain (3). Neurons are the most important structural and functional cells of the nervous system and sustain moment-to-moment neurological function by the transmission of electrical and chemical information. Once thought to be detrimental to neuronal recovery after injury, glial cells such as astrocytes provide metabolic and reparative support to neurons. Glia are spatially arranged throughout the brain and in contact with tens of thousands of synapses and each other via a network of gap junctions known as the astrocytic syncytium. This allows the rapid diffusion of molecules, particularly calcium, in response to glutaminergic synaptic transmission and facilitates local and long-distance synaptic modulation of the composition and concentration of multiple molecules in the extracellular milieu via uptake or release of multiple neurotransmitters, ions, and neuromodulators. These connections also allow intimate coupling with neuronal metabolism and, via astrocytic foot process, with neurovascular coupling (4). Under a myriad of pathological conditions, including hypoxia, ischaemia, and excitotoxicity, astrocytes are able to interact and modulate their environments in concert with neurons. Understanding the role of astrocytes in response to brain injury is crucial as they may serve as viable future targets for manipulation and treatment. Other cell types in the CNS include microglia. These are derived from mesoderm and enter the CNS via white matter tracts and blood vessels early during development. Microglia are in a ‘resting’ state in the mature brain until a pathological event triggers microglial activation when they transform into amoeboid phagocytic cells that rapidly proliferate and migrate in response to injury (5).
Cerebrospinal fluid Cerebrospinal fluid (CSF) is produced in the choroid plexus at a rate of 0.2–0.4 mL/min or 500–600 mL a day (6). It circulates through the ventricular system into the subarachnoid space and is absorbed into the venous system via arachnoid granulations that line the convexity of the brain. Equilibrium normally exists between CSF production and absorption, and disruption of this can lead to hydrocephalus and raised intracranial pressure (ICP). Hydrocephalus is generally categorized as communicating or non-communicating. In communicating hydrocephalus, CSF circulation
between the site of production and absorption is intact but abnormally decreased absorption (e.g. secondary to inflammation or infection) or increased production (e.g. choroid plexus papilloma) results in CSF accumulation. In noncommunicating hydrocephalus, CSF pathways are blocked such that CSF cannot circulate to the convexity of the brain to be absorbed. CSF circulation has many roles. It transports hormones, cofactors, and chemical messengers which aide various processes including neuronal metabolism and behaviour (6). It has a mechanically supportive role as a hydraulic cushion for the brain and spinal cord within their rigid enclosures and also can act as a compensatory mechanism as its volume decreases to maintain ICP in the presence of space occupying lesions (see Chapter 7). CSF absorption is driven by the hydrostatic differences in the CSF and venous compartments and is directly proportional to ICP. Hence increases in ICP lead to increased rate of CSF clearance (7) and CSF diversion plays a vital role in ameliorating increased ICP. The choroid plexus is the primary site of CSF production and comprises a capillary network that lacks tight junctions intertwined with ependymal cells. CSF was previously thought to be an ultrafiltrate of blood but its ionic composition differs from that of plasma. It has higher chloride and magnesium concentrations and a slightly lower pH due to lack of buffering capacity because of its low protein content compared to plasma (6). CSF production is an energy-dependent process utilizing adenosine triphosphate (ATP) and various transporters including sodium-potassium and other ATPase membrane pumps. The production of hydrogen (H +) and bicarbonate (HCO3−) ions required for these processes depends on the activity of the enzyme carbonic anhydrase which catalyses the formation of carbonic acid from water and CO2, a process that is inhibited by acetazolamide (6). CSF pH is tightly coupled to minute-to-minute control of breathing. Central chemoreceptors located in the ventral medulla are extremely sensitive and respond directly to changes in CSF pH and indirectly to PaCO 2. For example, a rise in PaCO2 leads to a rapid increase in CSF H+ concentration. Carbon dioxide is carried in the blood as H + and HCO3− but readily converts into CO2 in the brain when it can cross the blood–brain barrier (BBB) into the CSF and be converted back to H+ and HCO3−. The cerebral vasodilatation that accompanies increased PaCO 2 further enhances this diffusion. Liberated H+ acts on central chemoreceptors to stimulate respiration, which in turn reduces both arterial and CSF CO2 (6). Another, newer concept, of CSF dynamics is the so-called glymphatics system. Ilkiff et al. described this intricate network of paravascular pathways by which CSF and solutes can pass and eventually be cleared along paravenous routes (8). Aquaporin-dependent astrocytic water transport appears to be involved in this mechanism. Moreover, betaamyloid and possibly other ‘waste product’ substances may be cleared from the brain by the glymphatic system, with a notable link of these processes to sleep (9).
Blood–brain barrier The BBB has several roles including:
◆ promoting entry of nutrients into the brain and egress of waste products, and preventing entry of harmful molecules ◆ maintenance of an optimal milieu for neuron function by control of brain ionic homeostasis ◆ protecting the brain from fluctuations in systemic ionic composition which may inappropriately alter neuronal function ◆ separating neuroactive substances between central and peripheral compartments, allowing the same molecule to be used between compartments without crosstalk (4). The BBB is formed by endothelial cells joined by tight junctions, pericytes, basal lamina, and astrocytic foot processes (Figure 2.1) which together form the functional ‘neurovascular unit’ that maintains the chemical composition of cerebral extracellular fluid (ECF) relatively independent of changes in the blood (4). The astrocytic foot processes serve as conduits for water, nutrients, and ions between the ECF and capillaries, whereas tight junctions prevent movement of hydrophilic compounds and proteins (4). The BBB contains several channels and luminal and abluminal transport systems which move ions, glucose, proteins, vitamins, and drugs. The barrier is maintained by active transport using receptor-based and less specific adaptive transcytosis (4), and facilitated diffusion along ion gradients created by energy-dependent sodium-potassium pumps. It is thus unsurprising that virtually any insult to the brain, be it trauma, ischaemia, or seizures, leads to breakdown of the BBB with resultant brain oedema, oxidative stress, toxin accumulation, and neuroinflammation. The permeability of the BBB may also be increased by vasoactive substances
such as histamine and thrombin through increased expression of cell adhesive molecules via cytokines released in response to inflammation and growth factors, such as vascular endothelial growth factor (VEGF), in tumourigenesis (10,11). The importance of BBB function cannot be over-emphasized as it carries a myriad of clinical implications and offers potential targets in neuronal repair. The major elements and functions of the BBB are summarized in Table 2.1.
Click to view larger Download figure as PowerPoint slide Fig. 2.1. The blood–brain barrier. The blood–brain barrier is formed by capillary endothelial cells, surrounded by basal lamina and astrocytic perivascular endfeet. Astrocytes provide the cellular link to the neurons. The figure also shows pericytes and microglial cells. (A) Brain endothelial cell features observed in cell culture. The cells express a number of transporters and receptors, some of which are shown. EAAT1–3, excitatory amino acid transporters 1–3; GLUT1, glucose transporter 1; LAT1, L-system for large neutral amino acids; Pgp, P-glycoprotein. (B) Examples of bidirectional astroglial–endothelial induction necessary to establish and maintain the BBB. Some endothelial cell characteristics (receptors and transporters) are shown. 5-HT, 5-hydroxytryptamine (serotonin); ANG1, angiopoietin 1; bFGF, basic fibroblast growth factor; ET1, endothelin 1; GDNF, glial cell line-derived neurotrophic factor; LIF, leukaemia inhibitory factor; P 2Y2, purinergic receptor; TGFβ, transforming growth factor-β; TIE2, endothelium-specific receptor tyrosine kinase 2. Data obtained from astroglial– endothelial co-cultures and the use of conditioned medium. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience, 7, 1, Abbott NJ et al., ‘Astrocyte–endothelial interactions at the blood–brain barrier’, pp. 41–53, copyright 2006. Table 2.1 Elements of the blood–brain barrier
BBB element
Definition
Tight junction
A belt-like region of adhesion between adjacent cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane
Abluminal membrane
The endothelial cell membrane that faces away from the vessel lumen, towards the brain
Meninges
The complex arrangement of three protective membranes surrounding the brain, with a thick outer connective tissue layer (dura) overlying the barrier layer (arachnoid), and finally the thin layer covering the glia limitans (pia). The subarachnoid layer has a sponge-like structure filled with CSF
Circumventricular organs (CVOs)
Brain regions that have a rich vascular plexus with a specialized arrangement of blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, which allow the diffusion of large molecules. These organs include the organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence, and the area postrema
Receptor-mediated transcytosis
The mechanism for vesicle mediated transfer of substances across the cell, the first step of which requires specific binding of the ligand to a membrane receptor, followed by internalization (endocytosis)
Adsorptive-mediated transcytosis
The mechanism for vesicle-mediated transfer of substances across the cell, the first step of which involves non-specific binding of the ligand to membrane surface charges, followed by internalization (endocytosis)
Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience, 7, 1, Abbott NJ et al., ‘Astrocyte–endothelial interactions at the blood–brain barrier’, pp. 41–53, copyright 2006.
Cerebral energy metabolism Although the brain comprises approximately 2% of body weight it utilizes 20% of total energy consumption and receives 15% of total cardiac output (12). This reflects its critical dependence on a constant supply of glucose (and/or lactate from astrocytes) and oxygen to maintain metabolic function. The primary source of the brain’s energy is ATP via oxidative metabolism in the Krebs cycle and mitochondrial respiratory chain, and the vast majority of its energy requirement is to support the sodium-potassium ATPase pumps which maintain and restore ionic gradients and membrane potentials during excitatory neural transmission (12,13). ATP-dependent pumps also facilitate uptake of glutamate from the synaptic cleft and thus prevent inappropriate activation of excitatory postsynaptic receptors that would lead to massive calcium influx into cells and trigger cell death cascades (14). An increase in neuronal metabolic demand is first met with an increase in local tissue oxygen extraction followed by an increase in cerebral blood flow (CBF) (5). Astrocytes are key players in regulating blood flow to neurons via their foot processes that line cerebral arterioles and capillaries. Metabolism-related changes in CBF arise from local vasodilatory mediators such as nitric oxide (NO), arachidonic acid, potassium, and adenosine which are believed to be released from neurons and glia following excitatory glutaminergic transmission during synaptic activity rather than as a direct effect of the energy deficit (5). This reinforces the important concept that although energy utilization and local CBF operate in parallel they are not causally related. This is relevant in functional magnetic resonance imaging where blood oxygen level-dependent (BOLD) signals should be interpreted as a reflection of neuronal signalling and not necessarily as a locus of increased energy utilization (15). Glycogen can also support brain metabolism in conditions of low glucose supply or energy failure. Astrocytes play a key role in this process and therefore in neuronal metabolism and coupling of CBF to energy demand. As noted, neuronal activity releases chemical factors such as potassium, glutamate, and glucose that reach astrocytes through
the ECF and trigger changes in astrocytic function including activation of glucose metabolism. Glycogen is stored in astrocytes where it is converted to lactate and then shuttled to neurons to sustain their oxidative metabolism: the astrocyte–neuron lactate shuttle model of energy production (16). Glutamate uptake from the synaptic space into astrocytes occurs via the excitatory amino acid transporter (EAAT)-1 and EAAT-2. This process is sodium dependent and triggers ATP consumption and, through a series of events, stimulates glycolysis which produces the lactate that is released to neurons for utilization as an energy source (Figure 2.2) (16,17). The stoichiometry of this process is such that for each glutamate molecule that is taken up (with three sodium ions), one molecule of glucose enters an astrocyte resulting in the production of two ATP molecules through aerobic glycolysis and release of two molecules of lactate. The lactate is then taken up by neurons and, under aerobic conditions, converted to pyruvate which yields 17 ATP molecules per lactate molecule in the Krebs cycle and mitochondrial respiratory chain (17).
Click to view larger Download figure as PowerPoint slide Fig. 2.2. Schematic representation of the mechanism for glutamate-induced glycolysis in astrocytes during physiologic activation in vitro. At glutaminergic synapses, presynaptically released glutamate depolarizes postsynaptic neurons by acting at specific receptor subtypes. The action of glutamate is terminated by Na + coupled glutamate uptake system located primarily in astrocytes. The resulting increase in intracellular Na+ in astrocytes activates Na+/K+ ATPase, which in turn stimulates glycolysis with resultant glucose use and lactate production. Lactate, after release from astrocytes, is taken up by local neurons as an energy substrate. Reproduced from Magistretti PJ and Pellerin L, ‘Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging’, Philosophical Transactions of the Royal Society B: Biological Sciences, 1999, 354, 1387, pp. 1155–1163, by permission of the Royal Society. Although often associated with anaerobic conditions, lactate can also be generated in the non-anaerobic states as previously described and this situation can be identified by a rise in the microdialysis-monitored lactate pyruvate ratio in the presence of normal brain tissue oxygen tension (18). The now accepted role of lactate as an alternate cerebral energy source means that it can be neuroprotective in the context of glucose deprivation (19) and there is also some evidence to support a role for exogenous administration of lactate in several types of ischaemic insults (19,20). Some support for this derives from work of Smith and colleagues who used 2-fluoro-2-deoxy-D-glucose positron emission
tomography to demonstrate a decrement in brain glucose utilization associated with elevations in blood lactate levels during exercise (21). A clinical study by Bouzat et al. reported that hypertonic lactate administration decreased ICP and glutamate and spared brain glucose utilization (19). Lactate also has a signalling role in vascular regulation, memory, and axonal regeneration (20,22,23). An excellent foundational overview of brain energy metabolism relevant to several pathologies encountered on the neurocritical care unit (NCCU) can be found in Siesjö’s textbook (24).
Clinical syndromes leading to brain injury There are many clinical syndromes that may result in brain injury. The important unifying concepts are reviewed in the following sections and pathology-specific issues discussed in detail elsewhere in this book.
Ischaemia Ischaemia is defined as a decrement in blood flow sufficient to induce anaerobic metabolism and is seen in a variety of neurological disorders. Regional and global brain ischaemia are the primary pathophysiological processes in acute ischaemic stroke (AIS) and post-cardiac arrest respectively. Ischaemia and its resultant energy failure is associated with a massive increase in the levels of extracellular excitatory neurotransmitters, particularly glutamate, and intracellular calcium (25,26). Metabotropic glutamate receptors and agonist-gated ionotropic receptors activate phospholipase C which in turn results in production of phospholipid-derived second messengers such as inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (27,28). DAG stimulates protein kinase C (PKC) (29) and IP3 (30) leading to a further increase in intracellular calcium released from smooth endoplasmic reticulum via action on ryanodine receptors (25). Activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subset of glutamate receptors induces intracellular influx of sodium and calcium, and promotes intracellular hyperosmolarity and cellular swelling (31). Increases in intracellular calcium occur because of both exogenous and endogenous (e.g. endoplasmic reticulum) entry and activate calcium-dependent protein kinase (32) and a variety of other enzyme systems with multiple responses including alterations in gene expression involved with cell death (33). Gene expression takes several hours to develop and likely accounts for the delay in observable injury, particularly to vulnerable neurons (34), supporting the notion of delayed maturation of ischaemic neuronal injury (5,34,35) but with selective vulnerability of different neuron types (36). If the burden of ischaemia (in terms of duration and/or decrement in blood flow) is sufficiently substantial, cells die acutely and maturation of injury becomes irrelevant.
Cerebral oedema Brain oedema can occur as a result of a primary increase in brain water content or an increase in intracellular osmoles such as sodium and subsequent movement of water into the cell along the osmotic gradient. There are two main types of oedema—cytotoxic and vasogenic (37). In the context of ischaemia there can be progression from cytotoxic to vasogenic of oedema and, subsequently, to haemorrhagic conversion (38). Notably, progression to vasogenic oedema requires an element of perfusion to add fluid to the tissue and produce swelling which in turn reduces perfusion and function of adjacent tissue (Figure 2.3).
Click to view larger Download figure as PowerPoint slide Fig. 2.3. Schematic representation of oedema and its progression. Normally, Na + concentrations in serum and in extracellular space are the same, and much higher than inside the neuron. Cytotoxic oedema of neurons is due to entry of Na+ into ischaemic neurons via pathways such as NCCa-ATP channels, depleting extracellular Na+ and thereby setting up a concentration gradient between intravascular and extracellular compartments. Ionic oedema results from cytotoxic oedema of endothelial cells, due to expression of cation channels on both the luminal and abluminal side, allowing Na+ from the intravascular compartment to traverse the capillary wall and replenish Na + in the extracellular space. Vasogenic oedema results from degradation of tight junctions between endothelial cells, transforming capillaries into ‘fenestrated’ capillaries that allow extravasation (outward filtration) of proteinaceous fluid. Oncotic death of neurons is the ultimate consequence of cytotoxic oedema. Oncotic death of endothelial cells results in complete loss of capillary integrity and in extravasation of blood, that is, haemorrhagic conversion.
Reprinted from The Lancet Neurology, 6, 3, Simard JM et al., ‘Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications’, pp. 258–268, Copyright 2007, with permission from Elsevier. Vasogenic brain oedema occurs with breakdown of the BBB in the presence of continued perfusion and arises mainly in association with tumours and mass lesions. It can also be related to trauma, inflammation, infection and can develop several hours after AIS in those brain regions with residual perfusion. The compromise of regional perfusion and worsening of ischaemia by vasogenic oedema occurs because of direct compressive effects and also movement of fluid from the vasculature into tissue (37). Tumours such as high-grade gliomas express VEGF which increase angiogenesis and vascular permeability with the new vessels promoting increased cellular oedema. Cytotoxic oedema is the result of intracellular fluid accumulation because of failure of ion pumps, primarily sodiumpotassium ATPase, or osmotic disturbances in the presence of an intact BBB. It is primarily seen in ischaemia, hypoxia, metabolic derangements, and after traumatic injury brain injury (TBI) (37). It can be a primary driver leading to post-ischaemia vasogenic oedema (Figure 2.3) (38). Astrocytes are the cells primarily affected and swell early because of the presence of aquaporin 4 (AQP4) receptors in their cell membranes which promote intracellular influx of water. Continued cellular swelling compromises capillary perfusion because of swollen astrocytic foot processes and leads to local mass effect (39). After AIS, increased transport of sodium across an intact BBB contributes to oedema formation in the early hours after stroke onset, and the AQP4 inhibitor, bumetanide, has been shown to reduce brain oedema in rodent models of stroke (39,40).
Brain trauma The initial impact of TBI can result in widespread abnormalities including structural disruption, mass effect, and perfusion disturbances. At the cellular level there is loss of cellular integrity with failure of neuronal and astrocytic energy metabolism and ion channel dysfunction that leads to metabolic derangements from the moment of the initial impact but also related to secondary phenomena that cause further (secondary) injury (see Chapter 17) (41). Though cellular membranes are quite resistant to mechanical deformation, including those encountered with high-force sheer injury, ion channels are not so resistant (42). Damaged neurons release excitatory neurotransmitters, chiefly glutamate, which lead to calcium-mediated cellular injury and activation of multiple cell death cascades (41,42). There is also evidence that glutamate transporter levels in astrocytes decrease acutely following TBI, further decreasing synaptic cleft glutamate uptake and potentiating excitotoxicity (43). This leads to an increase in glucose metabolism to restore cellular integrity, membrane potentials, and clear toxic neurotransmitters from the synaptic space (41,44). However, in the presence of inadequate oxygen supply, anaerobic glycolysis ensues and leads to lactate production and tissue acidosis. Finally, local blood flow becomes dysregulated due to BBB disruption, compression of microvasculature due to oedema, and failure of local autoregulation, and this leads to secondary ischaemia because of insufficient supply of glucose and oxygen (41). These processes cumulatively result in cellular oedema and fluid and blood extravasation into the extracellular space leading to increases in brain tissue and intracranial blood volumes respectively. The resultant increases in ICP feed into the vicious cycles of further reductions in CBF, worsening oedema, and additional ischaemic brain injury (see Chapter 7) (42).
Seizures Seizures are caused by abnormal, hypersynchronous discharges from a group of cortical neurons in response to systemic or neurological insults (45). At a cellular level, neuronal excitability is normally supported by the electrochemical gradients maintained by sodium-potassium ATPases, and disruption of these membrane potentials may occur because of excitatory transmission and dysfunctional ion channels. Seizures themselves produce massive extracellular potassium shifts that increase neuron excitability and depolarize other nearby neurons (45). Glutamate is the major excitatory neurotransmitter in the CNS and acts via various receptors including AMPA, kainate, and Nmethyl-D-aspartate (NMDA) which facilitate depolarization at synapses. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter and it acts via two major receptor subtypes—postsynaptic chloride channel GABA A and presynaptic second messenger-mediated channel GABA B receptors (46). Enhanced NMDA receptor function and alteration in GABA receptor efficacy play important roles in seizure propagation and termination respectively (47). Though cellular excitation occurs because of these underlying mechanisms, neurons must also form a synchronized network in order to generate a seizure. Gap junctions and glutaminergic synapses generate rapid and effective synchronization (45), resulting in paroxysmal depolarizing shift or sustained neuronal depolarization that leads to a burst of action potentials followed by rapid GABA-mediated repolarization and hyperpolarization. Seizure propagation
occurs because of facilitation of the first phase of this response and failure of the second in specific macrocircuits (45,46). Animal (48,49,50) and human studies (51) confirm that seizures result in substantial brain injury. One animal study confirmed electron microscopic evidence of neuronal injury within 20–32 minutes of continuous seizure activity and potential for post-seizure maturation of brain injury (49). Notably, animal models of status epilepticus indicate increased cerebral metabolic rate (CMR) (52,53) with substantial decrements in glycogen, glucose and phosphocreatine but a relatively small decrement in ATP and other markers of energy availability (54). Excessive excitatory amino acid release appears to be the primary underlying driver of seizure-related brain damage (55,56).
Neuroinflammation The brain is an immunologically privileged site with the exception of microglia and endothelial cells which take part in immune responses via microglial activation and facilitation of the passage of mediating cells respectively. Multiple ion channels in microglia detect disturbances in the neuronal milieu and become activated and proliferate in response to neuronal injury (57). After activation, microglia take on an amoeboid appearance and produce receptors for many inflammatory mediators including histamine, bradykinin, platelet-activating factor (PAF), and complement, and release a number of proinflammatory substances such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and NO that attract more inflammatory cells to the injured tissue. They are ultimately involved in destroying invading organisms via phagocytosis, T-cell activation, and upregulation of cell adhesion molecules (57). Proinflammatory cytokines and chemokines also play a role in inflammation and immune mediated disorders. Cytokines such as IL-1, TNF-α and interferon-γ increase expression of vascular endothelium adhesion molecules including vascular cell adhesion protein 1 (VCAM-1), also known as vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 (ICAM-1). They also increase the activity of matrix metalloproteinases that promote the uptake of circulating leucocytes. These inflammatory mediators activate microglia and astrocytes and indirectly lead to the production of free radicals, proteases, and complement, all of which potentiate the inflammatory response (5,58,59,60).
Biochemical pathways to brain injury The survival of neurons depends on several factors including adequate supply of oxygen, glucose, and other substrates (particularly lactate and ketones), maintained mitochondrial metabolism and processing, and transport of proteins and growth trophic factors (5). All pathological processes affecting the CNS produce a loss of neurons and other cell types chiefly through one of two morphologically distinguishable, but not mutually exclusive, processes— necrosis and apoptosis (5,25,61,62). Though a steep rise in intracellular calcium is a key initiator of cell death in both mechanisms, the contribution of each to a cell’s ultimate fate is determined by the severity and abruptness of the insult. In general terms, more profound changes initiate necrosis whereas less severe ones induce apoptosis (62). Necrosis occurs after an abrupt cessation of oxygen and/or glucose supply leading to failure of ATP production and cell breakdown and inflammatory infiltration. It is associated with TBI, ischaemia/hypoxia, hypo- and hyperglycaemia, hyperthermia, and prolonged seizures. Acute failure of ATP production leads to neuronal cell depolarization following failure of sodium-potassium membrane pumps, and loss of neuronal excitability with massive release of glutamate. Neuronal injury stems from the accumulation of glutamate, whose uptake is an ATP-dependent process in both neurons and astrocytes (25,61,62,63). This leads to activation of postsynaptic AMPA, kainate, and, most importantly, NMDA glutamate receptors, resulting in massive calcium influx into cells (25) and, in turn, cell membrane degradation via action of calpains and caspases. Subsequent calcium entry into the mitochondria causes distortion of DNA, the production of oxygen free radicals, and failure of the mitochondrial respiratory chain. This process is collectively known as excitotoxicity (25,62). Mitochondrial failure is a critical component of cell necrosis and is induced primarily by NMDA glutamate receptormediated toxicity (64). Intracellular calcium influx leads to subsequent uptake into the mitochondria via the mitochondrial membrane calcium uniporter, mitochondrial membrane depolarization, and release of cytochrome c into the cytosol. It is believed that this change in mitochondrial membrane permeability is an important milestone in a cell’s transition to death (65,66) and therefore a potential target for neuroprotection (65). However, the cell does not become committed to death by this initial sequence of events but by subsequent calcium dysregulation as a result of downregulation of ion exchangers following calpain activation that occurs hours after the initial insult (64,67).
Apoptosis on the other hand results in selective cell death orchestrated by various genes following DNA damage and low energy supply. Although apoptosis plays a role in the pathological response to brain injury, it is also essential for normal brain development and cellular homeostasis (5,35,63). Even with apparently satisfactory return of blood flow and energy supply after transient global or focal ischaemia, delayed cell death may occur because of ischaemic apoptosis as well as acute necrosis, even in the absence of immediate structural damage (35,62,63,67). The apoptotic cascade involves three main steps—activation of death receptors (68), release of cytochrome c from the inner mitochondrial membrane as a result of interactions between proapoptotic and antiapoptotic proteins (25,35,62,64,68,69), and activation of proteolytic enzymes called caspases (35,68). Cells subsequently shrink and break into dense spheres called apoptotic bodies, and are subsequently absorbed by other cells without initiation of inflammatory cascades (63).
Mediators of brain injury Different brain injury types have a similar underling pathophysiological process associated with secondary injury. This is essentially a cascade of seemingly disparate and multiple biochemical reactions and their consequent mediators that each contributes to the death of neural tissue. The specific biochemical mediators involved in neuronal injury are discussed in the following sections and summarized in Figure 2.4 (70).
Click to view larger Download figure as PowerPoint slide Fig. 2.4. Mediators of neuronal injury. The multiple pathways contributing to neuronal death. Reprinted from Trends in Pharmacological Sciences, 31, 12, Loane DJ and Faden AI, ‘Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies’, pp. 596–604, Copyright 2010, with permission from Elsevier.
Calcium
Calcium plays a key role in secondary brain injury and subsequent neuronal death. It accumulates intracellularly as a direct result of glutaminergic activation in neuronal injury via several pathways (64,67,68). AMPA receptors, though thought to be primarily permeable to sodium and potassium, are now believed to be also permeable to calcium and, following upregulation in response to ischaemia, are likely responsible for the resultant increases in intracellular calcium concentration (25). Increased intracellular calcium also occurs via NMDA and kainate receptors through overstimulation and impaired reuptake of glutaminergic excitotoxic neurotransmitters, and other ion channels and transporters such as transient receptor potential (TRP) channels, Na +/Ca2+ exchanger channels (NCX), acid-sensing ion channels (ASICs), L-type voltage-dependent Ca2+channels, and hemichannels. In addition, malfunctions in internal calcium storage systems, especially in the endoplasmic reticulum and mitochondria, also contribute to elevated intracellular calcium concentration secondary to breakdown of membranes or dysfunction of the ryanodine receptor (71). There are numerous signalling pathway consequences of excitotoxin-mediated calcium dysautoregulation leading to apoptotic or necrotic cell death. Intracellular calcium becomes sequestered into the mitochondria, particularly during prolonged endoplasmic reticulum stress (71), leading to failure of respiratory chain function and formation of reactive oxygen species (ROS) that deplete ATP and cause further cell damage (64). This then triggers several catabolic enzymatic reactions that lead to further cell damage and death (Figure 2.4) (67). Moreover, calcium effects can be mediated via phospholipase A2 which acts on membrane phospholipids to release arachidonic acid. This is then metabolized to form several inflammatory and thrombogenic mediators, including prostaglandins and leukotrienes. Calcium also activates calpains, caspases, endonucleases, and kinases which lead to increased free radical production, damaged mitochondria and endoplasmic reticulum, acidosis, cellular oedema, cytoskeletal breakdown, loss of integrity of cell, and fragmented DNA. Together these several pathways kill the cell (25,61).
Reactive oxygen species ROS are highly unstable free radicals because of an unpaired electron in their outer electron shell. If not deactivated, they lead to neuronal destruction (5,41). Enzymes such as super oxide dismutase (SOD), glutathione peroxidase, and catalase scavenge free radicals, and astrocytes protect neurons against oxidative damage by providing precursors for glutathione synthesis and an array of antioxidant enzymes (72). The mitochondrial respiratory chain contains the chief source of electrons required to reduce molecular oxygen to form ROS which include hydrogen peroxide (H 2O2) and the hydroxyl (HO-) and superoxide (O2−) radicals (5,73,74). Interestingly, NO which has neuroprotective actions in ischaemia and TBI (75,76) may exert a double effect of membrane peroxidation and DNA destruction after reacting with superoxide radicals to form peroxynitrite (ONOO−) (72,74). Free radicals are produced following mitochondrial energy failure, glutamate-mediated influx of calcium (which activates NO synthase), activation of the phospholipase A2–cyclooxygenase pathway, and in the presence of free ferrous iron which serves as a catalyst for ROS generation (41,72,73). In addition, neutrophils yield a significant proportion of ROS through oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) (73,74) which results in peroxidation of cell membranes (5,41,72,73,74).
Stress proteins Several heat shock proteins (HSPs) are transcriptionally activated in response to cellular injury. HSP70 is the most abundant in normal cells and induced by denatured proteins (77). It mitigates cell damage by binding to denatured proteins in an attempt to salvage their enzymatic activity. HSP70 is upregulated and produced in massive quantities in response to ischaemic tissue damage, particularly in neurons and glia in penumbral regions of infarcts, resulting in ischaemia-induced tolerance and promotion of cell survival (77). HSP32, also known as haem-oxygenase-1 (HO1), is primarily synthesized in glia and regulates haem turnover and iron metabolism. It is upregulated in subarachnoid haemorrhage and may play a role in protection against oxidative stress (78). Nuclear factor kappa B (NF-κB) is a transcriptional factor that functions as a ‘stress sensor’ and is believed to play a dual role (79). It has neuroprotective actions during brief periods of ischaemia but prolonged proapoptotic actions. In unstimulated cells, NF-κB exists in a latent form complexed to an inhibitory protein called inhibitor of κB (IκB). It is activated by multiple stimuli including oxidative stress, bacterial and viral by-products, and proinflammatory cytokines such as IL-1 and TNF. This leads to the dissociation of IκB and translocation of NF-κB into the cell nucleus where it up-regulates mRNA transcription of several protective genes, including SOD (5,79).
Caspases
Like calpains, caspases are cysteine proteases which when active form tetramers that induce apoptosis (35,68). Caspase activation is regulated by interactions between proapoptotic and antiapoptotic proteins (68). Apoptotic signals trigger ‘initiator’ caspases such as caspase-2 (also -8, -9, and -10) which recruit ‘effector’ caspases, such as caspase-3 (also -4, -5, -6, -7, -11, -12, and -13), which carry out cell destruction (35,68,80). Caspase-3, and to a lesser extent caspase-8, inactivates polyadenosine diphosphate (ADP)-ribose polymerase (PARP), thus inhibiting DNA repair (35,80). Other caspases have a range of actions including destruction of nuclear lamina, inactivation of antiapoptotic proteins, and destruction of cytoskeletal structure. Caspases also induce cell death via proteolytic inactivation of effector molecules (68). There are several pathways that converge on caspase activation. The death receptor pathway includes transmembrane receptors such as TNF-α and cell death 95 (CD95), both of which have intracellular death domains. Binding of specific ligands to these receptors triggers activation of Fas-activated death domain and subsequent apoptosis via activation of caspases (68). The ceramide pathway involves cleavage of sphingomyelin in response to cellular stress with the production of membrane-bound ceramide and activation of ceramide-dependent protein kinase which promotes apoptosis via multiple mechanisms. The mitochondrial pathway involves release of cytochrome c and subsequent activation of caspase-8 which commits the cell to death (68).
Cell adhesion molecules Cerebral ischaemia precipitates adhesion and transendothelial migration of leucocytes with the potential for exacerbation of neuronal injury. Three families of leucocyte adhesion molecules have been identified—the immunoglobulin gene superfamily, integrins, and selectins such as P-selectin (81). The immunoglobulin gene superfamily includes ICAM-1 and VCAM-1. These are cell surface glycoproteins expressed on the vascular endothelium which facilitate leucocyte adhesion (81). Their expression is increased following transient and permanent ischaemia (81,82).
Proapoptotic and antiapoptotic factors Apoptosis is regulated by the balance of activity of pro- and antiapoptotic proteins. B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), and inhibitor of apoptosis (IAP) proteins are prosurvival (35,77), while BAX, BAK, and proteins from the BcL-2 homology 3 (BH3) subfamily, such as BAD, promote cell death (5,35,62,74,83). All form heterodimers which control opening of the mitochondrial permeability transition pore and allow dissipation of mitochondrial H+ and uncoupling of the respiratory chain. Antiapoptotic proteins prevent the transition pore from opening whereas proapoptotic proteins promote opening (35). Opening of the pore results in loss of the proton gradient across the inner mitochondrial membrane (the transmembrane potential) leading to intracellular influx of water and rupture of the outer mitochondrial membrane with subsequent release of cytochrome c into the cytosol (25,35,62,64,68,69,74). Proapoptotic proteins such as BAX polymerize to form pores in the outer mitochondrial membrane through which cytochrome c can also escape. Cytochrome c then binds with apoptotic protease-activating factor 1 (APAF-1) to form the apoptosome which recruits and activates caspase-9, triggering several cascades that ultimately lead to cell death (35,74).
Platelet-activating factor PAF is a potent phospholipid and mediator of neuronal injury. It causes free radical-associated damage and upregulation of gene expression of TNF-α and COX-2 which participate in inflammation and apoptosis (84). PAF antagonists such as LAU-0901 and the free radical scavenger alpha-phenyl-N-tertiary-butyl nitrone (PBN) reduce PAF-triggered inflammation and neurodegeneration in PAF-stressed neural cells (85). PBN most efficiently represses COX-2 and TNF-α, suggesting that a significant component of PAF-induced neuronal injury is related to oxidative stress and free radial damage.
Toll-like receptors Toll-like receptors (TLRs) are cell surface proteins that recognize foreign cell constituents such as lipids and proteins. They play a key role in immune surveillance (86). Once believed to be present only in leucocytes, TLRs are now known to be associated with different tissue types including cortical neurons and glial cells (86). Activation of TLRs initiates signal cascades primarily involving NF-κb which in turn induces expression of cytokines and pro-inflammatory molecules such as IL-6, IL-1β, and TNF-α, triggering neuronal apoptosis (86,87). In mice cortical neurons, TLR-2 and
TLR-4 promote neuronal death in the setting of glucose deprivation and elimination of TLRs protects neurons from cell death (87).
Erythropoietin Erythropoietin (EPO) is a member of the haematopoietic cytokine 1 superfamily whose expression is induced by the hypoxia-inducible factor (HIF) family of transcription factors in response to hypoxia (88). Activation of the EPO receptor (EPOR) by low oxygen conditions inhibits apoptosis in the bone marrow and leads to erythropoiesis and angiogenesis thereby increasing erythrocyte circulation (88). EPOR forms homodimers after binding to EPO, triggering autophosphorylation of EPOR-associated Janus-tyrosine kinase-2 (JAK-2) (89) which in turn leads to the phosphorylation of multiple protein kinases and transcription factors including NF-κB (89). These in turn upregulate the prosurvival protein Bcl-xL (88). In the brain, both EPO and EPOR play a critical role in neuronal survival, particularly after hypoxic/ischaemic injury. They are typically found in low concentrations in brain tissue but become upregulated in many conditions including AIS where there is particular expression in penumbral regions (90). EPO has additional neuroprotective effects including reduction of synaptic release of glutamate and amelioration of glutamate-induced excitotoxicity (90).
Aquaporins Aquaporins are transmembrane water-channel proteins that regulate cellular water balance. AQP4 is the most abundant aquaporin in the brain and chiefly located in the astrocytic foot processes. Water transport through AQP4 is driven by the osmotic gradient across the cell and regulated by receptor–ligand interactions. Activation of these receptors leads to phosphorylation of AQP4 with resultant activation of calcium and/or protein kinases, and either upor downregulation of AQP4 with variable effects on cellular oedema (39). Though AQP4 modulation might appear to offer a straightforward treatment option for cerebral oedema, inhibition of AQP4 has opposing roles in cytotoxic and vasogenic oedema making a simple targeted approach challenging (39,91). Hypertonic saline and bumetanide have been shown to reduce cerebral oedema via AQP4 modulation in clinical conditions such as AIS (40).
Sex hormones Progesterone is a steroid hormone synthesized in glial cells that has been shown to confer neuroprotective effects in a variety of neurological conditions (92). It has been particularly well studied in TBI in which the effects of progesterone were first identified when female rats were observed to recover better than male rats after brain trauma. Subsequent animal models have shown numerous protective effects for progesterone including reduction in cerebral oedema (93), decreased neuronal loss (94), anti-inflammatory effects via inhibition cytokine release (95), antioxidant effects (95), and improved cognitive outcomes (94).
The multifactorial nature of brain injury The impetus for elucidating the pathophysiological basis of brain injury is to allow rational development of neuroprotective strategies. The multiple pathways involved in the genesis of brain injury underscores the significant physiological and biochemical complexity involved in neuronal demise from various types of neurological insult. With this in mind, it is unsurprising that success in the development of neuroprotective strategies based on amelioration of one pathway has been elusive. At the time of writing, there are more than 23,000 publications dealing with stroke and its treatment in various animal models, and more than 2310 completed clinical trials listed on the Stroke Trials Registry. Despite the large volume of encouraging preclinical data, few neuroprotective therapies have translated into clinical effectiveness, illustrating the problems of dealing with complex pathophysiological processes. Donnan, in the 2007 Feinberg lecture, made this remarkable statement about neuroprotection research: ‘We have reached a stage at which research in this area should stop altogether or radical new approaches adopted’ (96). Various causes for the apparent futility in pathophysiologically based neuroprotection research have been suggested and these have been reviewed elsewhere by Kofke who promoted a multimodal therapy paradigm as the optimal solution (97).
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Neuropharmacology
Pharmaceuticals are central to the practice of neurocritical care. An overview of basic concepts can be found in most standard textbooks of pharmacology and this chapter will provide an overview of neuropharmacology relevant to neurocritical care. More detailed information about neuropharmacological issues relevant to specific disease states or situations is also available elsewhere in this book.
Antiepileptic drugs First-generation antiepileptic drugs (AEDs), such as phenytoin, phenobarbital, primidone, benzodiazepines, ethosuximide, carbamazepine, and valproate, have multiple drug interactions and adverse effects related to enzyme induction and/or inhibition. Second-generation AEDs have been developed since the early 1990s and include felbamate, vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, and zonisamide. The newer drugs offer advantages of fewer drug interactions, greater safety, unique mechanisms of action, and broader spectrum of activity, although most still do have significant adverse side effects and potential for drug interactions (98). AEDs act on diverse molecular targets through effects on multiple receptors and neurotransmitters, although their mechanisms of action can generally be categorized into modulation of voltagedependent ion channels, inhibition of synaptic excitation, and enhancement of synaptic inhibition (98,99). Efficacy is related to the degree of modification of the excitability of neurons such that seizure activity is attenuated without disturbing normal (non-epileptic) neuronal activity. The major mechanisms of AEDs are summarized in Figure 2.5 (99,100,101).
Click to view larger Download figure as PowerPoint slide Fig. 2.5. Principal mechanisms of action of antiepileptic drugs. Antiepileptic drugs display a spectrum of mechanisms of action, with effects on both inhibitory (left-hand side) and excitatory (right-hand side) nerve terminals.
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium- and chloride-dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Reproduced with permission from Macmillan Publishers Ltd: Nature Reviews Neurology, 8, 12, Wolfgang Loscher and Dieter Schmidt, ‘Epilepsy: Perampanel-new promise for refractory epilepsy?’, pp. 661–662 © 2012. Originally adapted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery, 9, 1, Bialer M and White HS, ‘Key factors in the discovery and development of new antiepileptic drugs’, pp. 68–82 © 2010.
Anaesthetic and sedative agents Several factors are important when designing a therapeutic paradigm that leads to a safe and comfortable patient in the NCCU (see also Chapter 6).
Hypnosis, anxiolysis, and amnesia The GABA receptor and its various subclasses play a central role in the action of many hypnotic agents (102). Stimulation of the GABA receptor leads to increase in cell membrane chloride conductance and hyperpolarization of the neuron such that the effects of neuroexcitatory neurotransmitters, which ordinarily cause depolarization, are neutralized. This leads to a dose-dependent decrement in the level of consciousness, on a continuum from minimal depression with disinhibition and electroencephalogram (EEG) activation to deep anaesthesia with significant metabolic suppression and an isoelectric EEG (103). In general, GABAergic drugs, such as barbiturates (103,104), benzodiazepines, propofol, and etomidate (103), produce a decrease in CMR and a coupled decrease in CBF (103) and therefore reduce ICP in a normally reactive brain (105). Non-GABergic hypnotic drugs include dexmedetomidine and ketamine. Dexmedetomidine is an alpha-2 adrenergic agonist thought to exert its effects primarily in the locus coeruleus (106) which produces mild analgesia and a reduced level of consciousness from which the patient can easily be aroused (107). It is associated with a small coupled decrease in CMR and CBF (108). Dexmedetomidine also has a role in the treatment of delirium (109). Ketamine acts by blocking NMDA receptors (110) and produces hypnosis and analgesia associated with a concomitant array of neuroexcitatory phenomena and increased CMR and ICP (103).
Analgesics The brain is richly supplied with opiate receptors and corresponding endogenous opiate ligands (111). There are multiple pain pathways and nerve fibre types. Peripheral receptors and their proteins (e.g. substance P) transduce pain through fast somatic fibres and smaller and slower visceral and sympathetic pain fibres. Pain pathways meet in the thalamus from which there is further transmission to multiple cortical areas (112). Interruption of these pathways by disease processes can lead to pain syndromes (113). Moreover, chronic exposure to opioids leads to downregulation of opioid receptors and upregulation of cAMP pathway associated with many chronic pain syndromes. Thus patients in the NCCU may have pre-existing pain syndromes, pathological alterations of pain pathways, or both (114,115), in addition to acute pain related to surgery, trauma, or prolonged immobility. The underlying taxonomy of pain describes nociceptive, inflammatory, neuropathic, and dysfunctional pain types. The mainstay of analgesia in the NCCU is centred on the use of mu opioid agonists, adjunct agents such as gabapentin, and occasionally nerve blocks. Mu opioids are agonists at endogenous mu opioid receptors which mediate analgesics via G-protein-linked increased inward potassium flux and decreased outward sodium flux (103,115). The attenuation of pain involves a significant element of thalamic depression among other mechanisms (53). At usual doses, mu opioids produce only modest decreases or minimal direct effects on global CMR and CBF (116), and all can cause respiratory depression, hypotension, and nausea and vomiting (117). Gabapentin is a useful adjunct in the management of acute (118) and neuropathic pain syndromes (119) and may have a role in the prevention of chronic neuropathic pain after surgery (119). Multiple putative mechanisms for the antinociceptive effect of gabapentin have been described including (but not limited to) upregulation of N-type calcium channels in the spinal cord (120), inhibition of catecholamine release from adrenal chromaffin cells (121), interference with development of opioid tolerance (122), inhibition of GABA release from the locus coeruleus cells (123), and increased concentration of cortical GABA (124).
Immobility and shivering control
Immobility can usually be achieved by producing a comfortable patient but additional pharmacological methods may be required to reduce the risk of injury during uncontrolled movements in delirious or agitated patients, or those with involuntary movements including shivering. All antipsychotic drugs that interfere with dopaminergic transmission may induce an element of hypokinesis (125).There are a multitude of antishivering drugs but the most commonly used are meperidine, dexmedetomidine, clonidine, and buspirone. Meperidine potently decreases shivering (126) although there is concern about potential proconvulsant effects of its metabolite normeperidine (127). Buspirone, a serotonin (5HT)1A partial agonist with minimal intrinsic sedative actions, is unimpressive in isolation but synergistically augments the antishivering effects of meperidine (126). Neuromuscular blockade may also be needed to effect control of shivering under certain circumstances.
Neuromuscular blocking agents Neuromuscular blocking drugs include depolarizing and non-depolarizing types. The depolarizing neuromuscular blocking agent suxamethonium produce an excessive nicotinic cholinergic stimulation that causes sodium channels adjacent to the endplate to remain in an inactivated state with consequent intense but short-lived neuromuscular blockade (128). Succinylcholine increases CBF and ICP briefly (129), likely related to the massive stimulus associated with fasciculations (129). It should be avoided in patients with ICU-acquired or pre-existing myopathy, recent lower motor neuron denervation, or after prolonged immobilization in whom it can lead to a precipitous and life-threatening increase in serum potassium. Non-depolarizing agents such as vecuronium and rocuronium directly and competitively block the nicotinic neuromuscular junction (128) and provide varying degrees of neuromuscular blockade which can be monitored by peripheral electromyography monitoring (128). Non-depolarizing neuromuscular blockade is reversed with an anticholinesterase agent such as neostigmine, edrophonium, or pyridostigmine in association with a muscarinic anticholinergic agent to prevent muscarinic acetylcholine-mediated bradycardia, bronchoconstriction, bronchorrhoea, and alimentary hyperperistalsis. Thus common problems associated with reversal of neuromuscular blockade include tachycardia and bradycardia which can confuse the evaluation, postoperative tachycardia, and bradycardia (128). Vecuronium and its congeners have minimal cerebrovascular effects (130).
Sympathetic hyperactivity Many syndromes are associated with ‘autonomic storms’, more accurately referred to as paroxysmal sympathetic hyperactivity (131), and this is likely to represent a lack of cortical inhibitory modulation of nociceptive inputs (132). Controlling sympathetic hyperactivity is an important element of management in some patient groups in the NCCU. After adequate sedation and analgesia is ensured, centrally acting sympatholytic drugs, such as dexmedetomidine, clonidine, and propranolol (131), may be effective. Dexmedetomidine and clonidine are central alpha-2 agonists that act predominantly at the locus coeruleus to diminish central adrenergic activity (106). Propranolol is a beta-adrenergic antagonist which crosses the BBB (133) and has been reported to be effective in controlling symptoms of sympathetic hyperactivity (131). Other possible therapeutic modalities include centrally (134) or peripherally administered baclofen (131).
Antipsychotic drugs Antipsychotic drugs including phenothiazines and structurally similar compounds such as butyrophenones, diphenylbutylpiperidines and indolones were developed for use in schizophrenia and other psychotic disorders. However, they also have a role in the management of delirium, amphetamine intoxication, paranoias, mania, and Alzheimer’s-associated agitation (135). Although there is chemical dissimilarity between different antipsychotic drugs, there are many pharmacological similarities. They are classified into typical and atypical subtypes (Table 2.2). Atypical antipsychotics have varied mechanisms compared to typical antipsychotics, are associated with a substantially lower risk of extrapyramidal side effects, and have become the preferred antipsychotic agents in the NCCU (135). Typical antipsychotic drugs include haloperidol and droperidol and primarily act as D 2 dopamine receptor antagonists (135). They are characterized as neuroleptic agents. In contrast, atypical antipsychotics provide a broader range of selective neurochemical effects including (to varying extents) antiserotonergic (5-HT 2A and 5-HT1A), antidopaminergic (D1 and D2), antiadrenergic, and antihistaminic (H1) actions with lower anticholinergic activity. The disparate receptor effects of various antipsychotic drugs are summarized in Table 2.3. Table 2.2 Antipsychotic drugs
Typical antipsychotics
Atypical antipsychotics
Phenothiazine
Non-phenothiazine
Acetophenazine Chlorpromazine Fluphenazine Promethazine Mesoridazine Perphenazine Perphenazine; Prochlorperazine Promazine Promethazine Thiethylperazine Thioridazine Trifluoperazine
Haloperidol (butyrophenone) Iloperidone Loxapine (tricyclic) Molindone Pimozide (butyrophenone) Sertindole Thiothixene Xanomeline Zotepine
Aripiprazole Clozapine Fluoxetine Olanzapine Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone
Data from Brunton LL et al. (eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition: McGrawHill, 2006. Table 2.3 Potencies of standard and experimental antipsychotic agents at neurotransmitter receptors a,b
Drugs
Receptor Dopami ne D 2
Seroton in 5HT 2
5HT /D ra tio 2A
2
Dopami ne D
D
4
Muscari nic choliner gic
Adrenerg ic 1
2
Histami ne H 1
1
Ziprasidone
×
×
1.0
4 ×
×× ×
5×
3×
4×
3×
cisThiothixene
×
4×
289
4 ×
3×
5×
3×
4×
2×
Sertindole
×
×
0.8
3 ×
3×
6×
×
5×
4×
Fluphenazin e
×
3×
24
3 ×
2×
5×
2×
5×
3×
Zotepine
2×
×
0.6
3 ×
2×
4×
2×
4×
2×
Perphenazin e
2×
2×
24
—
—
4×
3×
4×
—
Thioridazine
2×
3×
18
3 ×
3×
3×
3×
—
—
Pimozide
2×
3×
5.2
—
3×
—
—
—
—
Drugs
Receptor Dopami ne D 2
Seroton in 5HT 2
5HT /D ra tio 2A
2
Dopami ne D
D
4
Muscari nic choliner gic
Adrenerg ic 1
2
Histami ne H 1
1
Risperidone
2×
×
0.05
4 ×
3×
> 6×
2×
3×
3×
Aripiprazole
2×
2×
1.0
4 ×
3×
> 6×
3×
—
3×
Haloperidol
2×
3×
9.0
3 ×
3×
> 6×
2×
5×
5×
Ziprasidone
2×
×
0.09
4 ×
3×
6×
3×
—
3×
Mesoridazin e
2×
2×
1.26
—
3×
—
—
—
—
Sulpiride
2×
5×
135
5 ×
3×
4×
5×
—
—
Olanzapine
3×
2×
0.36
3 ×
2×
2×
3×
4×
2×
Chlorproma zine
3×
2×
0.07
3 ×
3×
3×
×
4×
2×
Loxapine
3×
2×
0.02
—
3×
3×
3×
5×
2×
Pipamperon e
3×
2×
0.01
5 ×
—
5×
3×
4×
5×
Molindone
4×
5×
40
—
—
—
5×
4×
>6×
Amperozide
4×
3×
0.14
4 ×
—
5×
4×
4×
4×
Quetiapine
4×
4×
1.84
4 ×
5×
4×
3×
5×
3×
Clozapine
4×
2×
0.01
3 ×
2×
2×
2×
4×
3×
Melperone
4×
3×
0.16
—
4×
—
—
—
—
Remoxipride
4×
6×
36
6 ×
5×
6×
6×
5×
6×
Data summarize approximate relative Ki values (nM) determined by competition with radioligands for binding to the indicated receptors. Data indicate on an approximate logarithmic scale K i values from 0–0.99 (×), 1.0–9.9 (2×), 10–99 (3×), 100–999 (4×), 1000–9999 (5×), and 10,000–99,000 (6×). Compounds are in rank-order of dopamine D2 receptor affinity; 5-HT2A/D2 ratio indicates relative preference for D2 vs serotonin 5-HT2A receptors. Compounds include clinically used and experimental agents. b Muscarinic cholinergic receptor Ki values are pooled results obtained with radioligands that are non-selective for muscarinic receptor subtypes or that are selective for the M 1 subtype. Data from Brunton LL et al. (eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition: McGrawHill, 2006. a
Nausea and vomiting Nausea and vomiting is a common symptom in the NCCU, particularly after surgery when it occurs in up to one-third of patients overall (136,137,138). It has been reported in one-half of patients after supratentorial craniotomy with an even higher incidence after infratentorial craniotomy (139,140). Vomiting is particularly unwelcome after neurosurgery when retching and associated systemic hypertension and increased venous pressure may predispose to postoperative intracranial bleeding. First-line treatment of nausea and emesis is typically with a single agent such as ondansetron, although multimodal therapy with agents with different mechanisms of action is required in many cases (see Chapter 16) (141). Ondansetron is a 5HT3 receptor antagonist (142) with reliable antiemetic actions after intracranial neurosurgery (139,140). It has no effect on cerebral haemodynamics or ICP (143) and causes minimal sedation (139,140), although headache, dizziness (137), and dystonic/encephalopathic reactions (144) have been reported. Low-dose droperidol is also an effective antiemetic after craniotomy (145). Droperidol is a butyrophenone with D2 receptor antagonist activity (146) and minimal cerebral haemodynamic, ICP, and sedative affects (147), although it causes a small decrease in systemic blood pressure (145). It is associated with extrapyramidal side effects (137) and can produce dysphoria when used without other sedative agents (148). Phenothiazines such as chlorpromazine, promethazine, prochlorperazine, and perphenazine are also D2 antagonists (146) but with additional moderate antihistamine and anticholinergic actions (137). They are effective in controlling postoperative nausea and vomiting but can also produce extrapyramidal reactions. Trimethobenzamide is believed to work by inhibiting the chemoreceptor trigger zone (149). It has less potential to cause extrapyramidal side effects than some other agents because it is only a weak D 2 antagonist (146). It causes minimal sedation. Scopolamine is a centrally acting anticholinergic which blocks impulses from vestibular nuclei to higher areas in the CNS to reduce vomiting (137). Its central cholinergic antagonism can lead to delirium which is reversible with physostigmine, a centrally acting cholinesterase inhibitor (150). Scopolamine produces mild sedation. Metoclopramide is an effective postoperative antiemetic (151) with both D2 and 5HT3 antagonist effects (146). It also increases gastric motility (152) but has the potential to produce dystonic reactions which can lead to life-threatening respiratory compromise (153). Hydroxyzine is an antihistamine and anticholinergic drug which blocks acetylcholine in the vestibular apparatus and histamine H 1 receptors in the nucleus of the solitary tract (137). Although an effective antiemetic, it is sedative (137). Two drugs primarily used for other indications in the NCCU also have antiemetic actions. Propofol in small doses has similar efficacy to established antiemetic drugs after surgery (154), although its antiemetic mechanism of action is unknown (137). Dexamethasone and other glucocorticoids are also effective antiemetics (141,151) with unclear mechanisms of action (137).
Catecholamines Dopamine, epinephrine, and norepinephrine are endogenous central neurotransmitters and as such have a role in normal neural function (155). However, catecholamines can also act as toxic neurotransmitters in multiple brain pathologies (156) and this has substantial implications during the use of exogenous catecholamines to maintain blood pressure in the NCCU. Catecholamines are centrally acting neurotransmitters whose synthesis is tightly regulated, largely through tyrosine hydroxylase (155). Following release into synaptic vesicles, catecholamines are either degraded by catechol-O-methyl transferase or monoamine oxidase, or taken up by the presynaptic membrane to be repackaged into new synaptic vesicles (155). Synthetic adrenergic analogue drugs such as phenylephrine, methoxamine, dobutamine, and isoproterenol can also be taken up and repackaged into presynaptic vesicles, thus theoretically becoming false
neurotransmitters with effects on their quantal potency (157). Exogenous catecholamines also undergo synaptic cleft degradation by the same enzymatic pathways as endogenous counterparts. Uptake of adrenergic compounds and their precursors from the blood is a regulated process involving transport proteins in the BBB (158,159). Notably, variations in blood concentration of catecholamines have a direct effect on their uptake and synthesis (159). Nonetheless, simple diffusion is a minor to absent element of transport of adrenergic compounds and their precursors into the brain with an intact BBB. The normal function of catecholamine neurotransmitters is to activate neural processes, generally enhancing cognitive processing (160).The net result is increased CMR and, in uninjured brain, a coupled increase in CBF (161). Notably the brain is sparsely populated with endothelial adrenergic receptors, although they are not absent (157). With these considerations in mind, adrenergic drug infusions have only a small, but not absent, effect on CBF in the normal brain with intact BBB (162,163). Further, any CBF effects are primarily believed to be indirect, occurring as a consequence of peripheral effects on systemic blood pressure. However, in the injured brain with a disrupted BBB, peripheral administration of adrenergic agents can have multiple CNS effects. Entry of the drugs into brain parenchyma via the disrupted BBB allows them to act in a similar manner to an endogenous neurotransmitter and cause neural activation and increases in CMR and CBF (Figure 2.6) (161,164). However, Dhar and colleagues reported no increase in CBF or CMR during administration of unidentified vasopressors to patients with SAH (165), presumably a group with disrupted BBB function (166). The role of the BBB in mediating the central effects of systemic catecholamines is summarized in Figure 2.6. Whilst the exact relevance to clinical practice in the NCCU is unsettled, it seems reasonable to maintain concern about potential deleterious effects of exogenous catecholamine administration on CMR and CBF pending more definitive information.
Click to view larger Download figure as PowerPoint slide Fig. 2.6. Effects of adrenergic drugs on cerebral blood flow and metabolism. This chart depicts the effects of intracarotid infusion of propranolol, noradrenaline (norepinephrine), and adrenaline (epinephrine) to subhuman and human primates. Baboon studies indicate that propranolol, which crosses the BBB acts to depress CMR. Noradrenaline infusion to baboons has minimal effect on CMR and CBF with an intact BBB. However, prior disruption of the BBB with urea results in noradrenaline increasing CMR and CBF. Comparable findings were reported in humans with intact BBB undergoing intracarotid infusion of adrenaline or noradrenaline during cerebral angiography.
These observations indicate that CBF and CMR are activated by adrenergic influences and that the BBB has an important role in mediating the effects of systemic administration of catecholamines. A, adrenaline; Bab, baboon; BBB, blood–brain barrier; CBF, cerebral blood flow; CMRG, cerebral metabolic rate for glucose; CMRO2, cerebral metabolic rate for oxygen; Hum, human; NA, noradrenaline; Ppl, propranolol. Data from MacKenzie E et al., ‘Influence of endogenous norepinephrine on CBF and metabolism’, The American Journal of Physiology, 1976, 231, p. 489; Olesen J, ‘The effect of intracarotid epinephrine, norepinephrine, and angiotensin on the regional CBF in man’, Neurology, 1972, 22, pp. 978–987; MacKenzie ET et al., ‘Cerebral circulation and norepinephrine: relevance of the blood brain barrier’, American Journal of Physiology, 1976, 231, 2, pp. 483–488. Multiple studies also support the notion of catecholamine-related neurotoxicity in the injured brain. Serum catecholamine levels increase dramatically after SAH, peak simultaneously with the peak incidence of SAH-related vasospasm, and high serum catecholamine levels correlate with the development of symptoms of delayed cerebral ischaemia (DCI) (167,168). Such observations support the hypothesis tested in laboratory models (169,170) that catecholamine-related hypothalamic injury may be an important factor in the genesis of DCI and cerebral infarction after SAH. Confirmation also comes from clinical reports that treatment with beta- and alpha-adrenergic antagonists is associated with an improvement in neurological outcome (171) and electrocardiographic abnormalities (167) after SAH. Data describing adrenergic neurotoxicity in human studies of SAH provide strong support for the use of sympatholytic drugs as preferred antihypertensive agents in the NCCU. In addition, beta-adrenergic blocking drugs have not been reported to cause cerebral vasodilatation or increase ICP (172,173).
Calcium channel blockers The dihydropyridine calcium channel antagonists nimodipine and nicardipine bind to the α1 subunit of the calcium channel and antagonize the slow and L-type voltage-sensitive calcium channels (174). These receptors mediate calcium entry into vascular smooth muscle cells and their blockade prevents increased cytosolic calcium and the consequent cascade of events leading to actin–myosin coupling resulting in arteriolar relaxation (174). Nimodipine is used routinely after SAH (see Chapter 18) (174,175), where its putative neuroprotectant actions may outweigh any actions to diminish vasospasm directly (176). Nicardipine is a systemic arteriolar vasodilator (including coronary arteries) which has been used as an intra-arterial dilator during interventional neuroradiology procedures for cerebral vasospasm (177,178). It has also been delivered intrathecally with encouraging early reports of efficacy against vasospasm after SAH (179,180). Intra-arterial infusions of nimodipine (181) and verapamil (182) have also been reported as treatment for cerebral vasospasm. Calcium channel blockers may also be reasonable choices for antihypertensive therapy in SAH based solely on the observations of their potential neuroprotective actions. However, as they are vasodilators they can modestly increase ICP (183). Nicardipine is a particularly useful antihypertensive drug in the acute phase after SAH (184) as its pharmacokinetics allow for convenient bolus administration (185).
Vasodilators Peripheral vasodilators such as nitroprusside, nitroglycerine, and hydralazine all have potential to induce cerebral vasodilatation and cause hyperaemic intracranial hypertension (186,187,188). Moreover they are associated with a compensatory increase in peripheral catecholamines and renin (189), factors which theoretically may worsen ischaemic brain injury (169,170). However, the lack of bradycardia and bronchoconstriction associated with their use may make them a useful option in some patient groups. Apart from direct cerebrovascular effects, there is concern that any antihypertensive agent may increase ICP in a normally reactive brain because of secondary cerebral vasodilation in response to reduction in systemic and cerebral perfusion pressure below relevant thresholds (190).
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Cerebral blood flow physiology, pharmacology, and pathophysiology Chapter: Cerebral blood flow physiology, pharmacology, and pathophysiology Author(s): Chandril Chugh and W. Andrew Kofke DOI: 10.1093/med/9780198739555.003.0003 Cerebral blood flow (CBF) is defined as the amount of blood received by the brain in a given time, and expressed in millilitres per 100 g of brain per minute. The adult brain receives around 15% of the resting cardiac output, approximately 700 mL of blood every minute, and accounts for 20% of basal oxygen consumption. Blood flow to the grey and white matter is around 50 mL/100 g/min and 20 mL/100 g/min respectively (1,2). CBF is very tightly regulated and understanding the physiological basis of this regulation is very important in the management of patients with brain injury.
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Anatomy of cerebral vasculature
The aortic arch gives rise to three arterial vessels which provide macrovascular arterial inflow to the brain as depicted in Figure 3.1. Unlike in other major organs, this anatomical arrangement provides the brain with inherent cerebrovascular reserve and collateral flow based on redundant inflow paths via the circle of Willis, thereby providing a first level of protection against conductance vessel obstruction. The cerebral microvasculature is a complex array of small arterioles supplying a hexagonal column of cortical tissue, with intervening boundary zones (1). This arrangement, with its extrinsic neural innervations (see ‘Neural Control of Cerebral Blood Flow’), prevents brain tissue from being exposed to surges in systemic blood pressure. Histologically, cerebral arteries and arterioles have only a single elastic lamina and this influences their response to alteration in luminal pressure. They are also lacking a vasa vasorum (3) and were believed to derive their nutrition from the cerebrospinal fluid (CSF) via adventitial hollow channels (4). However, it is tempting to speculate that the recently described glymphatic system of perivascular CSF flow is the primary mechanism by which CSF provides the endothelial nutritive source throughout the brain as well as being a functional waste clearance pathway (5).
Click to view larger Download figure as PowerPoint slide Fig. 3.1. Arterial supply to the brain. Schematic representation of the circle of Willis, arteries of the brain, and brainstem. Blood enters and flows up to the brain through the vertebral arteries and through the internal carotid arteries.
Figure reproduced with permission from http://commons.wikimedia.org/wiki/File:Circle_of_Willis_en.svg. Adapted from: This figure was originally published in Gray's Anatomy, Twentieth edition, thoroughly revised and re-edited by Warren H. Lewis, plate 722, Elsevier. Copyright the editors, 1918. Cerebral microvessels are notably different from systemic vessels through their intimate relation to perivascular astrocytic foot processes which, together, constitute the blood–brain barrier (BBB). The BBB and the vascular endothelium lack the fenestrations seen in systemic vessels and have fewer pinocytic vesicles but five to six times more mitochondria. Together these form the microvascular unit which exerts significant control on nutrient and metabolite ingress and egress, and regulation of the cerebral circulation (6). Taken together, the neurons, astrocytes and other glia, vascular endothelium as a constituent of the BBB, and vascular elements comprise a functional neurovascular unit which controls neurovascular, neurometabolic, and neurobarrier coupling and integration (7). This concept is illustrated in Figure 3.2, and its physiological consequences are reviewed subsequently in this chapter.
Click to view larger Download figure as PowerPoint slide Fig. 3.2. The neurovascular unit and neurovascular coupling. Neuronal activity triggers various responses that act together to adapt the delivery of energy substrate to the local neuronal needs. Neurovascular coupling involves the dilation of blood vessels to increase the local blood flow as needed, while neurometabolic coupling involves the stimulation of energy metabolism in line with cellular ATP consumption. It is proposed that neuronal activity brings about changes at the level of the blood–brain barrier (BBB), establishing neurobarrier coupling that acts to increase the transport of energy substrate, mainly glucose, across the barrier. Pial veins do not follow the same routes as pial arteries and do not significantly change in diameter with changes in CBF. The venous endothelium is part of the BBB and is the most frequent site of BBB breakdown (6). The venous drainage of the brain is via parenchymal venules and veins which, after traversing CSF-containing spaces, continue via endothelialized channels and sinuses embedded within the dura (Figure 3.3A). These ultimately drain into the jugular veins. Elevations in intracranial pressure (ICP) can obstruct venous outflow, thus creating a venous vascular ‘waterfall’ effect wherein intracranial venous pressure is effectively isolated from extracranial venous pressure (Figure 3.3B) (8,9,10,11). This might account for the notion that increases in venous pressure, for example, from positive endexpiratory pressure during mechanical ventilation, are not transmitted to the brain if ICP exceeds venous pressure (12). Increased ICP can increase intracranial venous pressure and thereby predispose to tissue oedema (13). It was previously believed that blood from the supratentorial compartment drained exclusively into the right internal jugular vein, and that from infratentorial brain tissue into the left internal jugular vein, but recent studies have shown that there is considerable variation between individuals (14).
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Click to view larger Download figure as PowerPoint slide Fig. 3.3. Cerebral venous drainage. (A) Cerebral veins and sinuses. The cerebral veins traverse the skull and the cerebrospinal fluid space as blood flows out of the brain. The sagittal sinus is depicted. Note the arachnoid granulations from which CSF is transported from brain to blood and the cerebral vein traversing from brain, across CSF to the sagittal sinus. http://www.netterimages.com/image/1369.htm. (B) Schematic illustration of the brain and its surroundings being enclosed in a rigid shell. When pressure in the CSF space exceeds pressure in the traversing veins a vascular waterfall condition can be established with increased P out which encourages brain oedema and further increases in ICP. Pa, intra-arterial hydrostatic pressure; Pc, intracapillary hydrostatic pressure; Pout, hydrostatic pressure in large cerebral veins; Ptissue, hydrostatic pressure in brain tissue; Pv, hydrostatic pressure in extracranial veins; R a, precapillary flow
resistance; Rout, venous outflow resistance which is affected by C pressure as the vein transits from brain to skull or sinus; Rv, venous flow resistance. Reproduced from Grände P-O et al., ‘Volume-targeted therapy of increased intracranial pressure: the Lund concept unifies surgical and non-surgical treatments’, Acta Anaesthesiologica Scandinavia, 46, 8, pp. 929–941, Copyright 2002, with permission from John Wiley & Sons and The Acta Anaesthesiologica Scandinavica Foundation.
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Physiology of the regulation of cerebral blood flow CBF is regulated via complex mechanisms involving neural, humoral, and myogenic processes (15,16,17) that together are responsible for cerebral autoregulation, flow–metabolism coupling, and neurogenic CBF regulation.
Pressure autoregulation Cerebral pressure autoregulation is the process by which constant blood flow to the brain is maintained in the face of changes in mean arterial (MAP) and cerebral perfusion (CPP) pressures. CBF is maintained at a relatively constant level when MAP is between 50 and 150 mmHg, but above and below these values varies directly with MAP (Figure 3.4). Although the MAP range of 50–150 mmHg has become a key part of traditional physiological teaching, questions have been raised about the validity of 50 mmHg as the lower limit of autoregulation (LLA). Presuppositions about the LLA underlie many clinical decisions but, in an editorial, Drummond argues that a higher pressure of around 70 mmHg might be a more appropriate LLA in many circumstances (18). His scepticism partly arises from the original value of 50 mmHg being derived from a 1959 study in which blood pressure was lowered in pregnant volunteers using a cerebral vasodilator (hydralazine) (19). Many subsequent studies have suggested that the LLA is likely to be higher than 50 mmHg, but this value has persisted in the literature. Of note, the investigations of Finnerty and colleagues (20), and Strandgaard (21,22), demonstrate that the LLA for individual non-anaesthetized patients occurs at a MAP level approximately 25% lower than basal MAP, and that symptoms of cerebral hypoperfusion arise when MAP reaches 40–50% of the basal value. Nonetheless, no studies have validated the existence (or the specific value) of a LLA above 50 mmHg in normal humans, although there is some inferential evidence that it might be higher in the context of traumatic brain injury (TBI) (23). In a study utilizing the pressure reactivity index (PRx) as a measure of autoregulatory function (see Chapter 10), Steiner and colleagues demonstrated that cerebral autoregulation was maintained in many TBI patients within a narrow MAP window (10–20 mmHg versus the conventionally accepted 100 mmHg range) that is unique to each patient, but generally in the 70–90 mmHg range of CPP (24). Overall we consider the LLA to be an unsettled issue and likely to be individual specific in pathological conditions.
Click to view larger Download figure as PowerPoint slide Fig. 3.4 Cerebral autoregulation. Within the autoregulatory range between 50 and 150 mmHg MAP (x-axis), CBF (yaxis) remains stable. Over this range there is no correlation between pressure and flow, whereas above and below the autoregulatory range there is a degree of correlation of CBF with MAP. Note also that changes in CBV arise secondary to normal autoregulation and that this can be important in the context of elevated ICP. This diagram indicates the potential for CBV changes in normally autoregulating brain areas to affect ICP in the context of reduced intracranial compliance (dashed line). Note that this neglects considerations of blood pressure effects on CBV on injured, poorly regulating brain areas, which can display pressure passive dilatation with increased pressure, rather than vasoconstriction that arises with normal autoregulation. CBF, cerebral blood flow; CBV, cerebral blood volume; ICP, intracranial pressure; MAP, mean arterial blood pressure. Reprinted from Journal of Clinical Neuroscience, 12, 6, Yam AT et al., ‘Cerebral autoregulation and ageing’, pp. 643– 646, Copyright 2005, with permission from Elsevier. The detailed mechanisms underlying cerebral pressure autoregulation are not fully elucidated, but vascular endothelium, vascular smooth muscle, and nerves appear to be directly involved. Endothelium is a mechanoreceptor that is very sensitive to changes in blood pressure and mechanical forces. Increased blood flow velocity (FV), shear stress, and transmural pressure are the strongest vasoconstrictor stimuli to the endothelium (25). Vascular smooth muscle is directly responsible for arteriolar vasoconstriction, and the presence of endothelial-derived vasoconstrictors in arteries exposed to high blood pressure has been demonstrated (26,27,28). In response to mechanical stress the endothelium responds by reflex vasoconstriction, the so-called Bayliss effect (26), via activation of endothelial mediators (Figure 3.5). The Bayliss effect underlies the myogenic hypothesis of cerebral autoregulation which caters to continuous constriction of vascular smooth muscle in the presence of mechanical stress (29). Myogenic tone thus develops and adjusts to blood pressure and underlies the notion of a cerebral critical closing pressure (CCP), which is defined as that acutely changed decrease in systemic blood pressure at which CBF falls to zero (30,31). Based on variations in basal myogenic tone in response to basal luminal pressure, CCP increases and decreases commensurate with changes in blood pressure. The net effect is to maintain a constant relationship between MAP and CCP and an alternate, physiological, definition of CPP is MAP-CCP (30,31,32). It has been suggested that CCP can also be defined clinically at the bedside by a combined extrapolation of transcranial Doppler and arterial waveforms to zero blood FV (Figure 3.6) (33,34,35,36,37,38,39,40).
Click to view larger Download figure as PowerPoint slide Fig. 3.5. The Bayliss effect. (A) Increasing pressure in certain blood vessels causes vasoconstriction, a phenomenon known as the Bayliss effect. (B) The Bayliss effect is mediated by the smooth muscle layer of the vessel, independent of the inner layer of endothelial cells. (C) Proposed mechanism for stretch-induced activation of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), in vascular smooth muscle membranes.
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Click to view larger Download figure as PowerPoint slide Fig. 3.6 Critical closing pressure (CCP). (A) Dynamic pressure–flow relationships (DPFRs) for the cerebral vascular bed in subhuman primates. Data were obtained by oscillating aortic pressures between 230 and 105 mmHg. All data points are obtained within a 4-second period. Closed squares represent averaged values for each heartbeat during the entire pump cycle. Open triangles represent data obtained during a prolonged diastole occurring during the run. The overall mean arterial pressure (MAP) is shown by the large closed circle. The CCP in this case is 70 mmHg. The perfusion pressure at any point along this line is the observed pressure − CCP. At the operating point, the perfusion pressure is MAP − CCP.
(B) Conceptual relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF) with ICP held constant. CBF is noted to follow the classic pattern, being constant within but pressure passive below and above the autoregulatory range, in this example 50–150 mmHg. Vasomotor tone (VT) adjusts across the autoregulatory range, increasing with higher MAP within the autoregulatory range. This results in critical closing pressure (CCP = VT + ICP) adjusting such that at higher MAP the CCP will be higher and the dynamic perfusion pressure (PP), MAP − CCP remains constant within the autoregulatory range. (C) Conceptual relationship between ICP and CBF reflecting the effects of increasing ICP on CBF, VT, CCP, and PP. ICP is raised continuously, as shown on the horizontal axis. Vasomotor tone compensates for this by decreasing to zero but is exhausted by the time ICP is 40 mmHg. The net effect is that critical closing pressure (CCP = VT + ICP) increases but with very high ICP the CCP eventually equals MAP with a coincident gradual decrement in PP, MAP − CCP. Panels A−C from Dewey R, Pieper H, Hunt W, ‘Experimental cerebral hemodynamics. Vasomotor tone, critical closing pressure, and vascular bed resistance’, J Neurosurg, 1974, 41, pp. 597–606. (D) Pressure–blood flow velocity relationships for 1-minute steady-state segments at rest and during exercise in humans demonstrating a method of evaluating zero flow pressure using transcranial Doppler ultrasonography. Representative data are presented for calculating CCP from systolic and diastolic values of arterial blood pressure from an arterial cannula and middle cerebral artery blood velocity (MCA V) at rest (filled circles) and during heavy exercise (open circles). In this case CCP appears to increase commensurate with increased MAP suggesting maintenance of constant perfusion pressure (MAP − CCP). Panel D reproduced from Ogoh S et al., ‘Estimation of cerebral vascular tone during exercise; Evaluation by critical closing pressure in humans’, Experimental Physiology, 95, 6, pp. 678–685, John Wiley & Sons, © 2010 The Authors. Journal compilation © 2010 The Physiological Society.
Flow–metabolism coupling In addition to the aforementioned myogenic processes which maintain appropriate flow with varying blood pressure independent of metabolic needs, blood flow to the brain also varies according to metabolic requirements (Figure 3.7). In this way regional blood flow and metabolism are tightly coupled. Action potential generation as well as interneuron interactions are potent stimuli of multiple mediators of neurovascular coupling (41,42), including potassium and hydrogen ions which relax vascular smooth muscles and cause cerebral vasodilatation (43). Cerebral metabolites also play an important role in regulation of CBF. The concentration of adenosine increases during neuronal transmission and in its turn causes vasodilation. Elevation of excitatory neurotransmitters such as glutamate also leads to increases in the concentration of adenosine and subsequent vasodilation (44). Nitric oxide (NO) has been known for some time to cause cerebral vasodilation but recent research suggests that it may primarily act as a second messenger supplying cGMP for other compounds to act on vascular smooth muscle (45).
Click to view larger Download figure as PowerPoint slide Fig. 3.7. Mechanisms involved in the regulation of regional cerebral blood flow in health and disease. The figure shows a neurovascular unit comprised of a cerebral resistance vessel in the vicinity of a neuron and an astrocyte illustrating many of the competing factors which regulate cerebral vascular tone. Arachidonate metabolism can produce prostanoids that are either vasodilators (e.g. prostacyclin) or vasoconstrictors (e.g. thromboxane A2). Endothelin (ET), produced by endothelin-converting enzyme in endothelial cells, balances the vasodilator effects of nitric oxide in a tonic manner by exerting its influences at ET A receptors in the vascular smooth muscle. A, astrocyte; CO, carbon monoxide; DA, dopamine; E, endothelium; ECE, endothelin-converting enzyme; ET, endothelin; ETA, ETA receptor; M, muscular layer; NO, nitric oxide; PGs, prostaglandins; TXA 2, thromboxane A2. Reprinted from Anaesthesia & Intensive Care Medicine, 5, 10, Nortje J and Menon DK, ‘Applied cerebrovascular physiology’, pp. 325–331, Copyright 2004, with permission from Elsevier. An important element of flow–metabolism coupling is the CBF response to physiological and metabolic abnormalities, including changes in carbon dioxide, oxygenation, and glucose, to maintain adequate nutritive flow.
Carbon dioxide Tissue acidosis, indicating anaerobic metabolism, causes an increase in CBF. Hydrogen ions have been implicated in mediating the vasodilatory effects of metabolically produced carbon dioxide and lactic acid, although NO may be the preferred mediator for hypercapnia-induced vasodilation as NO inhibition prevents carbon dioxide-induced
vasodilation (46,47). Hypercapnia produces acidosis and leads to hyperaemia, whereas hypocapnia produces significant decrements in CBF (Figure 3.8) (48,49). Notably, hyperventilation can decrease CBF enough to lead to increased lactate production (49,50,51,52), brain tissue hypoxia (49), and related electroencephalogram changes (51), although it has never been shown to produce histologically verifiable tissue damage. Nonetheless, the routine application of hyperventilation has been associated with worse outcome after TBI (53).
Click to view larger Download figure as PowerPoint slide Fig. 3.8. Factors affecting cerebral blood flow. Changes in cerebral blood flow due to alterations in PaCO 2 (dashed line), PaO2(parallelogram dashes), and blood pressure (solid line) are shown. This figure was published in Anesthesia, Miller RD, Chapter: Anesthesia effects upon cerebral blood flow, cerebral metabolism, and the electroencephalogram, pp. 795–798, Churchill-Livingstone, Copyright Elsevier 1981.
Oxygen Hypoxaemia is a potent cerebral vasodilator, producing significant hyperaemia when PaO 2 decreases below 6.7 kPa (50.25 mmHg) (Figure 3.8) (54), likely secondary to brain tissue lactic acidosis (55). Conversely hyperoxia produces mild vasoconstriction (53).
Anaemia CBF responds to changes in haematocrit according to oxygen delivery, such that anaemia produces increases in flow (56). Animal studies (57) and theoretical analysis (58) suggest that, with progressive decrement in haematocrit, CBF is initially increased due to anaemia-related reduction in viscosity. Subsequent active vasodilation increases CBF in a ‘dose-dependent’ manner as haematocrit is reduced to below 30%.
Glucose
In humans, significant hypoglycaemia is associated with cerebral hyperaemia (59), whereas laboratory studies indicate variable CBF responses, that is, no change, hyperaemia, and post-hypoglycaemic hypoperfusion (60,61,62). Conversely, CBF decreases with hyperglycaemia (63,64,65), possibly related to hyperosmolarity or viscosity effects (65).
Cerebrovascular reserve An important concept in understanding CBF physiology is the notion of cerebrovascular reserve. The above-described physiology of autoregulation indicates that the brain is normally actively vasodilating and vasoconstricting to maintain a constant nutritive blood flow. Such changes arise not only in the context of varying perfusion pressure (due to systemic blood pressure changes or proximal vessel occlusion) but also in the context of limitations in nutrient supply as may arise with vasodilatation due to anaemia (57,58), hypoglycaemia (59), and hypoxaemia (54,66,67). This means that CBF may be entirely normal but associated with a state of maximal vasodilatation compensating for a physiological stress. Under such circumstances, when the limit of cerebrovascular reserve is reached, there is no possibility for further vasodilatation in response to additional challenges to nutrient supply. Such considerations underlie the concept of haemodynamic stroke, wherein a maximally vasodilated brain develops a stroke related to a physiological challenge that would otherwise be well tolerated (68,69). This is supported by observations that patients with impaired cerebrovascular reserve are at increased risk for stroke (70,71), early deterioration after stroke onset (72), and anaemia- (73) and hypoxaemia-induced (74) stroke. Thus many clinical decisions in critically ill brain-injured patients, such as transfusion triggers or goals for blood pressure, PaO 2, and PaCO2, must take into consideration the patient’s likely current cerebrovascular reserve.
Endothelium and astrocytes As described earlier, cerebrovascular endothelium plays a central role in controlling CBF by secreting various vasoactive molecules, including NO, endothelins, eicosanoids, and endothelial-derived hyperpolarization factor (EDHF). Although NO plays a central role in cerebral vasodilation, inhibition of the NO pathway does not prevent vasodilation, suggesting that other pathways must also exist. EDHF is one factor responsible for non-NO-mediated vasodilatation (75,76), likely through hyperpolarization of membranes as its action is inhibited by potassium channel blockers (77). Eicosanoids are derived from the arachidonic acid pathway mediated by cyclooxygenase, epoxygenase, and lipoxygenase enzymes. Metabolites of the cyclooxygenase pathway, particularly prostaglandins (PGE2 and PGI2), are potent vasodilators but, under physiological conditions, do not have a prominent role. The cyclooxygenase pathway also produces poorly characterized vasoconstrictor molecules known as endotheliumderived contracting factors, and these may play an important role after TBI and subarachnoid haemorrhage (SAH) (78,79). Endothelins are vasoactive modulators secreted by the endothelium. There are two endothelin receptors (ET A and ETB) and three ligands (ET1, ET2, and ET3). The ETA receptor causes vasoconstriction and ETB vasodilatation. Endothelins have only a minor role under physiological conditions, but are important in pathological states such as cerebral ischaemia and vasospasm (80). Astrocytes as an integral element of the neurovascular unit link neuronal activity to blood vessels. Astrocytes are potassium ion buffers and facilitate cell-to-cell communications through gap junctions. They take up extracellular potassium and transport it to the foot processes which are in direct contact with the arterioles, and this process forms the basis of neuronal activity causing vasodilatation (see later) (81).
Neural control of cerebral blood flow Neural control of CBF occurs at intrinsic and extrinsic levels, and the intrinsic system is comprised of local and distal elements. Local intrinsic regulation arises from the cortex and interneurons projecting to nearby arterioles, and controls the micro-environmental concentrations of vasoactive metabolites such as CO 2, NO, vasoactive intestinal peptide, gamma-aminobutyric acid (GABA), and PGE2. Distal intrinsic CBF regulation arises when a distant brain nucleus affects CBF in other area, for example, the functions of the cerebellar fastigial nucleus, the locus coeruleus, raphe nuclei, and nucleus basalis magnocellularis in controlling supratentorial CBF (6,82), and when injury to one area of the brain affects CBF in another, uninjured, brain structure (83). Extrinsic neural control of CBF is primarily exerted by perivascular sympathetic and parasympathetic innervation of cerebral vessels. This is thought to have a neuroprotective effect in the context of hypertension in that associated
vasoconstriction of innervated vessels protects the parenchyma from haemorrhage-inducing pressure surges (6). Such effects are limited to conductance vessels because smaller vessels have minimal innervation.
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Effects of drugs on cerebral blood flow Control of CBF is the cornerstone of the clinical management of ICP, primarily through secondary effects on cerebral blood volume (CBV). CBV itself is difficult to measure so CBF is more often monitored and used as a therapeutic goal during neurointensive care unit (see Chapter 10). In the normal brain, CBV is approximately 5 mL/100 g of brain, and, over a PaCO2range of approximately 3.3–9.3 kPa (25–70 mmHg), changes by about 0.49 mL/100 g for each 1.3 kPa (10 mmHg) change in PaCO2 (Figure 3.8) (84).
Anaesthetic agents Anaesthetic agents cause dose-related changes in many aspects of cerebral physiology and play an important role in managing CBF and cerebral metabolism in disease states, particularly after brain injury. They are used to manipulate cerebral physiology to maintain an optimal environment for brain recovery and function. Intravenous GABAergic anaesthetic agents, such as thiopental and propofol, reduce cerebral metabolic rate (CMR) and, via vascular coupling, CBF (85). Anaesthetics which are N-methyl-D-aspartic acid receptor antagonists, such as ketamine, tend to produce neuroexcitation with an accompanying increase in CBF. Volatile anaesthetic agents, although decreasing CMR, have some inherent vasoactive properties which affect the CBF accordingly (Table 3.1) (85). Table 3.1 Effects of drugs on cerebral blood flow and metabolism
Drug
CBF
CMR
Barbiturates
↓
↓
Propofol
↓
↓
Etomidate
↓
↓
Narcotics
↓↑
↑↓
Benzodiazepines
↓
↓
Ketamine
↑
↑
Lidocaine
↓
≈↓
Volatile anaesthetics
↑↓
↓
Nitrous oxide
↑
↑
Xenon
↑
↑
Muscle relaxants
≈
≈
Vasodilators (hydralazine, nitroprusside)
−↑
≈
Non vasodilators (high-dose beta blockers)
↓
↓
Drug
CBF
CMR
Vasopressors (BBB injury)
↑
↑
BBB, blood–brain barrier; CBF, cerebral blood flow; CMR, cerebral metabolic rate.
Muscle relaxants Cisatracurium and rocuronium are reported to have no cerebrovascular effects based on transcranial Doppler FV measurements (86). Depolarizing muscle relaxants, such as succinylcholine, cause slight increases in ICP most likely due to cerebral activation caused by afferent activity of muscle spindle apparatus (87). However, a study in neurosurgical patients suggests that succinylcholine does not cause a clinically relevant increase in ICP (88).
Vasoactive drugs Vasoactive drugs have direct and indirect effects on CBF and these must be taken into account during their use in brain-injured patients.
Vasodilators Multiple studies report increases in ICP secondary to systemic administration of systemic vasodilators, presumed to be due to associated cerebral vasodilatation. However, it is seldom clear whether the cerebral vasodilation is related to a direct action of the drug on the cerebral vasculature or because of an autoregulatory response to the induced reduction in systemic blood pressure. Marsh and colleagues reported an increase in ICP in humans associated with the use of nitroprusside (89) and nitroglycerine (90), although another study found no CBF increase with nitroprusside (91). Intracarotid injection of either agent has not been found to increase CBF in humans (92,93), suggesting that the increases in ICP are due to indirect cerebral vasodilation arising in compensation for a decrease in systemic blood pressure. Nonetheless, nitroglycerine, long appreciated as a drug which induces headache, does have potential for direct large cerebral vessel dilation (94). Hydralazine has also been reported to increase ICP (95), in association with modest increases in CBF (96).
Non-vasodilator antihypertensive agents Angiotensin-converting enzyme inhibitors have little effect on CBF (97) or autoregulation (98). Beta blockers also have little effect on CBF and CMR at usual clinical doses (99), although they may attenuate the CBF response to hypercapnia and neuroexcitation (100). At higher doses, beta blockers such as propranolol, which can cross the BBB (101,102), may decrease CMR and CBF (103). Calcium channel antagonists, such as nimodipine and nicardipine, are dihydropyridines which bind to the α1 subunit and antagonize voltage-sensitive calcium channels (L-type or slow channels) (104). These receptors mediate entry of calcium into vascular smooth muscle cells and their blockade by calcium channel blockers produces arteriolar relaxation by preventing increased cytosolic calcium and the consequent cascade of events leading to actin–myosin coupling (104). Both nimodipine and nicardipine have been used to reverse or prevent cerebral vasospasm after SAH (105,106,107). Intravenous nimodipine infusion has little effect on CBF in the uninjured primate, but a vasodilator effect following intra-arterial infusion or in the context of BBB disruption (108). In contrast, when given intravenously to hypertensive patients with unilateral carotid artery occlusion, nicardipine increases CBF in the non-occluded side (109). Thus calcium channel antagonists appear to dilate vasospastic cerebral arteries and thereby have a context-sensitive potential to increase CBF (106,110).
Vasopressors In the normal brain, adrenergic drug infusions have only a small, but not absent, effect on CBF. The effects of catecholamine vasopressors on CBF and cerebral vascular resistance are thought to be indirect, occurring as a consequence of their effects on systemic blood pressure. Moreover, given the impermeability of the BBB to these drugs they also have little effect on CMR (111). However, in the injured brain with a disrupted BBB, systemic administration of adrenergic drugs can have multiple cerebral effects. Entry of the drug into the brain parenchyma presumably allows it to act like an endogenous neurotransmitter and cause neural activation, and increases in CMR and CBF (112). In addition, if there is concomitant cerebral dysautoregulation, the systemic blood pressure effects of
adrenergic agents will result in secondary increases in CBF. Both these effects to increase CBF may cause secondary increases in ICP (see Chapter 2).
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Cerebral blood flow in pathological states The important pathophysiological changes in CBF and CMR in various neurological conditions are discussed below and their clinical implications reviewed in subsequent, disease-specific, chapters.
Cerebral ischaemia Ischaemia by definition indicates a critical reduction in CBF below that required to meet metabolic demands. Depending on the extent of the CBF decrement there is a continuum of changes that lead ultimately to cell death. The critical CBF threshold for the development of irreversible tissue damage is 10–15 mL/100 g/min (113), and studies using xenon-enhanced computed tomography CBF measurement suggest that infarction ensues when CBF decreases to below 10 mL/100 g/min (114). The changes leading to irreversible cellular damage are multiple, including the development of acidosis, reduction in protein synthesis and the eventual loss of energy-requiring osmotic regulation and the Donnan equilibrium (115) consequent to failure of the energy-requiring reactions that maintain cellular ionic homeostasis. Cell death ensures. Clinical ischaemic stroke is associated with a core of very low blood flow and a penumbra of low flow with ‘at risk’ but potentially salvageable tissue (116,117).
Traumatic brain injury Brain tissue damage due to TBI is attributed to the primary insult and ensuing secondary pathological alterations. There is substantial temporal and regional heterogeneity in CBF that is significantly impacted by other pathophysiological changes as well as by the presence of an associated mass lesion (118). A contusion which is initially benign may mature days later to produce malignant intracranial hypertension, with associated dysautoregulation and wide variations in CBF (119). Conversely an initially hyperaemic state can change to one of persistent pathologically low CBF (118,120). This contrasts with pure shear injury with potentially limited ICP effects, and devastating diffuse axonal injury with early hyperaemia (121). A lower Glasgow Coma Scale score tends to correlate with reduced CBF in the first 24 hours after injury, and portends a poor outcome (118,121). In addition, TBI produces varying degrees of normal to depressed CO2 response (120) as well as pressure dysautoregulation (24,122,123). Mechanisms which contribute to CBF abnormalities after TBI include mechanical vessel injury, systemic hypotension, impaired autoregulation, inadequate NO production, release of endothelial vasoconstrictive factors, and local biochemical abnormalities (124). Thus, TBI can produce ischaemia, hyperaemia, or both, with substantial regional and temporal variation. Cerebral ischaemia is one of the most important determinants of outcome after TBI, and both focal and global ischaemia are very common (125). This might in part be related to vasospasm which has been reported to occur in up to 45% of patients (126). Smooth muscle depolarization, release of vasoactive factors, such as endothelins and prostaglandins, paucity of NO, and free radical damage may all be implicated in the pathogenesis of vasospasm in this context. However, hyperaemia also occurs commonly after TBI (118,120) and is associated with increases in CBV and ICP (120), and worsened outcome (127). Taken together, these findings suggest that CBF and metabolic demand are often uncoupled after TBI. When autoregulation is intact, changes in MAP produce no or small changes in CBF, blood FV, brain tissue oxygenation, and ICP but, when autoregulation is disrupted, changes in MAP result in a continuum of changes in all these variables. Correlation of slow wave changes in MAP with multiple neuromonitoring variables have been used as non-invasive assessments of cerebral autoregulatory reserve, and this is discussed in more detail in Chapters 9 and 10.
Subarachnoid haemorrhage SAH is a neurological emergency with high rates of morbidity and mortality (128). In the hyperacute phase there is a rapid increase in ICP and reduction in CPP (129,130,131) that can be so severe that a period of intracranial circulatory arrest is induced (132). A state of hypoperfusion may remain even after CPP normalizes (133). This period of
hypoperfusion resembles that seen after global brain ischaemia (134) and suggests that the initial period of intracranial circulatory arrest may be a physiological analogue to that situation. Other abnormal responses, including loss of CO2 reactivity (135), uncoupling of flow and metabolism (136), release of inflammatory mediators (137), and disruption of BBB function (138,139,140,141), have also been reported during this early phase after SAH. Moreover, endothelial injury leads to loss of collagen IV and activation of matrix metallopeptidase 9, resulting in vasoconstriction and cellular swelling (142). An intense prothrombotic response is exhibited by platelets and this can lead to mechanical blockage of cerebral vessels causing further decreases in CBF (143). Notably, CBF in the first few days after SAH is related to clinical grade and outcome: poor grade is associated with lower CBF and worse outcome. In the worst-case scenario this early period of low blood flow progresses to cerebral infarction, increased ICP, and, in extreme cases, brain death. In less severe cases there may be a return to more normal cerebrovascular physiology and functional recovery. Later stages of SAH may be marked by the development of cerebral vasospasm in 40–70% of patients, which is symptomatic in 17–40% of them (144). Although vasospasm is classically demonstrated angiographically, ischaemia can also arise in the absence of angiographic vasospasm suggesting the presence of microvascular spasm or other occlusive processes (see Chapter 18) (145). ET1 has been cited as the most important mediator of delayed vasospasm and may also be related to the early vasoconstriction that can lead to global hypoperfusion after SAH. ET 1 antagonists are being evaluated for their potential to prevent or treat cerebral vasospasm (146). Another mediator of CBF is 20-hydroxyeicosatetraenoic acid (20-HETE) which activates rho-kinase and protein kinase C to sensitize the vascular endothelium to calcium. 20-HETE may play a role in vasodilation and vasoconstriction equally, although studies have shown that increased CSF levels are associated with decreased CBF after SAH (147). Moreover, inhibiting 20-HETE improves hypoperfusion and chronic vasospasm (148). Another important aspect of delayed vasospasm is inadequate supply of NO. Oxyhaemoglobin, which spills into the subarachnoid space after SAH, scavenges NO stores and also triggers ischaemia by initiating spreading depolarization and releasing excitatory neurotransmitters. Unopposed vasoconstriction in the absence of NO can cause global hypoperfusion (149), and application of an NO donor reverses the vasoconstriction (150). The same principle applies in the use of statins which stimulate NO synthase, thereby increasing NO production (151).
Intracerebral haemorrhage In intracranial haemorrhage (ICH), three phases of CBF alteration have been described in the perihaematoma tissue (see Chapter 19) (152). The ‘hibernation’ phase, in the first 48 hours, is marked by perilesional hypoperfusion that is associated with decreased metabolism in excess of the decrease in CBF. Thus, although CBF is low it is usually sufficient to support the reduced metabolic demand. Although the duration of reduced CBF may be prolonged in some patients, depending on haematoma expansion and other contributing insults, a ‘reperfusion’ phase of variable CBF response usually follows after 48 hours. Despite persistence in some patients of a lower than normal perilesional CBF, the tissue may remain or become hyperaemic relative to metabolic demand because of impaired autoregulation and local release of inflammatory mediators. In the final ‘normalization’ phase, normal metabolism and CBF are restored as the haematoma resolves. However, low blood flow may persist in the centre of the haematoma because of the presence of non-viable tissue. Fainardi et al. (153) and Zhou et al. (154) evaluated CBF in lesional and perilesional tissue in the hyperacute (< 6 hours) and acute (7–24 hours) phases after ICH in humans. A clear gradient of blood flow, from near zero at the centre of the haematoma to progressive increase through the perihaematoma areas, was observed. Perihaematoma tissue with zero flow did not recover whereas some regions of ‘at-risk’ tissue (CBF of 10–20 mL/100 g/min) survived but others did not. Further, the extent of CBF compromise was related to the size of the ICH, with a larger haematoma associated with lower perilesional blood flow. Notably these authors reported hyperaemia in the contralateral hemisphere. Another study has also reported a relationship between CBF and ICH size, with diffuse hypoperfusion associated with haematomas greater than 4.5 cm in diameter (155). Importantly there was a greater decrement in perilesional tissue CMR than CBF, resulting in no significant decrease in oxygen extraction fraction (156). As in previous studies, this strongly suggests that the risk of perilesional ischaemia is somewhat less than might be expected from the degree of CBF reduction (156). Mayer et al. observed the development of perilesional oedema and suggested that restoration of flow in damaged tissue might be the cause of this (157).
Reperfusion injury after ischaemic stroke and carotid endarterectomy
Hyperperfusion injury has been reported after large arteriovenous malformation (AVM) resection, thrombolysis after acute ischaemic stroke, and carotid endarterectomy (CEA). It may also be a contributor to the encephalopathy of hepatic failure. Although thrombolysis after acute ischaemic stroke improves outcome in selected patient populations, it can lead to reperfusion injury which can manifest as either ischaemia or hyperperfusion. Ischaemia can paradoxically develop when blood flow is restored after thrombolysis because of an influx of leucocytes which have been sensitized to adhesion molecules on the endothelium as a result of the original tissue ischaemia (158,159). The leucocytes attach themselves to the endothelium and plug the capillaries leading to mechanical obstruction to blood flow (160,161). In a similar way platelets may also attach to the endothelium leading to microthrombi formation and capillary occlusion. Hyperperfusion can also occur after thrombolysis, and may be associated with oedema and haemorrhage. The physiological response to acute ischaemic stroke is to maintain blood flow to the ischaemic penumbra by increasing blood pressure. However, in the setting of ischaemia the BBB is also disrupted leading to highly permeable capillaries. Once blood flow is restored, these injured capillaries are unable to withstand the high systemic pressures and the endothelium is damaged leading to reperfusion injury and haemorrhagic transformation (162). Cerebral autoregulation normally protects the brain from changes in systemic blood pressure but autoregulation is also impaired in ischaemic brain, and there is therefore no check on transmission of systemic pressures to brain capillaries. After CEA, similar pathophysiology may apply in those with high-grade stenosis and chronic low-grade ischaemia (22). The endothelium secretes vasodilatory molecules to maintain CBF and hence capillaries are maximally dilated. Previously low, with chronic vasodilation and intracranial hypotension, CBF is restored after CEA but, in the context of the previous chronic compensatory shift of the cerebral autoregulation curve, capillary dilatation persists and leads to increased CBF resulting in hyperperfusion injury and a risk of postoperative ICH (163). In one study, 6.6% of 76 patients with bilateral CEA developed hyperperfusion syndrome, compared to 1.1% of 379 with unilateral CEA (164). Risk factors for post-ischaemic reperfusion injury after CEA include post-reperfusion hypertension, high-grade stenosis with poor collateral flow, decreased cerebral vasoreactivity, recent contralateral CEA (< 3 months), and intraoperative distal carotid pressure of less than 40 mmHg (162,165).
Fulminant hepatic failure The extensive effects of liver failure on brain physiology and function have recently been reviewed in detail (166). Fulminant hepatic failure is frequently complicated by cerebral oedema and increased ICP (167), but there are conflicting data regarding its effects on CBF. Aggarwal and colleagues reported variable changes in CBF and CMR and linked these to the temporal progression of worsening severity of hepatic encephalopathy (168,169) although, in general, fulminant liver failure is a hyperdynamic state. Similar to laboratory models of hepatic encephalopathy (170), Wendon and Harrison demonstrated that CMR falls drastically in patients with severe hepatic failure but, despite this, cerebral lactate production increases suggesting that the increased flow does not meet demand (171).
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Cardiorespiratory support in critically ill neurological patients Chapter: Cardiorespiratory support in critically ill neurological patients Author(s): Maria Vargas , Iole Brunetti , and Paolo Pelosi DOI: 10.1093/med/9780198739555.003.0004
Critically ill neurological patients present a complex management challenge. The injured brain may cross-talk with other organ systems via complex pathways that lead to non-neurological organ dysfunction, particularly involving the heart and lungs (1). Patients admitted to the neurocritical care unit (NCCU) may therefore have cardiopulmonary abnormalities that may be related to their underlying neurological pathology or occur incidentally. In a recent analysis by the Ventilia Study Group, 26.5% and 23.0% of mechanically ventilated patients with neurological disease developed cardiovascular and pulmonary complications respectively (2). This chapter will review the management of cardiorespiratory variables in critically ill neurological patients and highlight the management challenges.
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Cardiovascular system The cardiovascular and central nervous (CNS) systems are intimately related by the same disease processes and their risk factors. For example, age, gender, smoking, diabetes, hypertension, and dyslipidaemia are risk factors for both coronary artery disease and ischaemic and haemorrhagic stroke. Moreover, the CNS regulates cardiovascular function via complex neural pathways and mediators, and these processes may be deranged after brain and spinal cord injury leading to cardiovascular dysfunction (3). Conversely, cardiac and respiratory dysfunction adversely affects the injured brain and spinal cord (see Chapter 27). The brainstem is responsible for control of cardiovascular function. The nucleus of the tractus solitarius receives afferent information from peripheral arteries, cardiopulmonary chemoreceptors, and baroreceptors via the glossopharyngeal and vagus nerves, and the brainstem responds via parasympathetic and sympathetic efferent pathways. Parasympathetic cholinergic responses control heart rate and contractility as well as many gastrointestinal processes via the vagus nerve while sympathetic responses act on blood vessels, the heart, kidneys, and adrenal medulla in response to barosensitive, thermosensitive, and glucosensitive efferents (4).
Cardiovascular manifestations of central nervous system disease Acute brain injury (ABI) is associated with a profound and varied catecholamine response. Catecholamines act on receptors located in intracerebral and pial vessels and an excess may lead to systemic cardiovascular dysfunction, including effects on blood vessels and heart rhythm and contractility. The usual response to acute ischaemic or haemorrhagic stroke is hypertension, but blood pressure (BP) control can be challenging because of the substantial heterogeneity between stroke subtypes and an incomplete understanding of the cause of BP changes that occur with each subtype (5). Spinal cord injury may be associated with peripheral vasodilation, bradycardia, and hypotension because of interruption of peripheral sympathetic tone with unopposed vagal effects (6). Cardiac arrhythmias are also associated with ABI. Sinus bradycardia may occur if the brainstem is compressed by direct pressure or intracranial hypertension, whereas sinus tachycardia and atrial and ventricular arrhythmias are catecholamine related and associated with a poor prognosis. In addition, several acute intracranial disorders can have direct effects on the coronary circulation and/or contractile function of the heart, manifesting as myocardial ischaemia (7) and neurogenic stress cardiomyopathy respectively (8). These issues are discussed in detail in Chapter 27.
Blood pressure management BP is closely related to cerebral perfusion pressure (CPP), which is the difference between mean arterial pressure (MAP) and intracranial pressure (ICP). In physiological conditions, ICP is small compared to MAP, so MAP essentially determines CPP. Constant cerebral blood flow (CBF) is maintained over a wide range of MAP (60–150 mmHg in normotensive patients) because of cerebral autoregulatory mechanisms (see Chapter 3) (9). When MAP decreases below the lower limit of autoregulation, cerebral vessels dilate in an attempt to maintain CBF. When a critical MAP threshold (for an individual) is reached as autoregulatory mechanisms become exhausted, brain perfusion is compromised. If MAP increases above the upper limit of autoregulation, CBF is pressure passive and increases with MAP, leading to increases in intraluminal pressure, blood–brain barrier (BBB) disruption, and cerebral oedema.
Blood pressure management in specific disease states
Several acute neurological conditions such as subarachnoid (SAH) and intracerebral (ICH) haemorrhage, acute ischaemic stroke (AIS), and traumatic brain injury (TBI) are associated with hypertension as a physiological response to maintain adequate CPP in the context of an acutely injured brain. On the other hand, excessive hypertension may itself exacerbate oedema in injured brain regions or lead to further CNS dysfunction, as is the case in hypertensive encephalopathy and posterior reversible encephalopathy syndrome. The aim of cardiovascular support in critically ill neurological patients is to stabilize MAP and CPP, and thereby optimize cerebral perfusion and metabolism. There is little evidence to guide cardiovascular management after ABI and therapy should be guided by systemic and cerebral haemodynamic responses assessed by monitoring arterial BP, CPP, and ICP.
Acute ischaemic stroke More than 75% of patients with AIS have elevated BP (10), but the optimal level of BP control in an individual patient is unknown (5). The American Heart Association (AHA) and American Stroke Association (ASA) recommend that treatment should be instituted only if systolic blood pressure (SBP) is ≥ 220 mmHg and diastolic blood pressure (DBP) is ≥ 120 mmHg (11). It might be reasonable to lower BP by 15% during the first 24 hours after AIS in some patients (see Chapter 20) but a large decrease in BP should be avoided as this is associated with early neurological deterioration, increase in infarct volume, worse neurological outcome, and death (12). Although a degree of hypertension may be beneficial because of its effects to increase CBF (13), BP should be maintained lower than 180/105 mmHg in patients receiving thrombolysis to minimize the risk of haemorrhagic conversion (14). The first step in the pharmacological management of hypertension is intermittent intravenous boluses of a non-vasodilatory antihypertensive agent such as labetalol, although nicardipine is widely used in the USA. If BP is not controlled within 30 minutes, a continuous intravenous infusion should be used (15) in which case labetalol is also the preferred agent (16).
Intracerebral haemorrhage The ASA/AHA guidelines for the management of spontaneous ICH recommend reduction in BP if SBP and DBP are ≥ 200 mmHg and ≥ 150 mmHg respectively (17). The non-inferiority Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) and Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage (INTERACT) trials confirmed that lowering of SBP to 140 mmHg decreases the rate of haematoma expansion without causing neurological deterioration, but these studies were not powered to detect beneficial outcome effects (18,19). The subsequent INTERACT 2 trial, published in 2013, provides the best data to date on acute BP management after spontaneous ICH (20). In this large study, early intensive BP lowering (target SBP 140 mmHg within 1 hour) did not result in a significant reduction in the rate of death or major disability at 90 days compared to standard treatment (SBP < 180 mmHg) as most expected it would, although secondary outcome analysis suggested that intensive BP lowering improved functional outcomes in survivors. Intensive BP lowering was not associated with an increased rate of serious adverse events, so BP control might be a reasonable option after spontaneous ICH. BP control after ICH is discussed in more detail in Chapter 19.
Traumatic brain injury Reductions in BP compromise cerebral perfusion and haemodynamics after TBI so it is crucially important to optimize BP to maintain adequate CPP and minimize the risk of secondary ischaemic brain injury (see Chapter 17). The Brain Trauma Foundation recommends that CPP should be maintained between 50 and 70 mmHg (21). In the absence of ICP monitoring, SBP should be maintained greater than 90 mmHg because systolic hypotension is the most powerful predictor of poor outcome after TBI (22).
Spinal cord injury Primary and secondary spinal cord injury (SCI) lead to haemodynamic dysfunction, including decreased heart rate, systemic vascular resistance, and BP (23). A stepwise treatment approach incorporating volume resuscitation and pharmacological support with vasopressors controls BP in most patients after acute SCI (6). Occasionally pacemaker support is required for refractory bradycardia.
Principles of blood pressure management
Fluid resuscitation to euvolaemia is a prerequisite for optimal cardiovascular support after ABI and SCI. Fluid management is covered in detail in Chapter 5 and also in the pathology-specific chapters elsewhere in this book; it will not be consider further here. Although a hyperdynamic circulation is the acute response to ABI, this is often followed by a period of relative hypotension that can be aggravated by the negative cardiovascular effects of sedation. Many factors affect the ability to control CBF and CPP by manipulation of systemic cardiovascular variables including attenuation or loss of cerebral autoregulation (24) and variations in the arterial partial pressure of oxygen (PaO 2) and carbon dioxide (PaCO2) (25). BBB integrity, which is essential for optimal control of CPP by systemic interventions, may also be compromised after ABI (26). Despite these issues, inotropes or vasopressors are often the only realistic option to maintain and manage BP and CPP, particularly in the presence of sedation-related hypotension. Different inotropes and vasopressors have varying effects on cerebral haemodynamics and there is little evidence to support the use of one over another (see Chapter 2). In animal models of cortical injury, norepinephrine and dopamine increase MAP to similar degrees, whereas CPP is more effectively sustained by norepinephrine (27). However, in animal models of hypoxic hypotensive cerebral injury norepinephrine and dopamine are unable to increase CPP in the presence of severe acidosis (28,29). A study evaluating the effects of norepinephrine and dopamine on CPP in adult human TBI demonstrated that CBF velocity measured by transcranial Doppler ultrasonography was improved by norepinephrine but not dopamine (30). In another study, dopamine was associated with higher levels of ICP compared to norepinephrine at similar levels of MAP, but the two agents had similar effects on CBF presumably because of intact cerebral autoregulation (31). Another study in patients with severe TBI used positron emission tomography to evaluate the effect of increasing CPP from 70 to 90 mmHg with norepinephrine in ischaemic brain (32). An increase in CPP led to small increases in CBF in all regions of interest except the ischaemic core. Although pericontusional oedematous tissue was associated with lower absolute values of CBF and cerebral blood volume compared to non-oedematous tissue, there was no difference in their relative response to CPP elevation suggesting that the ischaemic core may be unaffected by CPP augmentation. In a retrospective study of patients with severe TBI, phenylephrine produced a greater increase in MAP and CPP compared to norepinephrine and dopamine, although the effects on ICP were similar (33). In brain-injured patients, vasopressors can be associated with side effects such as increased ICP and they may therefore not effectively increase CPP even if they have positive haemodynamic effects (29).
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Respiratory system Respiratory abnormalities, including pneumonia, neurogenic pulmonary oedema, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI), are frequently encountered in critically ill neurological patients (34). Although pulmonary complications have long been related to brain injury-induced increases in sympathetic activity (35), recent evidence also indicates a major role for inflammation (1). Local effects, such as pulmonary aspiration and trauma, also contribute to pulmonary dysfunction in neurological patients (see Chapter 27). Although ABI and ARDS/ALI are independent pathological entities they can interact, worsen, and trigger each other (1). A study in pigs confirmed the reciprocal and synergistic effects of ABI and ARDS on neuronal and pulmonary damage, and demonstrated that extravascular lung water was higher in animals with ARDS than in those with intracranial hypertension in isolation but highest in those with ARDS and raised ICP in combination (36). The lowest PaO2 in this study was seen in animals with intracranial hypertension and ARDS, and this was associated with the greatest degree of tissue damage in the hippocampus. The overarching aim of ventilation after ABI is to maintain oxygenation and normal PaCO 2 in order to optimize cerebral perfusion, but care must be taken to minimize its adverse effects, particularly ventilator-induced lung injury (VILI). VILI is a syndrome triggered by over-distension of the lung during mechanical ventilation, recruitment–derecruitment of collapsed alveoli, and activation of inflammatory processes. It can be minimized by the application of protective ventilation strategies (Figure 4.1) (37).
Click to view larger Download figure as PowerPoint slide Fig. 4.1Beneficial effects of different mechanical ventilation variables in neurocritical care.
Endotracheal intubation Endotracheal intubation is one of the most common interventions on the NCCU. Patients with acute neurological problems usually require intubation and ventilation for reasons other than primary pulmonary pathology (34). In a study of more than 2000 patients with ABI admitted to a NCCU, almost 90% required mechanical ventilation at some stage and the primary neurological disease was the indication for intubation and ventilation in two-thirds (38). There are both neurological and respiratory indications for intubation and ventilation in critically ill neurological patients (Box 4.1).
Box 4.1 Indications for intubation and mechanical ventilation
Neurological
◆ Coma ◆ Decreasing conscious level ◆ Predicted neurological deterioration ◆ Inability to protect the airway and clear secretions ◆ Intracranial hypertension ◆ Severe neuromuscular weakness.
Respiratory
◆ Pulmonary aspiration ◆ Pneumonia ◆ Acute respiratory distress syndrome/acute lung injury ◆ Pulmonary embolism ◆ Neurogenic pulmonary oedema ◆ Inability to handle and clear secretions. Patients with decreased consciousness have reduced oropharyngeal muscle tone which allows the tongue to be displaced posteriorly and cause varying degrees of airway obstruction. Furthermore, impaired swallow and poor cough and gag reflexes lead to a high risk of pulmonary aspiration and impaired clearance of secretions (39). Patients in whom these states are unlikely to be rapidly reversible require endotracheal intubation, and in such circumstances intubation can be a matter of life and death (40). With lesser degrees of compromise it may be sufficient to monitor a patient closely in a critical care unit where they can be rapidly intubated should their condition worsen. In some circumstances it is prudent to institute intubation and mechanical ventilation in anticipation of neurological and secondarily pulmonary deterioration. Brain injury also causes respiratory dysrhythmias. Normal control of breathing requires both conscious and automatic neural inputs as well as input from central and peripheral chemoreceptors. The centres for the automatic control of breathing are located in the pons and medulla and these regulate respiration via homeostatic mechanisms to maintain oxygenation and acid–base status. The conscious input to breathing which is beyond awareness interacts with automatic inputs via descending pathways from the cortex. In comatose patients, input from the cortex is absent and breathing is controlled by brainstem centres triggered primarily by changes in PaCO 2. The most common breathing patterns in patients with brain injury are tachypnoea and hyperventilation, and these are most commonly associated with cortical and subcortical injury (34). There are also classic respiratory patterns associated with lesions in specific brain regions, often in association with increased ICP. Cheyne–Stokes respiration is characterized by cyclical increases and decreases in respiratory rate and tidal volume and associated with disruption of inter-hemispheric connections and dysfunction of the medial forebrain. Apneustic breathing occurs with lesions of the lower tegmentum
and pons and is characterized by prolonged inspiratory pauses. Cluster breathing, seen in lesions of the lower pons or upper medulla, manifests as irregular rapid breaths interposed with long pauses. Ataxic breathing is similar except that there is complete loss of rhythmicity of breathing. Apnoea indicates total loss of brainstem inputs to breathing. Although endotracheal intubation can be life-saving, if poorly performed it may itself result in secondary brain injury because of hypoxaemia, large swings in BP, and increased ICP (41). This is more likely during rapid sequence induction. Airway manipulation, including laryngoscopy and endotracheal intubation, increases catecholamine levels and activates systemic and intracranial haemodynamic responses resulting in tachycardia, hypertension, and increases in ICP. This can provoke brain herniation in the presence of a critical mass lesion. Sedation is a prerequisite for successful endotracheal intubation to minimize the hyperdynamic responses to laryngoscopy but care must be taken to minimize sedation-related hypotension, particularly after the institution of positive pressure ventilation which diminishes venous return and therefore cardiac output. Sedation also obscures clinical neurological examination during the early and often most critical period of neurological and neurosurgical decision-making. Rapid patient stabilization must occur concurrently with well-documented and detailed neurological assessment which should ideally take place prior to the administration of sedative and paralysing medications in order to provide a baseline assessment (40). A recommended protocol for endotracheal intubation in brain-injured patients designed to minimize these adverse effects is shown in Figure 4.2.
Click to view larger Download figure as PowerPoint slide Fig. 4.2Algorithm for endotracheal intubation in critically ill brain-injured patients. Note: life-threatening contraindications, including concomitant crush injury, long-standing immobilization, myopathy, spinal cord injury with paraplegia, and a history of malignant hyperthermia, must be excluded prior to the use of succinylcholine. If any of these possibilities exist, an alternate form of neuromuscular blockade (or intubation without it) needs to be planned. The exact timing of endotracheal intubation in TBI patients has been a topic of considerable interest and research. Studies investigating the benefits of pre-hospital intubation are conflicting with some showing benefits and others harm possibly related to longer field times, misplaced tracheal tubes, and overly aggressive hyperventilation (42). In a retrospective study, 23% of almost 11,000 TBI patients with a Glasgow Coma Scale (GCS) score of 3 were intubated in a pre-hospital setting and the mortality rate was higher compared to those who were intubated in hospital (62% vs 35%) (43). A more recent study randomly allocated patients with severe TBI to paramedic rapid sequence intubation or transport to hospital for intubation by physicians and found that pre-hospital intubation significantly increased the rate of favourable neurological outcome at 6 months (44). However, a meta-analysis of 13 largely observational studies including more than 15,000 patients reported that the adjusted odds of in-hospital mortality for patients who underwent pre-hospital intubation and mechanical ventilation ranged from 0.24 to 1.42, suggesting that inadequate evidence exists to support a benefit of early advanced airway placement (42).
Mechanical ventilation
Mechanical ventilation is often necessary in critically ill brain-injured patients, providing essential life support in many cases. However, no large studies have systematically investigated the impact of different ventilator strategies on cerebral oxygenation. The ARDSNet protocol has been shown to reduce mortality in the setting of ARDS and advocates the use of low tidal volumes, relatively high levels of positive end-expiratory pressure (PEEP), and permissive hypercapnia to reduce VILI (45). Such protective ventilator strategies can be achieved in many patients with ABI and ALI without threatening cerebral perfusion. However, this can be less straightforward in patients with poor intracranial compliance and refractory intracranial hypertension, and the optimal balance between brain-directed and protective ventilator strategies is uncertain (37). In the Ventilia Study Group analysis, volume-cycled assist controlled ventilation was the most common ventilator mode applied in neurological patients, similar to that in the general ICU population (2). However, the majority of patients in this study were ventilated with tidal volumes between 6 and 12 mL/kg predicted body weight and more than 80% with PEEP equal to or less than 5 cmH 2O in the presence of adequate arterial oxygenation, suggesting that clinicians were (possibly inappropriately) focused on the injured brain at the expense of the lungs. This is a cause for concern as ARDS/ALI are frequently seen in critically ill neurological patients (34). Up to 35% of patients with TBI and SAH develop ARDS/ALI and this is associated with poor outcome (46,47,48,49). The optimal ventilator strategy to manage respiratory failure after ABI has not been determined with certainty and the following commentary represents the authors’ recommendations for the management of respiratory complication in critically ill neurological patients, based on current evidence.
Arterial oxygenation and carbon dioxide tension Hypoxaemia is a major cause of secondary brain injury and poor outcome after ABI. In animal models of focal brain injury, hypoxaemia results in neuronal death in vulnerable brain regions and is associated with functional motor deficits (50). Similarly after traumatic axonal injury, hypoxaemia is associated with greater degrees of axonal damage and macrophage infiltration, enhanced astrogliosis in the corpus callosum and brainstem, and delayed recovery compared to normoxic animals, suggesting that secondary brain injury in the context of hypoxaemia may be induced by enhanced neuroinflammation and a prolonged period of metabolic dysfunction (51). Hypoxaemia is also associated with a poor outcome in human TBI (52). In a meta-analysis of seven phase III randomized clinical trials and three TBI population-based series in the IMPACT database, hypoxaemia and hypotension were strongly associated with a poorer outcome (odds ratios 2.1 and 2.7 respectively) in moderate or severe TBI (22). Patients with both hypoxaemia and hypotension had worse outcomes than those with either insult alone. The occurrence of secondary systemic physiological insults prior to or on admission to hospital in TBI is strongly related to worse outcome and their prevention or immediate treatment is therefore a priority. The adverse effects of systemic hypoxaemia are unsurprising given that it has two effects—it decreases cerebral oxygen delivery and dilates the cerebral vasculature. A reduction in brain tissue oxygenation has well-known effects on cerebral metabolism, and the resultant hypoxic cerebral vasodilation increases ICP and reduces CPP, further reducing cerebral oxygen delivery (see Chapters 2 and 7). Although the avoidance of hypoxaemia is a priority, hyperoxaemia can also be deleterious after ABI particularly in the first 24 hours after injury when it has been associated with a higher mortality and worse functional outcome (53). High oxygen levels increase lipid peroxidation in the cerebral cortex and induce oxidative brain damage (54). In its guidance, the Brain Trauma Foundation recommends avoiding hypoxaemia, defined as PaO2 lower than 8.0 kPa (60 mmHg) or oxygen saturation less than 90% (55). Ideally PaO2 should be maintained between 10.7 and 13.3 kPa (80–100 mmHg), using appropriate nontoxic (as able) FiO 2 and levels of PEEP, to ensure adequate cerebral oxygenation (56). Although the primary ventilation goal after ABI is normocapnia, permissive hypercapnia is frequently incorporated into ventilation strategies on the NCCU to allow lower tidal volume and PEEP to minimize the risk of VILI, and has not been shown to induce brain injury (34). However, in patients with intact cerebral haemodynamic responses to PaCO 2, careful monitoring including ICP monitoring is required to minimize adverse effects of hypercapnia on the injured brain, including the potential for herniation syndromes.
Positive end-expiratory pressure A moderate level of PEEP avoids progressive alveolar collapse and pulmonary consolidation during mechanical ventilation and thereby improves arterial oxygenation and reduces the elastance of the respiratory system (56). PEEP
is a key component of the ARDSNet protocol but the use of PEEP is controversial in the critical care management of brain-injured patients. PEEP has been reported to increase ICP and this has been thought to be related to reduced venous return from the intracranial compartment as a result of increased intrathoracic pressure (ITP) (57,58). However, other studies have reported no such association, and the influence of PEEP on ICP therefore remains controversial (59,60). It has been suggested that only patients with compliant lungs will experience cerebral venous outflow compromise and increases in ICP with higher levels of PEEP. Non-compliant lungs, such as may occur in pneumonia or ALI/ARDS, are incapable of transmitting the pressure associated with PEEP to the central venous system and thus there is little effect on systemic or cerebral venous return. Moreover, increased venous pressure from PEEP (via compliant lungs) needs to approach or exceed the level of ICP in order to affect cerebral venous outflow. It therefore seems likely that in some patients at least the predominant mechanism by which elevated ICP is increased further by PEEP is via decreased systemic BP and reflex cerebral vasodilation, rather than a direct effect to reduce cerebral venous outflow. In a study of ABI patients with poor pulmonary compliance, varying levels of PEEP had no significant effect on cerebral and systemic haemodynamics but did improve systemic oxygenation (59). This study and theoretical considerations suggest that PEEP may be safe in brain-injured patients and that it might also have beneficial effects on the brain if it improves systemic and therefore cerebral oxygenation. Certainly allowing hypoxaemia because of concerns about PEEP is inappropriate after ABI. Venous blood flow from the brain is related to the balance between ICP driving in out of the cranium and jugular venous pressure impeding the exit of blood from the brain. It therefore seems likely that PEEP may be safe when it does not exceed ICP (58,60). The effect of PEEP on cerebral haemodynamics also depends on whether it results in recruitment or hyperinflation of alveolar units because of their different effects on PaCO 2 and therefore brain perfusion (36). In addition to potential adverse effects on ICP, PEEP can also decrease venous return, cardiac output, MAP, and thereby CPP. However, the use of appropriate levels of PEEP during mechanical ventilation appears to have limited effect on CPP and MAP in many patients (61). Overall, PEEP is a useful adjunct to improve pulmonary compliance and increase alveolar oxygenation and oxygen saturation in the setting of ABI and pulmonary dysfunction, but close monitoring of haemodynamic variables, pulmonary compliance, gas exchange, and ICP are mandatory to quantify the risks and benefits of its use.
Tidal volume Low tidal volumes (6 mL/kg ideal body weight) reduce ventilator days and mortality in patients with ARDS (45), whereas high tidal volume ventilation exacerbates the pulmonary and systemic inflammatory response of ARDS and leads to VILI (62). High tidal volume and respiratory rate are the most powerful independent predictors of early ARDS after TBI, with a dose response between tidal volume and risk of developing ARDS (62). Tidal volume should therefore be chosen to balance the adverse cerebral haemodynamic effects of low or high PaCO 2 secondary to overor under-ventilation against the risk of ARDS.
Recruitment manoeuvres A recruitment manoeuvre is a strategy to increase transpulmonary pressure transiently with the aim of reopening unventilated or poorly aerated alveolar units in patients with ARDS. Recruitment manoeuvres can be performed using an increase in airway pressure with an appropriate level of PEEP or by transiently increasing tidal volume. Both have potential adverse effects including increased ITP and ICP, and decreased preload, cardiac output, and CPP. In a study in patients with coexistent acute brain and lung injury, an increase in P max from baseline to 60 cmH2O over 30 seconds, and maintained for 30 seconds, decreased MAP and increased ICP, leading to a critical reduction in CPP and a decrease in jugular venous oxygen saturation (63). In another study comparing 35 cmH2O of continuous positive airway pressure (CPAP) for 40 seconds to pressure control ventilation (PCV) with 15 cmH 2O of PEEP and 35 cmH2O of pressure control above PEEP in patients with SAH and ARDS, the CPAP recruitment manoeuvre significantly increased ICP and decreased MAP and CPP whilst the PCV manoeuvre had no or little effect on ICP or cerebral haemodynamics (64). The effect of PEEP-induced recruitment manoeuvres on cerebral haemodynamics in braininjured patients is related to baseline respiratory system compliance and haemodynamic status, and such manoeuvres should only be performed with close monitoring of MAP, ICP, and CPP (65).
Prone positioning The prone position is an established rescue measure in patients with ARDS. It has been reported to increase oxygenation in up to 80% of patients (66). Likely mechanisms include alterations in thoracoabdominal compliance coupled with changes in regional ventilation and improvements in end-expiratory lung volume and ventilation– perfusion matching (67). However, concerns exist over use of the prone position in brain-injured patients (56,68). Transitioning into the prone position or maintaining prone ventilation may result in inadvertent removal or displacement of intracranial monitoring devices and invasive vascular catheters (56). Facial and truncal ulcers have also been reported in comatose patients managed in the prone position. A randomized controlled trial of 51 comatose patients found that prone position ventilation for 4 hours daily was associated with improved pulmonary function compared to ventilation in supine position, although this resulted in an increase in ICP from 11 mmHg to 24 mmHg by 1 hour after turning prone (68). The prone position had to be abandoned in two patients in this study because ICP increased above 30 mmHg. However, some recent studies have reported potential beneficial effects of the prone position in patients with ABI and ARDS. In a study in critically ill neurological patients with pulmonary complications, the prone position was associated with improved oxygenation compared with supine (69). Although there was a slight increase ICP in the prone position, there was improvement in CPP because of an increase in cardiac output and MAP. Prone positioning should be considered an option to prevent and ameliorate pulmonary complications during neurocritical care, but should only be used in association with comprehensive haemodynamic and cerebral monitoring to identify potential complications early.
Other rescue strategies Although many patients with ABI may be managed with the earlier mentioned strategies, some may require additional rescue procedures for failing oxygenation. As repetitive over-distension of lung units may exacerbate ALI and ARDS there has been recent interest in novel ventilatory strategies, such as high-frequency oscillation (HFO), which may be associated with less risk of barotrauma. HFO delivers extremely small tidal volumes (1–2 mL/kg) at very high respiratory rates (3–15 breaths/second). Although several randomized controlled trials suggested a benefit of HFO in non-neurological patients with ARDS (70), a recent systematic review of HFO in brain-injured patients concluded that its effect on patient outcome as well as on systemic and cerebral haemodynamics are largely uncertain (71). The use of extracorporeal membrane oxygenation has been described in patients with TBI and severe ARDS or neurogenic pulmonary oedema (72) and it has been suggested that nitric oxide may also be of benefit (70). However, the role of these interventions in brain-injured patients remains largely unknown.
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Weaning from mechanical ventilation Weaning from mechanical ventilation is classified according to temporal criteria as simple, difficult, or prolonged (68). Weaning is considered to be simple when patients are extubated on the first attempt, difficult when up to three spontaneous breathing trials (SBT) are required, but extubation is successful in less than 7 days from the first trial, and prolonged when a patient fails the first three SBTs or requires more than 7 days to be weaned from the ventilator. Critically ill neurological patients with brain injury or neuromuscular disease are more difficult to wean from ventilation than other ICU patients because of the contribution of their neurological illness to respiratory function and the high rate of associated pulmonary dysfunction (73). As a consequence, extubation is often delayed and this is associated with an increased risk of ventilator-associated pneumonia (VAP) and ICU length of stay (74). Furthermore, delayed extubation is relatively common in neurological patients who are otherwise ready to wean by conventional respiratory and haemodynamic criteria because of factors related to their neurological disease (75). In a retrospective review of 1265 patients who were intubated for neurological reasons, 844 (67%) were successfully extubated and only 129 (10%) required reintubation during their hospital stay (41). The most common reasons for reintubation in this study were ARDS associated with altered mental state, followed by pneumonia. A prospective clinical trial demonstrated that it is the presence of a cough associated with effective secretion clearance and not neurological status per se that is predictive of successful extubation in critically ill neurological patients (76). In this study, substantial numbers of patients meeting standard readiness criteria had extubation delayed because of concerns with neurological status
(depressed level of consciousness), but this delay was associated with a higher incidence of VAP and longer ICU and hospital lengths of stay. In a randomized clinical trial, a protocol-driven strategy using general cardiorespiratory readiness criteria for extubation, GCS score higher than 8, the presence of an effective cough, and tolerance of a 1hour SBT was compared to physician-driven discontinuation of mechanical ventilation (77). The reintubation rate was lower in the protocol-driven group but there was no difference in mortality, rate of tracheostomy, and duration of mechanical ventilation between the groups. Patients with infratentorial pathology deserve special mention because of the relatively high rates of bulbar dysfunction and conscious level disturbance. In a retrospective study, 18% of patients with an infratentorial lesion required elective tracheostomy because of extubation failure, and GCS score lower than 8 was a good predictor of the need for tracheostomy (78). A practical strategy for weaning from mechanical ventilation in neurocritical care includes ongoing assessment of neurological status, including level of consciousness, presence of protective airway reflexes, and effective secretion clearance, in addition to standard respiratory and cardiovascular readiness criteria. Overall the evidence suggests that there is often little justification for delaying extubation in patients who meet standard readiness criteria if the only indication for continued intubation is a depressed level of consciousness. An optimal level of oxygenation, BP, ICP, and CPP should be assured during the weaning process which should only be considered when ICP is stable.
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Tracheostomy Tracheostomy is indicated in patients requiring prolonged mechanical ventilation and/or those who are difficult to wean from ventilation. It offers many advantages over translaryngeal intubation including reduced work of breathing, lower incidence of pneumonia, and better tolerance by the patient resulting in reduced sedation requirements. Tracheostomy may also reduce the length of ICU stay and overall pulmonary complication rate in brain-injured patients (79). The largest randomized clinical trial investigating the timing of tracheostomy in a heterogeneous cohort of critically ill patients was performed in Italian ICUs, and early tracheostomy (performed after 6–8 days of mechanical ventilation) was associated with a reduction in ventilator-free days but not with the incidence of VAP, mortality, or length of hospital stay compared to late tracheostomy (performed after 13–15 days of ventilation) (80). The timing of tracheostomy in critically ill neurological patients remains a matter of intense debate. In a prospective randomized trial in patients with TBI, early tracheostomy was associated with fewer days of mechanical ventilation compared with prolonged endotracheal intubation but it did not reduce mortality, incidence of VAP, or ICU length of stay (81). In another study, 66 (2.7%) of 2481 patients with severe TBI required a tracheostomy and 16 of these were performed early and 50 late (82). The ICU length of stay was significantly shorter, the incidence of nosocomial pneumonia lower, and duration of antibiotic use shorter in the early tracheostomy group. However, a recent metaanalysis demonstrated that although the duration of mechanical ventilation decreases with early tracheostomy after severe TBI, the risk of hospital death increases (83). An important consideration when deciding on the timing of tracheostomy is the physiological stability of a patient in the early phase after ABI. The need to place the patient supine with the attendant risk of increased ICP, and the risk of interruption of oxygenation are important factors that can mitigate against early tracheostomy in such patients. Thus, routine early tracheostomy does not appear to be a prudent policy in many patients with severe brain injury. Based on limited evidence, physiologically stable patients with a GCS score lower than 8 at 1 week after admission to the NCCU, those with brainstem pathology with a reasonable prospect of survival, and those severely affected with neuromuscular syndromes with anticipation of prolonged mechanical ventilation should be considered for early tracheostomy (84).
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Ventilator-associated pneumonia The incidence of VAP in neurocritical care patients is between 30% and 50%, depending on the definition used (85), and the development of VAP adversely affects outcome (see Chapter 27). In a case–control study, patients with severe brain injury and VAP had an increased duration of mechanical ventilation and ICU and hospital lengths of stay (86). Early-onset VAP was primarily related to infection with Staphylococcus aureus, whereas Haemophilus influenza
and Pseudomonas aeruginosa were the most common pathogens in late-onset VAP. More severe injury, GCS score lower than 6, and/or the presence of cervical fracture with neurological deficit had a specificity of 97% for the prediction of VAP. Severity of injury has also been associated with the development of VAP after TBI (87). In a case– control series of 144 patients with severe TBI, approximately one-half developed VAP, of which 42% was early onset and 58% late onset (88). The development of VAP was associated with a higher mortality rate (20.8% vs 15.3%), increased duration of mechanical ventilation, and increased ICU length of stay. The diagnosis of VAP is based on the presence of new or progressive pulmonary infiltrates and at least two of fever or hypothermia (temperature ≥ 38°C or ≤ 36°C), leucocytosis or leucopoenia (> 12 × 109/L or < 3.5 × 109/L), purulent respiratory secretions, and clinical pulmonary infectious score higher than 6. Microbiological confirmation relies on the isolation of at least one potentially pathogenic organism in tracheobronchial aspirates (> 10 5 CFU/mL), blind bronchoalveolar lavage fluid (> 104CFU/mL), and/or bronchoscopic protected brush specimens (> 10 3 CFU/mL) (87). According to consensus guidelines (89), strategies to prevent VAP should include: o o o o o
◆ an oral hygiene programme for all intubated patients ◆ a programme to minimize aspiration of microbiologically contaminated secretions, including: • elevation of the patient’s head greater than 30° above horizontal • suctioning of pooled secretion in the oropharynx • avoidance of gastric distension • avoidance of medications to increase gastric pH • ventilator tubes clear of condensation ◆ frequent hand washing, use of gloves when in direct patient contact, and alcohol gel at every bedside ◆ standardized ventilator weaning protocols. In cases of suspected VAP, empirical antibiotic treatment directed against likely pathogens should be instituted as soon as possible after respiratory samples have been obtained, with de-escalation of treatment based on culture results and/or sensitivities. The duration of antibiotic treatment should be directed by the clinical response, avoiding predetermined lengths of treatments. In most cases, an appropriate clinical response will be noted and antibiotics can be stopped within 8 days.
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An updated study-level meta-analysis of randomised controlled trials on proning in ARDS and acute lung injury. Crit Care. 2011;15:R6.Find this resource: 68. Beuret P, Carton MJ, Nourdine K, Kaaki M, Tramoni G, Ducreux JC. Prone position as prevention of lung injury in comatose patients: a prospective, randomized, controlled study. Intensive Care Med. 2002;28:564–9.Find this resource: 69. Nekludov M, Bellander BM, Mure M. Oxygenation and cerebral perfusion pressure improved in the prone position. Acta Anaesthesiol Scand. 2006;50:932–6.Find this resource: 70. Papadimos TJ. The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis. J Trauma Manag Outcomes. 2008;2:1.Find this resource: 71. Young NH, Andrews PJ. High-frequency oscillation as a rescue strategy for brain-injured adult patients with acute lung injury and acute respiratory distress syndrome. 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Fluid management Chapter: Fluid management Author(s): Jonathan Ball DOI: 10.1093/med/9780198739555.003.0005 This chapter identifies and discusses the general issues surrounding the fluid management of critically ill patients. These are universal, regardless of whether or not there is significant brain or spinal cord pathology. Issues related to specific neurological conditions are covered in the relevant chapters elsewhere in this book. By way of introduction, a fluid is defined as a substance that continually deforms under an applied shear stress. This physical property lends itself to many biological processes, in particular as the medium for convective and diffusive transport.
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Water homeostasis Water is the predominant and essential fluid in human biology but its biophysical properties are still incompletely understood and remain the focus of much research (1,2,3,4,5).
Total body water Healthy humans comprise approximately 60% water overall (~ 42 L in a 70 kg adult). With the exception of fat, which is 10% water, all tissues, including the brain (6), are 70–80% water. Thus, the proportion of fat, which increases with age and in obesity, determines the percentage of body mass that is made up of water. Water is distributed between two compartments—intracellular and extracellular. The latter is subdivided into the extravascular, or interstitial, space and the intravascular space (see Figure 5.1).
Click to view larger Download figure as PowerPoint slide Fig. 5.1. The distribution of water between body compartments. TBW, total body water.
Brain water The average intracranial volume is approximately 1700 mL of which about 1400 mL is brain, 150 mL blood, and 150 mL cerebrospinal fluid (CSF). The average adult human brain weighs approximately 1350 g, and comprises about 77% water (70% of white matter is water and 80% of grey matter). CSF is 99% water and formed at a fairly constant rate of 0.2–0.4 mL/min or 400–600 mL/day. Production occurs via diffusion, filtration, pinocytosis, and active transfer by the choroid plexus (~ 50%), with the remainder forming around cerebral vessels and along the ventricular walls. CSF is passively absorbed through the arachnoid villi into the venous sinuses, and also drains directly into lymphatic vessels. The rate of absorption is primarily dependent on the CSF to venous hydrostatic pressure gradient. There is no feedback system between production and absorption of CSF so, if the latter is impaired, CSF accumulates leading to hydrocephalus. For a review of the different types of hydrocephalus and their management please refer to Chapter 7, or the article by Bergsneider et al. (7).
Homeostasis of total body water Table 5.1 details the organs involved in the control of total body water. Water is lost as a consequence of thermoregulation (heat loss via evaporation of sweat), ventilation (expiration of 100% humidified gas), digestion, and excretion. For a 70 kg, healthy human adult in a temperate climate undertaking normal levels of activity and eating a standard (mixed) diet, the total daily water loss is in the order of 2500 mL. Approximately 300 mL of water is produced as a metabolic by-product, leaving about 2200 mL to be replaced by enteral intake. Table 5.1 Daily water homeostasis for a 70 kg, healthy human adult, in a temperate climate, undertaking normal levels of activity, eating a standard (mixed) diet
Tissue
Net contribution
Components/dependent upon
Skin
Loss ~ 250– 500 mL
Respiratory tract
Loss ~ 500– 750 mL
Physiological process
Thermoregulation—heat loss through evaporation
Ambient temperature and humidity Heat production from activity: o ◆ Minimum ~ 100 mL o ◆ Maximum ~ 8000 mL
Kidney
Loss ~ 1500 mL
Total loss
~ 2500 mL
Gastrointestinal tract
Gain ~ 2200 mL o
As part of the conditioning process of inspired gas, it is filtered, becomes heated to core body temperature and takes up water to become ~ 100% humidified
Temperature and humidity of inspired gas Upper airway anatomy Ratio of nasal to oral breathing Minute ventilation Core temperature
Excretion and principal organ of water balance. Water retention (resorption) mediated by aldosterone (in response to systemic hypotension) and vasopressin (in response to plasma hyperosmolarity). Water loss mediated by the absence of the above hormones and enhanced by the natriuretic peptides (in response to cardiac stretch)
Cardiac output Systemic blood pressure Glomerular filtration rate Renal tubular function Plasma osmolarity: o ◆ Maximum concentration ~ 1400 mOsm/L o ◆ Minimum concentration ~ 50 mOsm/L o ◆ Assuming a daily clearance of 700 mOsm this equates to urine volumes of ~ 500–14,000 mL
o o o o o
Intake: ◆ Water in food ~ 1500 mL ◆ Water in beverages ~ 2000 mL Total ~ 3500 mL Output: ◆ Saliva ~ 1500 mL ◆ Stomach ~ 1500 mL ◆ Biliary system ~ 750 mL ◆ Pancreas ~
Volitional intake ± stimulated thirst Digestion Absorption Excretion
Tissue
Net contribution
Components/dependent upon
Physiological process
1500 mL ◆ Small bowel secretions ~ 1500 mL Total ~ 6750 mL Absorption: o ◆ Small bowel ~ 9000 mL o ◆ Large bowel ~ 1000 mL but capacity to increase up to 4500 mL principally under the control of aldosterone (systemic hypotension) Total ~ 10,000–14,500 mL Losses: o ◆ Large bowel stool ~ 200 mL o
Metabolic production of water
Gain ~ 300 mL
Total gain
~ 2500 mL
◆ Basal metabolic rate ◆ Level of activity
By-product of enzymatic conversion of fuels to energy
Assuming normal losses in a healthy adult, physiological adaption to changing circumstances can accommodate reductions in water intake to a minimum of approximately 1000 mL per day. Reductions beyond this threshold, and/or excessive losses of water with or without sodium or other osmolytes, result in progressive dehydration and adverse, but initially reversible, effects on all organ systems. The brain, skeletal muscle, and skin (heat loss) are the organs most affected initially, followed by cardiovascular decompensation. Both the rate of loss and cumulative deficit of water determine the point of irreversible organ injury. Acute deficits of greater than 15% of total body water may be fatal. Physiological adaptation to excess fluid intake is considerable and dependent not merely on the amount, but also the composition and rate of administration/ingestion. The limit of physiological renal excretion of ingested water is around 600 mL per hour for a 70 kg adult, beyond which water intoxication occurs. Water passes freely between the body compartments through a variety of semipermeable cellular membranes, extracellular matrices, and intercellular junctions. The permeability of these barriers varies with tissue type and is affected by physiological and pathological processes. Water flux between compartments is principally passive and determined by hydrostatic and osmotic forces (8). However, active co-transport of water against these gradients (uphill) does occur and there is increasing evidence of the importance of this mechanism (9). The critical intracellular and extracellular osmolytes are potassium and sodium respectively. Maintenance of this compartmental gradient, via plasma membrane-bound sodium/potassium adenosine triphosphatase (Na +/K+-ATPase), consumes around 20% of cellular energy expenditure. Exceptionally, this activity may account for 60–70% of energy expenditure in neurons, making them particularly vulnerable to sodium and water influx. The osmotic gradient between the extra- and intravascular compartments is the result of colloids, principally albumin. Thus any discussion of fluid management cannot be dissociated from issues affecting electrolytes and colloids.
The physiology of the intravascular compartment volume and composition
The intravascular space has a number of homeostatic mechanisms that maintain effective convective transportation despite significant changes in intravascular volume. The circulation is designed such that 60–70% of the circulating volume is contained within the venules and veins which act as a rapidly responsive reservoir to respond to both volume losses and gains. Volume changes in the intravascular space result in changes in venous, atrial, ventricular, and arterial pressures, which are detected by baroreceptors. The changes in the firing rates of these receptors result in changes in the autonomic output to the various components of the cardiovascular system, and compensatory changes aimed at preserving cardiac output and perfusion pressure. Thus, fluid loss triggers venoconstriction, tachycardia, positive inotropy, and arterial vasoconstriction. Failure of the vasoconstrictor response is commonly seen in acute severe illnesses, including the more severe forms of the systemic inflammatory response syndrome (SIRS). In addition to the cardiovascular compensatory responses, hormonally driven renal (and colonic) sodium and water retention, mediated by increased secretion of aldosterone (sodium and water, kidney and colon) and vasopressin (water, kidney) is triggered. By contrast, intravascular volume gains are initially absorbed by the reserve capacity of the compliant venous circulation. If isotonic volume gains continue, venous pressure and hence cardiac filling pressures rise, leading to increased cardiac output with a consequent diuresis. This is mediated by a combination of increased renal filtration and hormonally permitted (passive) renal sodium losses, generated to a greater extent by the absence of aldosterone and vasopressin than by the secretion of natriuretic peptides derived from increased cardiac stretch. From an evolutionary perspective, humans possess extensive, rapid (minutes), and effective physiological adaptations to limited water availability, moderate free water excess, and a paucity of sodium. By contrast, the response to sodium excess is very limited and slow, occurring over hours and days. The volume of blood in the microcirculation is locally controlled within tissues by rapidly responsive changes in vessel calibre in response to local oxygen tension and carbon dioxide and other waste acid concentrations. Of note, the effectiveness and efficiency of microcirculatory convective transportation is principally determined by blood viscosity (10), which in turn is determined by the haematocrit and concentrations of plasma proteins. The microcirculation has variable permeability in different tissues and in response to physiological and pathological processes, allowing a proportion of plasma to pass into the interstitial space. The driving force for this movement is the hydrostatic pressure gradient between the intravascular and interstitial spaces, but a number of factors limit the flow of water, solutes, and macromolecules down this pressure gradient. The Starling principle of microvascular downstream resorption of interstitial fluid back into the vascular space because of the colloid osmotic pressure of whole blood has repeatedly proven to be false, and recently been replaced by the glycocalyx model of transvascular fluid exchange (11). The differences between the old and new theories are summarized in Table 5.2. The glycocalyx model is based on the discovery of the endothelial glycocalyx layer (EGL), a web of membrane-bound glycoproteins and proteoglycans on the luminal side of the vascular endothelial cells. It is associated with various glycosaminoglycans which contribute to the volume of the layer and is the active interface between blood and vessel wall, functioning as a filter. The EGL varies in thickness from 0.2 μm in capillaries to 8 μm in larger vessels, and is semipermeable with respect to anionic macromolecules such as albumin and other plasma proteins, whose size and structure determine their ability to penetrate the layer. Table 5.2 Comparison of the old and the new paradigms that govern net fluid movement between the microvascular and interstitial spaces
Original Starling principle
The glycocalyx model of transvascular fluid exchange
Intravascular volume consists of plasma and cellular elements
Intravascular volume consists of glycocalyx volume, plasma volume, and red cell distribution volume
Capillaries separate plasma with high protein concentration from ISF with low protein concentration
Sinusoidal tissues (marrow, spleen, and liver) have discontinuous capillaries and their ISF is essentially part of the plasma volume Open fenestrated capillaries produce the renal glomerular filtrate Diaphragm fenestrated capillaries in specialized
Original Starling principle
The glycocalyx model of transvascular fluid exchange
tissues can absorb ISF to plasma Continuous capillaries exhibit ‘no absorption’ The EGL is semi-permeable to anionic proteins and their concentration in the intercellular clefts below the glycocalyx is very low
The important Starling forces are the transendothelial pressure difference and the plasma–interstitial COP difference
The important Starling forces are the transendothelial pressure difference and the plasma–subglycocalyx COP difference. ISF COP is not a direct determinant of J
Fluid is filtered from the arterial end of capillaries and absorbed from the venous end. Small proportion returns to the circulation as lymph
J is much less than predicted by Starling’s principle, and the major route for return to the circulation is as lymph
Raising plasma COP enhances absorption and shifts fluid from ISF to plasma
Raising plasma COP reduces J but does not cause absorption
At subnormal capillary pressure, net absorption increases plasma volume
At subnormal capillary pressure, J approaches zero. Auto transfusion is acute, transient, and limited to about 500 mL
At supranormal capillary pressure, net filtration increases ISF volume
At supranormal capillary pressure, when the COP difference is maximal, J is proportional to transendothelial pressure difference
Infused colloid solution is distributed through the plasma volume, and infused ISS through the extracellular volume
Infused colloid solution is initially distributed through the plasma volume, and infused ISS through the intravascular volume At supranormal capillary pressure, infusion of colloid solution preserves plasma COP, raises capillary pressure, and increases J At supranormal capillary pressure, infusion of ISS also raises capillary pressure, but it lowers COP and so increases J more than the same colloid solution volume At subnormal capillary pressure, infusion of colloid solution increases plasma volume and infusion of ISS increases intravascular volume, but Jv remains close to zero in both cases
v
v
v
v
v
v
v
COP, colloid osmotic pressure; EGL, endothelial glycocalyx layer; ISF, interstitial fluid; ISS, isotonic salt solution; J v, the net fluid movement between the intravascular and interstitial spaces. Reproduced from Woodcock TE and Woodcock TM, ‘Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy’, British Journal of Anaesthesia, 2012, 108, 3, pp. 384–394, by permission of Oxford University Press and the Board of Management and Trustees of the British Journal of Anaesthesia. Four microvascular phenotypes have been described in different tissues (see Figure 5.2). Each exhibits specialist structural features affecting the EGL, the presence or absence of cellular fenestrations, variations in intercellular junctions, and basement membranes. In health, the EGL acts to maintain the colloid osmotic pressure, limiting the hydrostatically driven filtration of plasma such that net fluid movement only occurs when the hydrostatic pressure gradient exceeds the plasma colloid osmotic pressure. Understanding the physiology and pathophysiology of the EGL is thus essential to allow a rational choice of intravenous fluid therapy (11).
Click to view larger Download figure as PowerPoint slide Fig. 5.2. A figure illustrating the anatomical differences between four capillary phenotypes. Reproduced from Woodcock TE and Woodcock TM, ‘Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy’, British Journal of Anaesthesia, 2012, 108, 3, pp. 384–394, by permission of Oxford University Press and the Board of Management and Trustees of the British Journal of Anaesthesia. Plasma and interstitial fluid sodium concentration is regulated by vasopressin and aldosterone (see above and below). In health, plasma colloid osmotic pressure is principally determined by plasma albumin concentration. Albumin is synthesized exclusively by hepatocytes, and immediately released into the circulation. The rate of production is dependent on substrate availability, hormonal status (principally insulin), and, most importantly, the colloid osmotic pressure of the interstitial fluid around hepatocytes (12). Thus, any increase in plasma colloid osmotic pressure, from either an endogenous or exogenous source, results in decreased albumin production and a resultant fall in plasma albumin concentration to maintain normal colloid osmotic pressure. By contrast, a fall in plasma colloid osmotic pressure results in increased albumin production, a response that is inhibited by inflammatory cytokines (12,13). An albumin molecule lasts about 30 days in healthy individuals. Around 10% of the body’s albumin is catabolized daily, with increased catabolism in response to protein and/or calorie deprivation, and acute systemic illness injury. The utility of monitoring plasma albumin concentration and the value of exogenous supplementation are discussed in the relevant sections below.
The physiology of the interstitial compartment volume and composition The interstitial space is very plastic. The volume (water content) of healthy tissues is kept to a minimum to facilitate rapid diffusion between the convective transport of the intravascular space and the intracellular environment. This is achieved by drainage of interstitial fluid into the intravascular space via the lymphatic system, a process driven by
gravity, skeletal muscle contraction, and negative intrathoracic pressure during breathing. In response to injury or inflammation, effectors of the innate immune system, principally toll-like receptors and integrins, modulate the structure of the extracellular matrix which results in an acute fall in compartment hydrostatic pressure. This can be sufficient to cause (up to) a 20-fold increase in transendothelial fluid flux as well as the compositional changes described below (11). Accumulation of excess fluid in the interstitial space is termed oedema, and originates principally from the vascular compartment. Not only does this limit diffusional transport but, as fluid accumulation continues, extravascular hydrostatic pressure exceeds venous and then microvascular pressure, resulting in tissue ischaemia. Extracellular fluid osmolarity is tightly controlled, principally by hypothalamic osmoreceptors that regulate the secretion of vasopressin from the posterior pituitary. Increases in osmolarity of more than 1% stimulate thirst and release of vasopressin which in turn increases the permeability of the renal collecting ducts to water. This results in increased water resorption from filtered plasma back into the circulation (14), thereby normalizing plasma osmolarity. Decreases in osmolarity have the opposite effects. Acute and chronic changes in osmolarity that exceed the limits of this homeostatic process, or are a consequence of its failure, have profound effects on brain function and can lead to permanent injury and even death. The brain’s physiological adaptation to osmotic challenges has been reviewed in detail by Verbalis (15). The colloid osmotic pressure of interstitial fluid, like that of blood, is principally determined by albumin concentration. It is worth noting that in healthy subjects around 60% of total body albumin is contained in the interstitial space, although at only 40% of its concentration in plasma (12). However, this albumin pool is not static. Five per cent of intravascular albumin crosses into the interstitial space each hour with an equivalent amount returning to the circulation via the lymphatic system. In response to injury and inflammation there is a small, acute, and transient efflux of albumin from the vascular to the interstitial space (16), although this is insufficient to explain the hypoalbuminaemia observed (17). Albumin has a circulation half-life of approximately 16 hours.
The physiology of the intracellular compartment volume and composition Cells must actively manage their volume (water content) to avoid lethal injury. In association with the central role of plasma membrane-bound Na+/K+-ATPase, the family of water channel proteins, the aquaporins (18), and the large variety of uphill co-transporters are pivotal in this regard (9). The complexity and regulation of cellular volume homeostasis remains incompletely understood but is an area of active research and rapid development (19). Much of this research has focused on brain tissue as these processes are central to acute and chronic brain pathologies (see Chapter 3). Cellular injury, regardless of pathology, frequently results in failure of water content homeostasis and an intracellular influx of water (20). As our understanding of these processes evolves, it is hoped that effective therapies will emerge (21). In contrast, adaptation to cellular dehydration as a consequence of hyperosmolar extracellular milieu (global water losses) is a highly conserved, fundamental stress response (22). Cells initially adapt to the osmotic efflux of water by active influx of inorganic solutes, in particular potassium, sodium, and chloride ions (23). However, these ions inhibit and/or become toxic to intracellular processes and cells start to synthesize heat shock proteins and accumulate nontoxic osmolytes, including neutral amino acids or their derivatives, polyols such as sorbitol and myo-inositol, and methylamines such as betaine. Although the precise detection and regulation of this process is not fully elucidated, the endoplasmic reticulum appears to play a key role by responding to cytoplasmic un- or misfolded proteins that accumulate as a direct consequence of critical water loss (24). Acute pathologies that may result in acute cellular dehydration include gastrointestinal infections and hyperglycaemic, diabetic emergencies. The natural histories and responses to therapy of these conditions is testament to the effectiveness of the cellular dehydration response. Maladaptation or failure of this response may be a central driver in many chronic degenerative diseases (24).
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Assessment and management of fluid status Although fluid management is a fundamental component of the care of critically ill patients, including those with neurological disease, our ability to assess patients’ needs for, and responses to, fluid therapy and titrate it accordingly remains surprisingly haphazard. Both inadequate and excessive fluid replacement is harmful and not infrequently
adds a significant iatrogenic insult to the burden of the underlying disease process. Given the long history of fluid management, the gaps in our knowledge are both surprising and regrettable. Indeed, in an attempt to address these deficiencies there has been a resurgence of both basic science and clinical trial data published on these topics in recent years. To mimic a patient’s journey, this chapter will first consider fluid resuscitation before discussing maintenance therapy and the active management of daily fluid balance.
Fluid resuscitation: cardiovascular optimization versus iatrogenic injury The primary role of the cardiovascular system is the convectional delivery of substrates (in particular oxygen) to within, and removal of wastes from, a diffusional distance of cells. There are two related components to this delivery—flow and pressure—although the latter cannot be used as a reliable surrogate for the former. There are many methods to assess the adequacy of single-organ and global perfusion, all of which have limitations (25,26). It is also important to remember that intravascular volume is but one of four physiological variables—heart rate and rhythm, myocardial contractility and relaxation, and vascular tone—that determine cardiac output and perfusion pressure. In addition to these variables, oxygen and other vital substrate delivery is affected by blood composition (viscosity and oxygen carrying capacity) and microcirculatory variables (functional capillary density and flow rate). Hence cardiovascular/oxygen delivery optimization requires at least consideration, if not direct measurement, of all six of these variables. All patients with acute severe illness or trauma, or undergoing major surgery, require cardiovascular monitoring and support, a major component of which is resuscitation and maintenance of an adequate intravascular volume using intravenous fluid and/or blood component products. Failure to provide such support results in tissue injury through hypoperfusion, the extent and duration of which adversely affect outcome (27). Fluid therapy in excess of restoration of adequate volume also leads to significant tissue injury through oedema formation, primarily affecting the lungs, brain, kidneys, bowel, and soft tissues, and is responsible for delays in the return of normal organ function, organ failure, prolonged hospital stay, and excess mortality. The following questions are a useful guide when assessing the amount and timing of fluid resuscitation. 1. 2. 3.
1. How much of what fluid has been lost and/or redistributed, and over what time period? 2. What is the cause of the fluid loss, is it still ongoing, and what can be done to minimize further losses? 3. How compromised is the cardiovascular system or, more importantly, is there any evidence of one or more hypoperfused organs? 4. 4. How much of what fluid should be administered and how quickly? By what means can the response to fluid therapy be judged? 5. 5. Having established that a patient is no longer fluid responsive, how long should one wait before rechallenging the patient’s physiology?
Assessment of fluid loss and/or redistribution Clinical history, physical examination, and routine blood tests (discussed later) should enable a reasonable estimation of fluid losses. The clinical signs of acute hypovolaemia are non-specific and include sinus tachycardia, atrial fibrillation, normotension, hypotension, absent jugular venous pulsation, tachypnoea, normal mentation, altered mentation, poor peripheral perfusion, reduced skin turgor, and dry mucous membranes. Historically, the gold standard physiological measure of intravascular volume status has been a static measure of central venous pressure, but this has repeatedly been shown to be no better than tossing a coin in predicting the stroke volume and cardiac output response to an intravenous fluid bolus (28,29). The same can also be said of the measurement of pulmonary artery occlusion pressure. There are a myriad of better static markers but all are derived from stroke volume/cardiac output monitors, and all demonstrate lower reliability than clinical care demands. Dynamic measures, in which the percentage change in a measured variable in response to the respiratory cycle or a vascular manoeuvre is used to predict volume responsiveness, are significantly better than static markers, although also subject to limitations (28).
Assessment of the cause of fluid loss
Initial fluid resuscitation should be guided by the working diagnosis of the degree of hypovolaemia and its cause. There are broadly three clinical scenarios that result in hypovolaemia: 1.
1. Excess fluid losses—most commonly renal or gastrointestinal losses secondary to diabetic ketoacidosis, hyperosmolar hyperglycaemic states, or norovirus infection. 2. 2. SIRS/sepsis—increased losses due to pyrexia and tachypnoea, reduced intake, vasodilatation, and fluid shifts out of the intravascular space. 3. 3. Haemorrhage—gastrointestinal tract, trauma, obstetric, ruptured aortic aneurysm, or surgical. Determining the likely aetiology is crucial because resuscitating patients following haemorrhage requires a significantly different approach to the hypovolaemia of water (± electrolyte) loss and SIRS/sepsis. There are substantial risks of significant iatrogenic secondary injury if aggressive fluid resuscitation is delivered before effective control of a bleeding source. Such resuscitation disrupts clots already formed, dilutes the coagulation system and accentuates both hypothermia and acidosis, thereby precipitating further blood loss and worsening of any coagulopathy (30). In short, if haemorrhage is known or suspected as the cause of hypovolaemia, don’t delay haemostasis especially to deliver fluid resuscitation. Intravenous fluids should of course be administered, but in the minimum volume necessary to achieve clearly defined and measurable endpoints. The optimal choice of fluid in this setting is discussed below. By contrast, the rapid correction of hypovolaemia in the scenarios of excess fluid loss or SIRS/sepsis is strongly advocated.
Assessment of the cardiovascular system and adequacy of organ perfusion Heart rate and blood pressure, except at extremes, are poor guides to cardiovascular adequacy. Normal mentation confirms adequate brain perfusion but altered mentation has multiple causes, only one of which is brain hypoperfusion. Poor peripheral perfusion can be chronic as well as acute and doesn’t necessarily reflect vital organ perfusion. Good peripheral perfusion may also occur in distributive shock. Urine output is an unreliable marker of renal perfusion (31). A diagnosis of oliguria can only be made by hourly observations for 4–6 hours and is the physiological response to stress hormones (catecholamines, aldosterone, and vasopressin) regardless of intravascular volume status and renal perfusion. Hence, the use of trend data of multiple variables, in particular stroke volume and cardiac output, arterial and central venous lactate and base deficit, central and mixed venous oxygen saturations, and central venous-to-arterial carbon dioxide difference, and their response to dynamic manoeuvres, is strongly recommended (25,26,32). Collectively these variables are surrogates for the ideal variables, namely the kinetics of global and organ-specific oxygen supply– demand balance (27).
Assessment of volume replacement and the responsiveness to fluid therapy For a hypovolaemic or shocked adult, 250 mL aliquots of the most appropriate (least harmful) fluid should be administered as rapidly as possible (< 5 minutes), and the response assessed by continuous measurement of stroke volume/cardiac output. All available monitoring methods have their limitations and can only reliably detect changes in excess of 15%, though increases of 10% or more are often considered a positive response. Repeat boluses of fluid should be administered until the monitored response is less than 10–15%. Arterial/central venous lactate and base deficit, central/mixed venous oxygen saturations, and central venous-to-arterial carbon dioxide difference after 15–30 minutes (the plasma half-life of lactate is ~ 20 minutes) should be reassessed. On the basis of the extent of change in all cardiovascular parameters, titration of vasoactive drugs should next be considered. The value of targeting fluid and vasoactive drug therapy to an oxygen delivery index of 600 mL/min/m 2 has biological plausibility but remains contentious (33), although it is certainly a reliable marker of prognosis. Adequately powered trials targeting this parameter in specific patient groups are currently underway and will hopefully clarify the utility of this target. In the absence of invasive monitoring, the response to fluid boluses can be judged against changes in heart rate, blood pressure, and mentation. This applies especially in the pre-hospital and acute admission setting. In the context of haemorrhagic hypovolaemia, the pragmatic advice is to aim for a palpable radial pulse, roughly equivalent to a systolic blood pressure of 80 mmHg. However, in the presence of significant brain or spinal cord injury current consensus opinion recommends targeting a systolic blood pressure of 100–110 mmHg.
Fluid unresponsiveness
In the absence of fluid responsiveness, the optimal length of time before re-challenging the patient’s physiology depends on the clinical circumstances. If fluid losses continue, if vasodilatation occurs, and as fluid shifts between body compartments ensues, the trends in cardiovascular parameters, in particular stroke volume/cardiac output, will decline. Given the limits of detectability, a greater than 10–15% decrease should prompt consideration of a further fluid bolus. A lack of response in this setting should trigger a systemic review of the cause of the hypovolaemia, and of the other five previously noted physiological variables that determine adequate perfusion.
Post resuscitation: doing the simple things well—daily fluid balance The resuscitated patient will commonly have received a water, sodium, and chloride load that exceeds their needs. This is in part the consequence of fluid shifts from the intravascular to the interstitial space, but also the result of (over-) enthusiastic fluid replacement. As explained previously, the physiological response to acute severe illness, injury, and major surgery, sometimes exacerbated by significant renal injury, is active retention of sodium and water and a limitation of the rate at which the kidneys can excrete excess fluid (31). Thus, although there is a theoretical minimum amount of water, sodium, and potassium that a patient requires each day, this must take into account the cumulative picture and make allowances for any predictable further losses together with unavoidable gains, in particular from intravenous therapies. Any calculated maintenance requirement is best delivered, along with nutritional support, via the enteral route. As a starting point, a euvolaemic patient with no excess fluid loading requires 25–35 mL/kg of water, 1–1.5 mmol/kg of sodium, and 1 mmol/kg of potassium each day. Beyond this, it would be ideal to measure all water and sodium losses and gains, thereby titrating the maintenance regimen to the patient’s requirements. It is standard practice in critical care to record hourly fluid inputs, enteral and intravenous, and outputs, urinary, nasogastric, surgical drains, and so on. From these hourly measurements, a cumulative balance is calculated for a 24hour period together with a daily reckoning of the cumulative balance since admission. Although estimates can be made of the additional unmeasured losses from the skin, respiratory tract, and gastrointestinal tract (based on the data in Table 5.1), this is inconsistently performed and may not take into account factors such as the patient’s temperature or presence of respiratory gas humidification. A simple, although somewhat unreliable, method to confirm cumulative fluid balance calculations is change in the patient’s daily weight, and some modern intensive care unit (ICU) beds have a built-in weighing facility. Alternatively, bed and patient weighing devices have been developed. Despite these simple technologies, concerns regarding the imprecision of daily weight results in it being rarely performed. Whether trend data of daily weight is sufficiently useful to guide daily fluid balance targets remains uncertain, not least because there is a paucity of published data on the subject. Daily clinical examination should attempt to estimate the degree of oedema, or perhaps more importantly any change in the degree of oedema, particularly in the dependant peripheries/soft tissues, lungs, gastrointestinal tract, and brain. The extent and change in lung oedema can be inferred from trends in derived variables of the efficiency of oxygenation, such as oxygenation index, and standardized dynamic lung compliance, but not reliably from plain chest X-ray series. Gastrointestinal oedema may result in ileus and/or intra-abdominal hypertension and trending regular, standardized measurements of intra-abdominal pressure may alert clinicians to the development of this complication of a positive cumulative fluid balance. In brain-injured patients, trending measures of intracranial compliance, and correlation of these to local and/or global measures of the adequacy of brain perfusion, may influence decisions regarding the active management of cumulative fluid balance. Additional insights into cumulative fluid balance can be gained from trends in routine haematological and plasma biochemical parameters, specifically haematocrit, sodium, urea, creatinine, and total protein, but not albumin. However, all are affected by multiple variables in addition to changes in intravascular and total body water. Haematocrit falls as a consequence of intravascular dilution and rises in response to intravascular water depletion. However, loss of red blood cells through bleeding and blood sampling on the ICU, and shortened red cell lifespan and inhibition of red cell production by acute severe illness confounds this relationship. Plasma sodium concentration is determined by multiple factors reflecting hydration and hormonal status, renal function, and sodium losses and gains. Unlike fluid balance, hourly/daily sodium balance is not routinely measured or used to titrate daily fluid administration. Critical care commonly results in significant sodium (and chloride) loading from intravenous drug therapies and other routine practices (34), and a positive cumulative sodium balance is probably detrimental and should be minimized. An increase in the plasma urea to creatinine ratio is often used as a marker of dehydration. Both are freely filtered by the kidney but only urea is passively reabsorbed; the degree of resorption is proportional to that of water and hence is
increased in dehydrated patients with good renal function. However, similar patterns of change are also seen following upper gastrointestinal haemorrhage, in hypercatabolic states, and in urinary tract outflow obstruction. Plasma total protein (TP) measurements can be used to estimate colloid osmotic pressure using the following formula (35):
Colloid osmotic pressure=(2.1×TP)+(0.16×TP2)+(0.009×TP3) This doesn’t account for the effect of administered synthetic colloids, so measuring colloid osmotic pressure using a relatively simple, quick, and reliable laboratory technique is preferred (36). However, given the controversies surrounding all colloid therapies, the value of knowing the colloid osmotic pressure and its trends is arguably no longer likely to influence fluid therapy (11). In summary, trend data and clinical acumen are required to interpret each of the relevant elements contributing to fluid status, and to reach a conclusion in setting daily fluid and electrolyte balance targets. This should take account of essential therapies such as nutrition and intravenous medication, and may necessitate the use of diuretics or renal replacement therapy to control fluid volume. It is vital to review these goals regularly and, if necessary, revise them. Dynamic challenges with fluid boluses or fluid removal may also be helpful in determining both fluid status and optimal strategy.
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Choice of intravenous fluid therapy Intravenous salt solutions (crystalloids) have been used since the 1830s. Sydney Ringer first described his physiological salt solution in the early 1880s, and Alexis Hartmann modified Ringer’s recipe in the 1930s. Despite their work, 0.9% sodium chloride, misnamed ‘normal’ saline, went on to become, and remains, the most commonly administered intravenous fluid. The first gelatin-based colloids were developed in 1915 and the first reported use of albumin infusion is ascribed to the American military in 1941. Yet, despite hundreds of clinical trials and countless meta-analyses, consensus statements, and evidence-based guidelines, the controversies and uncertainties surrounding the correct choice of intravenous fluid therapy remain. However, publication of the SAFE study in 2004 (37) and the subsequent large-scale trials it spawned, the paradigm shift in trauma resuscitation accelerated by the conflicts in Iraq and Afghanistan (30), the evolution of the glycocalyx model of transvascular fluid exchange (11), and the retractions of publications and inquiry into the work of Joachim Boldt (38) have resulted in significant recent advances in fluid management after years of stagnation. The questions that must be answered, most especially in the context of a vulnerable brain, are:
◆ Are the more physiological (‘balanced’) solutions less harmful than unphysiological 0.9% sodium chloride? ◆ Do any colloids provide outcome benefits over crystalloids, or over each other?
Balanced solutions versus 0.9% sodium chloride Table 5.3 details the composition, osmolarity, and pH of commonly prescribed crystalloid solutions using plasma as the reference solution. As 0.9% sodium chloride is mildly hyperosmotic and contains 50% more chloride ions per litre than plasma, infusion of significant volumes results in hyperchloraemic acidosis. Although the acidosis is rapidly buffered, the effects of hyperchloraemia are several and include impaired mental function, nausea, gastrointestinal dysfunction, renal vasoconstriction, hyperkalaemia, impaired coagulation, and a pro-inflammatory response (39). What is less clear is whether these effects are clinically important. Table 5.3 Comparison of plasma to commonly available intravenous crystalloid solutions
[Electrolyte] in mmol/L
Plasma
0.9% NaCl
5% Dextrose
4% Dextrose 0.18% NaCl
Hartmann’s
Ringer’ s
1.26% NaHCO
Cations Na
135–145
154
30
131
130
150
K
3.5–5.2
5.0
4.0
0.7–1.0
2.2–2.6
2.0
2.5
98–105
154
30
111
109
3− 4
0.8–1.4
Lactate
0.5–2.0
29
28
HCO
18–24
150
Others
Significant
Osmolarity mOsm/L
275–295
308
252
262
275
273
300
pH @ 37ºC
7.35–7.45
5.0
4.0
4.0
6.5
6.5
8.6
170
136
+
+
Mg
2+
Ca
2+
Anions Cl
−
PO
−
3
Calories kcal/L
Yunos and colleagues examined the renal effects of iatrogenic hyperchloraemia in a prospective, open-label, sequential period pilot study in 1533 ICU patients (40). They found that a 30% mean reduction in chloride loading resulted in a 50% reduction in both the incidence of acute kidney injury (AKI) and acute renal replacement therapy but no difference in hospital mortality, hospital or ICU length of stay, or the need for renal replacement therapy after hospital discharge. Shaw and colleagues examined the effects of iatrogenic hyperchloraemia in an observational study of adult patients undergoing major open abdominal surgery, comparing the outcomes of 30,994 patients who received 0.9% sodium chloride with 926 patients who received a balanced crystalloid on the day of surgery (41). For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced crystalloid group (P < 0.001). One or more major complications occurred in 33.7% of patients in the saline group and 23% in the balanced group (P < 0.001). The authors performed a 3:1 propensity-matched comparison and confirmed that treatment with the balanced fluid was associated with fewer major complications (odds ratio 0.79; 95% confidence interval 0.66–0.97) and less resource utilization. In particular, patients receiving 0.9% sodium chloride had a 4.8 times greater need for dialysis (P < 0.001) and a 40% higher incidence of major infection. The Cochrane group has undertaken a systematic review of trials comparing balanced solutions with 0.9% sodium chloride, and 13 randomized trials that together enrolled 706 very heterogeneous patients were identified (42). Clinically important outcomes were reported in only a minority of the trials, with most being assessed in fewer than 300 patients, and no significant differences between the fluid replacement groups were detected. However, this systematic review is based on inadequate data and the studies by Yunos et al. and Shaw et al. (40,41), though non-randomized, do suggest that iatrogenic hyperchloraemia may
3
cause significant harm and should be avoided. A large, multicentre, randomized controlled trial, analogous to the SAFE study, is required to confirm this conclusion. A largely uninvestigated option to limit chloride loading is the use of 1.26–1.4% sodium bicarbonate. The traditional role of intravenous bicarbonate has been the reversal of severe acidosis and, although it increases pH, it has never been shown to positively affect outcome (43). This is perhaps unsurprising given that it can be argued that acidosis per se is never the cause of the problem, but merely a marker of the severity of illness or injury (39,44,45). Human cells are very resistant to extracellular acidosis and, analogous with dehydration, cellular adaptation to, and recovery from, it is a highly conserved fundamental stress response. On the other hand, sodium bicarbonate has never been shown to be harmful and is recommended in the management of rhabdomyolysis (46), overdose of certain drugs (47), prevention of contrast-induced renal injury (48), and as the basis of replacement fluid in renal replacement therapies. To date, only two small studies, both in patients undergoing cardiac surgery, have compared routine sodium bicarbonate administration with 0.9% sodium chloride. In the first, a double-blind, randomized controlled trial enrolling 100 patients at high risk of postoperative AKI, the groups were well matched and there was a significantly lower incidence of AKI in the bicarbonate group (49). In the second trial, a retrospective cohort analysis of all patients treated during two sequential time periods in a single centre was undertaken (50). There was no outcome difference between 280 patients who received bicarbonate and 304 historical controls who received 0.9% sodium chloride. As this study has obvious methodological weaknesses, the only conclusion that can be drawn is that bicarbonate may benefit selected patients, probably those at high risk of AKI. Sodium bicarbonate may yet prove to be an important addition to fluid management regimens and a logical next step would be to include bicarbonate therapy in a chloride restrictive fluid strategy, perhaps based on that employed by Yunos and colleagues (40), and compare this to a standard, liberal chloride fluid strategy. From a neurointensive care perspective, 8.4% sodium bicarbonate has been shown to be as effective and as safe as 5% sodium chloride in the management of raised intracranial pressure following traumatic brain injury (TBI) (51).
Colloids Talk of the colloid verses crystalloid debate is akin to a fruit verses vegetable debate. Whilst there is the obvious distinction of colloid osmotic pressure, there are as many differences between the various colloids and crystalloids, as there are between fruit and vegetables. Table 5.4 sets out a summary and comparison of different colloid types. The discussion that follows has been dramatically simplified by the results of several recent landmark trials. Table 5.4 A comparison of albumin solutions and synthetic colloid solutions
Chemistry
Metabolism and excretion
Human albumin
Dextrans
Starches
Gelatins
Single polypeptide chain of 585 amino acids with a molecular weight of 69 kDa Derived from donated, pooled human plasma
Highly branched polysaccharide with average molecular weights of 40–70 kDa
Chemically modified hydrolysed amylopectin fragments with various mean molecular weights from 130 to 200 kDa
Chemically modified hydrolysed collagen fragments with molecular weights of 5–50 kDa
Lost into the gastrointestinal tract and catabolized to amino acids in a variety of organs
Smaller molecules excreted unchanged in urine. Larger molecules hydrolysed (days)
Smaller molecules excreted unchanged in urine. Larger molecules hydrolysed by amylase, excreted into bile or
Excreted unchanged in urine
Human albumin
Dextrans
Starches
Gelatins
sequestrated in reticuloendothelial system Common formulations
Claimed advantages
Known problems
4–5% albumin in 0.9% sodium chloride 20–25% in hypotonic NaCl
Physiologi
Anticoagulati
cal
on
Myriad of therapeutic binding properties
Enhance microvascular flow
Cost Risk of transmission of blood-borne pathogens
Comments
10% solution with an average molecular weight of 40 kDa in 0.9% sodium chloride 6% solution with an average molecular weight of 70 kDa in 0.9% sodium chloride
Anaphylaxis Anticoagulati on RBC opsonization and rouleaux formation —interferes with cross-matching Acute kidney injury
6–10% solutions of varying composition, mostly 0.9% NaCl but some in balanced crystalloids Efficacy in expanding the intravascular volume thereby reducing cumulative volume required when compared to crystalloids and gelatins. Proven not to be true (64,65) Cost Anaphylaxis Unpredictable anticoagulation Acute kidney injury Accumulation in all tissues, especially skin causing pruritus
3–5% solutions of varying composition. Na 145–155 mmol/L, Cl 105–145 mmol/L Some with K/Ca/Mg All pH 7.4 Least expensive colloid
Anaphylaxi s Unpredicta ble anticoagulation ? Acute kidney injury
Shortest intravascular halflife of all the colloids
Albumin There is an appealing logic to the argument that if any colloid is going to be beneficial it should be the predominant endogenous colloid, albumin. Importantly, albumin performs a myriad of vital molecular binding functions in addition to providing intravascular colloid osmotic pressure (12), and should therefore be considered a drug with distinct pharmacodynamic and kinetic properties. However, its binding properties make it vulnerable to chemical damage, in particular oxidation. Consequently, intravenous formulations exhibit a high degree of variability in binding potential (52), and this heterogeneity might be responsible for some of the inconsistency in clinical trial outcomes. Hypoalbuminaemia is a near ubiquitous consequence of acute severe illness, although the precise mechanisms contributing to its development remain obscure (17). The consequences are also widely debated as are the safety,
timing, and efficacy of maintenance and replacement strategies, sometimes coupled with aggressive fluid restriction and active diuresis (53). The SAFE study (37) was the first large-scale, pragmatic fluid trial of the current era of ICU trials and set a new standard for such studies. It put an end to the protracted and acrimonious debate about the safety of intravenous albumin that had resulted from a series of meta-analyses reaching diametrically opposing conclusions using the same flawed data. SAFE randomized 7000 ICU patients, covering the whole spectrum of severity of illness and diagnoses, to receive either 4% albumin in 0.9% sodium chloride or 0.9% sodium chloride, as resuscitation fluid during the first 28 days of ICU admission. There were no statistically significant differences in 28-day mortality or in any of a myriad of secondary endpoints. In short, 4% albumin is safe but, in the doses given to a deliberately heterogeneous ICU patient population, of no benefit. Of note, patients in the albumin group received, on average, 40% less resuscitation fluid than those receiving 0.9% sodium chloride. Further, subgroup analysis on the basis of admission diagnosis suggested that there might be benefit in patients with severe sepsis and that there was harm in those with TBI (54). Although there remains controversy in some quarters regarding the latter conclusion (55,56), this subgroup analysis of the SAFE study represents the largest fluid trial in TBI to date. There is some evidence to support the early use of a bolus of 25% albumin following acute stroke (57) and subarachnoid haemorrhage (58), with further trials in progress. A number of trials of albumin in patients with severe sepsis are also underway (59). In summary, albumin appears to be safe and may be efficacious in specific conditions. It should be avoided in patients with TBI, although a well-designed randomized controlled trial in this group could be justified. If a clear therapeutic role emerges, a cost–benefit analysis will be required.
Dextrans The dextrans were developed in the 1950s and have all but been consigned to history, with a few geographical exceptions. Their purported utility in peripheral and microvascular surgery (60) has been superseded by superior and safer fluid and antithrombotic strategies (61). In the only recently published study, a retrospective, historical, cohort analysis of 332 patients with septic shock treated in a single institution demonstrated no benefit of dextrans over Ringer’s solution (62). However, two additional findings of this study are noteworthy. First, the doses of dextran were large and perhaps not surprisingly associated with a significantly higher incidence of major bleeding—51/171 (30%) in the dextran cohort versus 31/161 (19%) in the Ringer’s cohort. Second, there was no difference in the total volume of fluid required for resuscitation, demonstrating that the claimed volume-sparing effect of dextrans appears to be false. The only other recent trials using dextrans have been in the pre-hospital resuscitation of shocked trauma patients, and these will be addressed in the trauma resuscitation section below. In summary, a resurgence of interest in the use of dextrans would appear both unlikely and unjustifiable.
Starches Due in no small part to the marketing by the manufacturers, the use of starches worldwide has grown exponentially over the last decade (63). However, increasing concerns about their safety and efficacy, coupled with the retraction of a number of studies supporting their use, led to two large-scale randomized control trials. The 6S study randomized ICU patients with severe sepsis to receive either starch (6% 130/0.42 in Ringer’s) or Ringer’s for resuscitation, with the primary outcome of the study being death or dependence on dialysis at 90 days (64). A total of 1211 patients were screened, 804 randomized, and complete data sets are available for 798. There was no demonstrable volume-sparing effect in the starch group, which had a 20% higher relative risk for receiving blood products. The primary outcome occurred in 51% of patients in the starch group but in only 43% in the Ringer’s group (P = 0.03), and Kaplan–Meier survival curve analysis demonstrates separation between days 10 and 50. Renal replacement therapy was required in 22% of patients in the starch group compared to 16% in the Ringer’s group (P = 0.04). In summary, the use of starch in this study conferred no benefits over Ringer’s solution and was associated with a higher mortality and incidence of renal failure. The Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care (CHEST) study randomized ICU patients who required intravenous fluid resuscitation to receive either starch (6% 130/0.4 in 0.9% sodium chloride) or 0.9% sodium chloride (65). The primary and secondary outcomes were death at 90 days and renal failure within 90 days respectively. A total of 19,475 patients were screened, 8863 were eligible, and 7000 were randomized. There was no
clinically significant volume-sparing effect and no difference in death at any time point in the 90 days between the two fluid regimens. There was also no difference in days receiving mechanical ventilation or renal replacement therapy, or ICU and hospital length of stay. There was, however, a significantly higher incidence of renal injury and pruritus in the starch group. In summary, use of starches confers no demonstrable benefit over crystalloids and may cause significant harm, most especially in the sickest patients. In association with the very high comparative costs, these recent clinical trials should result in the cessation of the use of starches.
Gelatins As a consequence of non-medical factors (63), gelatins have been geographically confined to Europe and their use has yet to benefit from the spotlight of a clinical trial akin to SAFE. In the inadequate and largely outdated trials comparing gelatins to crystalloids and other colloids, they appear to offer no benefits, and have a better safety profile than starches but a worse safety profile than crystalloids. Two systematic reviews are also worthy of note. An expert panel commissioned by the European Society of Intensive Care Medicine reviewed all data from published trials up to May 2011 and concluded that synthetic colloids should not be used outside clinical trials (66), and the Cochrane group also independently reached the same conclusion (67). Although they are the cheapest colloid, gelatins are still significantly more expensive than crystalloids. In short, it is increasingly difficult to justify the use of gelatins outside of a well-conducted clinical trial.
Resuscitation following major haemorrhage and haemorrhagic shock Regardless of the cause of haemorrhage, a large body of data, mostly from military and civilian trauma settings, supports minimal, delayed, titrated, and hypotensive fluid resuscitation until control of active bleeding and/or minimization of the risk of re-bleeding has been achieved (30). These data also support the concept of minimizing the volume of administered crystalloids or colloids, and, in their place, the early use of blood component products (uncross-matched if necessary) in a near physiological ratio. Initial resuscitation should use 1:1–2 packed red blood cells to fresh frozen plasma (FFP), supplied together in a ‘shock pack’ and administered simultaneously. The need for ongoing resuscitation beyond 2–4 units of red cells and FFP should include platelets, again in a physiological ratio (68). The volumes administered should be titrated to pragmatic cardiovascular endpoints, haematocrit (target 0.30) and normalization of thromboelastography parameters (69). This resuscitation paradigm encapsulates the early and simultaneous treatment of hypovolaemia, coagulopathy, and endothelial dysfunction (70). A high dose of FFP is critical in correcting fibrinogen concentration, which is the first and most important factor deficiency in haemorrhagic coagulopathy (71,72,73). In addition to clotting factors, FFP contains hundreds of other proteins, including immunoglobulins and albumin, and, as such, acts as a volume expander with physiological colloid osmotic pressures. Data from animal models also suggest that FFP, in contradistinction to synthetic colloids and Ringer’s, has restorative effects on endothelial permeability and vascular stability (see Figure 5.3) (70). A final word of caution regarding this approach is warranted. Transfused blood products have myriad negative effects as well as positive benefits (74), and they are also an expensive and limited resource. Thus titration to predefined cardiovascular and haemostatic endpoints, using the minimum of these resources, should be applied.
Click to view larger Download figure as PowerPoint slide Fig. 5.3 A working biological model of the mechanism of action of fresh frozen plasma. Haemorrhagic shock (HS) leads to a deviation of the vasculature from homeostasis. HS induces hypoxia, endothelial cell tight junction breakdown, inflammation, and leucocyte diapedesis. Fresh frozen plasma repairs and ‘normalizes’ the vascular endothelium by restoring tight junctions, re-building the glycocalyx, and inhibiting inflammation and oedema, all detrimental processes that are exacerbated by iatrogenic injury with synthetic colloid and crystalloids. Reproduced from Pati S et al., ‘Protective Effects of Fresh Frozen Plasma on Vascular Endothelial Permeability, Coagulation, and Resuscitation After Hemorrhagic Shock Are Time Dependent and Diminish Between Days 0 and 5 After Thaw’, Journal of Trauma and Acute Care Surgery, 69, 1, pp. 55–63, copyright 2010, with permission from Wolters Kluwer. So compelling is the evidence to support this approach to resuscitation that many pre-hospital services are now equipped with uncross-matched packed red blood cells and FFP for use in haemorrhagic shock. However, this is neither a universal nor necessarily practical option, nor one proven to be beneficial. What then are the best, or least worst, alternatives? There has been a longstanding enthusiasm for administering small volumes of hypertonic fluid for pre-hospital resuscitation of both haemorrhagic shock with or without presumed significant TBI. Both hypertonic and hyperoncotic (dextrans) fluids have been studied, but independent, systematic review of these options has found no evidence of benefit or harm when compared to either the mildly hypertonic 0.9% sodium chloride or the mildly hypotonic Ringer’s/Hartmann’s solution (67,75). The optimal strategy for resuscitating a patient with haemorrhagic shock and significant TBI remains a clinical paradox in which the risk of inducing further bleeding has to be weighed against the secondary brain injury associated with hypotension.
Maintaining hydration not maintenance fluids
The anachronistic dogma of giving x mL/kg/hour of ‘maintenance’ intravenous crystalloid solutions to all critically ill patients should be consigned to history. There must be a clear rationale and a measurable target endpoint to all fluid prescriptions. The desired endpoint will dictate the rational fluid choice and route of administration for the particular circumstances of an individual patient. For example, a haemodynamically stable patient with a significant positive fluid balance following resuscitation may develop large nasogastric aspirates. However, if as a consequence of this loss the patient achieves their daily fluid balance target (whilst any electrolyte derangement is avoided), the losses should be considered therapeutic.
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Conclusion Fluid management is a core task in critical care, including neurointensive care. Historically, there have been diametrically opposing views regarding optimal fluid management but a much clearer understanding of the physiology and pathophysiology of water and electrolyte homeostasis and intercompartmental fluxes, together with the effects of the various components of administered fluids, has recently emerged. Fluid therapy should be titrated to an individual patient’s needs and circumstances, avoiding fluids for which there is no evidence of benefit, at least some evidence of harm, and those with a cost that significantly exceeds a safer alternative.
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Sedation and analgesia in the neurocritical care unit Chapter: Sedation and analgesia in the neurocritical care unit Author(s): Mauro Oddo and Luzius A. Steiner DOI: 10.1093/med/9780198739555.003.0006 Sedation and analgesia play key roles in the management of critically ill patients to improve tolerance of intubation and mechanical ventilation, and generally facilitate patient management. Sedation has additional specific functions in the management of acute brain injury (ABI) during neurocritical care. It reduces the cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV) and thereby increases the tolerance of the brain to potential ischaemic insults, as well as playing a key role in the prevention of intracranial hypertension and the management of elevated intracranial pressure (ICP).
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Indications for sedation There are general and neurological-specific indications for sedation in patients with ABI.
General indications Sedative agents are routinely administered to critically ill patients to reduce anxiety, pain, and discomfort, to prevent agitation, and facilitate mechanical ventilation. They prevent surges of systemic blood pressure and ICP in response to interventions, thereby protecting the injured brain against secondary insults. Critically ill adult patients have historically been deeply sedated to ensure comfort and facilitate ventilator management, but prolonged and high-dose sedation is associated with intensive care unit (ICU)-acquired encephalopathy, weakness, and delirium. It is becoming increasingly clear that ventilator management with less or even no sedation (as tolerated) is associated with improved patient outcome. Limiting the dose of sedation using the ABCDE care bundle (awake and breathing coordination, delirium monitoring, early mobility, and exercise) has been associated with improvements in the management of
mechanically ventilated patients (1,2). While a more conservative approach to sedation management in patients in general ICU is now widespread, a blanket extension of such a strategy to patients with severe ABI is questionable and should only be applied when ICP and cerebral perfusion pressure (CPP) are normalized.
Brain-specific indications During the early phase after ABI, the imbalance between increased cerebral metabolic demand and limited energy reserve exposes the brain to a risk of secondary (ischaemic) insults. Sedative agents reduce CMRO 2 and improve the brain’s tolerance to ischaemia and energy dysfunction. In a normally reactive brain, sedative agents also decrease CBF thereby inducing a proportional reduction in CBV and ICP. Sedation titrated to patient needs reduces cerebral metabolic demand related to agitation, pain, motor hyperactivity, cough, patient–ventilator asynchrony, tracheal suctioning, shivering, and transportation, which may all increase ICP. Standard sedation is therefore part of the first-line management of elevated ICP. Deep sedation, titrated to maintain ICP below a predetermined level (usually < 20–25 mmHg) or to electroencephalogram (EEG)-monitored burst suppression, may be required in some cases. A combination of several sedatives agents, including propofol, midazolam, and barbiturates, may be required to manage intracranial hypertension refractory to first-line therapies (see Chapter 7). Many sedatives, including benzodiazepines, propofol, and barbiturates, have intrinsic antiepileptic properties and are also used in the management of refractory status epilepticus (see Chapter 23).
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Sedative and analgesic agents The following section reviews the pharmacological profile of the drugs available for sedation and analgesia in the neurocritical care unit (NCCU), emphasizing their cerebral haemodynamic and side effects (Table 6.1). Table 6.1 Cerebral haemodynamic and side effects of commonly used sedative and analgesic agents
Propofol
Mechanism of action
Effect on brain haemodynamics
Side effects
Comments
GABAergi c agonist NMDA antagonist
↓ ICP, ↓ MAP (particularly in hypovolaemic patients), thus may ↓ CPP; ↓ CMRO and CBF, preserved CO reactivity and cerebral autoregulation; ↓ cerebral electrical activity, can be used to induce burst suppression and treat status epilepticus (at high dose)
↑ triglycerides, ↓ MAP, peripheral vasodilation (venous > arterial), myocardial depression, propofol-infusion syndrome (↓ HR, ↑ pH, ↑ lactate, ↑ CPK, myocardial failure)
Relatively rapid awakening even with prolonged infusions; only drug that is recommended by the Brain Trauma Foundation guidelines to treat elevated ICP
↓ CMRO and CBF; mild ↓ of ICP, preserved CO reactivity and cerebral
Protracted coma, particularly during prolonged administration and if
2
2
Midazolam
GABAergic agonist
2
2
Mechanism of action
Effect on brain haemodynamics
Side effects
autoregulation; antiepileptic effect
kidney/liver function impaired; prolonged use can cause tachyphylaxis and withdrawal
Comments
Lorazepam
GABAergic agonist
↓ CMRO and CBF; antiepileptic effects
Exacerbation of ICU delirium; continuous infusion can cause ethylene glycol-induced metabolic acidosis
Long half-life (15 h); not suitable for continuous intravenous sedation in braininjured patients
Morphine
μ-opioid receptor agonist
↑ ICP via ↓ cerebrovascular resistance, ↑ CBF or ↑ PaCO ; disturbed cerebral autoregulation; opiate-related increase in ICP is mainly due to a decrease in MAP
Prolonged duration of MV, particularly in patients with kidney/liver failure; withdrawal symptoms in patients who received longterm sedation; opiate-induced hyperalgesia
The dose needed to produce analgesia is very variable
↑ ICP via ↓cerebrovascular resistance, ↑ CBF or ↑ PaCO ; disturbed cerebral autoregulation; opiate-related increase in ICP is mainly due to a decrease in MAP
Same as for morphine
Rapid onset of action
The effects of remifentanil on ICP, CPP, and CBF are overall comparable to those of other opiates, and are modest if MAP is kept stable
Bradycardia
Rapid clearance and highly predictable onset and offset of effect; terminal half-life of ~ 10– 20 min
2
2
Fentanyl, sufentanil
μ-opioid receptor agonist
2
Remifentanil
μ-opioid receptor agonist
Barbiturates
Mechanism of action
Effect on brain haemodynamics
Side effects
Comments
GABAergic agonist, via the inhibition of intracellular Ca influx and the blockade of glutamate receptors
↓↓ CBF that is proportional to the ↓↓ of CMRO ; during burst suppression, the ↓ of cerebral metabolism can be of about 60% compared to baseline; by ↓ CBF and CBV, barbiturates have a strong effect on ICP
↓ MAP/CPP; increased risk of infection; adrenal dysfunction
Barbiturates should be limited to the treatment of refractory ICP and refractory SE, in combination with other sedatives and titrated to the lowest effective dose; EEG may be helpful to titrate barbiturate therapy
Alpha-2 adrenoreceptor agonists
↓ CBF by DEX may be mainly related to a reduction in CMRO rather than to a direct cerebral vasoconstrictive effect; α /α adrenalreceptor ratio of DEX is approximately 7–8 times higher than clonidine; DEX elimination half-life is 2 h vs 8 h for clonidine
2
2+
Alpha-2 agonists (clonidine, dexmedetomidine, DEX)
2
2
Etomidate
GABA-like effects
Haloperidol
Dopamine antagonist
on Bradycard ia
1
↓ ICP, ↓ CBF, and ↓ CMRO ↓ MAP and CPP
↑ CBF
Hypotensi
2
Adrenal insufficiency; increased susceptibility to infections
Prolongation of the QT interval; torsades de pointes; may lower seizure threshold and increase epileptic activity; neuroleptic
No respiratory depression; clonidine can be particularly useful to treat delirium, especially in patients with symptoms of benzodiazepine or alcohol withdrawal
Not recommended as the first choice agent for rapidsequence intubation of NCCU patients; propofol is preferred to etomidate
Mechanism of action
Effect on brain haemodynamics
Side effects
Comments
malignant syndrome Ketamine
NMDA antagonist
No significant negative effects on ICP and cerebral haemodynamics; may be used as adjunct for the management of refractory SE
Hallucinations, dysphoria, blurred vision, nystagmus, diplopia
Inhaled anaesthetics
Not fully established: may act at several sites (reduction in junctional conductance; activation of Ca dependent ATPase; binding to the GABA receptor, the large conductance Ca activated K channel, the glutamate receptor, and the glycine receptor)
Dose-related suppression of cerebral electrical activity and hence cerebral metabolism, which leads to ↓ in CBF; dosedependent direct cerebral vasodilator effect that might ↑ CBF, CBV, and ↑ ICP; the net effect results from the balance between these two mechanisms; ↓ CBF at low concentrations, ↑ CBF and CBV at high concentrations; sevoflurane is the inhaled anaesthetic with the least vasodilator properties
In patients with decreased intracranial compliance, may ↑ ICP; myocardial depression; malignant hyperthermia
2+
2+
+
CBF, cerebral blood flow; CBV, cerebral blood volume; CMRO 2, cerebral metabolic rate of oxygen; CPP, cerebral perfusion pressure; EEG, electroencephalography; GABA, gamma-aminobutyric acid; ICP, intracranial pressure; ICU intensive care unit; LOS, length of stay; MAP, mean arterial pressure; MV, mechanical ventilation; NCCU, neurocritical care unit; NMDA,N-methyl D-aspartate; SAH, subarachnoid haemorrhage; SE, status epilepticus.
Propofol Propofol (2,6-diisopropyl phenol) is the most widely used sedative agent in the NCCU. It is insoluble in water and presented as a soybean oil-based emulsion with glycerol and egg lecithin emulsifiers. Two concentrations of propofol, 1% and 2%, are currently available. Propofol enhances gamma-aminobutyric acid (GABA) neurotransmission and is an N-methyl-D-aspartate (NMDA) antagonist. Although it has neuroprotective actions in animal studies, human data confirming neuroprotection are lacking (3).
Continuous infusion of propofol induces sedation in a dose-dependent manner. Despite elimination from poorly perfused tissues being slow, the volume of distribution of propofol is very large thereby guaranteeing rapid awakening even after prolonged infusion. Propofol is primarily eliminated in the liver. Renal and pulmonary clearance also occurs but renal dysfunction does not prolong propofol elimination.
Cerebral haemodynamic actions Propofol lowers ICP in patients with and without intracranial hypertension. However, it also decreases mean arterial pressure(MAP) and may therefore reduce CPP despite its ICP-lowering actions. Propofol is as effective as fentanyl or pentobarbital plus morphine at controlling ICP, but more effective than morphine alone or morphine plus midazolam (3). It is currently the only drug recommended in the Brain Trauma Foundation guidelines for the control of ICP (level II recommendation), except for high-dose barbiturates to control refractory intracranial hypertension (4). Propofol lowers CMRO2 and CBF but flow–metabolism coupling, CO2 reactivity, and autoregulation are typically preserved in the normal brain. However, there are reports that propofol has a cerebral vasoconstrictor effect which has been associated with a decrease in jugular venous saturation and also deterioration in static autoregulation at higher doses (5). High-dose propofol effectively suppresses cerebral electrical activity and is often used to induce burst suppression in the management of seizures and status epilepticus (see Chapter 23). Propofol may have proconvulsive actions at low doses but this phenomenon is not observed at higher doses (6). Nevertheless, caution has been advised when repeated small boluses of propofol are used during procedural sedation in patients with known seizure disorders. Despite its beneficial effects on cerebral haemodynamics, there are no clinical studies showing that propofol sedation is associated with improved outcome in critically ill neurological patients.
Side effects The main side effects of propofol are dose-dependent cardiovascular depression necessitating more frequent use and higher doses of vasopressors to maintain CPP. This is related to several mechanisms. Peripheral vasodilatation, more pronounced in the venous than in the arterial bed, myocardial depression, and interference with baroreceptor function have all been reported. This is a particular concern in older patients with diastolic dysfunction and in hypovolaemic patients susceptible to the preload reduction induced by propofol.
Propofol infusion syndrome A major concern regarding the use of propofol for sedation in the NCCU is the development of the propofol infusion syndrome (PRIS) (7,8). This was initially described in children but there have also been a large number of reports of PRIS in adults, particularly in critically ill neurological patients. It is characterized by metabolic lactic acidosis, elevated creatine kinase, myocardial failure, and death. Bradycardia is described in children but, in adults, tachyarrhythmias, including ventricular tachycardia, are more common (8). The underlying mechanism of PRIS is believed to be specific disruption of fatty-acid oxidation because of impairment of entry of long-chain acylcarnitine esters into the mitochondria, and subsequent failure of the mitochondrial respiratory chain (9). Because of the concerns regarding the development of PRIS, propofol is contraindicated for sedation in paediatric patients and doses exceeding 5 mg/kg/h should not be used for longer than 48 hours in adults. Propofol should also be avoided in patients with inborn errors of fatty acid metabolism and mitochondrial disorders (10). Because of the obligatory lipid load during propofol infusion it is also recommended that propofol should not be used for sedation in hypothermic patients, when metabolism of fatty acids is reduced, or when triglyceride levels exceed 4 mmol/L. The 2% solution was developed specifically to reduce exposure to the lipid vehicle, but it can still result in a significant increase in serum triglycerides. This suggests that triglyceridaemia during propofol infusion is not simply caused by the lipid vehicle, but also by pharmacodynamic effects consistent with the postulated mechanism of PRIS (11).
Benzodiazepines Benzodiazepines are GABA agonists with sedative, anxiolytic, amnesic, and antiepileptic actions. They are frequently used as sedative agents on the NCCU, often in association with an opioid such as morphine.
Midazolam is a short-acting benzodiazepine with a relatively short (1-hour) half-life and is often used for continuous intravenous sedation in the NCCU. It has a stable haemodynamic profile and fewer cardiovascular side effects than propofol. Lorazepam has a much longer half-life (15 hours) and is not suitable for continuous intravenous sedation. However, when administered as intermittent intravenous boluses, lorazepam may have a place as an alternative to midazolam during weaning of agitated patients from ventilation, particularly those at risk of benzodiazepine or alcohol withdrawal (12).
Cerebral haemodynamic actions Benzodiazepines reduce CBF and increase cerebrovascular resistance proportional to the decrease in CMRO 2 (13). Midazolam causes no or only a mild reduction in ICP, but preserves cerebrovascular autoregulation and CO 2 reactivity (14). Three randomized controlled trials comparing propofol to midazolam reported similar effects on ICP and CPP (11,15,16).
Side effects Benzodiazepines have few haemodynamic side effects. The main concern with midazolam is delayed awakening, particularly after prolonged administration or when kidney and/or liver function are impaired (17), but there is large inter-individual variability in this effect (18). Tachyphylaxis is common during prolonged use of midazolam, as are symptoms of withdrawal when the drug is stopped. Continuous infusion of lorazepam can lead to ethylene glycolinduced metabolic acidosis and is not recommended. All benzodiazepines, but particularly lorazepam, have been linked to the development of delirium in ICU patients (19).
Opioids Pain may occur as a consequence of surgery, trauma, or inflammation and, in ICU patients, because of the presence of an endotracheal tube, full bladder or bowel, chest drains, or immobility. Sedative agents do treat pain and analgesics are indicated. Opioids reinforce the effects of sedatives, and the combination of an opioid and a sedative is the general rule in the NCCU. Recent data suggest that ICU patients often suffer from inadequate pain management, and daily pain assessment and optimization of analgesia has been associated with reduced duration of mechanical ventilation and ICU length of stay (LOS) (20). As well as being part of general patient management, adequate analgesia is mandatory in patients with elevated ICP. Boluses of analgesia before potentially painful manoeuvres may attenuate unwanted increases in ICP. The morphine dose required to produce effective analgesia is variable and depends on factors such as opioid tolerance, metabolism, and excretion. The usual adult dose of morphine for a patient receiving mechanical ventilation is a continuous infusion at a rate of 1–10 mg/h, or 2–5 mg intermittent boluses. Morphine may accumulate in patients with renal failure and dose adjustment is required. Fentanyl is a synthetic opioid that is 75–200 times more potent than morphine. It penetrates membranes quickly and thus has a rapid onset of action. Its duration of action is relatively short, but prolonged infusion leads to accumulation. In patients requiring mechanical ventilation, fentanyl is infused at a rate of 100–200 mcg/h, or as 50–100 mcg boluses. Sufentanil is also a synthetic opioid, usually administered as a continuous intravenous infusion at a rate of 0.3–0.9 mcg/kg/h, or as bolus doses of 1–2 mcg/kg. Morphine, fentanyl, and sufentanil undergo hepatic metabolism, and continuous infusion can lead to accumulation and prolonged effects, including delayed recovery and respiratory depression. This is especially the case in critically ill patients in whom drug clearance may be substantially reduced. Agents with a shorter half-life, such as sufentanil, are often preferred. Remifentanil is a potent selective μ-opioid receptor agonist and an ultra-short acting agent originally designed for use in anaesthesia. It differs from other opioids in being metabolized by esterases which are widely distributed in all body tissues. Even during the anhepatic period of liver transplantation there is little change in remifentanil pharmacokinetics, highlighting its independence from the usual routes of metabolism. Because of its unique pharmacokinetic profile, remifentanil is characterized by a rapid and uniform clearance and a highly predictable onset and offset of effect. It has an effective biological half-life of 3–10 minutes (21), which offers potential advantage when weaning patients from sedation and analgesia (22). Remifentanil is metabolized to remifentanil acid which has very
weak opioid actions but even in renal failure remifentanil acid is unlikely to exert a clinically significant effect. The ability to provide intense analgesia with remifentanil means that lower doses of co-administered sedative agents are required.
Cerebral haemodynamic actions Morphine, fentanyl, and sufentanil are associated with increases in ICP and CBF, and disturbed cerebral autoregulation (23,24,25,26). Three randomized controlled trials have demonstrated that boluses or short infusions of opioids result in clinically and statistically significant increases in ICP, and decreases in systemic blood pressure and CPP (23,24,27). These effects are usually transient but, in one study, persisted for some hours (23). The ICP effects are likely to be related to reductions in blood pressure and consequent cerebral vasodilation leading to increased ICP (28). Thus, the ICP and CPP effects of opioids can be minimized by the prevention of hypotension with volume resuscitation and vasopressors. One trial found that morphine was associated with higher requirements for ICPlowering interventions and poorer ICP control after 3 days of infusion compared to propofol (29). Remifentanil has similar effects on ICP, CPP, and CBF to other opioids, which are also modest if systemic blood pressure is maintained.
Side effects The main side effects of opioids are respiratory depression in self-ventilating patients and prolonged duration of mechanical ventilation, particularly in patients with kidney or liver dysfunction. Withdrawal symptoms in those who have received long-term sedation/analgesia and opiate-induced hyperalgesia are also reported. Remifentanil can cause a significant reduction in heart rate and chest wall rigidity at high doses.
Other analgesics Paracetamol (acetaminophen) is a non-opioid analgesic that can be administered enterally, rectally, and intravenously in divided doses of 500–1000 mg. The maximum daily dose is 4 g. Non-steroidal anti-inflammatory drugs (NSAIDs) have several potentially adverse effects including antiplatelet actions, acutekidney injury, and gastrointestinal bleeding. Despite these risks, NSAIDs are often used as analgesics in neurological patients. The more commonly used NSAIDs include ketorolac (10 mg 6-hourly) and ibuprofen (400–600 mg 8-hourly).
Barbiturates Barbiturates act at multiple sites in the brain by increasing GABAergic activity, inhibiting the intracellular influx of calcium and blocking glutamate receptors (30). Given their numerous side effects, the indications for barbiturates are limited to the treatment of refractory elevated ICP and status epilepticus, when they are usually administered in combination with other sedative agents (4).
Cerebral haemodynamic actions Barbiturates decrease CMRO2 with a proportional reduction in CBF. At EEG burst suppression, cerebral metabolism is reduced by 60% compared to baseline. Barbiturates have a strong ICP reducing action secondary to their effects to reduce CBF and CBV (31,32). CBF and CMRO2 coupling, cerebrovascular autoregulation, and CO 2 reactivity are unaffected by barbiturate infusion. Because of the ICP lowering effects, barbiturate coma is a therapeutic option for refractory intracranial hypertension (4). In a small randomized controlled trial of 44 patients with severe traumatic brain injury (TBI) and elevated ICP, thiopental was more effective than pentobarbital in reducing the period of time with ICP greater than 20 mmHg (33). Although barbiturate therapy is usually titrated to the desired ICP, there is a weak correlation between barbiturate concentrations and ICP response (34) and EEG should be used to guide barbiturate therapy and minimize side effects (35,36).
Side effects
Barbiturates result in leucopoenia and immune suppression and therefore increase the susceptibility to infection (33). They also cause significant reductions in systemic blood pressure and CPP (33,37), and have been associated with adrenal dysfunction (38). These adverse effects often offset the beneficial effects of barbiturates on ICP reduction, and might explain why pentobarbital is less effective than mannitol in the management of intracranial hypertension (39).
Alpha-2 agonists Clonidine and dexmedetomidine are the two clinically available α 2-agonists. Although there is considerable interest in the use of these drugs in the general ICU, there are few studies in critically ill neurological patients. Both produce dose-dependent sedation, anxiolysis, and analgesia through actions at spinal and supra-spinal sites, without respiratory depression. Dexmedetomidine is a highly selective α2-adrenoreceptor agonist with an α2/α1 adrenoreceptor ratio approximately seven to eight times higher than that of clonidine. The elimination half-life of dexmedetomidine is 2 hours compared to 8 hours for clonidine, and the α-half-life is 6 minutes. This makes dexmedetomidine very suitable for intravenous titration and more suitable than clonidine as an ICU sedative.
Cerebral haemodynamic actions In a study in rabbits with and without intracerebral lesions, dexmedetomidine did not increase ICP over a wide dose range (40). It also had no effect on lumbar cerebrospinal fluid pressure in a study in 16 postoperative patients (41). There has been some concern about a dexmedetomidine-induced reduction in CBF and, in one study in healthy human volunteers, sedation with dexmedetomidine was associated with a 33% decrease in CBF (42). It was unclear whether this effect was related to direct α2-receptor-dependent vasoconstriction or to compensatory CBF changes as a result of dexmedetomidine-induced decreases in CMRO2. However, in another human volunteer study, the CBF/CMRO2 ratio was unchanged by dexmedetomidine (43). Dexmedetomidine impairs cerebrovascular pressure autoregulation in the healthy brain (44). Overall, these data suggest that dexmedetomidine-induced decreases in CBF are mainly coupled with a reduction in CMRO2 rather than related to direct cerebral vasoconstrictive actions (45). In animal models of drug-induced epilepsy, pro- and anticonvulsant effects of α 2-agonists have been reported. This is in contrast to findings in humans where no proconvulsant activity has been identified. Although dexmedetomidine did not reduce epileptiform discharges in one study of adult patients with epilepsy (46), there are no reports of dexmedetomidine-induced seizures in humans. Unlike other sedative drugs, dexmedetomidine does not adversely affect the recording of sensory and motor evoked potentials (47).
Comparison with other sedative agents In a pilot study, dexmedetomidine and propofol were equally effective for sedation in brain-injured patients and neither was associated with adverse cerebral physiological effects as assessed by multimodal monitoring (48). The potential for dexmedetomidine to prevent or treat delirium has been extensively studied in general ICU patients. A recent metaanalysis demonstrated that the incidence of delirium is not significantly different with dexmedetomidine compared to other sedative drugs (49). However, dexmedetomidine appears to preserve cognitive function, with specific preservation of focus and attention, in comparison to propofol (50). Data relating to the effect of dexmedetomidine on the duration of mechanical ventilation and ICU LOS are controversial, and there are none specific to critically ill neurological patients. After cardiac surgery, dexmedetomidine infusion (0.4 mcg/kg/h during the procedure and 0.2 mcg/kg/h in the ICU) reduced the time to extubation and ICU LOS (51). In a study comparing dexmedetomidine to haloperidol in agitated mechanically ventilated general ICU patients, those receiving dexmedetomidine were also extubated earlier (52). However, in a retrospective analysis comparing two doses of dexmedetomidine with propofol in trauma patients, those in the higher-dose dexmedetomidine group (> 0.7 mcg/kg/h) had higher rates of hypotension, longer duration of mechanical ventilation, and longer ICU and hospital LOS (53). There are no data on neurological outcome and mortality in patients sedated with α 2-agonists. Although α2-agonists, particularly dexmedetomidine, are promising sedative agents in neurological patients, further studies are needed to identify their exact role and utility in the management of sedation in the NCCU.
Side effects The haemodynamic effects of clonidine and dexmedetomidine are well described. An initial phase of hypertension is often seen, but the major side effects are (mild) hypotension and bradycardia. This has led to some controversy regarding the ideal loading dose and maximum infusion rate of dexmedetomidine. Typically a bolus of 1 mcg/kg is administered, followed by a 0.2–0.7 mcg/kg/h continuous intravenous infusion. As there appears to be a link between cardiovascular side effects and loading dose, some clinicians prefer to omit this and start with an infusion. Apart from these cardiovascular effects, no other relevant side effects of α 2-agonists have been described. In contrast to other commonly used sedative and analgesic agents, they do not cause respiratory depression.
Etomidate Etomidate has a rapid-onset effect and short duration of action, and has historically been used as part of a rapidsequence induction technique. It reduces ICP, CBF, and CMRO 2 (54,55) and, although it may cause hypotension and reduce CPP (55), etomidate is less hypotensive than barbiturates or propofol during induction of anaesthesia. However, it has potentially serious side effects, specifically acute adrenal insufficiency, and is therefore not recommended as the first choice for rapid sequence induction in the NCCU. Further, it does not adequately control the hypertensive (and therefore ICP) response to laryngoscopy, and propofol or barbiturates are preferable induction agents in cases of suspected or confirmed intracranial hypertension, providing blood pressure is maintained.
Side effects Etomidate increases the susceptibility to pneumonia in trauma patients (56) and is associated with increased acute adrenal insufficiency and higher mortality (57). Adrenal suppression can occur after only a single 0.3 mg/kg dose of etomidate (58). These effects are potentiated by severe sepsis (57,59).
Antipsychotic drugs for agitation Agitation and delirium are everyday challenges in the NCCU, but the distinction between agitation and delirium is often difficult. Agitation may be related to an underlying brain injury, while delirium is primarily related to the consequence of prolonged sedation and ICU interventions. Although therapeutic strategies differ, both agitation and delirium often require administration of antipsychotic agents. Haloperidol, a dopamine agonist of the typical class of antipsychotics, is the standard of care for treatment of agitation and delirium (60). However, it may cause prolongation of the QT interval and lead to the development of torsades de pointes. Atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are enteral agents acting on dopaminergic and serotonergic systems that have recently been introduced into the NCCU as alternatives to haloperidol. Although none of these drugs is licensed for use in agitated ICU patients, several studies have found that atypical antipsychotics have acceptable safety profiles (61,62,63). However, caution should be exercised during prolonged utilization of these agents given the FDA warning regarding mortality when they are used to treat agitation in elderly patients with dementia (64). Antipsychotic agents may also lower the seizure threshold and induce or increase the risk of epileptic activity.
Cerebral haemodynamic actions There are few data on the effects of antipsychotics on cerebral haemodynamics. Studies have typically been carried out in patients with schizophrenia, and are predominantly limited to haloperidol and risperidone. Haloperidol increases global (65) and regional (66) CBF compared to risperidone, but whether these differences are clinically relevant, or translate into effects on ICP, is unclear. In general, antipsychotics decrease the severity of symptoms of agitation by 43–70%, and 50–100% of patients respond to such treatment (67). Whether this is also the case in critically ill neurological patients is unknown. Quetiapine resolves several symptoms of ICU-related delirium more rapidly than placebo (61), but in a study in general ICU patients there was no difference in clinical improvement between olanzapine and haloperidol (63). There are no data comparing any of these drugs in the NCCU, and no studies have examined the effect of the treatment of delirium with antipsychotic agents on outcome.
Alternative drugs to treat agitation Potential alternatives to antipsychotic drugs warrant mention. As dysfunction of cholinergic transmission is one of the hypothetical causes of agitation, cholinesterase inhibitors such as rivastigmine may be a potential treatment option. However, a recent randomized controlled trial exploring the utility of rivastigmine as an adjunct to haloperidol was stopped prematurely because of an increased mortality in the rivastigmine group (68). Benzodiazepines have historically been used to treat agitation but, apart from their use in alcohol withdrawal-related delirium where they are clearly indicated (12), data suggest that they actually increase the risk of delirium and should be avoided (19). Alpha-2 agonists have also been used to treat agitation in the ICU, and clonidine can be particularly useful in patients with symptoms of benzodiazepine or alcohol withdrawal.
Side effects Haloperidol, risperidone, olanzapine, and quetiapine are all weak α-antagonists and hence peripheral vasodilators. Blood pressure changes are generally mild but profound hypotension following a single dose has been reported (69). The main concerns are prolongation of the QT interval and risk of development of torsades de pointes, and reduction in the seizure threshold. This is less pronounced in the more potent typical antipsychotics, so haloperidol has the least marked effect on seizure threshold. Atypical antipsychotics have a better safety profile in this regard. All antipsychotic agents might cause dyskinesia. Typical antipsychotics are contraindicated in Parkinson’s disease. Despite atypical antipsychotics also having dopamine antagonist actions, they have been used safely in patients with Parkinson’s disease, and olanzapine is recommended (70). The neuroleptic malignant syndrome is a rare but serious adverse reaction to antipsychotic drugs and has been associated with therapeutic doses of typical and atypical antipsychotics (71). The essential features of neuroleptic malignant syndrome are muscle rigidity and hyperpyrexia that may be associated, autonomic instability, mental state changes, and muscle catabolism. The suspected mechanism is dopaminergic blockade-related muscle rigidity that contributes to impaired heat dissipation and hyperthermia. Therapy is mostly symptomatic but intravenous dantrolene has been used successfully.
Comparative studies of sedative agents Three randomized controlled trials have compared maintenance doses of propofol (1.5–5 mg/kg/h) with midazolam (0.1–0.3 mg/kg/h) and found no difference in ICP control (11,15,16). In two of these, there was also no difference in ICU LOS or quality of sedation between propofol and midazolam (11,16). However, there was a higher rate of therapeutic failure with propofol when sedation was continued for more than 2 days (6–9 days), characterized by elevated triglyceride levels and the need for high doses greater than 6 mg/kg/h (11). Weaning and extubation occur earlier with propofol compared to midazolam (6,72) but, in the context of nurse-led, protocol-directed sedation, propofol and midazolam provide similar quality of sedation (73). A systematic review including 13 studies in 384 patients with TBI concluded that propofol and midazolam sedation have comparable effects on mortality, duration of mechanical ventilation, ICU LOS, and quality and depth of sedation (74). Of note, no data are available comparing propofol to midazolam for other types of brain injury. In a study comparing propofol with morphine, less adjunctive ICP therapy but increased vasopressor use was required in the propofol group (41). There are limited data comparing propofol with barbiturates during neurocritical care. In a small trial of ten patients with TBI, propofol was equally effective at controlling ICP when compared to fentanyl (75) or pentobarbital plus morphine (3). Two studies suggest that remifentanil might reduce the duration of mechanical ventilation compared to morphine (76) or fentanyl (77) in NCCU patients. In conclusion, propofol and midazolam are used interchangeably as first-line sedative agents after ABI, and there is no evidence that one is superior to the other. Practice varies between clinicians and countries, and is likely driven by individual clinician experience and cost. When choosing a sedative agent in brain-injured patients, some practical issues must be kept in mind:
◆ Propofol and midazolam are equally effective in controlling ICP. ◆ Sedative agents may cause hypotension and a reduction in CPP-maintenance of normovolaemia and MAP is essential.
◆ ICP control with midazolam may require increasingly high doses because of tachyphylaxis, with ensuing prolonged duration of coma, mechanical ventilation, and ICU LOS. ◆ Despite its ICP-lowering actions, propofol (particularly at high doses) may not guarantee an adequate CPP because of associated hypotension. ◆ Propofol is more costly than midazolam. Top Previous Next
Adjunct agents Several adjunct agents have been described in the management of sedation on the NCCU.
Ketamine Ketamine is an NMDA antagonist that is categorized as a dissociative agent because it causes brain functional and electrophysiological dissociation rather than true sedation. It creates a trance-like cataleptic state resulting in profound analgesia and amnesia, with retention of protective airway reflexes and maintenance of spontaneous respiration and cardiopulmonary stability. Ketamine is marketed as a racemic mixture but also as the (S)-ketamine form which has a threefold superior analgesic and anaesthetic potency but comparable pharmacokinetics to (R)-ketamine. It has been used as an adjunct to other sedative drugs in the NCCU.
Cerebral haemodynamic actions Early work found that ketamine has stimulating properties on the brain leading to an increase in CBF, CBV, CMRO 2, and ICP. However, more recent studies examining ketamine as an adjunct to other sedatives or analgesic drugs found no significant negative effects on ICP or cerebral haemodynamics (78,79). Given its effect at the NMDA receptor, ketamine is used as an adjunct in chronic pain management and after painful surgery (e.g. complex spine surgery with instrumentation), as well as for the management of refractory status epilepticus (see Chapter 23) (80).
Side effects The main side effects of ketamine, particularly when large doses are used, are neuropsychiatric, including hallucinations, unpleasant dreams, dysphoria, blurred vision, nystagmus, and diplopia. However, when ketamine is used in combination with midazolam or propofol these side effects are rare. Hypersalivation is a further unwanted effect. The bronchodilator activity of ketamine may be beneficial, although there is considerable tachyphylaxis when ketamine is used as a continuous infusion for the treatment of severe bronchospasm.
Inhaled anaesthetic agents Until recently, inhaled anaesthetics were only exceptionally used for sedation in the ICU because of difficulty in their delivery. The introduction of the AnaConDa™ device has allowed administration of isoflurane and sevoflurane via a syringe pump, that is, not via a vaporizer, allowing compatibility with ICU ventilators (81). Although environmental contamination with volatile anaesthetics is a concern with the AnaConDa™ device, in practice the measured atmospheric concentrations are very low (82). There is therefore increasing interest in the use of these drugs in the NCCU (see below) (83).
Cerebral effects Inhaled anaesthetics produce a dose-related suppression of cerebral electrical activity and cerebral metabolism leading to a secondary reduction in CBF because of preserved flow–metabolism coupling. However, all inhaled anaesthetics also have a dose-dependent direct cerebral vasodilator action that increases CBF, CBV and therefore ICP at higher doses (> 1 minimal alveolar concentration (MAC)). The net effect results from the balance between these two mechanisms, with a decrease in CBF at low inspired concentrations and an increase in CBF and CBV at higher concentrations. Sevoflurane is the inhaled anaesthetic with the least vasodilator properties and, at concentrations below 1 MAC, has almost no effect on CBV and CBF. Although sevoflurane has not been shown to increase ICP, most studies have been performed in patients with preserved intracranial compensatory reserve, that is, normal brain compliance. In
patients with decreased intracranial compliance, the effects of inhaled anaesthetics on ICP may be different and there is a risk that they may precipitate intracranial hypertension at higher doses. However, the inspired concentrations used for sedation in the ICU are typically lower than those used intraoperatively, so these effects are possibly less likely (84). Inhaled anaesthetics also have a dose-dependent depressive effect on cerebral autoregulation. Low-dose isoflurane (0.5 MAC) delays but does not reduce the autoregulatory response, whereas higher concentrations (1.5 MAC) significantly impair cerebral autoregulation. Sevoflurane is generally reported to have minimal impact on cerebral autoregulation at concentrations less than 1.5 MAC, although some studies demonstrate a deterioration of dynamic autoregulation (85). Carbon dioxide reactivity is preserved with inhaled anaesthetics in the normal brain, and at clinically used concentrations (84). All volatile anaesthetics suppress cerebral electrical activity and hence cerebral metabolism in a dose-related but nonlinear manner. One MAC of sevoflurane reduces CMRO2 by 47–74% and the cerebral metabolic rate for glucose by about 40%. Volatile agents also influence EEG activity in a dose-related manner, with agent-specific effects. Sevoflurane and isoflurane have similar EEG effects and MAC equivalent administration is associated with equipotent EEG suppression. With increasing concentrations the EEG evolves from a low-voltage, fast-wave to a high-voltage, slow-wave pattern, and finally to burst suppression. There are however concerns regarding epileptogenic effects of sevoflurane at higher concentrations (> 1.5 MAC) (86).
Comparative studies There are limited data on the use of volatile anaesthetics in the NCCU. In a small group of patients suffering from ischaemic stroke and intracranial haemorrhage it was possible to maintain therapeutic sedation levels with isoflurane for an average of 3.5 days without clinically relevant increases in ICP in patients in whom baseline ICP was low or only moderately elevated (87). However, a decrease in MAP and CPP was reported in this study. In a recent crossover trial in 13 patients with aneurysmal subarachnoid haemorrhage, regional CBF was almost doubled (from about 20 to about 40 mL/100 g/min) with 0.8% isoflurane sedation compared to propofol, but there were no significant difference in ICP and CPP (88). Whether volatile anaesthetics allow more rapid weaning from mechanical ventilation or faster awakening when compared to intravenous sedation is controversial (84,89), and most studies have investigated only short-term sedation. Furthermore, concerns regarding neurotoxicity advise caution for their use in the NCCU.
Side effects All inhaled anaesthetics have similar depressive effects on the cardiovascular system. Cardiac index declines, systemic vascular resistance decreases, and heart rate increases in a dose-dependent manner. Sevoflurane is better at preserving myocardial function than propofol and, in patients without cardiovascular disease, is superior to propofol in preserving left ventricular relaxation and maintaining targeted CPP. Inhaled anaesthetics may trigger malignant hyperthermia. Inhaled anaesthetics have both protective (90) and toxic effects (91) on the central nervous system mediated by different mechanisms that are dependent on exposure time and concentration. Almost all data on neurotoxicity are based on in vitro or animal models and it is often difficult to compare studies because of the different models, methods, and outcomes. There are no clinical data currently available that allow definitive conclusions to be drawn on the important topic of neurotoxicity.
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Monitoring sedation Sedatives may obscure or prevent neurological examination and can prolong the length of mechanical ventilation and ICU LOS. A recent review of sedation assessment tools in the NCCU concluded that the Sedation Analgesia Scale (SAS) and the Richmond Agitation Sedation Scale (RASS) are valid and useful (92,93,94).
Bispectral index monitoring The bispectral index (BIS) was developed for monitoring the depth of general anaesthesia in patients without brain pathology. Intracranial pathology may influence the BIS algorithm because of EEG changes related to the pathology itself rather than to the sedative state so its role in sedation monitoring in the NCCU is not defined. In a randomized clinical trial of 67 patients, BIS in addition to subjective scale clinical assessment reduced the amount of propofol sedation and the time to awakening compared to routine clinical sedation monitoring alone (95). However, three other studies did not confirm these findings, demonstrating only a weak relationship between BIS and level of consciousness in general ICU patients (96,97,98). Given the available data, BIS monitoring cannot currently be recommended for monitoring depth of sedation in the NCCU. However, in critically ill brain-injured patients BIS may be a potential alternative to standard EEG for monitoring the induction and maintenance of burst suppression in patients treated with barbiturate coma for refractory intracranial hypertension (99,100).
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Sedation holds Studies conducted in the early 2000s demonstrated that daily interruption of sedation and awakening (sedation hold) reduces the duration of mechanical ventilation and LOS in general ICU patients (1,101). These studies focused attention on the importance of strict sedation management in the ICU and led to the widespread introduction of protocolized sedation management strategies which have subsequently been shown to be more important in modulating outcome than sedation holds. In one study, the addition of daily sedation holds to a sedation protocol tool using validated sedation and analgesia scores did not provide additional benefits in terms of duration of mechanical ventilation or ICU LOS (102). Daily sedation holds might be appropriate in NCCU patients to allow neurological assessment, as well as for their general benefits of reducing duration of mechanical ventilation and the need for tracheostomy. However, these potential benefits are counter-balanced by the deleterious effects of sedation holds on cerebral haemodynamics, particularly in the early stages after brain injury. Interruption of sedation has been associated with increases in ICP and reductions in CPP (103). While there was a large variability in the ICP response to sedation hold in this study, it rose to dangerous levels (> 40 mmHg) in some patients with concomitant reductions in CPP. ICP elevations were greatest in the first few days after ABI, and sedation withdrawal after 4–5 days had modest ICP effects. Sedation holds are associated with increases in the level of several stress hormones such as cortisol and catecholamines (104). Helbok and colleagues showed that 34% of sedation interruption trials had to be aborted because of a significant increase in ICP and associated reduction in CPP, and 20% were associated with a significant decrease in brain tissue PO2 below the critical thresholds of cerebral hypoxia (105). In addition, new neurological deficits were observed in a small minority of wake-up tests in this study. Another important role of sedation after ABI is the prevention of shivering during targeted temperature management (106). In this setting, interruption of sedation must be postponed until normothermia is restored. In conclusion, daily interruption and weaning of sedation should be considered in all patients on the NCCU but only when ICP and brain tissue PO2 are no longer therapeutic targets, or when cerebral physiology has normalized. This is generally after 5–7 days.
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A practical approach to sedation management The application of a structured approach to sedation management, including the use of guidelines, protocols, and algorithms, reduces the likelihood of excessive and/or prolonged sedation. Many sedation protocols have been tested in clinical trials and are associated with shorter duration of mechanical ventilation, reduced ICU LOS, and superior sedation management compared to non-protocolized care (107). The advantages and disadvantages of different sedative agents are shown in Table6.2. Practical algorithms for sedation and analgesia management in patients with ABI are illustrated in Figures 6.1 and 6.2.
Table 6.2 Advantages and disadvantages of commonly used sedatives and analgesics in the neurocritical care unit
Propofol
Advantages
Disadvantages
Rapid onset and short duration of action Clearance independent of renal or hepatic function No significant drug interactions
No amnesia, especially at low doses No analgesic effect ↓ MAP, ↓ CPP (particularly in hypovolaemic patients) ↑ Triglycerides Propofol-infusion syndrome (↓ HR, ↑ pH, ↑ lactate, ↑ CK, myocardial failure)
Midazolam
Amnesia and analgesia Rapid onset of effect in acutely agitated
patient
Haemodynamic stability (may prevent CPP reductions)
Barbiturates
Morphine
By ↓↓ CBF and CBV, barbiturates have a strong effect on ↓↓ ICP Indications of barbiturates are limited to the treatment of refractory ICP, titrated to the lowest effective dose. EEG may help with the titration of barbiturate therapy Low cost In relay of long-term infusions of sedation/analgesia
Fentanyl and sufentanil
More potent opioids than morphine
Remifentanil
More potent opioid than morphine Rapid onset and short duration of action to permit neurological assessment Clearance independent of renal or hepatic function
Tolerance and tachyphylaxis Hepatic metabolism to active metabolite May accumulate in renal dysfunction May prolong the duration of MV May increase ICU delirium Hypotension, ↓↓ MAP/CPP Immune suppression, ↑ risk of infections (pneumonia) Adrenal dysfunction
Low predictability to control ICP Histamine release Accumulation with hepatic/renal impairment Accumulation with hepatic impairment May prolong the duration of MV Hyperalgesia at the cessation of drug infusion Limited effect to control ICP during painful procedures Tachyphylaxis High cost
Dexmedetomidine
Advantages
Disadvantages
Sedative, analgesic, and anxiolytic Short acting, no accumulation, patient may be frequently assessed neurologically Minimal respiratory depression May reduce incidence/severity of delirium
Limited clinical experience in the NCCU In non-neurointensive care population: Hypotension, bradycardia Arrhythmias including atrial fibrillation Hyperglycaemia May require high doses; deep sedation may not be possible High cost
Ketamine
Short acting, rapid onset of action Induces sedation, analgesia, and anaesthesia No respiratory depression Haemodynamic stability, preserves MAP May be used as an adjunct for refractory seizures No withdrawal symptoms
Hallucinations and emergence phenomena
CK, creatine kinase; CPP, cerebral perfusion pressure; HR, heart rate; ICP, intracranial pressure; MAP, mean arterial pressure; MV, mechanical ventilation.
Click to view larger Download figure as PowerPoint slide Fig. 6.1. Suggested algorithm for managing sedation in the neurocritical care unit. CBF, cerebral blood flow; EEG, electroencephalogram. Reproduced with permission from G. Citerio.
Click to view larger Download figure as PowerPoint slide Fig. 6.2. Suggested algorithm for targeting sedation to intracranial pressure. ICP, intracranial pressure; PbO2, brain tissue oxygen tension. Reproduced with permission from G. Citerio. The following is a recommended approach to sedation and analgesia management on the NCCU: 1. 2.
1. Critically ill brain-injured patients require sedation and analgesia in the acute phase. 2. When choosing a sedative it is preferable to use an agent with a short half-life, such as propofol, sufentanil/remifentanil, administered by continuous infusions, with the avoidance of bolus administration. 3. 3. Sedation should be titrated to the desired effect (e.g. ICP control) using the lowest dose in order to avoid unwanted effects, particularly hypotension. 4. 4. When cerebral physiology has stabilized, and there is no further risk of elevated ICP or reduction of CPP or brain tissue PO2, daily sedation holds should be instituted and consideration given to reducing or stopping sedation.
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Intracranial hypertension Chapter: Intracranial hypertension Author(s): Andrea Lavinio DOI: 10.1093/med/9780198739555.003.0007 Raised intracranial pressure (ICP), or intracranial hypertension, may occur as the consequence of numerous conditions including traumatic brain injury (TBI), subarachnoid haemorrhage (SAH), intracerebral haemorrhage (ICH), brain tumours, and hydrocephalus. Elevated ICP can precipitate cerebral hypoperfusion and herniation, resulting in secondary brain injury and death. This chapter will review the underlying pathophysiology of intracranial hypertension and outline a rational approach to its treatment.
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Pathophysiology
ICP is the pressure inside the skull and thus in the brain tissue, and is synonymous with the cerebrospinal fluid (CSF) pressure in the lateral ventricles. Normal ICP varies with age and body position. In healthy, resting supine adults, normal mean ICP is lower than 10 mmHg (1). In the presence of intracranial space-occupying lesions or cerebral oedema, a finite amount of CSF and venous blood can be displaced from the intracranial compartment into the extracranial subarachnoid space to maintain a constant ICP. When this compensatory reserve becomes exhausted, further volume increments in one of the intracranial contents lead to intracranial hypertension. The relationship between the relative volumes of the intracranial constituents and ICP is described by the Monro–Kellie doctrine and this is discussed in detail in Chapter 9. The pathophysiology of intracranial hypertension is summarized in Table 7.1. Table 7.1 The pathophysiology of intracranial hypertension. The incompressible contents of the cranial cavity—brain, blood, and cerebrospinal fluid (CSF)—are bounded by a rigid skull with a fixed capacity. Unless the volume of one of the other constituents is displaced out of the cranium, an increase in volume of CSF, cerebral blood volume or brain parenchyma, or the presence of a space-occupying lesion will result in raised intracranial pressure. This table provides an overview of its pathogenesis of intracranial hypertension. The classification is arbitrary and artificial as, in many instances, different mechanisms coexist and contribute synchronously or in a sequential manner to the development of intracranial hypertension. For example, vasogenic and cytotoxic oedema coexist in traumatic brain injury and ischaemic stroke, and obstructive hydrocephalus complicates subarachnoid haemorrhage
Pathogenesis
Subtype
Mechanism
CSF dynamics
Obstructive hydrocephalus
Impaired CSF outflow
Examples
Cerebral oedema
Aqueduct stenosis (congenital or acquired) Intraventricular haemorrhage
Communicating hydrocephalus
Impaired CSF absorption at the arachnoid granulation
Post-traumatic hydrocephalus Post-infective hydrocephalus
Excess CSF production
Tumours of the choroid plexus
Ependymoma
Cytotoxic oedema
Cellular swelling due to ischaemic energy depletion and rise in intracellular Na and water +
Ischaemic stroke Hypoxia Trauma Acute liver failure
Vasogenic oedema
Expansion of the extracellular compartment due to increased permeability of the blood– brain barrier
Malignancy High-altitude cerebral oedema Inflammatory/infective malignant hypertension
Osmotic oedema
Rapid reduction in plasma osmolarity resulting in a reversal of the brain– plasma water gradient
Dialysis disequilibrium syndrome Acute hyponatraemia (SIADH)
Interstitial oedema
Increased CSF pressure results in permeation of
Obstructive hydrocephalus with periventricular ‘lucency’
Pathogenesis
Subtype
Mechanism
Examples
CSF in the adjacent brain Cerebrovascular
Space-occupying lesions
Subarachnoid haemorrhage
Hyperacute increase in CSF pressure due to free communication between arterial blood and subarachnoid space
Ruptured cerebral aneurysm
Cerebral venous sinus thrombosis
Impaired cerebral venous outflow
Cerebral venous sinus stenosis
Impaired cerebral venous outflow
Idiopathic intracranial hypertension
Increased central venous pressure
Impaired cerebral venous outflow
Superior vena cava syndrome Jugular vein thrombosis
Thrombophilia Meningitis Homocystinuria
Haematomas (extradural, subdural, intraparenchymal) Tumours Abscess Foreign bodies
The largest body of clinical evidence relating to ICP and its management comes from severe TBI. ICP in excess of 20–25 mmHg is associated with poor functional outcome and death after TBI in a time-dependent fashion (2). For this reason, ICP thresholds of 20 and 25 mmHg have pragmatically been adopted to define intracranial hypertension in adults, and to trigger the administration of ICP-lowering therapies. Thresholds vary in the paediatric population in which it is recommended that treatment should be initiated when ICP exceeds 15 mmHg in infants, 18 mmHg in children up to 8 year of age, and 20 mm Hg in older children and teenagers (3). Following severe TBI, intracranial hypertension can develop immediately or over a period of hours and days. Although the majority of patients suffer maximum ICP elevation in the first 3 days post injury, around one-quarter develop profound intracranial hypertension after the fifth day (4). Aside from large haemorrhagic contusions and haematomas amenable to surgical evacuation, the main cause of sustained intracranial hypertension after severe TBI is cytotoxic brain oedema, that is, intracellular fluid accumulation (mostly into astrocytes) because of the failure of ion pumps and osmotic disturbances. This is followed by a period of vasogenic brain oedema related to disruption of the blood–brain barrier (BBB) and extracellular fluid extravasation (5). Thrombosis of the cerebral venous sinuses is a relatively rare but potentially treatable cause of delayed intracranial hypertension following severe TBI (6). The contribution of intracranial hypertension to secondary brain injury and poor functional outcome is not restricted to TBI. Large ICH compounded by perihematomal oedema (7,8) is also associated with intracranial hypertensive crises requiring ICP-lowering treatments and consideration of surgical decompression. The rupture of a cerebral arterial aneurysm into the subarachnoid space during SAH results in a hyperacute increase in ICP to values close to that of mean arterial blood pressure (MAP) leading to global cerebral ischaemia and, in severe cases, transitory cerebral circulatory arrest (9). This can result in significant irreversible neurological damage and is frequently accompanied by
a transitory Cushing response with associated neurogenic cardiomyopathy and pulmonary oedema (see Chapter 27) (10). Intraventricular blood can lead to acute obstructive hydrocephalus and increased ICP requiring immediate ventricular drainage (11). The general pathophysiology and treatment of intracranial hypertension is best considered by differentiating the effects of elevated ICP on cerebral haemodynamics from the mechanical effects on brain parenchyma, that is, between intracranial hypertension-related cerebral hypoperfusion and herniation. The disease-specific aspects of intracranial hypertension are discussed in the relevant chapters elsewhere in this book.
Intracranial hypertension as a cause of cerebral hypoperfusion Bridging veins in the subdural and subarachnoid spaces drain venous blood from the cerebral cortex into venous sinuses. When ICP exceeds venous pressure, these bridging veins collapse thereby reducing cerebral venous outflow and hence cerebral perfusion. Abnormally elevated ICP can therefore result in inadequate cerebral perfusion even in the presence of normal systemic blood pressure. Cerebral circulatory arrest occurs when ICP approaches MAP and cerebral perfusion pressure (CPP) approaches zero.
Intracranial hypertension as a cause of cerebral herniation Elevated ICP can also cause death and disability because of the development of pressure gradients across dural folds or the foramen magnum. When space-occupying lesions or brain oedema obliterate the subarachnoid space and impede free circulation of CSF, intracranial hypertension and the development of intracranial or craniospinal pressure gradients may lead to herniation of the brain across the falx cerebri (subfalcine herniation), the tentorium cerebelli (ascending and descending transtentorial herniation), and foramen magnum (tonsillar herniation) as shown in Figure 7.1. Herniation syndromes result in catastrophic focal necrosis from direct mechanical injury and vascular compression, and lead to potentially lethal ischaemic brain damage, including brain death (12).
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Download figure as PowerPoint slide Fig. 7.1. Cranial imaging showing brain herniation states 1.
1.Subfalcine (cingulate) herniation—is the most common herniation state. Compression of the pericallosal arteries (arrowheads) may result in infarction of the distal anterior cerebral artery territory. 2. 2.Transtentorial (uncal) herniation—the temporal lobe herniates downwardly across the tentorium cerebelli, compressing the midbrain and pons (leading to Duret’s haemorrhage), the III cranial nerve (causing ipsilateral fixed mydriasis), the posterior cerebral artery causing (ipsilateral occipital and thalamic infarction), and the aqueduct (causing obstructive hydrocephalus). 3. 3.Transforaminal (tonsillar) herniation—herniation of the cerebellar tonsils through the foramen magnum compresses the medulla oblongata (causing respiratory arrest and haemodynamic instability) and the posterior inferior cerebellar arteries (causing brainstem and upper cervical spinal cord infarction). 4. 4.Transcalvarial herniation—herniation through a craniectomy defect may lead to compression of cortical vessels and result in ischaemic necrosis of the portion of the herniated brain.
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Principles of treatment ICP-lowering treatments are aimed at maintaining adequate cerebral perfusion and preventing cerebral herniation. Mortality is dramatically increased in severely brain-injured patients that do not respond to ICP-reducing therapy. The odds ratio for death in ICP unresponsive patients is 114 (95% confidence interval 40.5–322.3) compared to those in whom ICP is responsive (13). While ICP control is a cornerstone of neurocritical care, it is important to note that treatment itself is not devoid of potentially serious adverse effects and that ICP greater than 25 mmHg doesn’t (in isolation) always warrant treatment (14). The decision to initiate ICP lowering therapy should be determined for each patient individually after consideration of three factors: 1.
1. The pathophysiological burden of the intracranial hypertension, that is, its duration, magnitude, and clinical context. 2. 2. The risk–benefit ratio of potential treatment options. 3. 3. The reliability of the ICP monitoring device, that is, exclusion of artefactual elevations of ICP.
Pathophysiological burden of intracranial hypertension The pathophysiological burden of intracranial hypertension is context sensitive, and ICP elevations that require aggressive treatment in the acute phase after TBI may be tolerated when physiological compensatory mechanisms are preserved. Clinical experience acquired during CSF infusion studies in patients with hydrocephalus provides an illuminating example. In such diagnostic studies an isotonic solution is infused at a constant rate into the cerebral ventricles or lumbar subarachnoid space of awake, self-ventilating patients. CSF pressure is continuously monitored and an estimate of CSF dynamics obtained by analysis of the CSF pressure waveforms. During the infusion ICP can exceed 40 mmHg for several minutes with negligible effects on cerebral blood flow (CBF) and no neurological symptoms (15). These very same levels of ICP are strongly associated with death and disability following severe TBI. The explanation for this differential response lies in the presence (in the case of hydrocephalic patients undergoing infusion studies) or absence (in the case of severe TBI) of two key compensatory mechanisms—free circulation of CSF and cerebral pressure autoregulation (16). Circulation of CSF between intracranial and spinal subarachnoid spaces neutralizes regional pressure gradients and nullifies the risk of cerebral herniation irrespective of absolute ICP. At the same time, pressure-flow autoregulation maintains CBF over a wide range of CPP. It would therefore seem reasonable to assume that TBI patients with open basal cisterns and preserved pressure autoregulation may tolerate ICP exceeding the 20–25 mmHg thresholds without negative consequences. This is clinically relevant during shortlived ICP spikes caused by coughing and desynchronization from mechanical ventilation during sedation holds in the subacute phase after severe TBI. In this case, the ICP spikes are probably similar to those experienced by healthy subjects during a Valsalva manoeuvre (17). Thus, in the presence of radiological appearances suggestive of preserved intracranial volume-buffering reserve (i.e. open basal cisterns, normal appearances of ventricles, and cortical sulci), short-lived episodes of ICP exceeding the 25 mmHg threshold should not necessarily prompt immediate ICP-lowering treatment. In this situation, re-establishing sedation is likely to result in unnecessarily prolonged duration
of sedation and mechanical ventilation whilst providing no benefit to the injured brain. At the opposite end of the spectrum are patients with large space-occupying lesions or severe cerebral oedema resulting in compressed cortical sulci and basal cisterns, and midline shift. These radiological features suggest that CSF pathways are obliterated and that there is a high risk for the development of intracranial pressure gradients and cerebral herniation. In this context, intracranial hypertension can be rapidly fatal and ICP should be aggressively controlled. Further, ICP-lowering treatments should only be de-escalated after careful review of clinical status and other brain monitoring variables in patients with radiological evidence of exhausted intracranial volume-buffering reserve. Normal ICP values in the presence of radiological evidence of impending cerebral herniation may be falsely reassuring and should always prompt review for ICP probe malfunction.
Reliability of ICP monitoring techniques Commercially available ICP monitors are robust and provide reliable clinical data, although they are not completely immune to measurement bias. The possibility of over-estimation of ICP should always be considered before applying ICP-lowering treatments with potentially significant side effects, and ICP probe malfunction should be excluded in patients with persistently elevated measured ICP and normal brain radiographic appearances. The reliability of ICP monitoring technologies is discussed in detail in Chapter 9.
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Treatment ICP-lowering strategies have distinct risk–benefit profiles, ranging from relatively safe to extremely dangerous. Relatively safe measures include head-up positioning, sedation, seizure management, and controlled normothermia, whereas hyperventilation, barbiturate-induced burst suppression, therapeutic hypothermia, and surgical decompression are associated with significant complications. ICP-lowering therapies should be administered in a stepwise fashion, starting with first-line, safe interventions (Figure 7.2). Higher-risk treatment options should be reserved for patients at immediate risk of cerebral herniation or those with multimodality brain monitoring evidence of critically reduced brain tissue oxygenation or cerebral metabolic derangement, such as increased lactate/pyruvate ratio.
Click to view larger Download figure as PowerPoint slide Fig. 7.2. Intracranial management protocol. A rational approach to the treatment of intracranial hypertension consists of a stepwise escalation of ICP-lowering therapies. AED, antiepileptic drugs; CK, creatine kinase; EEG S.R, electroencephalographic suppression ratio; EVD, external ventricular drainage; PbtO2, brain tissue oxygen tension; SjO2, jugular venous oxygen saturation; SOL, spaceoccupying lesion.
Basic measures First-line treatments are directed towards the maintenance of cerebral physiological homeostasis and prompt diagnosis and correction of a remediable underlying intracranial abnormality. Intracranial lesions exerting mass effect
should be evacuated, hydrocephalus drained, and oedema associated with intracranial tumours treated with high-dose steroids (18). ICP-lowering treatments can provide a life-saving bridge to these definitive treatments.
Blood pressure Haemodynamic stability is crucial because of the direct effects of arterial hypotension on CPP and also because an acute reduction in MAP can precipitate intracranial hypertension via the vasodilatory cascade. In patients with decreased intracranial compliance but preserved cerebrovascular reactivity, systemic hypotension is followed by compensatory cerebral vasodilation, increased cerebral blood volume (CBV), a further increase in ICP, and reduction in CPP (19). Further compensatory vasodilation results in sustained ICP plateau waves as intracranial volumebuffering reserve becomes exhausted (Figure 7.3).
Click to view larger Download figure as PowerPoint slide Fig. 7.3. The vasodilatory cascade. The vasodilatory cascade illustrates how a reduction in mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) is followed by cerebral autoregulatory vasodilation and increased cerebral blood volume (CBV). In patients with exhausted intracranial volume-buffering reserve, the increase in CBV results in an increase in ICP. If MAP remains unchanged, CPP will further decrease feeding the vicious cycle until exhaustion of autoregulatory reserve and ICP plateau waves. Note that the cascade may be initiated at different points of the cycle by pathophysiological stimuli causing an increase in ICP, direct cerebral vasodilation, or a reduction in MAP. Conversely, augmentation of MAP can interrupt the vicious cycle and terminate the ICP plateau wave.
CMRO2, cerebral metabolic rate of oxygen. Arterial blood pressure should be maintained within age-appropriate normal values. In young adults, systolic blood pressure should be supported above 100 mmHg (20) whereas in patients with a history of uncontrolled hypertension, in whom the autoregulatory curve is shifted to the right, adequate cerebral perfusion might require significantly higher MAP and CPP targets (21). On the other hand, uncontrolled arterial hypertension can cause or accelerate intracranial haemorrhage and should be avoided, especially in patients with haemorrhagic contusions. Malignant arterial hypertension, defined as MAP exceeding the upper limit of cerebral autoregulation (> 140 mmHg), can cause endothelial dysfunction and cerebral oedema, leading to intracranial hypertension in the absence of haemorrhage. If antihypertensive therapy is required, short-acting agents with no direct cerebral dilatory actions such as labetalol are preferred to vasodilators such as nitrates (22,23).
Airway and ventilation Comatose patients and those unable to protect their airway require prompt endotracheal intubation. Careful administration of opioids, sedatives, and muscle relaxants facilitates laryngoscopy and prevents coughing and increases in ICP during tracheal intubation. Central vasomotor depression should be anticipated and short-acting vasopressors used to treat haemodynamic instability (24). Hypoxaemia defined as PaO2 less than 8.0 kPa (< 60 mmHg) or SpO2 less than 90%, and hypercapnia defined as PaCO2 greater than 6.0 kPa (> 45 mmHg), are major causes of secondary brain injury and should be avoided (20). Their adverse effects are related to the direct detrimental effects of low PaO2 on the injured brain as well as increases in ICP consequent to hypoxic and hypercapnic cerebral vasodilation. There is a strong correlation between hypoxaemia and poor outcome after TBI, and intubation and mechanical ventilation may be required to optimize cerebral physiology even in conscious patients. However, care should be taken to avoid hyperventilation and hypocapnia as the consequent cerebral vasoconstriction and reduced CBF may precipitate or worsen cerebral ischaemia (25). Despite previous enthusiasm for the potential benefits of normobaric hyperoxia, a convincing body of clinical and experimental evidence confirms that it can be detrimental following TBI, stroke, and hypoxic-ischaemic neurological injury (26,27,28). Standard clinical practice is therefore directed towards controlled re-oxygenation (maintaining SpO 2 ≥ 94%). Therapeutic hyperoxia (PaO2 > 300 mmHg) should be restricted to experimental studies.
Fluid resuscitation Fluid resuscitation is directed towards maintenance of euvolaemia and plasma osmolarity. Hypo-osmotic solutions such as 0.45% NaCl or 5% dextrose worsen brain oedema and should be avoided in all patients at risk of intracranial hypertension (29).
Transfusion strategies The precise haemoglobin concentration to optimize oxygen delivery to the injured brain is undefined. While there is widespread consensus in support of restrictive transfusion strategies in critically ill patients without neurological injury, there is a body of evidence suggesting that brain-injured patients are susceptible to anaemia-related secondary brain insults. Cerebral vasodilation proportional to the reduction in blood oxygen content during haemodilution is described in both experimental and clinical studies (30,31), and this can be sufficient to trigger the vasodilatory cascade and precipitate intracranial hypertension. Recent clinical studies suggest that a haemoglobin concentration lower than 9 g/dL is associated with an increased incidence of brain hypoxia and cellular energy dysfunction after SAH, and increased mortality after TBI (32,33). In 67 patients with moderate to severe TBI, a ‘restrictive’ transfusion strategy (haemoglobin 7–9 g/dL) was associated with a non-significant higher mortality (17% versus 13%) compared to a ‘liberal’ strategy (haemoglobin 10–12 g/dL) (34). A haemoglobin target of 9 g/dL or higher seems reasonable in patients with increased ICP, especially if multimodal monitoring confirms cerebral hypoxia and metabolic failure at lower haemoglobin levels.
Seizures Seizures increase cerebral metabolic rate, dramatically increase ICP, and adversely affect outcome (35). They should be treated promptly in all patients but particularly those at risk of intracranial hypertension. Current TBI management guidelines recommend prophylactic anticonvulsants for 7 days post injury in those at high risk of seizure development (20), including patients with a depressed skull fracture, penetrating wound, subdural, epidural, or intraparenchymal
haematomas, cortical contusions, or previous seizures. Phenytoin has historically been used to prevent early posttraumatic seizures after TBI, but it has significant side effects including multiple drug interactions (see Chapter 2). Levetiracetam has equal efficacy and is rapidly becoming the anticonvulsant of choice in many centres although its superiority over phenytoin remains unproven. Levetiracetam has a superior safety profile compared to phenytoin, is available for intravenous administration, and does not require regular measurement of plasma levels because of its wider therapeutic index (36,37). The prophylactic use of anticonvulsants is not recommended after aneurysmal SAH because of the low risk of seizures and high rate of antiepileptic drug-related complications (38,39). Adverse drug effects have been reported in 23% of patients after SAH (40), in which prophylactic phenytoin is independently associated with worse cognitive outcome (41).
Fever management Fever is a frequent event following TBI and SAH and worsens ischaemic neurological damage (42). Current consensus supports controlled normothermia to maintain core temperature around 36.5°C in critically ill neurological patients (43,44). Paracetamol is used widely. Non-steroidal anti-inflammatory drugs also effectively reduce body temperature (by ~ 0.6°C) but should be used with caution because of the increased risk of bleeding. Automated noninvasive cooling devices are effective and should be utilized as part of a multimodal approach for the maintenance of normothermia in patients with TBI (45,46,47).
Head elevation Brain-injured patients are traditionally nursed with the head of the bed elevated to 30°. This lowers ICP by a hydrostatic effect and improved jugular venous drainage. Head elevation is also associated with a similar hydrostatic reduction in carotid blood pressure but without significant changes in CPP or CBF (48). In hypovolaemic patients, head elevation can result in a significant reduction in venous return, and subsequent reduction in MAP, CPP, and CBF, but systemic hypotension can be prevented by adequate fluid resuscitation and judicious use of vasopressors. Special care must be taken when positioning the arterial pressure transducer in semi-recumbent patients. The definition of CPP as the difference between MAP and ICP relies on blood pressure measured at the level of the brain, that is, with the transducer sited and ‘zeroed’ at the level external acoustic meatus. If the transducer is positioned at the level of the heart, as is common practice in general intensive care units, calculated ‘CPP’ overestimates actual CPP by approximately 10 mmHg in the 30° head-up position (49). Thus, the blood pressure transducer should always be sited at the level of the external acoustic meatus in critically ill brain-injured patients.
Sedation and analgesia Sedation and analgesia are required to provide endotracheal tube tolerance and facilitate mechanical ventilation. In addition, sedation is used to reduce cerebral metabolic rate, lower ICP, and control seizures after TBI (24). Appropriate levels of sedation and analgesia are therefore key components of the management of patients at risk of intracranial hypertension. Muscle relaxants should be restricted to patients who require escalation of treatment of intracranial hypertension (50). There is limited evidence to guide the choice of sedative agent in patients with ABI, with each agent having specific advantages and disadvantages (see Chapter 6) (51). Propofol and midazolam are the most commonly used sedatives in clinical practice, with barbiturates reserved for management of ultra-refractory intracranial hypertension (Figure 7.2) (52).
Propofol Propofol is a gamma-aminobutyric acid type A (GABAA) receptor agonist with rapid onset and offset of action. Its context-sensitive half-life compares favourably with other commonly used sedatives, allowing rapid wake-up and reliable neurological examination even after prolonged infusion (53). Compared to midazolam, propofol provides improved quality of sedation and a faster recovery of consciousness, making it the preferred sedative for haemodynamically stable neurological patients (54). It reduces ICP and cerebral metabolic rate, and can maintain electroencephalographic (EEG) burst suppression without affecting cerebrovascular CO 2 reactivity or pressure autoregulation (55,56). Propofol reduces MAP in a dose-dependent manner through centrally mediated suppression of sympathetic tone and it is therefore relatively contraindicated in haemodynamically unstable patients (57). Prolonged
infusion at doses exceeding 4 mg/kg/h can be associated with the relatively rare but sometimes fatal propofol infusion syndrome (see Chapter 6) (58,59), which is particularly common in brain-injured patients (60). Sedation can be guided by monitoring the EEG suppression ratio (SR), although any potential benefits of propofol sedation targeted to SR are unproven (61). A SR of 50% is indicative of EEG burst suppression and 100% of electrical ‘silence’ (isoelectric EEG). Propofol-induced burst suppression does not necessarily protect the brain from secondary injury. It is not associated with a decrease in the number of jugular desaturation episodes during cardiopulmonary bypass or in the ischaemic burden in brain-injured patients with normal ICP (62,63). Thus, targeting propofol sedation to burst suppression should be restricted to patients with refractory intracranial hypertension and multimodal monitoring evidence of brain hypoxia or cerebral metabolic failure. There is limited theoretical benefit by deepening sedation from burst suppression to electrical silence and the author proposes that the target SR should be no higher than 50%. Additional increments in plasma propofol concentration cannot cause further electrophysiological benefits if the SR is already 100%, so using this as a sedation target risks inadvertent overdose of propofol. Special concerns are raised by the use of propofol in hypothermic patients because a temperature lower than 34°C can impair propofol metabolism and result in significant increases in plasma concentration (64).
Midazolam Midazolam has a stable haemodynamic profile and no temperature-related effects on metabolism so is the preferred sedative in unstable and hypothermic neurological patients (65). Another reason that midazolam is preferable to propofol in hypothermic patients is that hypothermia itself can induce reversible ECG changes (66) thereby limiting ECG as a monitoring tool for the propofol infusion syndrome. Midazolam has a relatively short context-sensitive half-life of 2–2.5 hours (67) but has a number of active metabolites that can accumulate during prolonged infusion and lead to delayed wake-up times, particularly in the elderly and those with hepatic impairment. Benzodiazepines are associated with an increased incidence of delirium (68) and withdrawal symptoms (69) compared to propofol. Midazolam reduces cerebral metabolic rate, CBF, and ICP but does not affect cerebral autoregulation and CO2 reactivity. However, the level of metabolic suppression that can be achieved with midazolam is less profound than with propofol and barbiturates, and even large doses of midazolam do not induce an isoelectric EEG or burst suppression in normothermic patients (70,71). Burst suppression can be induced if high-dose midazolam is used in conjunction with other central nervous system depressants such as anticonvulsants (72).
Barbiturates Prior to the introduction of propofol, oxybarbiturates (pentobarbitone) and thiobarbiturates (thiopental) were used extensively for sedation and ICP reduction in brain-injured patients (73,74). Barbiturates have sedative, anaesthetic, and antiepileptic properties via allosteric modulation of GABA A chloride ion channels that leads to neuronal hyperpolarization and inhibition of the action potential. They also inhibit excitatory L-glutamate AMPA receptors and reduce the flow of calcium through several types of voltage-gated calcium channels on neurons (75) suggesting that they may have neuroprotective effects that are independent of metabolic suppression. The potential neuroprotective effects of barbiturates include inhibition of excitotoxicity and free radical-mediated lipid peroxidation (76,77) and are used to justify their role as potential third-line treatment for refractory intracranial hypertension. Burst suppression is not required to elicit maximal neuroprotective efficacy of barbiturates in animal models of brain ischaemia (78). Barbiturates have many side effects that significantly limit their clinical use. They cause direct myocardial and central vasomotor depression leading to profound haemodynamic instability, and also accumulate during intravenous infusion. Barbiturates have a long context-sensitive half-life (thiopental 6–46 hours, pentobarbitone 15–48 hours) and elimination kinetics that change from first-order to zero-order at plasma levels required to achieve EEG burst suppression (24). This means that there is only a weak correlation between rate of infusion, plasma concentration, and clinical effect of barbiturates, a situation that is aggravated by their numerous active metabolites. Barbiturates should therefore be administered in incremental doses titrated to an EEG SR of 50%. Studies investigating the use of high-dose barbiturates for the treatment of intracranial hypertension were performed in an era when high-dose steroids, prophylactic hyperventilation, and fluid restriction were routine (20), and their applicability to current practice is debatable at best. A 2012 Cochrane review concluded that barbiturates are no longer indicated for maintenance sedation after TBI (79), and they should restricted to patients with refractory
intracranial hypertension who have not responded to other treatments and then only when the likely risks and potential benefits have been assessed.
Osmotic agents Brain volume is extremely responsive to changes in water content. If plasma osmolarity is rapidly increased by solutes that do not easily diffuse across the BBB, the brain–plasma osmotic gradient that develops results in net water diffusion from brain parenchyma into the circulating volume. Vice versa, when plasma osmolarity decreases, free water diffuses across the BBB from the circulation into brain parenchyma, leading to cerebral oedema (80). The effects of the rapid infusion of hyper- and hypo-osmolar solutions on CSF pressure were first described in 1919. During an experiment designed to determine whether intravenously administered sodium would diffuse into the CSF space of anaesthetized cats, Weed and McKibben serendipitously observed that hypertonic sodium solution resulted in a rapid reduction in CSF pressure and, conversely, that intravenous administration of water and dextrose solutions caused a protracted increase in CSF pressure (81). Substances that generate clinically relevant osmotic gradients across the BBB include mannitol and sodium.
Urea Concentrated urea was the first osmotic agent used in the treatment of intracranial hypertension in humans but is now only of historic interest (82). Its clinical effectiveness is hindered by diffusibility across cell membranes and it is no longer used clinically. However, it is important to note the effects on the central nervous system of rapid reductions in plasma urea concentration because this situation can arise in patients undergoing haemodialysis. In chronically uraemic patients, cerebral osmolality tends to equilibrate over time with the higher plasma osmolality. Haemodialysis can result in a rapid reduction of plasma urea and osmolality and an acute reversal of the brain–plasma water gradient leading to water diffusion across the BBB and cerebral oedema. This is called the dialysis disequilibrium syndrome which is characterized by nausea, tremor, disturbed consciousness, and seizures. In rare cases, significant brain oedema has resulted in cerebral herniation and death (83).
Mannitol Mannitol has been used for decades to treat intracranial hypertension (84,85,86). It is a sugar alcohol with osmotic diuretic properties. In contrast to concentrated urea, mannitol does not diffuse easily across cell membranes and the resulting lower volume of distribution, coupled with its ability to dehydrate erythrocytes, makes it a vastly superior osmotic agent. Mannitol reduces ICP through three different mechanisms: 1. Haemodynamic and antiviscosity effects: mannitol dehydrates erythrocytes, reducing their volume, rigidity, and cohesiveness. The subsequent reduction in blood viscosity, along with a mild positive inotropic effect and reduction of systemic vascular resistance, leads to increased cardiac output and improved cerebral perfusion and oxygenation. Due to metabolic coupling, the CBF increase is accompanied by rapid cerebral vasoconstriction with subsequent reduction in ICP and further improvements in brain perfusion (87). This accounts for the rapid onset of action of mannitol. 2. 2. Osmotic effects: mannitol creates an osmotic gradient across the BBB resulting in osmotic mobilization of water from brain parenchyma into the circulating volume. The reflection coefficient is a measure of how well solutes cross a membrane, and the reflection coefficient of mannitol is 0.9. This means that 90% of the drug remains in the capillaries and exerts an osmotic gradient across the intact BBB. Clinically relevant doses of mannitol generate substantial blood–brain osmotic gradients and direct removal of water from brain parenchyma. This accounts for the more prolonged effects of mannitol. 3. 3. Diuretic effects: mannitol can theoretically cause systemic dehydration and a sustained increase in plasma osmolality which, if not corrected, results in a long-lasting brain dehydrating effect. This effect is of little clinical relevance as the diuretic actions of mannitol are compensated by proportionate volume resuscitation to maintain euvolaemia (88). Mannitol is usually given as bolus doses of 0.25–2.0 g/kg, over 30–60 minutes, repeated as required. It is available as 10% and 20% solutions and both can be administered through central or peripheral venous catheters. The 20% solution tends to precipitate and a 15-micron in-line filter should be used. Care should be taken to avoid extravasation which is associated with painful thrombophlebitis. Following TBI, a single dose of 20% mannitol reduces ICP within 10–15 minutes, with a maximal effect within 20–60 minutes (89).
1.
Hypertonic saline Hypertonic saline (HS) solutions have gained popularity for the treatment of intracranial hypertension since the 1990s (85,90). Like mannitol, sodium does not cross the BBB. Its reflection coefficient is 1, meaning that 100% remains in the capillaries and exerts an osmotic gradient across the intact BBB. Like mannitol, the ICP-lowering effects of HS depend on a direct increase in plasma osmolality and a net flow of water from brain parenchyma into the circulating volume, and also on dehydration of erythrocytes with reduced blood viscosity, improved CBF, and compensatory reductions in CBV and ICP (91). There are important difference between mannitol and HS. Mannitol causes an osmotic diuresis and volume depletion whereas HS results in sustained intravascular volume expansion. Although this can precipitate congestive heart failure in susceptible patients, volume expansion is generally helpful in the management of critically ill patients, especially in the context of trauma. Boluses of HS cause a short-lived and generally clinically irrelevant hyperchloraemic acidosis (92). Several cases of central pontine myelinolysis have been reported during rapid sodium correction in patients with chronic hyponatraemia. For this reason, HS is not considered safe in the context of chronic hyponatraemia, although central pontine myelinolysis has never been reported in normonatraemic TBI patients treated with HS (20). HS is available as 3%, 7.5%, and 23.4% solutions, and is typically administered in 150 mL, 75 mL, and 30 mL boluses respectively. A 3% HS solution can be administered peripherally but 7.5% and 23.4% solutions must be infused via a central venous catheter. Some experts recommend administration of HS as a continuous infusion titrated to a plasma sodium concentration of 145–155 mmol/L. No significant side effects or significant rebounds in ICP on discontinuation of therapy have been reported with such a regimen (93). Plasma sodium levels should be routinely measured at the bedside and, if serum sodium concentration exceeds 160 mmol/L, additional doses of HS are unlikely to have further beneficial effects on ICP (80). At the time of writing there is no definitive evidence to guide the optimal method of administration (bolus versus continuous infusion) of HS, duration of therapy, or plasma sodium targets. Compared to mannitol, equiosmolar boluses of HS achieve similar reductions in ICP after TBI (94) and equal or superior brain relaxation during elective brain surgery (95). A recent meta-analysis argued that HS may be superior to mannitol in terms of safety and efficacy (96), but the choice between an osmotic diuretic and a volume-expanding agent should always be based on individual assessment of volume status and renal, cardiac, and respiratory function.
Complications of hyperosmolar therapy The ICP effects of hyperosmolar therapy are primarily exerted by dehydration of normal brain tissue, and in injured brain regions the free diffusion of solutes across the BBB negates its dehydrating effects. Although such considerations might seem to indicate that osmotic agents can worsen ICP gradients and precipitate brain herniation in patients with large focal injuries, this theoretical concern appears largely unfounded. Osmotic therapy has negligible effects on midline shift even in patients with hemispheric infarcts (97,98). Acute kidney injury (AKI) is a clinically relevant risk of high-dose mannitol but not HS because of renal vasoconstriction and intravascular volume depletion. This risk is higher if more than 200 g of mannitol are administered each day, or if plasma osmolality exceeds 400 mOsm. A previously proposed upper limit of plasma osmolality of 320 mOsm during hyperosmolar treatment is arbitrary and this threshold is often exceeded in clinical practice without significant repercussions on renal function (88). In response to prolonged brain dehydration, astrocytes and neurons produce polyols, amino acids, and other osmotically active molecules that contribute to gradual re-equilibration of the osmotic gradient between the extracellular space and brain parenchyma. When a state of serum hyperosmolarity has been maintained over a number of days, care should therefore be taken to prevent a rapid reversal of the brain–plasma water gradient on discontinuation of therapy as this can lead to rebound brain oedema similar to that previously described in the dialysis disequilibrium syndrome.
Arterial carbon dioxide tension Carbon dioxide is a potent dilator of pial arterioles (99). Hypercapnia increases CBV and can precipitate intracranial hypertension in patients with exhausted volume-buffering reserve. Controlled normocapnia is crucial to minimize the risk of secondary brain injury and, in this regard at least, pre-hospital intubation and controlled ventilation guided by
continuous end-tidal CO2 monitoring has been shown to improve functional outcome when compared to delayed, inhospital intubation (100). Hyperventilation reduces PaCO2 and lowers ICP within seconds as a result of cerebral vasoconstriction. The induction of hypocapnia by hyperventilation can be life-saving in patients at risk of imminent cerebral herniation because of its fast onset of action, but prolonged hyperventilation risks cerebral vasoconstriction sufficient to reduce CBF below critical thresholds and can precipitate or worsen cerebral ischaemia (101). This is particularly relevant in the first 24 hours after severe TBI when CBF may already be critically reduced. Positron emission tomography (PET) studies have demonstrated that hyperventilation to a target PaCO 2 of 4.0 kPa (30 mmHg) in patients with moderately increased ICP can result in significant regional ischaemia in the first 10 days after TBI (102). Notably, PET-confirmed regional ischaemia is undetected by jugular venous oxygen saturation monitoring suggesting that the ischaemic burden associated with modest hyperventilation is not always detected by global monitors of cerebral oxygenation. As is the case with other ICP-lowering strategies, PaCO 2 targets should be determined on an individual basis. Ventilation is routinely targeted to normocapnia, that is, PaCO 2 4.5–5.0 kPa (33–38 mmHg), and modest hyperventilation to PaCO2 4.0 kPa (30 mmHg) should be considered only in patients in whom ICP remains elevated despite first- and second-line treatments. Cerebral oxygenation and microdialysis monitoring can provide some degree of reassurance regarding the adequacy of cerebral perfusion during hyperventilation, and to fine-tune PaCO 2 and CPP targets in an individual patient (101,103,104). More aggressive hyperventilation to PaCO2 less than 4.0 kPa (< 30 mmHg) provides limited additional benefits in terms of ICP control and should be avoided (105). Current guidance from the Brain Trauma Foundation recommends that prophylactic hypocapnia (PaCO 2 < 4.0 kPa (< 30 mmHg)) should be avoided, and that hyperventilation should only be used as a temporizing measure for the reduction of elevated ICP in patients at imminent risk of herniation (20).
Hypothermia Although there is a wealth of experimental data describing beneficial effects of hypothermia on the brain, at the time of writing, perinatal asphyxia is the only indication supported by level 1 evidence (106). There is some evidence supporting targeted temperature management to 36°C for anoxic-ischaemic encephalopathy following out-of-hospital cardiac arrest (see Chapter25) (107,108,109,110). The outcome effect of therapeutic hypothermia in patients with refractory intracranial hypertension after TBI is currently being addressed in the Eurotherm3235 Trial (111). The potential benefits of therapeutic hypothermia are best understood by distinguishing between its ICP-lowering effects which are primarily mediated via a temperature-dependent reduction in cerebral metabolic rate and CBV, and its ICP-independent neuroprotective effects via inhibition of excitotoxicity and neuronal apoptosis (112,113), suppression of the inflammatory cascade (114,115), reduction of BBB disruption (116), and reduced cytotoxic oedema (117). As intracranial hypertension plays only a minor role in secondary brain injury following perinatal asphyxia and cardiac arrest, it could be argued that the neuroprotective effects of hypothermia that are independent from its ICPlowering properties are likely to be the most clinically relevant in these contexts. On the other hand, hypothermiainduced improvements in outcome in conditions such as TBI where intracranial hypertension is a determining factor remain unproven (118). It has long been argued that a delayed initiation of hypothermia has contributed to the inconsistent findings in clinical studies but a recent study confirmed that even early hypothermia does not improve outcome after TBI (119). Although there is no evidence to support the use of hypothermia as a primary neuroprotective strategy following severe TBI, there is evidence for its use as an ICP-lowering strategy in patients with intracranial hypertension refractory to first-line medical treatment (89). Sedative agents lower the cerebral metabolic rate associated with neuronal function whereas hypothermia reduces cellular metabolism associated with the maintenance of transmembrane ion gradients and brain tissue viability (120). Thus moderate hypothermia can reduce brain metabolism irrespective of the depth of sedation, and also generate significant ICP reductions in patients with sedation-induced EEG burst suppression (109). Therapeutic hypothermia should be titrated to ICP response with depth and duration determined by an individualized risk–benefit assessment. Preliminary data suggest that hypothermia should be maintained for at least 48 hours and that rewarming should be slow (1°C every 4 hours) to prevent rebound increases in ICP and followed by controlled normothermia (121,122). Deep hypothermia to a core temperature of 16°C is associated with profound metabolic suppression and can be used to extend the ‘safe’ brain ischaemic time during major vascular procedures requiring circulatory arrest. Despite
theoretical neuroprotective advantages, there is no evidence to support the use of deep hypothermia following TBI (123). Further, life-threatening cardiac arrhythmias and profound haemodynamic instability prevent its clinical use during neurocritical care (124). In the context of intracranial hypertension, the depth of hypothermia should not exceed 32°C but even higher temperatures are associated with coagulopathy, immunological suppression, and electrolyte disturbances (125). Such complications are time and temperature dependent, are usually treatable, and rarely lifethreatening. Safe, rapid, and inexpensive induction of hypothermia can be achieved by intravenous infusion of ice-cold fluids. In combination with surface cooling, the infusion of 30 mL/kg 4°C saline reduces core temperature by 4.0 ± 0.3°C within 60 minutes without adverse effects on haemodynamic stability (126). Cooling devices with automated temperature feedback minimize the risk of under- or over-cooling that can be associated with ice packs and cold air blankets (106). A number of intravascular cooling catheters are commercially available and reported to deliver shorter time-to-targettemperature and maintenance of more stable temperature compared to surface cooling methods (127). Endovascular cooling devices are associated with potentially severe complications such as deep venous thrombosis (DVT) and catheter-related infections. The reported incidence of asymptomatic DVT is around 50% and a sixfold increase in the incidence of bloodstream infections has been reported with endovascular-cooling devices compared to surface cooling (128,129). The clinical superiority of endovascular devices remain to be proven and surface cooling technologies may offer a superior safety profile when hypothermia needs to be continued for more than 24 hours as is often the case in the management of intracranial hypertension.
Surgery Surgical management of intracranial hypertension includes evacuation of space-occupying lesions, drainage of CSF, and decompressive craniectomy.
Space-occupying lesions Immediate surgical evacuation is indicated for extradural and acute subdural haematomas if there is clinical or radiological evidence of mass effect (130). The surgical management of intraparenchymal haemorrhages and contusions remains controversial, with indications for surgery being related to the size, number, and location of haematomas, and presence or absence of intraventricular haemorrhage extension. Patients with large lobar spontaneous haemorrhagic lesions causing intracranial hypertension benefit from prompt surgical evacuation (131,132), but the role of surgery for traumatic haemorrhagic contusions remains a matter of controversy. The issue has been investigated in the Surgical Trial in Traumatic Intracerebral Haemorrhage (133) unfortunately terminated earlier than planned.
Cerebrospinal fluid drainage Placement of an external ventricular drain (EVD) allows therapeutic drainage of CSF to control intracranial hypertension as well as monitoring of ICP (20). ICP monitored via an EVD can be grossly underestimated during CSF drainage and should not be measured via an open drain (see Chapter 9) (135). CSF drainage is a second-tier option for the treatment of intracranial hypertension. In patients with compressed ventricles, placement of an EVD can be technically difficult and the effects of CSF drainage on ICP marginal and short lived. The major complications associated with EVDs are discussed in detail in Chapters9 and 24.
Decompressive craniectomy Decompressive craniectomy involves removal of a large skull segment and opening of the underlying dura. It rapidly controls ICP in patients with intracranial hypertension refractory to maximal medical treatment, hypothermia, and CSF drainage. A number of different techniques of decompressive craniectomy have been described related to the location (frontal, temporal, parietal, or occipital), laterality (unilateral or bilateral), and dural technique (opened in wide surgical flaps or ‘stabbed’). Surgical closure can include suturing of the dural flaps or only scalp closure. Unilateral decompression is indicated in patients with unilateral lesions or brain swelling resulting in a midline shift, whereas a large bifrontal decompression is indicated in patients with diffuse cerebral oedema (136). Despite the publication of a single, small trial supporting the use of decompressive craniectomy in the paediatric population (137), the impact of decompressive craniectomy on outcome following TBI in adults remains controversial.
There is little doubt that decompressive surgery is effective in controlling intracranial hypertension but concern remains that it might result in increased rates of disability in survivors. A randomized trial evaluating the role of early decompressive craniectomy in patients with intracranial hypertension following severe TBI (DECRA) demonstrated worse 6-month outcome in patients undergoing decompression (138). The clinical relevance of DECRA is limited because the differences in outcome between the groups were no longer significant after adjustment for pupil reactivity at baseline; 27% of patients randomized to surgical decompression had bilaterally fixed and dilated pupils before randomization compared to 12% in the medical management group. Another limitation of the DECRA study is the relatively low ICP burden that triggered surgical decompression. Patients underwent surgery when ICP exceeded 20 mmHg for 15 minutes despite first-tier interventions, and this is considered too early by many experts (139). The surgical technique in this study involved cruciate opening of the dura without sectioning the falx cerebri and the effectiveness of this has also been questioned by some experts. DECRA has increased rather than resolved the controversy about the indications, technique, timing, and selection of patients for decompressive craniectomy and it is hoped that RESCUEicp, a UK-based, international randomized trial evaluating surgical decompression compared to best medical management after severe TBI, will answer some of these outstanding questions (140). There is limited value in routine ICP monitoring or placement of a ventriculostomy in patients with a large supratentorial hemispheric stroke (141). However, in malignant middle cerebral artery (MCA) infarction and decreased level of consciousness, surgical decompression with dural expansion reduces mortality and increases favourable outcomes, irrespective of ICP or whether the infarction is in the dominant or non-dominant hemisphere (142). The benefit of surgical decompression in patients older than 60 years of age with malignant MCA syndrome is uncertain as the overall prognosis in this age group is poor. For all these reasons, the indications for surgical decompression following malignant MCA infarction should be considered carefully on an individual basis taking into account age, comorbidities, and the patient’s wishes (143). Suboccipital craniectomy with dural opening can be life-saving in patients with posterior fossa stroke and brainstem compression. As in supratentorial stroke, neurological deterioration rather than ICP monitoring should guide surgical intervention. If ventriculostomy is indicated to relieve obstructive hydrocephalus after a cerebellar infarct, it should be accompanied by a posterior fossa craniectomy to prevent upward cerebellar displacement. In the absence of established brainstem infarcts, surgery after a cerebellar infarct is associated with acceptable functional outcomes in most patients (144). Significant brain swelling and intracranial hypertension can occur in patients with encephalitis, and the term ‘fulminant’ encephalitis refers to infectious encephalitis associated with clinical or radiological evidence of brainstem compression. In this context, the limited evidence available suggests that surgical decompression results in excellent recovery of functional independence in both children and adults, even in the presence of early signs of brainstem dysfunction (145,146).
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106. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and metaanalysis of trial data.BMJ. 2010;340:c363.Find this resource: 107. Rivera-Lara L, Zhang J, Muehlschlegel S. Therapeutic hypothermia for acute neurological injuries. Neurotherapeutics. 2012;9(1):73–86.Find this resource: 108. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.Circulation. 2010;122(18 Suppl 3):S768–86.Find this resource: 109. Schreckinger M, Marion DW. Contemporary management of traumatic intracranial hypertension: is there a role for therapeutic hypothermia? Neurocrit Care. 2009;11(3):427–36.Find this resource: 110. 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J Cardiothorac Vasc Anesth. 2010;24(4):644–55.Find this resource: 124. Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab. 2003;23(5):513–30.Find this resource: 125. Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med. 2009;37(3):1101–20.Find this resource: 126. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. 2005;33(12):2744– 51.Find this resource: 127. Finley Caulfield A, Rachabattula S, Eyngorn I, Hamilton SA, Kalimuthu R, Hsia AW, et al. A comparison of cooling techniques to treat cardiac arrest patients with hypothermia. Stroke Res Treat. 2011;2011:690506.Find this resource: 128. 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130. Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, et al. Surgical management of traumatic parenchymal lesions. Neurosurgery. 2006;58(3 Suppl):S25–46.Find this resource: 131. Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005;365(9457):387–97.Find this resource: 132. Mendelow AD, Gregson BA, Mitchell PM, Murray GD, Rowan EN, Gholkar AR. Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol. Trials. 2011;12:124.Find this resource: 133. Gregson BA, Rowan EN, Mitchell PM, Unterberg A, McColl EM, Chambers IR, et al. Surgical trial in traumatic intracerebral hemorrhage (STITCH(Trauma)): study protocol for a randomized controlled trial. Trials. 2012;13:193.Find this resource: 134. Mendelow AD, Gregson BA, Rowan EN, Francis R, McColl E, McNamee P, et al. Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): the first randomized trial. J Neurotrauma. May 21 2015. [Epub ahead of print]Find this resource: 135. Li LM, Timofeev I, Czosnyka M, Hutchinson PJ. Review article: the surgical approach to the management of increased intracranial pressure after traumatic brain injury. Anesth Analg. 2010;111(3):736–48.Find this resource: 136. Hutchinson P, Timofeev I, Kirkpatrick P. Surgery for brain edema. Neurosurg Focus. 2007;22(5):E14.Find this resource: 137. Taylor A, Butt W, Rosenfeld J, Shann F, Ditchfield M, Lewis E, et al. A randomized trial of very early decompressive craniectomy in children with traumatic brain injury and sustained intracranial hypertension. Childs Nerv Syst. 2001;17(3):154–62.Find this resource: 138. Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D’Urso P, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;364(16):1493–502.Find this resource: 139. Kolias AG, Hutchinson PJ, Menon DK, Manley GT, Gallagher CN, Servadei F. Letter to the Editor: Decompressive craniectomy for acute subdural hematomas. J Neurosurg. 2014;120(5):1247–9.Find this resource: 140. Hutchinson PJ, Corteen E, Czosnyka M, Mendelow AD, Menon DK, Mitchell P, et al. Decompressive craniectomy in traumatic brain injury: the randomized multicenter RESCUEicp study (www.RESCUEicp.com). Acta Neurochir Suppl. 2006;96:17–20.Find this resource: 141. Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, et al. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(4):1222–38.Find this resource: 142. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6(3):215–22.Find this resource: 143. Kirkman MA, Citerio G, Smith M. The intensive care management of acute ischemic stroke: an overview. Intensive Care Med. 2014.Find this resource: 144. Juttler E, Schweickert S, Ringleb PA, Huttner HB, Kohrmann M, Aschoff A. Long-term outcome after surgical treatment for space-occupying cerebellar infarction: experience in 56 patients. Stroke. 2009;40(9):3060–6.Find this resource: 145. Adamo MA, Deshaies EM. Emergency decompressive craniectomy for fulminating infectious encephalitis. J Neurosurg. 2008;108(1):174–6.Find this resource: 146. Perez-Bovet J, Garcia-Armengol R, Buxo-Pujolras M, Lorite-Diaz N, Narvaez-Martinez Y, Caro-Cardera JL, et al. Decompressive craniectomy for encephalitis with brain herniation: case report and review of the literature. Acta Neurochir (Wien). 2012;154(9):1717–24.Find this resource:
Ethical and legal issues in neurocritical care Chapter: Ethical and legal issues in neurocritical care Author(s): Leslie M. Whetstine , David W. Crippen , and W. Andrew Kofke DOI: 10.1093/med/9780198739555.003.0008
The place of bioethics in medicine generally, and neurocritical care in particular, has evolved over the past several decades, spurred at least in part by the extraordinary advances in life-supporting and life-sustaining technology. Nonetheless, bioethics as a discipline has maintained a consistent adherence to a core set of principles that include beneficence, nonmaleficence, autonomy, and justice (1). 1.
1. Beneficence is the active obligation to remove harm when possible, promote welfare, and act in the best interest of the patient and of society at all times. 2. 2. Nonmaleficence is the passive obligation to do no harm to a patient. 3. 3. Autonomy is an individual’s right to hold views and make choices according to their own values, so long as those actions don’t impinge on the rights of others. 4. 4. Justice is the provision of fair, equitable treatment in light of what is due or owed to persons. The spectrum of bioethics is huge so this chapter will overview ethical and legal issues relevant to neurocritical care.
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Ethical decision-making The American College of Physicians’ Ethics Manual provides an excellent overview of the major ethical issues in medicine (summarized in Table 8.1) and a structured approach to dealing with ethical dilemmas (2). Important elements of this approach are discussed in detail in the following sections. Table 8.1 Major areas in bioethics
Major ethical category
Subtopics
Professionalism Physician–patient relationship
Initiation and discontinuation
Obligations in healthcare system catastrophes
Evaluations for a third party
Disability certification
Confidentiality
Complementary/alternative care
The medical record
Medical care to self, family, friends, VIPs
Disclosure
Physician–patient sexual contact
Reproduction decisions
Boundaries and privacy
Genetic testing
Gifts from patients
Medical risk to physician and patient Care of patients near the end of life
Making decisions
Futile treatments
Advance care planning
Determination of death
Withdrawing or withholding treatment
Physician-assisted suicide and euthanasia
Major ethical category
Subtopics
Professionalism
Ethics of practice
The physician and society
Physician’s relationship to other clinicians
Artificial nutrition and hydration
Disorders of consciousness
‘Do-Not-Resuscitate’ orders
Solid organ transplantation
Dealing with the changing practice environment
Financial conflicts of interest
Financial arrangements with patients
Advertising
Obligations of the physician to society
Ethics committees
Resource allocation
Medicine and the law
Relation of physician to government
Expert witnesses
Cross-cultural issues
Strikes and other joint actions by physicians
Volunteerism
Futile care conflicts
Attending physicians and physicians in training
Peer review
Consultation and shared care
Conflicts within a healthcare team
The impaired physician Research
Protection of human subjects
Scientific publication
Use of human biological materials
Sponsored research
Placebo controls
Public announcement of research discoveries
Innovative medical therapies Data from Snyder L, ‘American College of Physicians Ethics Manual: sixth edition’, Annals of Internal Medicine, 3, 156 (1 Pt 2), pp. 73–104.
The primary wishes of the patient Ethical considerations always presuppose that the wishes of the patient are paramount and the primary driver in medical treatment decision-making (2). In coming to a treatment decision, the problem should first be framed within the relevant context, and then the physiological facts, medical uncertainties, benefits, and harms of various treatment options elucidated. In the course of this process a decision maker must be identified. For a competent patient this can only be the person themselves but for an incompetent patient the decision maker may be the primary caring clinician
or a surrogate, depending on the jurisdiction. Clear and understandable information about treatment options and their likely outcome should be provided to the patient or their decision maker. In forming the treatment decision, it is crucial that the wishes and values of the patient are established, either from the patient themselves or their appointed surrogate. A health professional’s values should never override those of a patient. The concept of patient autonomy in decision-making based on provision of comprehensive information about the benefits and risks of treatment is illustrated by the 1914 Schloendorff case in the United States (Box 8.1) in which the judge found that a patient has a right to refuse medical intervention despite a physician’s judgement that it is medically indicated (3). This ruling was fundamental in establishing the principle of informed consent. The right of competent patients to refuse any and all treatment, based on the right to self-determination and informed consent, is supported internationally. In the Sidaway v.Bethlem Royal Hospital and Maudesley Hospital Health Authority case in the United Kingdom, Lord Scarman ruled in 1985 (4): A doctor who operates without the consent of his patient is, save in cases of emergency or mental disability, guilty of the civil wrong of trespass to the person: he is also guilty of the criminal offence of assault. The existence of the patient’s right to make his own decision, which may be seen as a basic human right protected by the common law, is the reason why a doctrine embodying a right of the patient to be informed of the risks of surgical treatment has been developed …
Box 8.1 Schloendorff—issues in rights to self determination Ms Schloendorff suffered from stomach problems and consented to exploratory surgery under ether to determine the nature of a lump that had been found on palpation. She clearly stated that she did not wish any surgery other than the exploration at that time. During the ether examination the doctor located and removed a large tumour despite the patient’s previous instructions to the contrary. In the court opinion, Justice Cardozo famously penned ‘Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient’s consent, commits an assault, for which he is liable in damages. This is true except in cases of emergency where the patient is unconscious and where it is necessary to operate before consent can be obtained’. Data from Poland SC, ‘Landmark Legal Cases in Bioethics’. Bioethical Issues: Scope Notes Archive; 1997’ [cited 2014. Accessed January 16, 2014]; Available from:https://repository.library.georgetown.edu/bitstream/handle/10822/556889/sn33.pdf?sequence=1
Doctor–patient relationship Clinicians’ obligations are to hold the welfare and best interests of their patients as the primary goal, even if there are conflicting personal, societal, or institutional pressures to make non-patient-centred decisions. Thus what is medically most appropriate for the patient always takes precedence over issues such as cost containment or bed triage. In countries where medical care is based on a fee for service, decisions regarding patient care should never include considerations of a patient’s financial or social status, or clinician or institution compensation. Such principles are simply an extension of the notions of professionalism in which clinician self-interest is irrelevant.
The role of legal processes in clinical decision-making Although case law can be useful in guiding difficult clinical decisions, law and ethics are not synonymous. Laws tend to beprohibitive and tell us what not to do (e.g. don’t kill), whereas ethics inform us about what we should do (e.g. act in the patient’s best interests). Furthermore, ethical obligations often demand that we go beyond what the law requires. For example, whilst a young mother can legitimately refuse an appendicectomy because she doesn’t want to live with a scar, one could make the ethical claim that exercising that legal right might violate the obligation of beneficence that she owes to her family. In this way the law informs ethics, rather than being the final arbiter of right and wrong.
Confidentiality It is an ethical as well as a professional obligation to maintain confidentiality when providing medical care to a patient. This may be more difficult in the digital age when clinicians have little control over how clinical data are managed or
stored. Moreover, good medical care typically mandates electronic communications between physicians and other healthcare workers, and thus it is incumbent on institutions to develop infrastructures, such as firewalls and e-mail encryption systems, to facilitate communication whilst safeguarding privacy. There are also work habits that can diminish the possibility of breaches of confidentiality such as not discussing patient information in public areas, using institutional rather than public communication tools, and not discussing the condition of any patient (including ‘VIP’ or celebrity patients) with individuals who are not approved by the patient. Clinicians should also not assume that all family members and visitors are familiar with a patient’s past medical history, and must never discuss this or new diagnoses with anyone not approved by the patient or their surrogate. Notably, physicians have no obligation to keep secret from the sentient patient relevant information provided by family or friends, but must not provide a private, social context of a disease presentation to others without patient consent. For example, if a patient develops a stroke whilst in a sexual relationship with someone other than their spouse or partner, the clinician’s duty of confidentiality remains to the patient and, assuming that they would wish this information to be kept private, informing the family of the circumstances of the disease onset is inappropriate.
Assessing capacity to provide informed consent The notion of informed consent presupposes that consent be obtained and that it be informed, that is, that it is based on due consideration of the risks and benefits of a given choice or choices. This principle applies to both clinical activities and research involving human subjects. The process of procuring informed consent and the information provided to achieve that consent is extremely important and a physician must always provide information that is understandable to allow a reasoned decision to be made by the patient. Concurrently the physician must make an assessment of the patient’s competence to understand and synthesize the issues into a cogent decision. Notably the consent needs to be freely given and not be coerced. The capacity to make an informed decision is a judgement usually made by the physician, and is defined as the ability to receive and express information and to make a choice consonant with that information and one’s values (2). Whilst seemingly straightforward, this assessment may not necessarily be so in critically ill neurological patients where the ability to receive, understand, and express information can be complicated by the underlying disease process. For example, a patient with a frontal lobe tumour might have impaired executive functioning, or an acutely quadriplegic patient might not consent to life-saving treatment because of clinical depression. In such difficult cases psychiatric assessment can be useful, and advice from local ethics committees, court, or other legal authorities may be required depending on local statutes. Once a condition of incompetence has been determined a surrogate decision-maker must be identified. The process for this varies between jurisdictions. One widely accepted approach is to prioritize the identification of a surrogate decision maker in the following rank order—pre-designated proxy, spouse, adult children, parent, and other relative/friend. For an incompetent patient with no legally appointed surrogate, a decision maker may be appointed by the hospital or local legal authority depending on local laws and customs. In many jurisdictions, such as the United Kingdom, the clinician acts on the incompetent patient’s behalf, informing relatives or friends of clinical decisions whilst seeking their agreement, rather than asking them to make them. In any event, it is important that surrogates understand that they are deciding what is in the patient’s best interests, not what they would want for themselves. For example, a Jehovah’s Witness surrogate cannot refuse blood transfusion in a non-Jehovah’s Witness incompetent adult based on their own values. Concurrently the physician should be evaluating the capacity of the surrogate and also any potential conflicts, such as the surrogate receiving money that is contingent on the patient being alive or dead. In some jurisdictions it can be difficult to remove a legal proxy, as illustrated in the Howe case in the United States (Box 8.2), although this is not true everywhere.
Box 8.2 Howe—cannot legally remove a proxy in the United States Ms Barbara Howe was a patient with a debilitating brain condition (amyotrophic lateral sclerosis) that left her ‘locked in’ and therefore unable to move or communicate. During her 4 years in this condition as an inpatient at Massachusetts General Hospital, there was disagreement between the attending physicians and her family regarding prognosis and patient comfort (81). The patient’s daughter believed that her mother exhibited some recognition of her environment justifying continued aggressive intensive care, including mechanical ventilation. The physicians believed that there was no potential for improvement and that the patient was in perpetual distress. Complicating the situation,
the patient’s health insurance company served notice that it would cut off funding for her hospital services, on the basis that the patient was now receiving custodial care. In March 2005, the hospital filed suit in Massachusetts family court to revoke Ms Howe’s daughter as the patient’s healthcare proxy. Probate and Family Court Judge John M. Smoot ruled that the daughter’s authority as her mother’s healthcare proxy should stand and that the hospital could not discontinue life support. Data from Kowalczyk L, ‘Woman dies at MGH after battle over care: daughter fought for life support’, Boston Globe, 8 June 2005. In some jurisdictions, including the United States, a duly appointed surrogate retains the right to make treatment decisions on behalf of a patient in the long term. Further, even if the decisions of a proxy who has the patient’s best interests in mind seem ill-considered to the healthcare team, such decisions may be supported by a court. This principle was exemplified by the Wanglie case (Box 8.3) in which a proxy’s reliance on a miracle was legally supported. There is a contrasting approach in other jurisdictions. For example, the Canadian government Consent and Capacity boards can be asked to consider whether a designated decision-maker is making decisions in a patient’s best interest and can order the proxy to make different decisions or even replace him or her (5). This board tends to rely heavily on the input of the local clinical team. An overview of international norms confirms that the arrangements in the United States are not universal and that the surrogate’s decision in the Wanglie case would have been overturned or the surrogate replaced in other jurisdictions (6).
Box 8.3 Wanglie—waiting for a miracle legally supported In 1989, Helga Wanglie, aged 86, fractured her hip and was treated at Hennepin County Medical Center (HCMC) in Minneapolis, Minnesota (82). She was ultimately discharged to a nursing home. Subsequently, she developed respiratory failure and became ventilator dependent for several months but experienced cardiopulmonary arrest, with severe and irreversible anoxic brain injury. Her husband resisted an ethics committee recommendation to limit life support, and requested that Mrs Wanglie be transferred back to HCMC for continued life support. This was done. Over the next several months, repeated evaluations confirmed that Mrs Wanglie was in a persistent vegetative state (PVS) and ventilator dependent. The medical staff considered her to be moribund. However, the immediate family insisted that all forms of treatment be continued, though they did agree to a do-not-resuscitate order. Some of the family’s desires were based on the patient’s strong religious background (‘only God can decide’). There was no living will or specific discussion of end-of-life desires. On 8 February 1991, the hospital filed papers with the Fourth Judicial District Court, Hennepin County, asking the court to find Mr Wanglie incompetent to speak for his wife and to appoint an independent guardian, who presumably would permit unilateral withdrawal of the ventilator against the family’s wishes. The court ruled that Mr Wanglie was ‘the most suitable and best qualified person’, from among the available potential guardians, to serve as guardian for his wife. The court decided the case strictly as a guardianship matter and did not address the appropriateness of treatment (83). In essence this judgment determined that an individual who knows the patient and his or her value system can better approximate the patient’s wishes regarding end-of-life decisions than can healthcare providers. Data from Jecker NS and Schneiderman LJ, ‘When families request that “everything possible” be done’, Journal of Medicine and Philosophy, 1995, 20, 2, pp. 145–163; and Cantor NL, ‘Can healthcare providers obtain judicial intervention against surrogates who demand “medically inappropriate” life support for incompetent patients?’, Critical Care Medicine, 1996, 24, 5, pp. 883–887.
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Care of patients near the end of their lives Consumer demand for healthcare resources has been and will continue to be a political as well as a social issue. Wellness has always been a high priority, and populations have gone to great lengths to achieve it. In antiquity, little
was known about the physiological processes of the human body that led to or away from wellness so the demand for wellness produced many questionable manipulations. Ancient Egyptian medicine was mentioned in Homer’s Odyssey around 700 BC (7), bloodletting, the oldest known medical procedure, was a treatment for virtually any ill until the early nineteenth century (8), and trephining, the oldest form of surgery involving drilling a hole in the skull to allow egress of bad ‘humours’, was widely practised (9). Demand for these and many other counterintuitive medical treatments demonstrate the public’s willingness and determination to seek wellness through any means, including those with no convincing evidence of efficacy. Modern medicine offers new technologies that appear to promise (falsely) near immortality.
The introduction of life-sustaining technologies and the growth of bioethics The advent of life-support technology and intensive care units (ICUs) in the 1950s radically altered the course of medicine and introduced a new and complex set of ethical issues (10). Prior to these advancements there were relatively few bedside ethical dilemmas with respect to end-of-life care, resource allocation, medical futility, or surrogate decision-making but, after their introduction, accurately prognosticating which patients would actually benefit from complex life-supporting interventions became important although difficult. This lead to carte blanch treatment with little consideration or discussion about what would happen to patients who might survive but not recover a reasonable quality of life. The yield of such a strategy ultimately becomes apparent in an individual but, by that point, patients have often been treated with various life-supporting measures, including mechanical ventilation, dialysis, enteral feeding tubes, and even recurrent rounds of cardiopulmonary resuscitation (CPR). Death is too often perceived as the enemy of modern medicine and doctors sometimes see it as their ultimate failure. Technology has become regarded as an imperative despite the ‘life-in-death’ prospect it often creates (11). As a result of technological advances, the following questions have become increasingly pervasive in the ICU: 1. 2.
1. Should patients be able to refuse, or be refused, artificial life support even if death will result? 2. If patients are not competent to decide whether or not to refuse life-supporting treatments, who should be enabled to decide for them? 3. 3. What is the role of medical professionals in this process? 4. 4. What should be done if the patient is not terminally ill but unlikely to regain functional independence to a degree that it is acceptable to them? As advances in technology and medical care forced such questions, the nascent field of bioethics grew in earnest (12). In the early days after the introduction of life-sustaining technologies, there was significant concern in some jurisdictions that removal of life support could be regarded as murder such that it could not be forgone no matter how little benefit or how much suffering it might cause. Indeed, for a time in the United States, hotline phone numbers were posted in neonatal ICUs inviting notification to authorities that life support was about to be withdrawn from a patient (13). However, as societal and medical attitudes evolved, a consensus on the legitimacy of forgoing (withholding or withdrawing) life-supporting treatment gradually emerged. This shift was advanced by case law, and evaluated through philosophical and theological enquiry. The criminality and civil liability of withdrawing life support was tested in the Barber case in the United States (Box 8.4) (14) and the Bland case in the United Kingdom (Box 8.5) (15). Both legal decisions determined that withdrawal of lifesupporting treatment (WLST) must be viewed in terms of benefits and burdens. If there is a reasonable chance of recovery, the benefits of therapy will outweigh the burdens but when there is no such chance of recovery, life support can be defined as extraordinary. The Barber and Bland decisions held that doctors could honour requests to discontinue extraordinary life support without being guilty of homicide or subject to civil liability.
Box 8.4 Barber—non-criminality of terminating life support The Quinlan decision (Box 8.11) authorized a surrogate to speak on behalf of the patient, but it was unclear whether physicians would be free legally to abide by wishes regarding termination of life support. In 1983, Barber v. Superior Courtclarified the potential for criminality following removal of life support. Two California physicians performed surgery on a patient, who experienced cardiopulmonary arrest postoperatively and was rendered persistently vegetative. The patient was placed on a mechanical ventilator and enterally fed, and physicians determined that the
vegetative state would most likely be permanent. Upon request of the patient’s family, the physicians removed the artificial life-support systems, and the patient died several days later.
Box 8.11 Quinlan—stopping ventilator support for an incompetent patient The 1976 case of Karen Ann Quinlan was the first major dispute to centre on an incompetent patient’s right to refuse treatment (85). Ms Quinlan was diagnosed as being in a PVS after mixing drugs and alcohol. She was mechanically ventilated and fed enterally. Eventually, her family requested that the mechanical ventilator be removed and she be allowed to die naturally. The physicians refused to comply, expecting death would follow and that this death would be attributed to those who removed the support modalities. The family sued to force the issue. A New Jersey appellate court held that the government had an interest in maintaining the ‘sanctity of life’ and that removing life support (however artificial) was tantamount to criminal homicide. The New Jersey Supreme Court eventually heard the case, and held that Ms Quinlan’s father, as a surrogate, was the authoritative decision maker with the incompetent patient’s best interests in mind (86). Accordingly, Ms Quinlan was removed from the ventilator, but she did not die until 9 years later because she unexpectedly breathed and continued to receive artificial nutrition. Data from Hughes CJ, ‘In the matter of Karen Quinlan, an alleged incompetent’, 70 N.J. 10; 355 A.2d 647; 1976 N.J. LEXIS 181; 79 A.L.R.3d. 1976 March 31, 1976 [cited 2014 February 5, 2014]; Available from:http://euthanasia.procon.org/sourcefiles/In_Re_Quinlan.pdf; and Kennedy IM, ‘Focus: current issues in medical ethics. The Karen Quinlan case: problems and proposals’, Journal of Medical Ethics, 1976, 2, 1, pp. 3–7. The surgeons were charged with murder by the state of California and went to trial. The court held that the actions of the defendants did not volitionally cause harm and that withdrawal of life support constituted further appropriate medical care. The court held that the physicians were not liable in their actions stating that ‘Further treatment would be considered disproportionate to any positive outcome’ (14). Data from Compton J. Barber v. Superior Court (People) (1983) 147 Cal. App. 3d 1006 [195 Cal. Rptr. 484]. 1983 [cited 2012 November 27, 2012]; Available from: http://law.justia.com/cases/california/calapp3d/147/1006.html
Box 8.5 Bland—stopping nutrition for an incompetent patient Anthony Bland sustained an anoxic injury at age 17 years and had survived for 3 years in a PVS with life supported entirely through artificial enteral nutrition (15). He had no advance directive and had not expressed his wishes for such a circumstance. Both his physicians and his parents believed that stopping support was in the patient’s best interests but there were uncertain regarding the criminality of such an act. They thus petitioned the UK courts for an opinion on the matter, and the court agreed that removing such support was legal finding that the physicians: 1.
1. ‘may lawfully discontinue all life-sustaining treatment and medical supportive measures designed to keep the defendant alive in his existing persistent vegetative state including the termination of ventilation nutrition and hydration by artificial means’; and 2. 2. ‘may lawfully discontinue and thereafter need not furnish medical treatment to the defendant except for the sole purpose of enabling him to end his life and die peacefully with the greatest dignity and the least of pain suffering and distress’. Data from United_Kingdom_House_of_Lords. Airedale NHS Trust (Respondents) v. Bland (acting by his Guardian ad Litem) (Appellant). 1993 [cited 2013 November 15, 2013]; Available from: http://www.bailii.org/uk/cases/UKHL/1992/5.html Ethics is of course not a by-product of modernity but has permeated medicine since its inception. The Hippocratic oath has long served as the enchiridion for practitioners instructed by the primary precept primum non nocere—first do no harm. However, the medical culture of Hippocrates and subsequent physicians was one dominated by paternalism even well into the twentieth century. Patients were expected to abide by doctors’ orders under the pretence that ‘doctor knows best’. Bioethicist Robert Veatch refers to this tendency for doctors to want to make decisions for patients as the generalization of expertise (16). Because doctors are experts in medicine they may also regard themselves as authorities in all spheres of medical decision-making for all patients, despite the unique differences that individuals have with respect to their expectations of treatment goals and interpretation of quality of life. Such philosophical conundrums spawned an international dialogue on the rights of patients (17). The differences of opinion
that emerged between healthcare consumers and providers eventually led to involvement of legal systems for the purpose of primary guidance and finally to legal mandates with respect to forgoing treatment (18).
Withholding and withdrawing treatment To forgo treatment means either to withhold a treatment before it is started or to withdraw a treatment after it has been started. While ethics and the law traditionally regard withholding and withdrawing as equivalent actions, withdrawing therapy tends to be more difficult for families and sometimes even for clinicians (19). When treatment is withdrawn the patient typically dies, leaving the uneasy feeling that those who withdrew the treatment caused the death or were somehow complicit in it. On the other hand, if a treatment could never be withdrawn, patients might reasonably decline potentially beneficial treatment for fear of being reliant on long-term life-support. Time trials are often necessary to determine whether a treatment will be effective in a given individual, meaning that judgements cannot always be made in advance but often only sometime after life-supporting therapy has been implemented when prognosis becomes clearer. Thus, by regarding withholding and withdrawing as ethically equivalent options, patients or surrogates are able to reassess care goals and plans as time progresses. Neurocritical care encompasses a significant element of care to patients who are near the end of life, mandating therapies directed to control of distressing symptoms and concurrent empathic physical, psychological, and spiritual support. Such treatment can only be decided after review of the patient’s condition in the light of the likelihood and quality of survival and in association with consideration of the suffering that may be incurred in achieving such outcomes. Decisions are typically made in the context of the patient’s values and previous known wishes (written or verbal), perceptions of the nature of the terminal illness, and understanding of the logical equivalence of not starting versus withdrawing support at a later time.
Principle of double effect Though not without debate, there has long been a distinction between killing a patient versus allowing a patient to die (20). The law, as well as the dominant Judeo-Christian ethical framework in the Western world, does not regard forgoing burdensome medical treatment as an act of suicide or killing, a distinction rooted in Catholic tradition and buttressed by the principle of double effect (PDE). This construct, attributed to Thomas Aquinas, asks whether it is morally legitimate to perform an act that has two or more consequences, one of which is good and rightly intended and another that is bad but unintended (21). Although the PDE has its origins in a faith tradition, it is also used in secular philosophical analysis most clearly illustrated in palliative care where it is considered an ethical obligation to alleviate pain and discomfort during the dying process (22). In this context, the PDE justifies the actions of a clinician who administers increasing doses of morphine knowing that this may hasten death, provided the intent is only to relieve pain. Although there are many critics of the PDE (23), its application is pervasive in both medicine and law. The PDE was referenced by the US Supreme Court in its 1997 ruling on physician-assisted suicide in the case of Vacco v.Quill (24). The court held that there is a fundamental difference between directly causing death and removing life support that allows a patient to die of a natural disease process. The opinion concludes: The distinction comports with fundamental legal principles of causation and intent. First, when a patient refuses life sustaining medical treatment, he dies from an underlying fatal disease or pathology; but if a patient ingests lethal medication prescribed by a physician, he is killed by that medication. (25) When a competent patient refuses treatment or determines that the treatment creates burdens disproportionate to benefits, forgoing interventions is therefore regarded as allowing the patient to die rather than an act of killing. Accordingly it is licit for technology that is prolonging the natural dying process to be removed so that a patient can die from their underlying disease, whereas killing a patient is wrong because the patient dies as a result of an intentional act. The latter is often categorized as euthanasia and is currently deemed a violation of ethics and the law in nearly all countries except Belgium, Luxembourg, the Netherlands, Albania, and Colombia (26). Some argue that the end result of these two processes is identical despite verbal gymnastics to obscure that fact (27). That is, the patient will ultimately die whether he or she dies because of their underlying disease or by an overdose of medication, or whether the physician intends death or not. These arguments raise particularly thorny problems, but the distinction remains despite such disagreement.
Futile care
The usual definition of futile treatment is that which is not effective in bringing about a desired therapeutic goal (28). For example, if a patient demands craniotomy to allow evil humours to escape from their brain, physicians are not mandated to perform the procedure because it is not effective at any level and may in fact be deleterious. Medically futile treatments need not, and ought not, to be given because they violate overarching standards of care. This position is supported by UK and New Zealand legal opinions (4). Moreover, several international professional societies have argued that medically futile treatment is unethical as well as inappropriate. These include the Italian Society of Anaesthesia, Analgesia, Resuscitation and Intensive Care (29), the American Medical Association (30,31), the American Society of Critical Care Medicine (32), and the UK General Medical Council (33). The situation is unsettled in the United States where the patient or proxy can often successfully demand futile or unreasonable treatments. Under current US definitions, any treatment that sustains vital signs is not necessarily considered futile because a therapeutic goal, that is, maintenance of life, can be achieved (34). Thus, if a surrogate demands dialysis for acute kidney injury in a 100-year-old terminally ill patient with dementia who can never improve under any circumstances, a physician cannot claim medical futility and unilaterally refuse treatment. However, the situation in the United States is slowly shifting. Since 1999, Texas law allows physicians to discontinue extraordinary life-sustaining treatment against the objections of the family if such treatment is determined to be medically futile, this is agreed by an ethics committee and the family is given ten days to seek another hospital that will treat the patient. Virginia law is similar but the law in California law is vague, invoking ‘generally accepted health care standards’. Ethicists in many other states have not lobbied for a Texas-style law because of the philosophical difficulties associated with defining futile care and the expected opposition from right-to-life advocates. This is despite the American Medical Association’s code of ethics supporting the notion that futile treatment should not be provided, even if demanded by a patient or surrogate (30,31). At the time of writing, case law in the United States continues to be piecemeal and there is no overriding legal precedent one way or the other. Requests by surrogates to provide or continue support in the context of futile care creates myriad conflicts within families, and with caregivers, institutions, and legal authorities. The complexity of the interplay between medical, social, religious, and family factors may lead to requests to ‘do everything possible’ or advice that ‘we are waiting for a miracle’, rather than to a decision to withdraw life support congruent with medical advice. The desire to continue inappropriate or futile care based on an expected miracle has been upheld in the United States (Box 8.3), but in similar circumstances in Canada it is likely that the surrogate would have been overruled or replaced (5). In the United Kingdom, as illustrated in the Bland case (Box 8.5), the courts have determined that there is no requirement to provide futile care. The expectations of the public for the delivery of futile and inappropriate care are international. In one study, 73% of Israeli and European ICUs frequently admitted patients with no realistic hope of survival despite only 33% of treating physicians believing that such patients should have been admitted (35). The dominant causes of moral distress reported by ICU nurses in this study were the requirement to deliver futile care, unsuccessful patient advocacy and difficulties with communication of unrealistic prospects to patients and families. More recently, 87% of 114 Canadian ICU physician directors reported that futile care was provided in their ICU, and 48% of ICU patients supported the provision of open-ended care regardless of the chances for good recovery (36). As discussed later in the chapter, diminishing resources mean that this is not just an issue of ethics, but also of economics and distributive justice.
Advance directives and surrogate decision makers A recurring theme in the neurocritical care unit (NCCU) is the difficulty in determining the wishes and desires of patients who do not have capacity to make decisions. As discussed earlier, a surrogate decision maker (sometimes called a proxy) is charged with making decisions on behalf of a patient who cannot speak on their own behalf. Ideally the surrogate should make the same decision the patient would make but, since most people do not explicitly state their medical preferences in advance, the surrogate is typically placed in the position of having to interpret general statements that may not directly pertain to the current medical condition or status. People have an understandable tendency to avoid topics that force consideration of personal debility and, when they do, often use terms like ‘I don’t want to live like a vegetable’ rather than providing clear guidance on which surrogates and clinicians could act. Nonetheless, advanced planning is becoming more common and allows an individual to indicate care preferences and identify a surrogate decision maker ahead of time. Although advance directives, or living wills, are legal documents they should ideally be created with advice from medical professionals. Failure to do so can result in medically naive documents that, for example, forbid intubation under any circumstance including during elective surgery. Physicians should routinely discuss care issues and expectations when patients are competent and institutions should routinely
enquire about the availability of advance directives and offer assistance in creating one on admission to hospital. Lack of availability of an a priori designated surrogate should prompt a search (including via social media) for a proxy and failing that it may be necessary to appoint a guardian, according to local regulations. In some jurisdictions the physician becomes the surrogate by default. Common law has long protected a competent patient’s right to refuse medical treatment, but what should be done regarding end-of-life care in an incompetent person if he or she has not previously indicated their wishes is less clear. Whilst a surrogate must make some kind of choice, the criteria by which they should do so is seldom apparent. In the Cruzan case (Box 8.6), the court held that requiring clear and convincing evidence of the incompetent patient’s wishes is constitutional and that if such evidence is presented, withdrawal of life support is lawful (37). This position is supported in the Bland case in the United Kingdom and by case law in New Zealand and South Africa (15).
Box 8.6 Cruzan—requirement to know patient’s wishes prior to withdrawing care, the case for advance directives The 1990 Nancy Cruzan case was the first of many similar cases to reach the US Supreme Court, where it would finally cohere sporadic case law regarding incompetent patients and the right to refuse treatment (41). Ms Cruzan was a young woman who was involved in a motor vehicle accident that resulted in a PVS. Physicians inserted a long-term feeding tube. After an extended delay, the patient’s parents requested that the feeding tube be removed so that she could die naturally. The hospital refused to do so without approval from the state court. The US Supreme Court ultimately held that, whereas autonomous individuals may invoke the right to refuse medical treatment under the ‘due process of law’ clause, surrogates for incompetent persons are not enabled to exercise such rights until they satisfy the burden of proof required by the state. Missouri (where Ms Cruzan’s injury occurred) required ‘clear and convincing’ evidence of the patient’s wishes before life support could be removed. The US Supreme Court held that states had the right to select and enforce their evidentiary standard (84). Data from Lewin T, ‘Nancy Cruzan dies, outlived by a debate over the right to die’, New York Times, December 27, 1990 [cited 2012 November 27, 2012]; Available from: http://www.nytimes.com/1990/12/27/us/nancy-cruzan-diesoutlived-by-a-debate-over-the-right-to-die.html; and Arnold RM and Kellum J, ‘Moral justifications for surrogate decision making in the intensive care unit: Implications and limitations’, Critical Care Medicine, 2003, 31, Suppl 5, pp. S347–S353. The Cruzan case proved to be pivotal in the battleground between right-to-life and right-to-die advocates, all of whom developed progressive interest in using the legal system to bolster their causes (38,39,40). A spokesperson for the Society for the Right to Die publicly noted: While it’s been a horrible agony for the Cruzans, having intimate private details on the public stage, and having to defend themselves, we owe them a debt for educating us and giving so much impetus to living wills and legislation that helps people plan ahead. (41) The leader of a Georgia antiabortion group disagreed noting: I sympathize with the hardship of caring for a helpless woman, but I have no sympathy for a family who solves their problems by starving their daughter to death when there were hundreds of bona fide offers to care for her regardless of her condition. Even a dog in Missouri cannot be legally starved to death. (41) The Cruzan action also reinforced the value of advance directives in avoiding intra-family differences of opinion and even court battles (42). If it can be proved that an incompetent patient has given an authoritative opinion as to the direction of his or her medical care, this is clear and convincing evidence that trumps differing opinions of surrogates or even a court. However, in the absence of an advance directive providing clarity regarding a patient’s values and preferences, decisions should be made in the patient’s best interests, informed by a family member or surrogate best acquainted with the patient. Even with advance directives and prior statements as to wishes, disagreements and concerns over their interpretation continue to lead to legal proceedings. The 2001 California case of Robert Wendland (Box 8.7) (43) illustrates the
problems that arise when surrogates are forced to rely on general statements made by the patient, and when family members disagree as to what such statements actually mean.
Box 8.7 Wendland—family disagreement as to patient’s wishes with minimal consciousness Robert Wendland suffered a traumatic brain injury during a motor vehicle accident in 1993. Ultimately he was diagnosed in a minimally conscious state where he could follow some simple commands (he could grab a block, for example) but was profoundly cognitively and physically disabled, unable to communicate, and could not perform any activities of daily living. He was sustained by artificial nutrition and hydration (ANH). Over a period of 2 years Wendland repeatedly pulled the feeding tube out until his wife requested it not be reinserted. His wife and children contended that Wendland was unable to recognize himself or others and that he would find this quality of life objectionable based on previous declarations he had made. Wendland’s wife argued that he was clear in his previous wishes, declaring that if he couldn’t be ‘a father, husband, or a provider’, or if he was ‘ever in a diaper’, he would refuse treatment. Wendland did not have advance directives granting his wife authority to make medical decisions for him, and problems arose when Wendland’s mother disagreed with his wife’s decision. After 6 years of court proceedings, the California Supreme Court ultimately ruled that Wendland’s wife could forgo ANH if she presented clear and convincing evidence of his wishes, or if she could establish that forgoing ANH was in his best interests. The court held that Wendland’s general declarations were too vague and that his wife would have to provide ‘an exact on all fours account of his wishes’ before the ANH could be removed. In other words, Mr Wendland would have to have predicted his current situation and specifically proscribed it. Phrases like ‘not wanting to live like a vegetable’ were found to be too general and unpersuasive. This ruling only applied to conscious, non-terminally ill patients. It can be assumed that if Wendland had been in a PVS the court may well have decided differently. Since he was not permanently unconscious, and because it was determined that he should be afforded greater protection as an incompetent person, the court ruled that his wife could not forgo ANH. Wendland died from pneumonia during the legal battle (43). Data from Nelson LJ and Cranford RE, ‘Michael Martin and Robert Wendland: beyond the vegetative state’, The Journal of Contemporary Health Law and Policy, 1999, 15, 2, pp. 427–453. Another example of family disagreement and court involvement is the case of Terri Schiavo (Box 8.8), a patient in a persistent vegetative state (PVS) whose family disagreed about her wishes in the absence of an advance directive. This case confirmed that surrogates are able to speak on behalf of a patient but confirmed that their judgement is less authoritative than that of a competent patient. Clearly this brings particular difficulty when there is family disagreement. While a competent patient can refuse treatment, even beneficial treatment, a surrogate must never act contrary to a patient’s best interest. Notably in the United Kingdom, physicians have no duty to provide futile care despite family or patient wishes to the contrary (15), and this is now a common position in many other countries.
Box 8.8 Schiavo—family disagreement as to a patient’s wishes with persistent vegetative state In 1990, Terry Schiavo experienced a cardiac arrest of unknown aetiology and entered a PVS (40,41). During the subsequent months, computed tomography brain scans showed severe atrophy of the cerebral hemispheres, and electroencephalograms were flat, indicating no functional activity of the cerebral cortex. Her husband and her paternal family vehemently disagreed about what types of medical treatment Ms Schiavo would want in her current situation (42). The patient’s husband was considered her legal guardian under Florida law, which designates the spouse as the decision maker if the patient has not previously specified another decision maker. The paternal family however did not accept the diagnosis of PVS, insisting that Ms Schiavo could improve with continued rehabilitation. They also objected to the ‘starvation’ that would result from withdrawal of feeding. Advised by physicians that there would be no improvement, the husband requested that ANH be stopped. Ms Schiavo had no advance directive, though her husband maintained that she had spoken about not wanting to be sustained artificially if there was no hope of recovery. Her parents disagreed with the husband, and the situation escalated to intense public and media support of one side or the other by multiple special interest groups. The issue quickly spilled into court. Ultimately, after years of political manipulation and court investigation, the patient’s husband
wishes prevailed and Ms Schiavo’s feeding tube was removed. She died shortly thereafter. Autopsy revealed that her brain anatomy was incompatible with cortical activity consistent with awareness of her environment (43). Data from various sources (see References). Advance directives are not a panacea and do not always dictate a clear course of action. This is illustrated by the 1987Evans v. Bellevue case (Box 8.9) which found that while a competent patient’s refusal of treatment is protected, a surrogate will likely be held to a higher standard such that ambiguity usually results in a decision to support life (44).
Box 8.9 Wirth—ambiguous advance directive with a potentially reversible condition Tom Wirth was a 47-year-old patient diagnosed with aids-related complex (ARC) and suffering from probable toxoplasmosis which was causing lesions in his brain. Wirth was unable to communicate his wishes but had executed a living will stating: ‘I direct that life sustaining procedures should be withheld or withdrawn if I have illness, disease, or injury or experience extreme mental deterioration, such that there is no reasonable expectation of recovering or regaining a meaningful quality of life.’ Wirth also had a durable power of attorney (DPA) authorized to make treatment decisions on his behalf. The court ruled that there was sufficient ambiguity in the living will, however, to prevent the DPA from forgoing treatment because, although the patient was terminally ill, he was only temporarily incapacitated since toxoplasmosis was reversible. Surrogate decision-making on behalf of patients who are not legally competent because of their age (e.g. children), or due to certain medical conditions (e.g. learning difficulties, developmental disabilities, or dementia) pose particular problems. Surrogates should still use the best interest standard of decision-making, assessing the burdens and benefits of treatment from a hypothetical ‘reasonable person standard’ to the extent that this is possible (45). The supposition is that reasonable people would, on balance, refuse treatments that carry greater risks or burdens than potential benefits, but would accept those that offer benefit without obviously causing pain and suffering. However, jurisdictions vary in the authority of a proxy to agree to WLSTs because any surrogate, be it a family member or appointed guardian, may have some conflicts in their ability to make end-of-life decisions no matter how well intended their motives. The issue with an appointed guardian not permitted to give permission for WLST in the United States was illustrated in the Tschumy case in 2012 (46). Surrogate decision-making involves making judgements about quality of life for others. This is inherently suspect because quality of life is fundamentally a subjective concept and discussions about medical interventions cannot be considered without evaluating their effect on quality of life. The goal is to assess quality of life by objectively examining benefits and burdens of treatment without making social worth judgements about individuals. The case of Joseph Saikewicz illustrates how this concept is used clinically (Box 8.10) (3). The Saikewicz case represents a scenario in which the guardian of an institutionalized individual with severe learning difficulties and an inability to communicate refused treatment on his behalf based on what would traditionally be deemed to be ‘best interests’. The guardian considered the burdens of chemotherapy(many) with the benefits (few) and advised that the treatment be forgone. Importantly, this recommendation was not made because the patient was disabled but because the means to attaining (an unlikely) temporary remission would have been cruel and inhumane. This case determined that it is possible to use the best interest standard to make decisions for individuals who have never expressed a preference regarding treatment, and for those who have never had such decisional capacity.
Box 8.10 Saikewicz—best interests of a mentally disabled patient in refusing chemotherapy for new-onset malignancy In 1976, Joseph Saikewicz was a 67-year-old man who had been institutionalized for more than 50 years. He was profoundly cognitively and physically disabled and interacted only by grunts and gestures. Saikewicz developed leukaemia that, if treated aggressively with chemotherapy, could result in a temporary 2–13 months of remission, although this was less likely in a patient older than 60. The question was whether Saikewicz would have to undergo treatment or if a guardian could refuse on his behalf despite his never having been competent. The court ruled that Saikewicz had the right to refuse treatment grounded in his fundamental right to privacy and informed consent. This ruling was curious because the notion that Saikewicz could have refused or consented was a
fiction because he never had decisional capacity. However, the standards of surrogate decision-making had yet to be clearly defined, so the court was navigating in uncharted territory (3). Data from Poland SC, ‘Landmark Legal Cases in Bioethics Bioethical Issues: Scope Notes Archive 1997’ [cited 2014 Accessed January 16, 2014]; Available from:https://repository.library.georgetown.edu/bitstream/handle/10822/556889/sn33.pdf?sequence=1 Inevitably there are times when physicians disagree with a surrogate’s interpretation of burdens and benefits and a stalemate occurs, increasing the pressure for legal resolution. A surrogate’s reasoning may be based on unrealistic expectations in any circumstance but may be particularly associated with certain religions. For example, Islam and Judaism do not support withdrawal of care (47), nor do some religious and cultural traditions in India (48). While refusal of the clinical team to follow what they believe to be unrealistic surrogate decisions may be impossible in some countries, it is supported in others such as South Africa (49), Canada (5), and Germany (50). In the United States, three professional critical care societies support a shared-decision model, believing that this can minimize intractable disagreements, but do not support the notion that physicians are the ultimate decision makers (51).
Limitations of care Although withdrawing and withholding care are equivalent from an ethical perspective, there is legal variation in different jurisdictions. In the United Kingdom, the concept that medical treatment can lawfully be withdrawn was articulated by Lord Browne-Wilkinson in the Bland case (Box 8.5) (15). Such rulings mean that treatment must never be withheld based on the notion that it cannot be withdrawn. One of the early legal precedents supporting the practice of limitation of care in an incompetent patient was the Quinlan case described in Box 8.11. Full supportive treatment is usually indicated initially after admission to the NCCU because it is often impossible to accurately prognosticate early after an acute neurological event and families often need time to come to terms with an event that has a likely poor prognosis. Thus it is common for discussions and decisions to limit or withdraw care to occur over several days, allowing time for family updates and education about likely outcomes. When decisions to limit treatment are made they generally fall along a continuum: 1. 2.
a. Do everything except CPR. b. Specific treatment limitations including vasoactive drugs, dialysis, intubation, ventilator support, antibiotics, and dialysis. 3. c. Withdrawal of all life-supporting therapies and provision of comfort care only. Each institution must develop its own protocols and nomenclature consistent with local laws, culture, and regulations. Often a ‘Do Not Resuscitate’ order, or some similar descriptor, is applied to indicate where on the continuum of care limitation the patient resides. Notably, anything that constitutes support is subject to withdrawal, following the principle of allowing a disease process to run its natural course. Such support includes not only ventilator and haemodynamic support, but also antibiotics, fluids, and, in some specific circumstances and in certain jurisdictions, nutrition (see ‘Limitation of Artificial Nutrition and Hydration’). Once a decision has been made to move to comfort care, organ donation should be considered prior to withdrawal of life-sustaining therapies (see Chapter 30).
Limitation of artificial nutrition and hydration As noted earlier, the outcome of critically ill neurological patients is often uncertain in the acute phase and it may be difficult to limit care early in the course of an illness. However, this is the period during which removing ventilation and haemodynamic support is most likely to lead to death. When treatment is continued for a period of time to allow better assessment of prognosis, the patient may become more stable and therefore less dependent on ventilator or haemodynamic support. Thus ‘early’ withdrawal of support after acute brain injury is likely to result in more rapid death, lower risk of survival with severe disability, and a lower societal burden, although at the risk of greater uncertainty about prognosis and insufficient time for considered decisions by surrogates (52). Conversely, delayed withdrawal is associated with less uncertainty about prognosis and more time for surrogates to come to terms with the prognosis, but at the risk of a prolonged dying process and a higher risk of survival with severe disability. At this stage, nutrition and hydration may be the only remaining life-support measures in place and their cessation is ethical if it is clear that the patient would not wish to survive with the likely level of disability and quality of life. However, removal of
hydration and nutrition inevitably results in a longer period before death ensues and there are concerns about discomfort in sentient patients. Together, these considerations have fuelled many disagreements regarding this aspect of end-of-life care, and forgoing enteral and parenteral nutrition is contentious. Artificial nutrition and hydration are rightly considered life-supporting therapies in patients who are unable to seek and ingest food and water independently. They are therefore logically no different than any other form of intensive care support in that they may both benefit and harm a patient. Very often, and understandably, surrogate decision makers may not grasp or accept this concept and are uncomfortable withholding such therapy. The US Supreme Court established in 1990 that artificial nutrition and hydration are medical treatments and can removed in the same way as any other treatment intervention (see Box8.6), though this concept has been challenged. Additionally, the Brophy (Box 8.12) and Bland (Box 8.5) cases confirmed the legitimacy of removing artificial nutrition and hydration in vegetative patients (15). There is broad international legal support for this practice including in the United States, United Kingdom, New Zealand, and South Africa (53), although in the United Kingdom the General Medical Council, based on case law, recommends seeking a judicial order when contemplating stopping nutrition (33).
Box 8.12 Brophy—stopping nutrition for an incompetent patient The Paul Brophy case extended the Quinlan ruling (3). Mr Brophy experienced a ruptured cerebral aneurysm on 22 March 1983, resulting in a PVS. A percutaneous gastrostomy tube was placed, through which he was fed and hydrated. After months of no improvement, the patient’s wife requested that the feeding tube be removed and her husband be allowed to die naturally. Mr Brophy’s physicians refused to withdraw the tube because they believed that doing so was euthanasia, and the matter went to court. Ultimately, the Massachusetts Supreme Judicial Court authorized Mr Brophy’s wife to transfer him to a facility that would honour her wishes. This ruling was based on evidence that Mr Brophy had previously expressed a wish that he did not want to be maintained on artificial life support should he ever require it. The Brophy case was the first case in the United States in which courts authorized a patient in PVS to die following the withdrawal of artificially supplied nutrition and hydration. Data from Poland SC, ‘Landmark Legal Cases in Bioethics Bioethical Issues: Scope Notes Archive 1997’ [cited 2014 Accessed January 16, 2014]; Available from:https://repository.library.georgetown.edu/bitstream/handle/10822/556889/sn33.pdf?sequence=1
Organ donation As well as being in a patient’s best interests, withdrawal of life support may lead to a positive outcome for others in the form of organ donation. In a brain-dead organ donor the ethical issues are relatively straightforward because the patient is pronounced dead based on neurological criteria prior to consideration of organ donation. Given the critical need for organs and a growing shortage of donors, donation after circulatory death (DCD) is playing an increasingly important role (see Chapter 30) (54). In the NCCU, controlled DCD is possible following a decision to WLST when death is predicted to occur within a relatively short timescale, usually 60 or 120 minutes after treatment withdrawal. In such circumstances, death is declared following cardiac arrest using the usual cardiorespiratory criteria of irreversible cessation of circulatory and respiratory functions. DCD is now widely practised in a number of countries despite continued controversy in many. The main point of contention is whether the usual cardiorespiratory criteria are adequate to determine death when the need for speed is paramount but the integrity of the ‘dead donor rule’ (DDR) must be maintained. Additional issues relate to the use of medications or interventions that preserve organ function but offer no benefit to, and/or may potentially harm, the donor or whether the delays that are inherent in withdrawing treatment to allow identification of potential recipients and mobilization of the retrieval team are reasonable.
The dead donor rule and autoresuscitation The DDR stipulates that patients cannot be killed for or by the removal of organs for donation (55). Much attention has been given to the minimum period of continuous cardiorespiratory arrest that is sufficient to permit the diagnosis of death and indicate the point at which organ retrieval might begin without breaching the DDR. A review of the continuous observation of asystole, apnoea, and unresponsiveness concluded that a period of no less than 2 minutes
and no more than 5 minutes of observation is adequate to allow the confirmation of death (56). Thus a minimum period of 5 minutes of continuous cardiorespiratory arrest prior to the start of organ retrieval has been recommended in the United Kingdom (57), Canada (58), and the United States (59), and 10 minutes or longer in some parts of Europe (60). Despite such evidence, some critics argue that DCD violates the DDR and that donors may be dying but not yet dead when organs are retrieved (61). This argument is based entirely on the perceived risk of spontaneous resumption of cardiac function sometime after the onset of apparently irreversible asystole, the so-called Lazarus phenomenon or autoresuscitation. The anxiety is that autoresuscitation might result in a (partial) return of neurological function. Critics of DCD point out that autoresuscitation is a poorly understood phenomenon that has not been sufficiently studied and that it cannot be guaranteed that it will not occur within 5 minutes after asystole. They argue that removing organs during a period of time in which a patient could spontaneously resume circulation would be considered homicide. A recent review identified 32 reported cases of autoresuscitation all after failed CPR, with times ranging from a few seconds to 33 minutes (62). The continuity of observation and methods of monitoring were highly inconsistent between reports but, in the eight studies reporting continuous electrocardiogram (ECG) monitoring and exact times, autoresuscitation did not occur beyond 7 minutes after failed CPR. In the absence of CPR, as in the context of controlled DCD after WLST, autoresuscitation has not been reported. Further, it is important to recognize that the time for return of circulation in reports of autoresuscitation is the time after asystole at which the circulation was noticed to have returned spontaneously. This is quite different to the specific recommendations for the confirmation of death by cardiorespiratory criteria cited earlier which require a period of 5 minutes of continuous observation for asystole, apnoea, and unresponsiveness before death can be confirmed (57,58). Any spontaneous return of cardiac or respiratory activity during this period should prompt a further 5-minute observation from the next point of cardiorespiratory arrest. Clinical observation should be supplemented with continuous ECG and intra-arterial blood pressure monitoring during WLST on the NCCU. Given such restrictions, the possibility of a spontaneous recovery of functional cardiac activity appears remote in the extreme, and has not been reported (62). Determining when someone is ‘irreversibly’ dead is fundamental to the ethical and legal delivery of controlled DCD. Critics continue to argue that death cannot be declared with certainty because it is not an instant event but a process, and that intervening in the process would mistake a dying patient for a dead one (63). Advocates of controlled DCD argue that because resuscitation is proscribed as part of WLST a patient could not possibly be resuscitated because it would be a violation of their wishes to do so. On the other hand, opponents counter that this confuses respect for an ethical norm with the reality of a clinical situation. Ethically and legally a patient cannot be assaulted with life support if refused or deemed not in their best interests but this does not change the empirical reality that one cannot be dead faster just because resuscitation is refused or organ donation is a possibility. Critics point out that we do not routinely regard people as dead 5 minutes after cessation of spontaneous circulation otherwise we would never attempt CPR.
Interventions to benefit the recipient The processes of warm and cold ischaemia threaten the viability of potentially transplantable organs. Cold ischaemia is minimized by virological screening and tissue typing of the potential donor prior to death, thereby allowing early identification of potential recipients and the earliest possible transplantation. While this requires additional antemortem blood sampling, it is supported in most jurisdictions with the informed agreement of the patient’s next of kin. To minimize warm ischaemia it is necessary as a minimum to maintain the potential donor on the current level of cardiorespiratory support until the retrieval team is mobilized and ready in the operating theatre to begin the retrieval process. Ante-mortem medications such as heparin or phentolamine are sometimes recommended in DCD protocols to optimize potentially transplantable organ function. The US Institute of Medicine recommends that these be considered on a case-by-case basis rather than as a blanket policy (64). In the United Kingdom, the Donation Ethics Committee advises that interventions aimed solely at maintaining or optimizing organ function are ethically acceptable providing they do not cause harm or distress (65). Thus heparin would be contraindicated in a patient with an intracranial haemorrhage. None of the interventions necessary to facilitate controlled DCD, even the prolongation of current levels of cardiorespiratory support until the retrieval team is mobilized, are easy to accommodate under a narrow interpretation of ‘best interests’. It is difficult to see how continued treatment can be in a patient’s physical interests if such treatment has already been judged to be futile. However, if the best interest concept is extended to include the broader wishes
and aspirations of a patient, an indication that they would wish to donate their organs after death, such as through registration with a national donation registry or discussion with the next of kin, can be interpreted by clinicians as authorization to take reasonable steps to facilitate donation (65). Such an approach is in line with other aspects of healthcare delivery where the best interests concepts is not limited to best ‘medical’ interests, but incorporates the patient’s wishes and beliefs when competent, and their spiritual and religious welfare. While not relevant to NCCU practice, there is a specific issue relating to uncontrolled DCD that is worthy of mention. This is the use of extracorporeal membrane oxygenation (ECMO) to preserve organ function during confirmation of the suitability for donation (66,67). Some DCD protocols, notably in Spain, restore vital organ perfusion after death is confirmed but avoid brain perfusion by placement of a balloon catheter to occlude blood flow to the brain (66). Despite myriad plausible ethical concerns, the Barcelona protocol receives widespread public support in Spain, one of the countries with the highest rates of organ donation anywhere in the world. However, reproducing this level of success and introducing ECMO as a routine to facilitate uncontrolled DCD are unlikely to be straightforward in other countries. It is also likely to be prohibitively expensive.
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Allocation of resources for critical care All of the ethical issues discussed so far in this chapter converge at the interface between quality of care and resource constraint. Significant international disparities in mores and financial resources have created a variety of approaches to the ethical issues that are raised by limited healthcare resources. The reader is referred elsewhere for a detailed discussion of these issues (6). Crippen sampled global attitudes about ICU resource allocation by surveying online subscribers to the Critical Care Medicine List, an international multidisciplinary group of nearly 1000 critical care providers from 12 countries in five continents (68). Nearly all countries surveyed sustain a ‘closed’ economic system in which there is a finite amount of money to spend on healthcare and most or all citizens are indemnified against the cost of illness. In general terms, healthcare costs are capped in such systems so nations must prioritize resources. Invariably, this means not offering some treatments or interventions with a poor benefit/expense ratio to allow general services to be financed for the entire population. The one country that stands out from the rest of the world is the United States where the healthcare system indemnifies only a portion of its population at great expense and runs on a ‘customer satisfaction’ maxim. Facing the prospect of unlimited expenses, third-party reimbursers (insurance companies) ration implicitly (i.e. without public debate) by denying payment on technicalities after services have been rendered or through a pre-certification process that can limit care deemed appropriate by treating physicians. In times of financial constraint, or in the face of high levels of healthcare inflation as is now the norm, healthcare systems areexpected to do more with less. Healthcare services around the world are therefore caught between the immovable object of diminishing resources and the seemingly irresistible force of increasing demand. Distributive justice refers to societal and individual duty to individuals in need (69). In the context of constrained resources, including in healthcare systems, it can involve withholding resources with little benefit to society or individuals, or redirecting them to benefit more individuals. Thus decisions may have to be made that limit expensive but futile care for a few in favour of providing care that benefits many. Such political and societal decisions are enormously complex.
Healthcare rationing Healthcare rationing has become a reality in critical care because of national resource allocation systems that limit the availability of ICU beds or, in reimbursement-driven healthcare systems, because insurers and hospitals limit access to expensive therapies. Kerz reviewed rationing of healthcare and reported that German intensivists conflicted by societal versus patient pressure had occasionally limited therapy that they believed had poor risk–benefit for a patient without disclosing this to the individual (50,70). Similar implicit rationing has been reported in the United Kingdom (71), Canada (5), New Zealand (72), South Africa (49), Switzerland (70), and Norway (70). In Italy, Law 229 established the general principles of healthcare, including equality of access to quality care and assurance of dignity, but also, and perhaps paradoxically, the need for savings in resource utilization (29). Within this context, ICU bed availability in Italy
is a form of implicit economic rationing, and limiting treatment is a relatively common occurrence and has even been suggested as a quality metric. Although decisions to ration healthcare are ultimately politically driven, politicians tend to refrain from pursuing policies on explicit rationing as too controversial and likely to threaten their own political aspirations. Political reticence to grapple publicly with these important issues is an international phenomenon that has been reviewed elsewhere (70). The National Institute for Health and Care Excellence in the United Kingdom, which approves drugs and treatments based on efficacy and cost-effectiveness, is an example of national explicit rationing that appears to receive public and clinical support (71). In the United States, attempts to control end-of-life costs led to opponents creating the spectre of ‘death panels’, thus stalling any attempt to develop an explicitly discussed rationing policy.
Limiting inappropriate admission to intensive care units One element of limiting inappropriate or futile care is the development and enforcement of explicit ICU admission and discharge criteria. The Italian Society of Anaesthesia, Analgesia, Resuscitation and Intensive Care developed guidelines outlining the clinical appropriateness of admission to an ICU that include the presence of an acute but reversible pathology, a reasonable likelihood of benefit from intensive care taking likely treatment costs into account, and a reasonable expectation that the acute critical illness will resolve as a result of the provision of intensive care (29). Although other nations have promulgated similar guidance (49,72), there are notably difficulties with uniform implementation of policies to limit ICU admission primarily related to disparate local laws and culture. Further, different recommendations within an individual country add to these difficulties. For example, the Society of Critical Care Medicine in the United States recommends giving admission priority to patients most likely to benefit from ICU care (73), whereas the American Thoracic Society recommends admission on a first come, first served basis (51).
Limiting futile care Although many patients and surrogates opt for palliative care when it becomes clear that technology cannot cure but will only protract the dying process, an increasing number have an unrealistic understanding and expectation of what ICU interventions can actually accomplish (74). There are several reasons why patients and surrogates may demand care that is deemed inappropriate (if not futile) by physicians. First, although withholding and withdrawing life support are regarded as equivalent in law and medical ethics, patients and surrogates often view them as starkly different. Second, the Internet and popular media have become the new resource for families seeking more optimistic opinions but often promulgate poorly authenticated opinions from pseudo-experts. Third, the ethical principle of autonomy is increasingly cited as justification for interventions based on a belief that any chance for life is better than no chance. Many of the issues of limitations of healthcare resources have not been addressed because they are either sociopolitically too volatile or arouse the interests of too many special interest groups to permit consensus. For example, although many publications and focus groups extol communication as a way to persuade surrogates to accept limitation of care decisions in the interests of individuals and sometimes society more broadly, virtually all stop short of supporting refusal by physicians of providing inappropriate or futile care (75). Further, physicians do not have an admirable track record of predicting death so there is always the potential for unexpected survival. Reporting of such cases is often widespread and surrogates cite such reports as reasons for continuing care. Saying no to an intervention, such as ICU admission, can be seen by some as synonymous with hastening death and a way to save money. There is also an increasingly held view that healthcare ‘consumers’ have a right to access as many resources as they need or wish and that in developed nations society must underwrite that care no matter the cost.
Making best use of intensive care resources Intensive care is the most expensive resource in a hospital and its provision is complicated by limited healthcare resources, particularly after a global financial crisis that is directly affecting the delivery of healthcare worldwide (76). It is undisputed that the daily cost of maintaining a patient in a critical care bed is already high and will continue to rise (77), or that healthcare systems will become untenable if inappropriate care, including inappropriate admission to ICU, is provided on demand (78). One way to limit waste of healthcare resources (including intensive care) on those who cannot conceivably gain benefit is to establish objective limits on its provision based on accumulating global databases that can accurately predict outcome and therefore define outcome futility on the basis of objective bedside physiological data and
premorbid status. Based on these considerations, Crippen explored the creation of a system that would maintain the cost-effectiveness and affordability of healthcare by prioritizing and thus rationing healthcare resources by refusing them (79). In this model, demonstrated effectiveness of particular treatments would be recorded in a world clinical database and providers would consult this in order to prioritize treatment for an individual. Such databases would be made accessible electronically and, when based on outcome data of many thousands of patients with a similar condition, used to inform a decision to withhold treatment on outcome futility grounds. Such an arrangement would involve saying no to a treatment or intervention, such as admission to an ICU, which would be expensive out of proportion to its benefit. Although such a plan is employed in Rie’s Oregonian ICU, those with sufficient personal funds are empowered to authorize and personally pay for whatever futile care they desire (80), a situation that would be unacceptable in many other countries. It seems certain that many of the concepts espoused in a cost-effectiveness assessment, however it is delivered, are likely to become elements of health systems worldwide.
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Monitoring 1. 2. 3. 4. 5. 6. 7.
9 Intracranial pressure monitoring Federico Villa and Giuseppe Citerio 10 Monitoring cerebral blood flow Chandril Chugh and W. Andrew Kofke 11 Cerebral oxygenation monitoring Matthew A. Kirkman and Martin Smith 12 Brain tissue biochemistry Imoigele Aisiku and Claudia Robertson 13 Multimodal brain monitoring and neuroinformatics Hooman Kamel and J. Claude Hemphill III 14 Electrophysiology in the intensive care unit Neha S. Dangayach and Jan Claassen 15 Neuroimaging Yanrong Zhang, Peter Komlosi, Mingxing Xie, and Max Wintermark
Intracranial pressure monitoring Chapter: Intracranial pressure monitoring Author(s): Federico Villa and Giuseppe Citerio DOI: 10.1093/med/9780198739555.003.0009 Intracranial pressure (ICP) is defined as the pressure exerted inside the dura mater onto the brain tissue by external forces, such as those caused by cerebrospinal fluid (CSF) and blood. Historically, ICP is synonymous with CSF pressure and is defined as the pressure exerted against a needle introduced into the CSF space to just prevent escape of fluid (1). In the adult, approximately 87% of the intracranial volume is occupied by the brain, 9% by CSF in the ventricles, cisterns, and subarachnoid space, and 4% by blood. In normal conditions, these volumes, encased within the dura mater, produce a low pressure that is reflected throughout the central nervous system (CNS). Conventionally, the normal mean ICP in adults is 5–10 mmHg (2). Head and body position, as well as pressure transmitted from other body compartments such as thorax and abdomen can cause important variations in ICP, mainly by reducing venous blood return from the head to the central circulation (3). In particular, the supine position may cause an increase in ICP as can high intrathoracic or elevated abdominal pressure (4). In physiological conditions, baseline ICP and the amplitude of the pulsatile components of the ICP waveform remain constant despite a variety of transient perturbations. The brain parenchyma is nearly incompressible and, because CSF is produced and absorbed at a constant rate, the volume of the blood in the cranial cavity is therefore almost constant. Thus, a continuous outflow of venous blood from the cranial cavity is required to make room for continuous incoming arterial blood. In health, ICP is determined by cerebral blood flow (CBF) and CSF circulation. Davson’s equation describes this relationship and states that ICP is the sum of sagittal sinus pressure and the product of CSF formation rate and resistance to CSF outflow (5). Normal values for sagittal sinus pressure, CSF formation rate, and resistance to CSF outflow are 5–8 mmHg, 0.3–0.4 mL/min, and 6–10 mmHg/mL/min, respectively. The production of CSF and equivalent re-adsorption dynamically maintains CSF volume, and therefore ICP, within the normal range, with fluctuations of only around 1 mmHg in normal healthy adult subjects. The existence of clinically relevant pressure gradients within the CNS is the subject of debate (6,7). Uniformly distributed ICP can be seen when CSF circulates freely between all its natural pools, equilibrating pressure throughout. When little or no CSF volume remains in the intracranial cavity, for example, because of brain swelling, the assumption of one, uniform value of ICP is questionable and there is considerable experimental and clinical evidence that ICP is not then evenly distributed throughout the CNS. Moreover, in patients with focal intracranial lesions, interhemispheric ICP gradients exist (6). These disappear with time and this may indicate an increase in the size of the lesion. The clinical relevance of such ICP gradients must be considered in patients with mass lesions, and the ICP monitoring probe should be located in the damaged hemisphere, as described later in this chapter. ICP therefore depends on the relative constancy of the constituents within the intracranial cavity, that is, CSF, blood, and brain tissue. The following equation describes this relationship:
VCSF+VBLOOD+VBRAIN+VOTHER=VINTRACRANIAL SPACE=Constant where ‘other’ encompass all the pathological volumes, such as haematomas, oedema, and tumours. The importance of these relationships is that, because the skull cannot easily accommodate any additional volume, ICP is a direct consequence of the volumes of brain tissue, blood, and CSF, and compensation for any added volume within its space. Small increases in the volume of any of the components of the intracranial cavity can be offset by an equal, compensatory decrease in the others. For example, if a new intracranial volume, such as haematoma, tumour, or oedema, is introduced, venous blood and CSF are displaced and initially there is little change in the ICP (Figure 9.1). In this way, small changes in the volume of one of the intracranial constituents are buffered so that there is minimal change in ICP, reflecting the compensatory reserve of the cranial space. However, when the compensatory capacity is exhausted, further increases in a constituent of intracranial volume may lead to a substantial increase in ICP.
Click to view larger Download figure as PowerPoint slide Fig. 9.1. Pressure–volume curve. Note that in the normal range, towards the origin of the x-axis (point a), intracranial pressure remains normal in spite of small additions of volume until a point of decompensation (point b) occurs. After this, each subsequent increment in volume results in an even larger increment in intracranial pressure (point c). Reproduced with permission from Citerio G. ICP Monitoring in Encyclopedia of Intensive Care Medicine, Vincent JL, Hall JB eds. Springer Verlag Ed 2012. At very high levels of ICP the amplitude of the ICP wave decreases as CBF is reduced by a reduction in intracranial compliance and perfusion pressure. Changes induced by the heart rate, systemic blood pressure, fluid status, and intrathoracic pressure invoke transient changes, compensated by CSF displacements into the lumbar space and are considered part of the steady state. For example, coughing often produces ICP exceeding 30–50 mmHg but with rapid return to baseline levels. The ICP waveform is normally pulsatile, and the mean level is commonly referred to as the ICP. Rhythmic fluctuations superimposed on this are associated with cardiac and respiratory activity, reflecting their cyclical effects on cerebral blood volume (CBV). The respiratory contribution to the ICP waveform is the result of fluctuations in arterial blood pressure and cerebral venous outflow during the respiratory cycle, generated by pressure changes in the thoracic cavity. Changes in these pulsatile fluctuations can be the earliest signs that the ICP is beginning to rise, as a reflection of the increased transmission of pressure waves through a less compliant brain. Although ICP levels greater than 15 mmHg are considered abnormal, data from the Traumatic Coma Data Bank (8) show that it is an ICP equal to or greater than 20 mmHg that is associated with poor outcome after severe traumatic brain injury (TBI) (9). Moreover, the time spent over this threshold is important. The proportion of hourly ICP readings greater than 20 mmHg is a highly significant contributor to the poor outcome noted. Episodic ICP measurements are unable to provide information regarding severity and duration of insult. Using continuous, high-resolution capture of elevated ICP over time and computer analysis, a more accurate estimation of the time spent over the threshold,
expressed as an area under the curve or ‘pressure × time dose’ (PTD) of intracranial hypertension, has been evaluated (10,11). Increasing elevated intracranial PTD is associated with mortality. Although this approach is clinically useful, it is quite simplistic and, as early as 1977, Miller stressed the uncertainty of the concept of any threshold for ICP, and the need for adaptability in treating intracranial hypertension (12). This has indeed subsequently proven to be correct (13). There is strong correlative evidence that high ICP is associated with a greater likelihood of impaired recovery after acute brain injury, and that markedly uncontrolled intracranial hypertension, leading to global ischaemia and cerebral herniation, are predictive of poor outcome. More importantly, ICP is known to be an important cause of secondary brain injury, and high ICP is consistently associated with a worse neurological outcome in patients following TBI and other neurological emergencies. Therefore ICP monitoring in the presence of a suspected disequilibrium of intracranial volumes has a sound physiological as well as clinical rationale. This chapter will provide an historical overview of the concept of ICP, of its physiological determinants, and of the technology available to monitor ICP.
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Historical overview Although cerebral swelling and the consequences of opening the skull were understood by Galen, Hippocrates, and early Egyptian physicians, the modern understanding of volume regulation within the intracranial cavity began with Kellie and Monro. In their 1783 Observations on the structure and function of the nervous system they wrote: For, as the substance of the brain, like that of other solids of our body, is nearly incompressible, the quantity of blood within the head must be the same, or very nearly the same at all times, whether in health or disease, in life or after death, those cases only excepted in which water or other matter is effused, or secreted from the blood vessels; for in these a quantity of blood, equal in bulk to the effused matter, will be pressed out of the cranium. These concepts were formalized physiologically in 1824, and became known as the Monro–Kellie doctrine. This states that, once the fontanelles and sutures are closed, the brain becomes enclosed in a non-expandable case of bone and that changes in ICP can therefore be attributed to a volume change in one or more of the constituents of intracranial contents. Physiological exploration of human CSF started in the late nineteenth century when Heinrich Quincke published his studies on the diagnostic and therapeutic applications of lumbar puncture at a medical congress in 1891 (Verhandlungen des Congresses für Innere Medizin, Zehnter Congress, Wiesbaden 10. pp. 321–31). He credited Walter Essex Wynter with the use, in 1889, of lumbar cannulation as a treatment of raised ICP in patients with tuberculous meningitis. Quincke subsequently standardized the technique and introduced a method to measure the pressure of the CSF by connecting the lumbar puncture needle to a fine glass pipette in which the fluid was allowed to rise. In the first decades of the last century, lumbar CSF pressure measurement was refined and considered to be a good and reliable indicator of ICP. However, even at that time, reports were published demonstrating that patients showing clinical signs of brain compression can have normal lumbar CSF pressure and that they were at high risk of dying during the lumbar puncture procedure. The reasons for this phenomenon were believed, quite rightly, to be the possibility of inducing brainstem compression through tentorial or tonsillar herniation during the release of CSF from the lumbar region (Figure 9.2).
Click to view larger Download figure as PowerPoint slide Fig. 9.2. Schematic representation of brain herniation syndromes. According to the Monro–Kellie doctrine, an increased volume and pressure in one compartment of the brain may cause shift of brain tissue to a compartment in which the pressure is lower. M1is an expanding supratentorial lesion; M2 is an expanding mass in the posterior fossa. A Increased pressure on one side of the brain may cause tissue to push against and slip under the falx cerebri toward the other side of the brain, B Uncal (lateral transtentorial) herniation. Increased ICP from a lateral lesion pushes tissue downward, initially compressing third cranial nerve and, subsequently, ascending reticular activating system, leading to coma, C Infratentorial herniation. Downward displacement of cerebellar tissue through the foramen magnum producing medullar compression and coma. Reproduced with permission from Citerio G. ICP Monitoring in Encyclopedia of Intensive Care Medicine, Vincent JL, Hall JB eds. Springer Verlag Ed 2012. Partly because of this apparent dissociation between ICP and clinical symptoms, emphasis switched from ICP measurement towards a focus on the relationship between craniospinal volume and pressure, particularly the importance of the elastic properties of the craniospinal system. Ryder was the first to characterize the craniospinal
volume–pressure relationship as non-linear, describing it as a hyperbolic function, which implies an increase in elastance as pressure increases (14). Furthermore, it was also partly the work of Ryder that demonstrated a differential between intraventricular and lumbar CSF pressures, thereby restoring confidence in ICP measurement. In 1895, Bayliss reported that it was impossible to obtain valid ICP measurements below the tentorium during the later stages of progressive supratentorial brain compression (15,16). For this reason, and the risk of underestimation of ICP if the two systems do not communicate, measurement of lumbar CSF pressure fell into disuse for the diagnosis of intracranial hypertension. Researchers moved to direct puncture and cannulation of the ventricular system. The first true ICP measurements were performed by Guillaume and Janny in 1951 using an electromagnetic transducer to measure ventricular fluid pressure signals in patients with various intracranial lesions (17,18,19). However, it was not until the 1960s, when Lundberg published his now classic monograph (20,21), that interest in clinical ICP measurement was rekindled (22,23,24,25,26,27,28). Using ventricular fluid pressure recording in brain tumour patients over several weeks, Lundberg was the first to delineate the frequency with which raised ICP occurs clinically, and showed that, at times, ICP could reach pressures as high as 100 mmHg. Lundberg also described three types of spontaneous pressure wave fluctuations:
◆ A waves or ‘plateau waves’ have amplitudes of 50–100 mmHg, and last 5–20 minutes. These are always associated with intracranial pathology and commonly with impending brain herniation. It has been postulated that, as cerebral perfusion pressure (CPP) becomes inadequate to meet metabolic demand, cerebral vasodilatation occurs in an attempt to restore adequate perfusion and, as a consequence, CBV increases. This leads to a vicious cycle where further decreases in CPP cause additional plateau waves and, if adequate flow is not restored, lead to irreversible ischaemic brain injury. ◆ B waves are oscillating waves up to 50 mmHg in amplitude with a frequency of 0.5–2/min. They are believed to be related to vasomotor centre instability and occur when CPP is unstable or at the lower limit of pressure autoregulation. ◆ C waves are oscillating waves up to 20 mmHg in amplitude with a frequency of 4–8/min. They have been documented in healthy individuals and are believed to occur because of interactions between cardiac and respiratory cycles. A and B waves are always pathological and require intervention to reduce ICP and maintain CPP (6,29,30). Lundberg, anticipating modern practice, wrote in 1965: The greatest value of recording the ventricular fluid pressure is the information it gives in cases of severe injury of the brain without hematoma. In these cases, intervention to decrease ICP by such means as hypertonic solutions, hyperventilation, hypothermia, drainage of fluid and removal of localized contusions, may be more rationally applied. (9,23,31,32,33,34,35,36,37,38,39,40,41,42,43) It was therefore Lundberg who suggested the absolute need for the continuous monitoring of ICP because, without it, the correct timing and evaluation of the efficacy of the therapy is impossible.
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Intracranial pressure waveform and cerebral compliance The ICP waveform reflects the arterial waveform (Figure 9.3). Brain tissue pressure and ICP increase with each cardiac cycle and the ICP waveform can thus be seen as a modified arterial pressure wave with three distinct components that are related to distinct physiological parameters (1,44): 1.
1. The first peak (P1) is the ‘percussive’ wave and related to the transmission of arterial pressure from the choroid plexus to the ventricle. It is sharp and fairly constant in amplitude. 2. 2. The second peak (P2), the ‘tidal’ wave, represents the rebound after initial arterial percussion and is related to brain tissue compliance. It generally increases as compliance decreases. A marked decrease in cerebral compliance is present if the amplitude of the P2 waveform exceeds that of P1. 3. 3. The third wave (P3) occurs because if the closure of the aortic valve, and therefore represents the dicrotic notch.
Click to view larger Download figure as PowerPoint slide Fig. 9.3. Intracranial pressure waveforms. The figure shows the waveform in a compliant system (A) and a high pressure wave recorded from a noncompliant system (B). Reproduced with permission from Citerio G. ICP Monitoring in Encyclopedia of Intensive Care Medicine, Vincent JL, Hall JB eds. Springer Verlag Ed 2012. If the craniospinal system is closed, the ICP waveform changes as ICP increases. Initially the amplitudes of both P1 and P2 increase, and then P2 increases to a greater extent than P1 so that P2 becomes predominant. As ICP rises further, all peaks finally become indistinguishable. These modifications are blunted or abolished when the system is not closed, as in the presence of a CSF leak. A rise in ICP is unfortunately a delayed phenomenon that occurs only when intracranial compensatory mechanisms have become exhausted. Therefore, earlier indicators of an impending imbalance of the system would help the
clinician in the timely detection of a potentially dangerous situation. A potential way of improving the detection of intracranial hypertension is to identify the early changes in the ICP waveform that can be extracted from continuous ICP signals. In this way, impending ICP elevation can be recognized prior to its occurrence. In an early study, Contant et al. investigated several ICP metrics to differentiate transient from refractory ICP elevation (45,46), but this seminal work has not yet translated into the clinic or been integrated into clinical monitoring systems. However, investigation of these issues is still ongoing and, in association with the development of improved computation systems and algorithms, it is likely that systems for the prediction of intracranial hypertension will be developed (26,31,47,48,49,50,51,52). Marmarou, interested in CSF dynamics, was the first to provide a full mathematical description of the craniospinal volume–pressure relationship. He developed a mathematical model of the CSF system which produced a general solution for CSF pressure (12,53,54). The model parameters have subsequently been verified experimentally in an animal model of hydrocephalus. As a corollary, Marmarou also demonstrated that the non-linear craniospinal volume– pressure relationship could be described as a straight-line segment relating the logarithm of pressure to volume, implying a mono-exponential relationship between volume and pressure. The slope of this relationship is termed the pressure–volume index (PVI), that is the notional volume required to raise ICP tenfold (13,23,55,56,57,58,59). PVI is expressed by the formula:
PVI=ΔV/(log10Po/Pm) where ΔV expresses the volume (in mL) added or withdrawn from the ventricular system, P o the initial pressure, and Pm the final pressure. Unlike elastance, that is, the change in pressure per unit change in volume (dP/dV), or its inverse, compliance, that is, change in volume per unit change in pressure (dV/dP), the PVI characterizes the craniospinal volume–pressure relationship over the whole physiological range of ICP. However, the PVI calculated from the pressure change resulting from a rapid injection or withdrawal of fluid from the CSF space has found limited use as a measure of reduced craniospinal compliance both clinically and experimentally. This is likely in part to be related to the disadvantages of the PVI method, which include the following:
◆ Manipulation of the CSF access system (e.g. ventricular drain) to test the PVI increases the risk of infection. ◆ Variability exists between measurements because of the difficulty of manually injecting consistent volumes of fluid at a constant rate of injection—as a result an average of repeated measures is usually required, further increasing the infection risk. ◆ Cerebral autoregulation status can affect PVI estimation despite a normal CPP, and the PVI may overestimate the tolerance of the intracranial system to volume loads in patients with disturbed cerebral autoregulation (14,60,61). ◆ The procedure is time-consuming and requires highly trained personal. Because of these limitations, the PVI is not routinely used in clinical practice. Top Previous Next
Cerebral perfusion pressure CPP is the difference between the mean arterial blood pressure (MAP) and ICP (16,62,63). It represents the vascular pressure gradient across the cerebral vascular beds and should be measured at the level of these beds (18,59,64,65,66). A correct setting of the arterial blood pressure transducer level is therefore crucial for the accurate calculation of CPP. At a 30° head elevation, hydrostatic pressure forces mean that measured MAP is approximately 15 mmHg lower if the transducer is ‘zeroed’ at the external auditory meatus compared to the mid-axillary level, resulting in an underestimation of actual CPP. Conversely, if the arterial blood pressure transducer is placed at midaxillary level, CPP is overestimated. It is the authors’ practice to keep both transducers (ICP and MAP) at the level of the tragus. Cerebral blood flow is determined by both CPP and cerebrovascular resistance (CVR):
CBF=CPP/CVR CVR (and thus CBF) are affected by a number of physiological variables including arterial carbon dioxide gas tension, which has a near linear relationship with CBF within the physiological range (producing a 3% increase of CBF for each mmHg of PaCO2 increase) (21,67,68,69,70), and cerebral metabolic rate for oxygen and glucose, which has a direct relationship with CBF (see Chapters 2 and 3). Another example is core body and brain temperatures. An increase in temperature produces a rise in cerebral metabolism and a coupled increase in CBF. The key point is that when intracranial compliance is reduced, even a small increase in CBF and CBV will increase ICP. Physiologically, cerebral pressure autoregulation has been defined as the ability of the cerebral vasculature to maintain flow over a wide range of CPP (~ 50–150 mmHg) (23,25,27,67,71,72,73,74). This process, termed pressure autoregulation, occurs because of reflex variations in arterial calibre and is a fundamental physiological premise governing the CPP/CBF relationship. In subjects with intact autoregulation, a rise in systemic blood pressure within the limits of cerebral autoregulation results in constriction of cerebral vessels and secondary reduction in CBV, and thus in ICP. The opposite occurs during reduction in arterial pressure. On the other hand, in patients with deranged autoregulation the cerebral vasculature is non-reactive and a rise in blood pressure leads to an increase in CBF, CBV, and ICP. The critical CBF threshold for the development of irreversible tissue damage after TBI is 15–18 mL/100 g/min. Techniques for measuring CBF at the bedside are largely experimental so most clinicians use CPP as a surrogate of CBF. However, Czosnyka has demonstrated that deranged autoregulation after TBI makes it difficult to derive a relationship between CPP and CBF (75,76,77,78,79). Several methods have been developed to assess the state of cerebral autoregulation after brain injury. Among these, the pressure reactivity index (PRx) is derived from calculation of a moving correlation coefficient between mean ICP and MAP over a few minutes (77,79,80,81,82). PRx can be measured at the bedside using computer-based analysis of the ICP and MAP signals. Patients with intact autoregulation have a PRx less than 0 (minimum value −1), that is, there is no or negative correlation between ICP and MAP, and an increase in MAP is likely to produce a reduction in ICP. On the other hand, patients with disturbed autoregulation (PRx > 0.2, maximum value 1) have a positive correlation between ICP and MAP and an increase in MAP will result in a rise in ICP. It is important to note that during calculation of PRx no constituent of intracranial volume should be changed by external interventions such as CSF drainage. Abnormal values of PRx, indicating impaired autoregulation and disturbed cerebrospinal pressure reactivity, have been demonstrated to be predictive of a poor outcome following TBI (22).
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Indications and prognostic value of intracranial pressure Clinically, increased ICP may be suggested by the presence of headache, and the Cushing triad of hypertension, bradycardia, and irregular respiratory pattern or apnoea. Increases in ICP can lead to brain herniation syndromes if not reversed or relieved (83,84,85,86). Under such circumstances outcome is largely dependent on the primary pathology and the reversal or progression of herniation. High ICP is correlated with acute neurological deterioration (87,88). Nearly one-third of severely head injured patients develop clinically manifest neurological deterioration during their hospital course, including a spontaneous decrease in Glasgow Coma Scale (GCS) motor score of at least 2 points, a further loss of pupillary reactivity, development of pupillary asymmetry of 1 mm or more, and deterioration in neurological status sufficient to warrant immediate medical or surgical intervention (89,90). The most powerful predictor of neurological worsening is the presence of intracranial hypertension (ICP ≥ 20 mmHg), either initially or during the neurological deterioration. The almost sixfold higher mortality rate in the subgroup of patients who develop such deterioration clearly indicates the need for earlier identification of impending intracranial hypertension, as well as earlier and more effective treatment. In every condition in which a pathological increase in one of the constituents of intracranial volume is likely, ICP monitoring should be considered, weighing the benefits that the knowledge of ICP will bring to the patient’s management against the costs and (small) risks of the procedure.
Traumatic brain injury
Although several researchers have demonstrated the prognostic value of ICP monitoring after TBI (8,91,92,93,94,95,96,97,98,99,100,101,102,103), there are no randomized studies that support the use of ICP monitoring to guide management. In a multicentre, randomized controlled trial conducted in Bolivia and Ecuador (BEST-TRIP), 324 patients with severe TBI were randomly assigned to receive either guideline-based management guided by monitored ICP or treatment guided by imaging and clinical examination in the absence of ICP monitoring (102,104,105,106). This study found that care focused on maintaining monitored ICP at 20 mmHg or less was not superior to care based on imaging and clinical examination in terms of the primary outcome, that is, a composite of survival time, impaired consciousness, functional status at 3 and 6 months, and neuropsychological status at 6 months. Misinterpretation of these data might lead to the conclusion that ICP monitoring and management after TBI should be abandoned, but this would be inappropriate. Even the Principal Investigator of BEST-TRIP agrees that the use of a safe and accurate quantitative index of ICP that monitors the temporal changes in ICP and response to treatment is much preferable to interventions based on semi-empirical assessment or waiting for pupillary changes to learn that we have been unsuccessful in adequately treating the patient (13,91,102,104,107,108,109,110,111). Marmarou, reporting on data from the National Institute of Health’s Traumatic Coma Data Bank, showed that following the usual clinical predictors of age, admission motor score, and abnormal pupils, the proportion of hourly ICP recordings greater than 20 mmHg was the next most significant predictor of poor outcome after TBI (9,109,112). Other data from large prospective trials carried out in single centres, and from well-controlled multicentre studies, have also provided most convincing evidence for a direct relationship between ICP and outcome (11,92,94,96,98,113,114,115,116,117,118,119). It is the authors’ opinion that, given its ease of use, safety, and cost-effectiveness, ICP monitoring should remain a key part of the monitoring strategy after TBI because of the possible catastrophic and often rapid consequences of increased ICP. However, clinical methods for interpreting ICP in the setting of individual patients must be developed, and ICP should be interpreted in association with other physiological variables that assess the adequacy of brain perfusion, such as brain tissue oxygenation (see Chapter 11). The Brain Trauma Foundation guidelines make the following evidence-based recommendations for ICP monitoring after TBI (53):
◆ Level I—there are insufficient data to support a Level I recommendation for this topic. ◆ Level II—ICP should be monitored in all salvageable patients with a severe TBI (GCS score of 3–8 after resuscitation) and an abnormal computed tomography (CT) scan, which is defined in this guideline as one that reveals haematomas, contusions, swelling, herniation, or compressed basal cisterns. ◆ Level III—ICP monitoring is indicated in patients with severe TBI with a normal CT scan if two or more of the following features are noted at admission: age over 40 years, unilateral or bilateral motor posturing, or systolic blood pressure less than 90 mmHg. Top Previous Next
Subarachnoid haemorrhage Following aneurysmal subarachnoid haemorrhage (SAH), ICP is elevated in more than 50% of cases, usually as an immediate response to aneurysm rupture (120,121,122,123,124). This is particularly evident when a re-bleeding episode occurs. The rise in ICP that accompanies SAH has been attributed to several factors including the volume of the initial haemorrhage, CSF outflow obstruction causing hydrocephalus, diffuse vasoparalysis, and cerebral swelling following massive bleeding. Intracranial hypertension after SAH has been associated with several detrimental effects, including delayed cerebral ischaemic deficits, and changes in cerebral metabolism and blood flow. Intracranial hypertension in patients with SAH has a profound impact on outcome, but unequivocal benefits of ICP monitoring and management have not been demonstrated. This might in part be related to the complexity of the underlying pathophysiology, including reduced CBF, impaired autoregulation, decreased CO 2reactivity, systemic abnormalities such as decreased intravascular volume, and biochemical abnormalities such as excitotoxicity, each of which may contribute individually to poor outcome. Despite this it seems reasonable to consider ICP monitoring in patients with poor grade SAH, particularly those who are comatose or sedated and in whom prompt and accurate clinical detection of an ongoing intracranial problem, such as cerebral oedema or hydrocephalus, is not possible. The American Heart
Association/American Stroke Association (AHA/ASA) guidelines recommend that SAH-associated acute symptomatic hydrocephalus should be managed by cerebrospinal fluid diversion (125). It has been suggested that ICP monitoring should be undertaken in patients with more severe SAH (World Federation of Neurosurgeons score ≥ 3), and that a ventricular catheter should be used as the ICP monitoring device because it offers the possibility of therapeutic draining of CSF to treat hydrocephalus (126).
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Miscellaneous There is no strong evidence for ICP monitoring in other neurosurgical emergencies (127), although it can reasonably be used in any acute brain pathology that may be associated with increased ICP and a risk of brain compartmental herniation. These include metabolic disorders, brain ischaemia (128), haemorrhagic stroke (15), and meningitis/encephalitis (129,130). The AHA/ASA guidelines for the management of intracerebral haemorrhage (15) recommend that:
◆ ICP monitoring and treatment should be considered in patients with a GCS score less than 8, those with clinical evidence of transtentorial herniation, or those with significant intraventricular haemorrhage or hydrocephalus, and that it might be reasonable to maintain CPP between 50 and 70 mmHg, depending on the status of cerebral autoregulation ◆ ventricular drainage as treatment for hydrocephalus is reasonable in patients with a decreased level of consciousness. In Reye’s syndrome, which is characterized by substantial brain swelling, there is evidence that an ICP monitoring and management strategy similar to that used for severe TBI is associated with reduced mortality and morbidity (17,19). The duration of monitoring will depend on normalization of ICP, and is highly dependent on individual patient characteristics and underlying pathology. It is the authors’ policy to stop monitoring 12–48 hours after the cessation of interventions to control ICP, and after normalization of PaCO 2.
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Intracranial pressure monitoring techniques A summarized comparison of the different ICP measurement technologies is shown in Table 9.1. Table 9.1 Comparison of the different systems available for ICP monitoring
Technology
Accurac y
Rate of infection
Rate of haemorrhaging
Cost per patient
Miscellaneous
External ventricular drainage
High
Low to moderate
Low
Relatively low
Can be used for drainage of CSF and infusion of antibiotics
Microtransducer ICP monitoring devices
High
Low
Low
High
Some transducers have problems with high zero drift
Transcranial Doppler ultrasonography
Low
None
None
Low
High percentage of unsuccessful measurements
Tympanic
Low
None
None
Low
High percentage of
Technology
Accurac y
Rate of infection
Rate of haemorrhaging
Cost per patient
membrane displacement
Miscellaneous
unsuccessful measurements
Optic nerve sheath diameter
Low
None
None
Low
Can potentially be used as a screening method of detecting raised ICP
MRI/CT
Low
None
None
Low
MRI has potential for being used for noninvasive estimation of ICP
Fundoscopy (papilloedema)
Low
None
None
Low
Can be used as a screening method of detecting raised ICP, but not in cases of sudden raise in ICP, that is, trauma
Reproduced from Raboel PH et al., ‘Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods—A Review’,Critical Care Research and Practice, 2012, pp. 1–14. Copyright © 2012 P. H. Raboel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Non-invasive intracranial pressure monitoring Several techniques for the non-invasive (i.e. without trephining the skull) assessment of ICP have been proposed over the years (20). These are usually episodic rather than continuous estimations and are not really a monitoring system. They include transcranial Doppler ultrasonography (22,24,26,28), tympanic membrane displacement (29), and optic nerve sheath diameter (32,33,34,35,36,37,38,39,40,41,42,43). Transcranial Doppler has been used to estimate ICP by calculating the difference between systolic and diastolic flow velocity, divided by the mean flow velocity, that is, the pulsatility index (PI). The PI has been found to correlate with invasively measured ICP, with correlation coefficients varying between 0.439 and 0.938 (31). Apart from being imprecise, the technique requires training and there are large intra- and interoperator differences. Moreover, the technique cannot be used in 15% of patients because of the lack of an acoustic window. A technique using the measurement of optic nerve sheath diameter (ONSD) has recently been introduced for the noninvasive detection of raised ICP, particularly in patients with severe brain injury, and is physiologically interesting. The optic nerve is part of the CNS and surrounded by a dural sheath. Between the sheath and the white matter is a small subarachnoid space (< 0.2 mm) which communicates with the intracranial subarachnoid space. In cases of increased ICP, the sheath expands (Figure9.4). Unfortunately the specificity and positive predictive value of ONSD for ICP greater than 20 mmHg are substantially less in patients demonstrating acute fluctuation of ICP between high and normal, the very population in whom knowledge of ICP is important (44). This may be because of delayed reversal of nerve sheath distension. ONSD measurement is of clinical interest because enlargement of the sheath on initial CT scan has been associated with increased mortality after severe TBI. However, the method of measuring ONSD using CT itself needs further confirmation, as does the link between early ONSD enlargement and raised ICP (45). Thus, ONSD measurement is currently not a clinical tool.
Click to view larger Download figure as PowerPoint slide Fig. 9.4. Schematic of the optic nerve image surrounded by its sheath. Reproduced from Kristiansson H et al., ‘Measuring Elevated Intracranial Pressure through Noninvasive Methods: A Review of the Literature’, Journal of Neurosurgical Anesthesiology, 25, 4, copyright 2013, with permission from Wolters Kluwer. The non-invasive techniques for measuring ICP are captivating because they are without the risks of invasive methods. However, they fail to measure ICP sufficiently accurately to be used as routine alternatives to invasive measurement, or to offer continuous monitoring of intracranial dynamics. Currently, invasive techniques are the only options for accurate measurement of ICP (31).
Invasive intracranial pressure monitoring techniques The optimal ICP monitoring device should be accurate, reliable, cost-effective, and cause minimal patient morbidity (53), concepts first described by Lundberg in 1965 (23). Accuracy and reliability are defined by the Association for the Advancement of Medical Instrumentation (AAMI) standards (http://www.aami.org/standards/index.html). An ICP measuring device should have the following specifications—pressure range 0–100 mmHg, accuracy ± 2 mmHg in the 0–20 mmHg range, and maximum error of 10% in the 20–100 mmHg range. According to the available evidence, ICP monitoring devices have been ranked according to their accuracy, reliability, and cost as follows (Figure 9.5) (5): 1. 2. 3. 4. 5. 6.
1. Intraventricular devices incorporating a fluid-coupled catheter and an external strain gauge transducer 2. Intraventricular devices incorporating microstrain gauge or fiberoptic technology 3. Parenchymal pressure transducer devices 4. Subdural devices 5. Subarachnoid fluid-coupled devices 6. Epidural devices.
Fig. 9.5. Different sites of ICP monitoring.
Click to view larger Download figure as PowerPoint slide Reproduced with permission from Citerio G. ICP Monitoring in Encyclopedia of Intensive Care Medicine, Vincent JL, Hall JB eds. Springer Verlag Ed 2012.
Ventricular catheters Measurement of ventricular fluid pressure is the established reference standard for measuring ICP (60). A catheter placed into one of the ventricles through a burr hole and connected to an external strain gauge transducer is the most accurate, low-cost, and reliable method of monitoring ICP (62) (Figure 9.5). This method has been proven to be reliable over time, and permits periodic recalibration and therapeutic drainage of CSF. The major pitfalls of this standard ventricular system are that obstruction of the catheter can occur, and for correct interpretation the external transducer must be maintained at a fixed reference point, usually the external auditory meatus. Changes in position of the transducer may lead to inaccurate assessment of ICP during clinical use. The small holes at the tip of the catheter can become obliterated by blood clots or fibrin deposits and, if this happens, CSF drainage will generate significant pressure gradients between the ventricular catheter lumen and the ventricles resulting in a gross underestimate of ICP. Moreover, a traditional ventricular catheter connected to an external strain gauge transducer system allows only intermittent ICP monitoring when the ventricular drain is closed. Another potential pitfall is the recording of ICP while the ventricular catheter is draining CSF. In this situation the recorded ICP is always equal to or lower than the drainage level because of the hydrostatic laws of communicating vessels. If the actual ICP value is higher it will be underestimated. Some commercially available ventricular catheters have a pressure transducer within their lumen, allowing simultaneous ICP monitoring and CSF drainage. It is the authors’ opinion that, before making a clinical decision based on ICP measured via a ventricular catheter, the correct position of the transducers should be verified and the ‘three-way’ tap system between catheter and transducer system checked to ensure that CSF is not being drained during ICP measurement. Dependence on such human factors, as well as the need for calibration and choice of reference level, is a major disadvantage to monitoring ICP using a ventricular catheter.
Although surgical placement of the external ventricular catheter is often seen as a minor procedure with few risks, it can be associated with serious haemorrhagic and infectious complications. Based on a meta-analysis, the overall haemorrhagic complication rate from ventriculostomy placement by neurosurgeons is approximately 7%, with a risk of significant haemorrhage of approximately 0.8% (64). An important caveat has to be kept in mind when considering these figures, namely that normal coagulation variables are advocated before inserting external ventricular drains (EVDs) in order to reduce the haemorrhagic risk. Catheter-related ventriculitis and meningitis are potentially life-threatening complications caused by direct catheter contamination during introduction or by subsequent retrograde bacterial colonization of the catheter (67,68,70). Ventriculostomy-related infection (VRI) is characterized by (67):
◆ one or more positive CSF culture or Gram’s stain ◆ progressively declining CSF glucose level ◆ increasing CSF protein profiles ◆ worsening CSF pleocytosis ◆ a paucity of clinical symptoms other than fever. The use of closed drainage systems, aseptic CSF sampling techniques, and prompt removal of unneeded ventricular catheters minimizes the risk of catheter-related infections. The quoted incidence of VRI is wide, ranging from 0% to greater than 20%, depending on the definition of infection used and the clinical characteristics of the study population. A large meta-analysis evaluating 23 major studies of ventriculostomy use in 5261 patients with 5733 EVD insertions confirmed a cumulative rate of positive CSF culture of 8.80% per patient, or 8.08% per EVD placement. As noted in other reports, studies that defined infection using clinical indicators in addition to a positive CSF culture showed an infection rate of 6.62% per patient or 6.10% per EVD. Risk factors for VRI include those that are known to be associated with CSF infection, such as intraventricular and subarachnoid haemorrhage, operated depressed cranial vault fracture, skull base fracture with CSF leak, intracranial surgery, ventriculostomy irrigation, duration of ventricular catheterization, and systemic infection (67). In addition, factors that are possibly associated with CSF infection, including the site of ventriculostomy insertion, corticosteroid use, CSF pleocytosis, catheter manipulations, and CSF leak around the catheter insertion site, are also likely risk factors for VRI. The most commonly found pathogens in VRI have traditionally been skin flora, but Gram-negative organisms are increasingly being recognized as causative agents. No recommendations can be made regarding the administration of prophylactic antibiotics for EVDs (80), but it is not the authors’ practice to use antibiotic prophylaxis while a ventriculostomy is in place. However, the use of a comprehensive care bundle (83,85), and antibiotic or silverimpregnated catheters (131,132,133,134,135), may decrease the incidence of catheter-related CSF infection. In highrisk populations, antibiotic-impregnated catheters delay the occurrence of infection compared with non-antibiotic coated systems, and a recent meta-analysis supports the general use of antibiotic-coated ventricular catheters to minimize the risk of VRI (87).
Intraparenchymal transducers The most common alternative location for ICP monitoring is the brain parenchyma, and ICP measurements that correlate well with the ‘gold standard’ values obtained from intraventricular catheters can be obtained using intraparenchymal microtransducers (89). Such devices are of two types—solid-state devices based on pressuresensitive resistors forming a Wheatstone bridge, or those that incorporate a fibreoptic design (FOD). Fibreoptic devices, such as the Camino ICP Monitor (Integra LifeSciences, Plainsboro Township, New Jersey, USA) (95,100,110) transmit light via a fibreoptic cable towards a displaceable mirror at the tip. Changes in ICP distort the mirror and the differences in intensity of the reflected light are translated into an ICP value. Solid state devices, such as the Codman MicroSensor (Codman & Shurtleff, Raynham, MA, USA) (136,137), the Raumedic Neurovent-P ICP sensor (Raumedic, Helmbrechts, Germany) (102,104,106), and the Pressio sensor (Sophysa, Orsay, France) (138), belong to the group of piezoelectric strain gauge devices. When the transducer is bent because of a change in ICP its resistance changes and this is converted into an ICP value. Intraparenchymal ICP probes are usually placed in the right frontal region at a depth of approximately 2 cm. The Codman and Raumedic sensors are compatible with magnetic resonance imaging (MRI) without any danger to the patient but the Camino and Pressio sensors contain ferromagnetic components and are not.
All microtransducers share a common drawback—it is not possible to recalibrate them after placement. Although both types of system are very accurate at the time of insertion, there is a degree of zero drift over time (91,102,104,107,108,109,110,111), which can result in a measurement error after several days (65). Zero drift expresses the difference between the starting ICP value when the sensor is calibrated (0 mmHg) and the measured value after removal. A large difference between these two values, rarely encountered in clinical practice, indicates that the ICP measured while the device was in use was not the actual ICP at any given moment. It is always advisable to check any catheter for zero drift at removal. Data regarding differences between microtransducer ICP monitoring devices are summarized in Table 9.2. Table 9.2 Comparison of the different invasive transducers available for ICP monitoring
Technology
Camino ICP Monitor
Rate of infection
Fibreoptic
Rate of haemorrhaging
8.5 % 4.7 5%
2.50% (0.66% clinical significant) 1.1%
Technical errors
Zero drift
4.5 % 10 %
3.1
4%
Codman MicroSensor
Strain gauge
0% 0%
0% ~ 0.3% (0% clinical significant)
n/a
Raumedic Neurovent-P ICP sensor
Strain gauge
0%
2.02% (0% clinical significant)
n/a
Pressio
Strain gauge
n/a
n/a
n/a
Mean 7.3 ± 5.1 mmHg (range –17 to 21 mmHg) Mean – 0.67 mmHg (range –13 to 22 mmHg) Mean 3.5 ± 3.1 mmHg (range 0 to 12 mmHg) Mean 0.9 ± 0.2 mmHg (range –5 to 4 mmHg) Mean 0.1 ± 1.6 mmHg/100 hours of monitoring Mean 2.0 mmHg (range –6 to 15 mmHg) Mean 0.8 ± 2.2 mmHg (range –4 to +8 mmHg) 1.7 ± 1.36 mmHg (range –2 to 3 mmHg) In vitro: 0.6 ± 0.96 mmHg (range 0 to 2 mmHg) Mean – 0.7 ± 1.6 mmHg/100 hours
Technology
Rate of infection
Rate of haemorrhaging
Technical errors
Zero drift
Spiegelberg
Pneumatic
0%
0%
3.45%
of monitoring In vitro: 7-day drift 80%)
Causes
2
↑ CBF or ↓ CMRO
2
2
↓ ABP ↓ PaO ↓ PaCO ↑ ICP or ↓ CPP Seizures 2
2
Failure of oxygen utilization (cellular metabolic failure) Cerebral hyperaemia Arteriovenous shunting Brain death
ABP, arterial blood pressure; CBF, cerebral blood flow; CMRO 2, cerebral metabolic rate for oxygen; CPP, cerebral perfusion pressure; ICP, intracranial pressure; PaCO 2, arterial partial pressure of carbon dioxide; PaO 2, arterial partial pressure of oxygen; SjvO2, jugular venous oxygen saturation. There are several limitations of SjvO2 monitoring. It is an invasive technique with risks of haematoma and carotid puncture during catheter insertion, and jugular vein or sinus thrombosis during prolonged monitoring. The catheter must be correctly sited to avoid contamination from the extracranial circulation which is minimal when the catheter tip lies at the level of the lower border of the first cervical vertebra on a lateral cervical spine radiograph. The facial vein is the first large extracranial vein draining into the internal jugular vein and rapid aspiration of blood samples (> 2 mL/min) will result in contamination of samples from this source. Further, since SjvO 2 is a global measure it is unable to detect regional ischaemia (31). Notably, areas of critically low perfusion can be missed by SjvO 2 monitoring as their effluent blood might have only a small impact on the flow-weighted SjvO 2 value which will then be predominantly determined by venous return from well-perfused areas, and therefore normal. Evidence from a combined PET and SjvO2 monitoring study demonstrated that more than 13% of the brain must become ischaemic before the SjvO 2 falls below 50% (32). SjvO2 values accurately reflect global cerebral oxygenation only if the dominant jugular bulb is cannulated but, despite this, the right side is almost exclusively chosen in clinical practice (33). Although widely used for decades, SjvO2 monitoring is being superseded by PtiO2 monitoring.
Brain tissue oxygen tension monitoring Intraparenchymal PtiO2 monitoring is increasingly being utilized whenever intracranial pressure (ICP) monitoring is indicated, and has become the ‘gold standard’ bedside monitor of cerebral oxygenation (34,35). Whilst PtiO2 values can be influenced by CBF, PtiO2 is not a direct measure of blood flow but a complex and dynamic variable representing the interaction between cerebral oxygen delivery and demand (oxygen metabolism) (35), as well as tissue oxygen diffusion gradients (36). PET studies have identified correlations between PtiO 2, regional CBF (37), and regional venous oxygen saturation (38) and, as such, PtiO2is likely to represent a balance between CBF, OEF, and PaO2. PtiO2 is influenced by several physiological variables in addition to PaO 2, including mean arterial pressure (MAP) and CPP (7,39). Whilst reductions in PtiO2 may occur because of reduced CBF, PtiO2 can also be decreased in the presence of normal CBF reflecting the key influence of PaO 2 (18), and also because of increased brain tissue gradients for oxygen diffusion following ABI (40). PtiO2 should therefore be considered as a biomarker of cellular function rather than a simple monitor of hypoxia/ischaemia, making it an appropriate therapeutic target after ABI.
Technological and practical aspects PtiO2 monitoring devices used in clinical practice incorporate closed polarographic Clark-type cells with reversible electrochemical electrodes. The catheters are approximately 0.5 mm in diameter and can be inserted into the brain parenchyma using single or multiple lumen bolts, through a burr-hole or at craniotomy. The PtiO 2 probe is usually placed in subcortical white matter and measures local PtiO 2 within a radius of approximately 17 mm2 (41). The correct placement of the probe should be confirmed with a non-enhanced cranial CT scan as knowledge of location is important for correct interpretation of readings. A ‘run-in’ period is required because PtiO 2 readings are unreliable in the first hour after insertion. It is important to perform an ‘oxygen challenge’ when first commencing PtiO 2 monitoring, and then on a daily basis, to ensure both the function and responsiveness of the probe. FiO 2 is increased to 1.0 for approximately 20 minutes and a normal response is indicated by an increase in baseline PtiO 2 of 200% or more at the 20-minute point compared to baseline, although responsiveness will obviously be influenced by pulmonary function (42). As highlighted earlier, knowledge of the location of the probe is crucial when interpreting PtiO 2 values. Some recommend that PtiO2 monitoring should be conducted in ‘at risk’ perilesional tissue, such as the region immediately surrounding intracerebral haemorrhages or contusions (Figure 11.2D and 11.2E), and in appropriate vascular territories in cases of aneurysmal SAH. PtiO2 values in these ‘at-risk’ regions are lower than in normal appearing brain tissue (43). For the neurosurgeon, attempting such precise placement can be technically challenging, occasionally producing an undesired intralesional location (Figure11.2F). Conversely, it is sometimes technically impossible to place a PtiO2 probe near a lesion (Figure 11.2B) and some argue for routine placement in ‘normal appearing’ areas of brain (Figure 11.2A, C). Thus, in many instances, and especially after diffuse cerebral injury, PtiO 2 is measured in normal appearing frontal subcortical white matter, preferably in the non-dominant (right) side. Notably, heterogeneity of brain oxygenation even in ‘undamaged’ areas of brain is well recognized (44). Placement directly into an area with no expected blood flow, for example, in an infarction or haemorrhage (Figure 11.2F), does not yield useful information.
Fig. 11.2. Brain tissue PO2 probe locations relative to injury on post-placement computerized tomography scan. (A) Diffuse injury and global cerebral oedema with a left frontal probe—note the right frontal EVD. (B) Focal injury with contralateral probe placement. (C) Focal injury (right basal ganglia ICH) with ipsilateral probe placement—note the bilateral external ventricular drains. (D) Perilesional probe placement (large left basal ganglia ICH). (E) Perilesional probe placement (right basal ganglia ICH)—note the effacement of the lateral ventricle and left frontal EVD. (F) Probe placement within right MCA infarction. EVD, external ventricular drain; ICH, intracerebral haemorrhage; MCA, middle cerebral artery. Adapted with kind permission from Springer Science + Business Media: Neurocritical Care, ‘Intracranial multimodal monitoring for acute brain injury: a single institution review of current practices’, 2010, 12, pp. 188–198, Stuart RM et al., Neurocritical Care Society. The measured PtiO2 value is influenced by the composition of the microvasculature and the relative dominance of arterial or venous vessels in the region of interest around the probe. PtiO 2 is assumed to largely reflect venous PO2 because venous vessels constitute more than 70% of the cortical microvasculature (37). Since normal arterial PO2 is approximately 12 kPa (90 mmHg) and cerebral venous PO2 is 4.66 kPa (35 mmHg), a wide range of values for PtiO 2 is observed (45).
Indications PtiO2 monitoring is primarily used in the management of TBI and poor-grade aneurysmal SAH, but in some centres also during cerebral angiography (46) and surgery for intracranial aneurysms (47) and arteriovenous malformations (48). Low PtiO2is associated with poor outcome after severe TBI (44,49,50,51,52,53), with evidence for a dose– response relationship (44). The Brain Trauma Foundation recommends incorporating the monitoring and management
of PtiO2 as a complement to ICP/CPP-guided management in patients with severe TBI (30). After SAH an association between low PtiO2 and outcome has been reported in some (54,55) but not all (56,57) studies. Nevertheless, guidelines from the Neurocritical Care Society recommend PtiO 2 monitoring in comatose SAH patients (58) as it can identify patients at high risk of delayed cerebral ischaemia (DCI) (57,59). PtiO2 is a valid complement to transcranial Doppler and radiological monitoring after SAH, but its focal nature means that it will miss vasospasm arising in remote brain regions. PtiO2 monitoring has raised questions about the efficacy of triple H therapy (hypertension, haemodilution, and hypervolaemia) in the treatment of DCI after SAH. Induced hypertension improves CBF and PtiO 2, whereas hypervolaemia and haemodilution have negligible or even negative effects (60). As a result, induced hypertension alone is now the preferred treatment of DCI (58). PtiO2 monitoring has been used to identify CPP targets for optimal brain tissue oxygenation in comatose patients with intracerebral haemorrhage (ICH), and reduction in perihaematomal PtiO 2 is correlated with poor outcome (61). Further, brain tissue hypoxia improves as ICP reduces and CPP increases following decompressive craniectomy, suggesting that PtiO2monitoring might assist in the selection of those who might benefit from surgical decompression (62). Despite a current lack of evidence from randomized controlled trials confirming the utility of PtiO 2-directed therapy on outcome following ABI, PtiO2 monitoring and management is widely considered to be a useful complement to ICP/CPP standard care.
Thresholds for therapy Normal brain PtiO2 values are considered to be in the region of 4.66–6.65 kPa (35–50 mmHg) (63), and a PtiO2 value less than 2.66 kPa ( lighter indicates increased intensity, y-axis low to high frequencies). Rows 6 and 7—asymmetry index. Row 8—asymmetry relative spectrogram. Rows 9 and 10—amplitude integrated interval. Row 11—suppression ratio (duration of suppressed EEG; i.e. < 5 mv for > 0.5 s). Row 12—alpha delta ratio (power of alpha frequency divided by delta frequency). Other EEG data reduction display formats include the cerebral function analysing monitor (CFAM), EEG density modulation, automated analysis of segmented EEG, and the bispectral index monitor ( 7,8). Rhythmicity indices, such as the rhythmic run detector (see Figure14.3), indicate increasing periodic activity or rhythmicity ( 9). Spectral measures are well suited for signals with easily identifiable signatures in the frequency domain, while temporal recurrences in the time domain are useful for the detection of patterns which may have a much more complicated frequency domain representation because of compound morphologies or non-periodic repetitions. For complex signals, recurrence analysis provides a convenient and complementary measure to spectral characteristics that can
be used either as a sole analysis method or to augment existing seizure detection or prediction algorithms. Applying more sophisticated analytical algorithms, such as empirical orthogonal functional analysis, to the spectral analysis data may further aid the detection of seizures and brain ischaemia ( 10). In practice, a combination of measures may yield the highest success rate for the analysis of the wide range of patterns of interest in acutely brain-injured patients. Detailed descriptions of the various qEEG methods have been published elsewhere ( 11,12,13,14). With the advent of powerful microprocessors, data processing of this type can now be performed in real time at the bedside. qEEG analysis equipment is readily available and most manufacturers have integrated it to some extent into their software packages. Importantly, qEEG should never be interpreted in isolation but always in the context of the underlying raw EEG and always by those with proper training in electroencephalography. It is unrealistic to expect 24hour coverage by a trained electroencephalographer in all NCCUs but it is now possible for well-trained NCCU staff to obtain qEEG recordings and seek interpretation through a web-based link from a remotely stationed specialist with access to at least one excerpt of the correlating raw EEG ( 15,16).
Automated seizure detection Early seizure detection software was primarily based on machine learning algorithms and analyses of seizures in patients in epilepsy monitoring units (EMUs) with ictal activity that has a clear onset and offset, and easy to recognize changes in maximum EEG frequency. Unfortunately, artefacts and non-seizure related EEG changes result in low sensitivity and specificity for detecting seizures outside an EMU and particularly in the ICU. Further, seizures in the ICU are rarely classic in nature. Borderline-type seizure activity is frequently encountered leading to a high falsenegative rate with automated seizure detection algorithms.(17) Additionally many EEG patterns encountered in the ICU do not fulfil classic seizure definitions and are often described by the term ‘ictal-interictal continuum’( 18). Compared to classic seizures these EEG patterns are less organized and lack clear on- and offset ( 3). Substantial research effort has been spent on defining such patterns unequivocally ( 10,19). Automated seizure detection software has been used on ICU EEG datasets to train algorithms and, anecdotally, appears to have increased specificity and sensitivity for seizure detection on the ICU. Again, none of the algorithms are sufficiently accurate to replace trained interpretation of the raw EEG and, given the variability of qEEG findings encountered following acute brain injury, there is some doubt that this will ever be accomplished. Seizure detection programs make use of specialized EEG processing software that can be used to screen large amounts of cEEG data and mark sections containing activity that are suggestive of seizures. Based on an FFT analysis of the EEG, CSA graphs can be generated to determine the occurrence of subclinical seizures. Once the CSA ‘signature’ of a seizure in an individual patient has been determined it can quickly be used to screen a 24-hour recording and quantify the seizure frequency (20). Paroxysmal events may at times be identified using the CFAM, though the sensitivity of this system for detecting partial seizures is limited. Gotman and Vespa et al. have developed automated seizure detection algorithms with limited success (21,22).
Depth and surface EEG recording as part of multimodality monitoring Invasive multimodality brain monitoring is increasingly used in comatose patients with severe brain injury and has many promising applications including early detection of evolving brain injury, prevention of secondary injury such as vasospasm, and individualizing treatment in the aftermath of acute brain injury. A number of different devices are available to measure and track either upstream effectors or downstream indicators of neuronal health, including neuronal activity, and brain tissue metabolism, oxygenation, and perfusion ( 23). These modalities are described in detail elsewhere in this book. Surface and depth EEG monitoring may become an integral part of multimodality monitoring, although few studies have investigated this to date ( 24,25,26,27,28). Following acute brain injury, electrographic seizures have been associated with tachycardia, tachypnoea, elevated ICP, increased cerebral perfusion pressure (CPP), elevated lactate:pyruvate ratio monitored by microdialysis, reduction in jugular bulb oxygen saturation followed by decreasing partial brain tissue oxygenation, and a delayed increase in regional cerebral blood flow (CBF) ( 24,25,26,28,29). There may be differences between focal depth seizures (Figure14.4) and more widespread seizures detected on surface EEG, with the latter requiring higher levels of cerebral glucose to be sustained (27). Depth seizures may be associated with a worse functional outcome than surface seizures and are clearly associated with a poorer prognosis than no seizures in the setting of a relatively preserved EEG background (27).
Click to view larger Download figure as PowerPoint slide Fig. 14.4. A 62-year-old woman with poor grade subarachnoid haemorrhage (Hunt Hess grade 5) and large intracerebral haematoma (panel A) underwent clipping of a left MCA aneurysm. (A) Cranial CT scan demonstrating large intracerebral haemorrhage. (B) and (C) Surface EEGs are artefact contaminated but depth recordings at the bottom of the panels show intermittent runs of ictal discharges.
EEG applications There are multiple applications for EEG monitoring in critically ill neurological patients.
Subclinical seizures and status epilepticus Acute seizures and status epilepticus (SE) are common in all acute brain injury types and not restricted to patients with pre-existing epilepsy or those admitted with seizures or SE (Figure14.5). A substantial proportion of seizures seen in the NCCU setting are non-convulsive in nature and therefore detectable only if EEG monitoring is employed. Although some patients with non-convulsive seizures (NCSz) may have very subtle clinical signs such as face and limb myoclonus, nystagmus, eye deviation, pupillary abnormalities, and autonomic instability ( 30,31,32,33), many have purely electrographic seizures (34,35). None of these clinical manifestations, even if present, are specific for NCSz and cEEG is necessary to confirm or refute the diagnosis of NCSz. The underlying aetiologies for convulsive SE and non-convulsive SE (NCSE) are similar and include structural brain lesions, infections, metabolic derangements,toxins, alcohol withdrawal and epilepsy, all of which are common diagnoses in the critically ill ( 36).
Click to view larger Download figure as PowerPoint slide Fig. 14.5. A 30-year-old woman presented post-partum day 6 with decreased mental status. Her poor mental status persisted after clot evacuation and angiography suggested reversible cerebral vasoconstriction syndrome (Call– Flemming syndrome). (A) Cranial CT shows a right frontal intracerebral haemorrhage. (B) and (C) Surface EEG revealed ongoing electrographic seizures arising from the right hemisphere which were controlled by levetiracetam and phenytoin. NCSz occur in 48% and NCSE in 14% of patients with generalized convulsive SE (GCSE) following control of convulsions (37). In ICUs, patients without any clinical signs of seizure activity, and after excluding those with a history of neurological disease, 8% have been reported to have NCSE ( 35,38). However, in the NCCU, up to 34% patients may have NCSz and up to 76% NCSE (39). Patients receiving continuous intravenous antiepileptic drugs (AEDs) for the treatment of refractory SE should always be monitored with cEEG since subclinical seizures may occur in more than half during treatment. Further, the majority of such patients have subclinical seizures after discontinuation of therapy and cEEG should therefore be monitored to detect or exclude ongoing seizure activity in any patient who does not quickly regain consciousness after a convulsive seizure. This includes those who are sedated and/or paralysed during the treatment of SE in whom level of consciousness cannot be assessed adequately. NCSE is associated with high morbidity and mortality in critically ill patients ( 40,41,42,43). Experimental models and pathological studies confirming neuronal damage from SE pertain primarily to GCSE and, as no randomized controlled study has conclusively proven that treating NCSz or NCSE alters outcome, it is not entirely clear if treating these EEG phenomena is beneficial. However, overwhelming evidence has emerged that NCSz and NCSE have potential to further damage the injured brain. Studies have demonstrated elevations of neuron-specific enolase (NSE) ( 44,45), brain interstitial glutamate (25), lactate:pyruvate ratio (46,47), and ICP (47), brain tissue hypoxia (29,46), increasing mass effect (47,48,49), and hippocampal atrophy on follow-up MRI (50) after NCSz and NCSE.
Duration of monitoring There are no prospective studies that have evaluated different durations of cEEG monitoring in patients with SE. One compared routine EEG to continuous video EEG and found that routine EEG monitoring detected fewer than half of electrographic seizures identified by cEEG (11% versus 27%) (51). In a retrospective analysis of electrographic data obtained from patients with depressed conscious level from an undetermined cause, 20% did not have a first seizure until after 24 hours of monitoring and 13% until more than 48 hours after monitoring was begun ( 52). However, the yield from further cEEG monitoring is low in a patient not in coma if no clinical or electrographic ictal activity is detected within the first 24 hours of monitoring (34). Recently published guidelines recommend that delays in initiating cEEG monitoring should be minimized as the cumulative duration of SE affects neurological outcomes and mortality (53). These guidelines further recommend at least 48 hours of monitoring for comatose patients with acute brain injury and at least 24 hours for those not in coma.
EEG findings Efforts are underway to standardize, at least for research purposes, definitions of ictal and ictal-interictal EEG patterns (19). A wide range of epileptiform discharges has been described following SE ( 54,55), and controversy exists regarding the interpretation and therapeutic implications of periodic epileptiform discharges (PEDs) that do not meet formal seizure criteria (18,56). Periodic lateralized epileptiform discharges (PLEDs) may be both ictal and interictal (57,58) and additional information regarding their nature can be determined by using serial EEG data ( 55,59), focal hyperperfusion on single-photon-emission CT (60), and increased metabolism on fluorodeoxyglucose positron emission tomography (61). PEDs may represent ictal activity in the comatose patient if they are associated with some type of evolution in frequency, amplitude, and location. Supplementary testing, including a trial of benzodiazepines, imaging, measurement of serum markers, and invasive brain monitoring, may guide the physician in managing patients with these EEG findings (62). The importance of focal findings and EEG pattern recognition in critical care lies in generating appropriate differential diagnoses and prognosis, and some common EEG patterns are shown in Table14.1. Another frequent EEG pattern in encephalopathic ICU patients is ictal or interictal appearing activity that is triggered by stimulation or arousal. This evoked activity is typically on the ictal-interictal continuum and has been termed stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) (63). As with most ICU seizures there is usually no clinical correlate, although a small portion of patients do exhibit focal motor seizures that are consistently elicited by alerting stimuli ( 64). Table 14.1Common electroencephalographic patterns
EEG pattern
Clinical association
PLEDS
Acute ischaemic stroke Herpes encephalitis
FIRDA
ICP dysregulation Hydrocephalus after SAH
Alpha or beta coma
Treatment with barbiturates or benzodiazepines
Generalized slowing
Metabolic encephalopathies
Triphasic waves
Metabolic encephalopathies
Burst suppression
Arrhythmic theta/delta
Induced by propofol, barbiturates, or benzodiazepines in the treatment of SE Post-cardiac arrest Various medications
EEG pattern
Clinical association
activity FIRDA, frontal intermittent rhythmic delta; PLEDs, periodic lateralized epileptiform discharges; SAH, subarachnoid haemorrhage.
Metabolic and infectious encephalopathy Critically ill patients are susceptible to many toxic, metabolic, and electrolyte imbalances that may cause both mental status changes and seizures. The incidence of non-convulsive seizures in conditions such as hypo- and hyperglycaemia, hyponatraemia, hypocalcaemia, drug intoxication or withdrawal, uraemia, liver dysfunction, hypertensive encephalopathy, and sepsis has been variably reported to lie between 55% and 22% ( 41). Sepsis and acute kidney injury may also be associated with electrographic seizures ( 36,40). While certain periodic discharges are more closely related to systemic metabolic abnormalities, such as triphasic waves in hepatic encephalopathy, the significance of others such as PLEDs, recently renamed as lateralized periodic discharges (LPDs), is controversial. A benzodiazepine trial may be useful to differentiate ictal from non-ictal EEG patterns in selected critically ill patients. However, almost all periodic discharges including periodic triphasic waves seen in metabolic encephalopathy are attenuated bybenzodiazepines (65) and, unless there is clinical improvement accompanying the EEG change, the test remains non-diagnostic. Unfortunately, clinical improvement can take a substantial amount of time even if the EEG activity of NCSE is aborted with benzodiazepines and it is important to recognize that lack of immediate clinical improvement does not exclude NCSE and that the use of benzodiazepines simply helps determine its presence or absence.
Traumatic brain injury Between 15% and 22% of patients with moderate or severe traumatic brain injury (TBI) develop convulsive seizures and although the incidence of NCSz is less well-studied rates between 18% and 28% have been reported (66,67,68). As well as being used to diagnose seizures, EEG monitoring after TBI may be used to monitor clinical course, to guide titration of sedative medications (particularly during the management of raised ICP) and to diagnose post-traumatic complications. The goal is to individualize therapeutic approaches in order to detect and treat secondary brain injury as early as possible and prevent further ischaemic damage ( 69). Craniotomy defects create breach artefact (i.e. higher amplitude of EEG activity due to the skull defect) and scalp oedema and subgaleal haemorrhages may lead to attenuation of the EEG, and must be taken into account when interpreting the EEG after TBI. High-dose benzodiazepines, propofol, or barbiturate infusions may be needed to manage intracranial hypertension after TBI and EEG may be used as an endpoint of such therapy. Burst suppression has been proposed as a titration goal during such treatment. A simple two-channel left and right hemisphere recording is sufficient to titrate the therapeutic dose needed to induce burst suppression, monitor steady-state conditions, and avoid unnecessarily high doses which may result in significant cardiovascular side effects. A number of EEG findings are associated with outcome following TBI including seizures, periodic discharges, lack of sleep architecture, and EEG reactivity. A qEEG monitoring approach using changes in the EEG variability has been used to predict outcome after TBI (70,71). In this study, data reduction was achieved by focusing on the percentage of alpha-frequencies (PA) at multiple electrodes and determination of PA variability (PAV) over time. A low PAV, and particularly a decrease in PAV over time, strongly correlated with fatal outcome especially in patients presenting with low Glasgow Coma Scale (GCS) score. In particular, PAV during the initial 3 days after injury was significantly associated with outcome independent of clinical and radiological variables. Another interesting approach to outcome prediction after TBI utilizes EEG background attenuation and low-amplitude EEEG events ( 72). In a study of 32 TBI patients, periods of EEG suppression were quantification to derive the EEG silence ratio (ESR), and outcome at 6 month was closely related to the ESR during the first 4 days after injury ( 73). Limitations of this method include artificial increases of the ESR by some sedative agents, and ESR monitoring is most useful in comatose TBI patients undergoing sedation with benzodiazepines and opioids. In the Co-operative Study for Brain Depolarisation (COSBID), patients with TBI underwent electrocorticographic recordings with subdural electrodes and prolonged depolarizations
were associated with isoelectricity or PEDs, prolonged depression of spontaneous activity, and occurrence in temporal clusters, all of which were associated with poor prognosis ( 74).
Subarachnoid haemorrhage In patients with SAH, seizures may occur at the time of the ictus, at any point during the hospital stay, and long after discharge. While the underlying mechanisms differ, all seizures are associated with worse outcome after SAH. Studies have reported convulsive seizures rates of 4–9% at the time of the initial bleed often in the setting of a focal clot or rebleeding episode (75). However, several more recent cEEG studies suggest that the incidence of electrographic seizures following SAH, especially in comatose patients, is actually much higher. In the Columbia series of 570 patients who underwent cEEG for altered mental status or suspicion of seizures, 19% of 108 SAH patients had seizures, primarily NCSz, and 70% of the patients with seizures went on to develop NCSE ( 76). Quantitative analysis of cEEG has been used to detect delayed cerebral ischaemia (DCI) after SAH (Figure14.6) (70,76,77). The qEEG parameter that best correlates with clinically significant ischaemia is controversial but most authors agree that using a ratio of fast over slow activity (e.g. alpha over delta activity, or relative alpha variability) is the most practical approach (12,13,70) A number of qEEG parameters including trend analysis of total power (1–30 Hz) (77), variability of relative alpha (6–14 Hz/1–20 Hz) (70), and post-stimulation alpha:delta ratio (PSADR, 8–13 Hz/1–4 Hz) (76) have been shown to correlate with DCI or angiographic vasospasm. In a retrospective study of 34 poor-grade SAH patients monitored from postoperative day 2–14, a reduction in the post-stimulation ratio of alpha and delta frequency with a power of greater than 10% relative to baseline in six consecutive epochs of cEEG was 100% sensitive and 76% specific for DCI, whilst a reduction of more than 50% in a single epoch was 89% sensitive and 84% specific (76). All studies have found that focal ischaemia sometimes results in global or bilateral changes in the EEG, and importantly that EEG changes may precede clinical deterioration by several days ( 70). Rathakrishnan and colleagues measured relative alpha power and variability in the anterior brain quadrants and termed this the composite alpha index (CAI) (78). In 12 patients with DCI, the sensitivity of predicting clinical deterioration with cEEG improved from 40% to 67%, and clinical improvement from 8% to 50%, using this modification of more usual methods. In three patients in this study, cEEG was predictive of deterioration more than 24 hours prior to clinical changes. Tracking the daily mean alpha power accurately has also been used to identify DCI recurrence and poor responders to first-line therapy at pre-clinical stages (79). A small feasibility study reported that intracortical mini-depth electrodes may have a role in detecting ischaemia from vasospasm in poor-grade SAH patients, and that it may be superior to scalp EEG and allow automated detection, particularly using the alpha:delta ratio ( 80). cEEG monitoring provides independent prognostic information in patients with poor-grade SAH, even after controlling for clinical and radiological findings, and unfavourable findings include PEDS, electrographic SE, and the absence of sleep architecture ( 81).
Click to view larger Download figure as PowerPoint slide Fig. 14.6. Detection of delayed cerebral ischaemia from vasospasm after subarachnoid haemorrhage. A 57-year-old woman was admitted with acute subarachnoid haemorrhage (admission Hunt–Hess grade 4) from a right posterior communicating aneurysm that was clipped. cEEG was performed from SAH days 3 to 8 (right panel). The alpha:delta ratio (ADR) progressively decreased after day 6, particularly in the right anterior region (thick vertical grey arrow), to settle into a steady trough level later that night, reflecting loss of fast frequencies and increased slowing over the right hemisphere in the raw cEEG. On day 7, the GCS dropped from 14 to 12 and a CT scan showed a right internal capsule and hypothalamic infarction. Angiography demonstrated severe distal right MCA and left vertebral artery spasm intra-arterial verapamil and papaverine were infused. This resulted in a marked but transient increase of the right anterior and posterior alpha/delta ratios (right panel). Reprinted fromClinical Neurophysiology, 115, 12, Claassen Jet al., ‘Quantitative continuous EEG for detecting delayed cerebral ischemia in patients with poor-grade subarachnoid hemorrhage’, pp. 2699–2710, Copyright 2004, with permission from Elsevier. The combined use of somatosensory evoked potentials (SSEPs) and cEEG monitoring is a unique example of dynamic brain monitoring (82). The temporal variation of these two parameters evaluated by continuous monitoring can establish whether treatments are properly tailored to the neurological changes induced by the lesions responsible for secondary brain damage. Using a logistic regression model, progressive deterioration on the basis of EEG was associated with a 24% increased risk of dying compared to no worsening of the EEG ( 82). SSEP changes were also significantly associated with outcome; for patients with worsening SSEPs, the odds of dying increased to approximately 32%.
Intracerebral haemorrhage ICH is associated with a 3–19% rate of in-hospital convulsive seizures ( 49,83,84,85,86), and 18–21% of patients have cEEG-confirmed NCSz (48,49). Vespa et al. demonstrated that NCSz were associated with increased midline shift and a trend toward worse outcome even after controlling for haemorrhage volume ( 48). In another study, Claassen et al. found that NCSz were associated with haematoma expansion and mass effect and a trend towards poorer outcome (49). In addition, PEDs were an independent predictor of poor outcome after ICH but it remains unclear whether their presence should change management.
Ischaemic stroke
It has long been known that cerebral infarction may result in polymorphic delta activity, loss of fast activity and sleep spindles and focal EEG attenuation. These EEG findings reflect abnormal CBF and cerebral metabolic rate of oxygen as demonstrated by positron emission tomography and xenon-CT-CBF imaging ( 87,88). EEG is very sensitive for ischaemia and usually demonstrates changes at the time of reversible neuronal dysfunction when CBF is in the 25–30 mL/100 g/min range (89). It is also very sensitive at detecting restoration of blood flow and may demonstrate recovery of brain function from reperfusion earlier than the clinical examination ( 90). A population-based cEEG study in 177 patients with acute ischaemic stroke (AIS) reported a 7% incidence of seizures (> 70% of them NCSz) in the acute (within 24 hours) phase ( 86), and hospital-based studies have reported rates of acute clinical seizures following ischaemic stroke ranging from 2% to 9% ( 83,84). Acute clinical seizures are associated with increased mortality after AIS (83,84,91,92). In a prospective study of 232 stroke patients (177 ischaemic and 55 haemorrhagic strokes), EEG recording was performed within 24 hours of admission to hospital and follow-up lasted 1 week (93). Fifteen patients (6.5%) had early (within 24 hours) seizures and ten of these had focal SE with or without secondary generalization. There were sporadic epileptiform focal abnormalities in 10% and PLEDs in 6%. SE was identified in more than 70% of the patients with PLEDs and multivariate analysis confirmed that early epileptic manifestations were independently associated with PLEDs ( 93). EEG may be of additional value by confirming or excluding definite stroke after resolution of symptoms in lacunar and posterior circulation syndromes of presumed ischaemic origin, and for prognostication of short-term functional status in lacunar and anterior circulation syndromes ( 94,95) In the subacute setting of ischaemic stroke, EEG may be of prognostic value for disability, dependency, and death at 6 months. In a study of 110 ischaemic stroke patients, the pairwise-derived Brain Symmetry Index (pdBSI) and (delta + theta)/(alpha + beta) ratio (DTABR) were significantly correlated with the modified Rankin Scale (mRS) score at 6 months ( 96). Dependency was independently predicted by the National Institute for Health Stroke Scale (NIHSS) and DTABR with odds ratios (ORs) of 1.22 and 2.25 respectively. Six-month mortality was independently associated with age at stroke onset (OR 1.18), NIHSS (OR 1.11), and DTABR (OR 2.04). In a study of EEG power spectra analysis, six of ten patients displayed a peak in the EEG power spectrum at 5–10 Hz and all sixhad a Glasgow outcome score (GOS) of 3 and level of consciousness (LOC) score of 7 or higher at discharge, whereas the patients without faster EEG activity had a GOS of 2 and LOC of 6 or lower ( 97). In contrast, the 4 patients without faster EEG activity had a GOS of 2 and LOC 6 or lower. Discharge GOS, LOC, and NIHSS significantly correlated with the presence of 5- to 10-Hz activity but not with age, time to hemicraniectomy, duration of hospital stay, or baseline NIHSS scores. Three-month outcome was significantly correlated with age and the presence of faster EEG activity. In a prospective study of cEEG monitoring in 25 patients with malignant middle cerebral artery (MCA) territory infarction, the absence of delta activity and presence of theta and fast beta frequencies within the focus were found to be predictive of a benign course, whereas diffuse generalized slowing and slow delta activity in the ischaemic hemisphere predicted a malignant course (98). Decrease in CPP is associated with a reduction in faster EEG activity (99) and rapid improvements in background EEG activity have been observed when CPP/CBF increase following mannitol therapy or haemodilution (100,101).
Post-cardiac arrest In patients with post-cardiac arrest hypoxic-ischaemic encephalopathy, the presence of seizures has important prognostic value and may also be a contributor to decreased conscious level ( 102). In addition, as therapeutic hypothermia is more widely implemented after cardiac arrest (see Chapter25), cEEG may become an important tool for identifying NCSz especially during re-warming (103). Convulsive and non-convulsive SE is common in comatose post-cardiac arrest patients undergoing therapeutic hypothermia and most seizures occur within 12 hours. About 20– 35% of cardiac arrest patients develop NCSz and NCS (34,104,105) and outcomes are poor in those who go on to NCSE and convulsive SE (102,106,107). In patients treated with hypothermia after cardiac arrest, EEG monitoring during the first 24 hours after resuscitation can contribute to the prediction of both good and poor neurological outcome. Low-voltage EEG after 24 hours predicts poor outcome with a sensitivity almost twice that of the bilateral absence of SSEP responses ( 108). EEG reactivity has a particularly high predictive accuracy for outcome after cardiac arrest in those treated with hypothermia ( 109). In a study of 111 patients with prolonged coma, continuous amplitude-integrated EEG and SSEP monitoring, repeated sampling of NSE and brain MRI were undertaken (110). In patients with NSE blood concentration greater than 33
ng/mL, all ten who underwent MRI had extensive brain injury, 12 of 16 had absent cortical responses on SSEP monitoring, and all six who underwent autopsy had extensive severe histological damage. NSE levels also correlated with EEG pattern but less uniformly because only 11 of 17 patients with NSE blood concentration less than 33 ng/mL had electrographic SE, although only one recovered. A reactive cEEG pattern correlated with NSE blood concentration less than 33 ng/mL. In summary, hypothermia-treated cardiac arrest patients with good neurological outcome have different early qEEG suppression and epileptiform activity compared to those with poor outcome ( 110). A scoring system based on a combination of clinical and EEG findings has been used to predict the absence of early cortical SSEP response and, in settings without access to SSEPs, may aid decision-making in a subset of comatose cardiac arrest survivors (111). In 192 post-cardiac arrest patients of whom 103 were hypothermic and 89 normothermic, myoclonic SE was invariably associated with death as were malignant EEG patterns and global cerebral oedema on cranial CT scan (112). qEEG and auditory P300 event-related potentials were studied in 42 conscious survivors of cardiac arrest 3 months after the incident and no difference was found in any assessment of cognitive function between those treated with hypothermia and normothermia ( 113). Sixty-seven per cent of patients in the hypothermia group and 44% in the normothermia group were cognitively intact or had only very mild impairment, whereas severe cognitive deficits were present in 15% and 28% of patients in the hypothermia and normothermia groups respectively. All qEEG parameters were more normal in the hypothermia-treated group, but these differences did not reach statistical significance.
Postoperative patients Seizures can occur in any postoperative setting in which there is an acute neurological injury, a high risk of metabolic derangement, or neurotoxicity. Postoperative cEEG monitoring may be indicated in selected patients undergoing surgery for supratentorial lesions or those with pre-existing epilepsy ( 114,115). Other high-risk groups for seizure development include patients undergoing cardiac surgery (116) and solid organ transplantation (117,118), although the incidence of NCSz and NCSE in these patient groups has not been studied systematically.
Top Previous Next Evoked potentials
Evoked potentials (EPs) are used for diagnosis and monitoring in the ICU and operating theatre. EPs are electrical potentials recorded from the nervous system following presentation of a stimulus and evaluate conduction along neural pathways. EPs can be auditory, visual, or electrical and are essentially an event (stimulus)-gated averaged EEG recording. The amplitude of EPs is orders of magnitude smaller than EEG signals and requires signal averaging and precise localization of the recording electrode to measure a response ( 119). For example, when measuring a SSEP multiple stimuli are applied rapidly and the cortical responses from a fixed time segment (e.g. 0–120 milliseconds) following the stimuli are averaged. The EEG signal averages out at each time point following the stimulus, whereas the peaks and troughs of the evoked response increase in amplitude. At the end of the repetitive simulations the average of all the time segments produces the displayed EP. Diagnostic EPs are evaluated on the basis of their latency and amplitudes of the waveform peaks and troughs compared to laboratory-established norms in healthy individuals, or to contralateral recordings in an individual patient. In the operating theatre, EPs are compared to initial baselines. SSEPs allow assessment of the integrity of different sensory pathways from the periphery to the central integrator. The latency is the time taken for a stimulus to travel between two measurement points, such as between the stimulating electrode and the cortical recording electrode, and is expressed in milliseconds. The amplitude is typically reported in microvolts (μV) and, by convention, negative signals are displayed as upward deflections and positive as downward. SSEPs are the second most frequently used electrophysiological investigation after EEG in the NCCU and are less affected by sedation and hypothermia than EEG (120). EPs have many other advantages over EEG and other techniques and these are summarized in Box14.2(121).On the downside, significant technical expertise is required to record and interpret EPs, strict grounding and electrical safety procedures have to be followed, and in awake patients EPs may be perceived as painful.
Box 14.2Advantages of evoked potential monitoring
◆Non-invasive ◆May be used serially ◆Provides objective quantitative values that can be tracked over time and compared between patients ◆Relatively stable in the presence of mild hypothermia ◆Relatively resistant to many commonly used sedatives ◆Provides information about subcortical structures ◆Inexpensive.
Types of evoked potentials Evoked potentials can be sensory or motor and there are several types of sensory EPs.
Somatosensory evoked potentials SSEPs test the integrity of the dorsal column-lemniscal system (121). This pathway is responsible for carrying light touch, vibration, and deep proprioception via the sensory component of spinal nerves to the dorsal root ganglion and then via the dorsal column of the spinal cord to the cuneate (upper extremities) and gracilis nuclei (lower extremities), both located in the lower brainstem. The tracts cross over at the level of the medulla and project via the medial lemniscus to the ventroposterior lateral thalamus and then to the primary somatosensory cortex Brodmann area 3,2,1 and finally to a wide network of cortical areas involved in somatosensory processing. Although different peripheral spinal nerves can be used for assessing the integrity of the dorsal column-medial leminscal system, the median and tibial nerves are most often stimulated during SSEP monitoring (Table14.2). Table 14.2Normal values for evoked potentials from healthy volunteers
Recording site
Latency, mean (ms)
Latency, upper limit (ms)
N9
Erb’s point (brachial plexus)
9.8
11.5
N13
Cervical spine (C7)
13.3
14.5
N20
Contralateral cortex (CP3 or CP4)
19.8
23.0
—
5.6
6.6
N8
Popliteal fossa
8.5
10.5
N22
Lumbar spine (L1)
21.8
25.2
P30
Fz–Cv7
29.2
34.7
P39
Cz–Fz
38.0
43.9
Median SSEP
Intervals median CCT (P14– N20) Tibial SSEP
Intervals tibial
Recording site
Latency, mean (ms)
Latency, upper limit (ms)
N22–P30
—
7.4
10.2
P30–P39
—
8.7
13.4
CCT, central conduction time; SSEP, somatosensory evoked potential. This table was published inMonitoring in Neurocritical Care, Le Roux Pet al. (eds), ‘Brainstem Auditory Evoked Potentials and Somatosensory Evoked Potentials’, Carrera Eet al., pp. 175, Copyright Elsevier 2010. The SSEP stimulus is a brief electric pulse delivered by a pair of electrodes placed on the skin above the relevant nerve, with a ground electrode placed between the stimulation and the recording sites. The recording electrodes can be standard disc or plate electrodes. For upper limb median nerve SSEP recording, stimulating electrodes are placed over the anterolateral wrist area. Recording electrodes are located at the clavicle between the heads of the sternocleidomastoid muscles (Erb’s point) to confirm transmission of the impulse from the peripheral nerve, on the skin overlying cervical bodies 6–7 to confirm entry into the central nervous system and over the cortex to identify the cortical potential. Cortical recording electrodes are placed according to the international 10–20 system depending on the stimulated nerve. For example, CP3 and CP4 are used for median nerve SSEPs. For tibial nerve SSEPs, stimulating electrodes are placed at the ankle between the Achilles tendon and medial malleolus and recording electrodes in the popliteal fossa, over the lumbar vertebra and over the cortex. This electrode configuration produces a standard pattern of EP waveforms from each recording electrode (Figure14.7). For clinical purposes the early responses, known as ‘short latency’ SSEP signals, are used. These are usually the waveforms recorded at about 20 milliseconds after stimulation and designated N20. The later signal components are more susceptible to the effects of medications and level of consciousness. Although they are currently neglected during clinical monitoring, they carry significant information that may be utilized in the future (121).
Click to view larger Download figure as PowerPoint slide Fig. 14.7. Median nerve somatosensory evoked potential (SSEP) recording. From the bottom of the figure upwards, the four anatomical sections are:
•cervical spinal cord axial section •brainstem axial section •midbrain axial section •brain coronal section including basal ganglia and cortex. The waveforms reflect recording made from cortical and cervical electrodes. This figure was published inMonitoring in Neurocritical Care, Le Roux Pet al. (eds), ‘Brainstem Auditory Evoked Potentials and Somatosensory Evoked Potentials’, Carrera Eet al., pp. 175, Copyright Elsevier 2010. At least two bipolar channels (e.g. CPz–FPz and CP3–CP4) should be used to record the cortical component of the SSEP whose waveform is obtained by averaging between 500 and 2000 stimuli. It is necessary to repeat at least two independent averages to demonstrate reproducibility. SSEPs are recorded using a broad pass-band filter with highpass and low-pass filters typically set to 30 and 2000 Hz respectively. Notch filters are used to eliminate electrical noise (60 Hz) but can sometimes produce an oscillatory ‘ringing’ artefact.
Brainstem auditory evoked potentials Brainstem auditory evoked potentials (BAEPs) are produced by an auditory stimulus which activates the cochlea, auditory nerve, and the brainstem auditory pathways (122). The first 10 milliseconds of the recorded signal represent conduction of the stimulus through the brainstem and this is the BAEP ( 122). Recording electrodes are placed between Cz (according to the international 10–20 system) and the ipsilateral ear. The normal BAEP typically shows
five to six waves which are attributed to different generators and labelled with corresponding Roman numerals (Figure14.8):
◆Wave I—auditory nerve ◆Wave II—auditory nerve as it exits the porus acoustics or the cochlear nerve ◆Wave III—cochlear nucleus or ipsilateral superior olivary nucleus ◆Wave IV—superior olivary nucleus or axons of lateral lemniscus ◆Wave V—inferior colliculus and ventral lateral lemniscus.
Click to view larger Download figure as PowerPoint slide Fig. 14.8. Brainstem auditory evoked potentials (BAEPs). The figure shows a BAEP in response to a 90 db click in a 49-year-old woman with a right frontal brain tumour. Although the exact identity of short-latency BAEP waveforms remains somewhat uncertain, commonly recognized generators include:
•the distal auditory nerve (wave I) •the auditory nerve as it exits the porus acousticus or the cochlear nucleus (wave II) •the cochlear nucleus or ipsilateral superior olivary nucleus (wave III) •the superior olivary nucleus or axons of the lateral lemniscus (wave IV) •the inferior colliculus and ventral lateral lemniscus (wave V). Because waves II and IV are less reliably recorded across individuals, clinical interpretation is based primarily on assessment of waves I, III, and V. This figure was published inCarrera Eet al., ‘Evoked Potentials’, in LeRoux PDet al. (eds),Monitoring in Neurocritical Care, Copyright Elsevier 2013. The stimulus used to generate a BAEP consists of a brief ‘click’, typically delivered at approximately 10 Hz. The stimuli are presented to one ear at a time using headphones or ear inserts whilst the non-stimulated ear is ‘masked’ with white hissing noise to prevent sound stimulation being conducted through the cranium. Standard surface or needle electrodes may be used to record BAEPs which are typically recorded using a two-channel montage from the ipsilateral ear to vertex (channel 1) and contralateral ear to vertex (channel 2). Averaging of 2000–4000 stimuli is typically required and, as with SSEPs, at least two independent averages must be recorded to prove reproducibility of
waveforms. BAEPs are recorded using a broad pass-band filter with the high-pass filter typically set to 100 Hz or 150 Hz and the low-pass filter to 3000 Hz. If the auditory nerve is damaged, wave I will be absent. The absence of waves II–V with a recordable wave I indicates structural or functional disruption of the auditory pathway between the site of the absent wave and the auditory cortex.
Visual evoked potentials Visual evoked responses (VEPs) are monitored from a recording electrode over or near to the visual cortex following the application of a visual stimuli such as a flashing light or a flickering checkerboard ( 123). Measured from the primary recording electrodes over the primary visual cortex, these stimuli typically produced a negative deflection at approximately 75 milliseconds (N75) and a positive deflection at approximately 100 milliseconds (P100). VEPs are rarely used in the ICU.
Motor evoked potentials Motor evoked potential (MEPs) interrogate the integrity of the motor pathway and are primarily used in the operating theatre. They are generated using magnetic stimulation at or close to the primary motor cortex and recorded from electrodes placed in relevant muscles. MEPs are rarely used in the ICU.
Evoked potential monitoring in the intensive care unit In the ICU, EPs are primarily used for prognostication, particularly after cardiac arrest and TBI. Diagnostically, they have largely been replaced by imaging studies, invasive neuromonitoring (e.g. brain tissue oxygen monitoring and cerebral microdialysis) and cEEG. However, serial and even continuous EP monitoring is possible ( 120,124) and may be considered where continuous invasive or other non-invasive neuromonitoring modalities are of limited value or contraindicated such as in evolving spinal cord or brainstem injury. The reader is referred to recently published consensus recommendations for the use of EPs in the ICU for further information ( 125).
Technical considerations There are many issues that must be taken into account during EP monitoring on the ICU. Effect of sedative medications The subcortical components of EPs are relatively unaffected by level of consciousness and sedative medications but the cortical components are more easily depressed in a dose-dependent manner ( 126,127). However, interpeak changes are more stable and comparing left- and right-sided recordings may be useful, particularly during SSEP monitoring. Neuromuscular blockade does notaffect SSEPs, VEPs, or BAEPs but is contraindicated during MEP monitoring (119). Electrical artefact Electrical artefact or ‘noise’ may interfere with recordings in the ICU and this will influence the accuracy and interpretation of the recordings (128). Notch filters may eliminate electrical artefact but can introduce a ‘ringing’ oscillatory artefact. Hypothermia Therapeutic temperature modulation or mild therapeutic hypothermia is increasingly being used in the ICU. The prognostic accuracy of EP variables that have been associated with outcome, such as the N20 SSEP after cardiac arrest, is not significantly affected by mild hypothermia (33°C) ( 129). Risks EP studies are non-invasive and considered safe. However, several ICU-specific considerations regarding electrical safety must be kept in mind (130). ICU patients are at a high risk for electrical injury and induction of cardiac arrhythmias and, to reduce these risks, all electrical equipment must be appropriately grounded ( 122).
Indications There are several indications for EP monitoring in the ICU. Post-cardiac arrest EPs can be used for prognostication after cardiac arrest and absence of short latency (N20) SSEPs is the most reliable predictor of poor outcome in anoxic-ischaemic encephalopathy. Neurological examination does not reliably predict the presence or absence of specific SSEP patterns, particularly the N20 responses ( 131). In a meta-analysis of 4500 patients with post-cardiac arrest cerebral anoxia, bilaterally absent N20s within the first week had 100% specificity for the prediction of poor outcome (132). A prospective study of 407 cardiac arrest patients demonstrated bilaterally absent N20s in 45% of patients who were comatose at 72 hours and all of these had poor outcome ( 133). Combining SSEPs with other predictors of outcome after cardiac arrest, such as EEG or serum markers of neuronal injury, improves prognostic accuracy (134,135). However, whilst some predictions can be made for poor recovery it is much more difficult to predict good outcome. In a prospective study of 111 cardiac arrest patients who underwent therapeutic hypothermia, none with absent SSEPs 24 hours after discontinuation of sedation had a favourable neurological outcome (109). In a retrospective study of 185 post-cardiac arrest patients treated with therapeutic hypothermia, 36 had bilaterally absent SSEPs and only one made a good recovery ( 136). In a smaller control study of 60 cardiac arrest patients, 30 of whom underwent therapeutic hypothermia, no patient (in either hypothermia or normothermia groups) with absent SSEPs at 24 hours post arrest regained consciousness ( 129). In contrast, a recent study reported recovery of consciousness and normal cognitive function in two post-cardiac arrest patients treated with hypothermia with absent or minimally detectable cortical N20 responses on day 3 after arrest ( 136). In summary, SSEPs have a high specificity for poor outcome in comatose post-cardiac arrest patients and are easy to use, low cost, and minimally affected by drugs and metabolic derangements. A major limitation is their relative low sensitivity for poor outcome (137). The large majority of studies supporting the robust prognostic accuracy of SSEPs were conducted before the use of hypothermia and further investigation of their prognostic accuracy in patients treated with hypothermia, with investigators blinded to the test result to avoid a self-fulfilling prophecy, is crucial. However, a recent meta-analysis of the use of SSEPs to predict neurological outcome in patients treated with therapeutic hypothermia after cardiopulmonary resuscitation demonstrated that the false positive rate assessed the false positive of a bilaterally absent SSEP N20 response was low and comparable with that reported in patients treated with normothermia ( 138). Several other SSEP variables are associated with outcome after cardiac arrest but they are less robust than absent cortical SSEP responses. These include central conduction time (CCT), the time from cervicomedullary (N20) to cortical (P14) peaks, the N20-to-P25 amplitude ratio ( 139), and the N70 latency (140). False positives are common (between 4% and 15%) and make it impractical to base treatment decisions on these parameters. Late SSEP components may be better associated with long-term cognitive outcome than short-latency components but are not routinely used (141). The role of BAEPs after cardiac arrest has not been systematically studied. In one study they were not found to be useful for prognostication (129), although in a small cohort study of 13 patients, middle latency auditory evoked responses (MLAEPs) were absent in all patients who died or remained in a persistent vegetative state ( 142). A recent study combined EEG and BAEPs in patients with post-anoxic coma and used two sets of recordings, the first performed within 24 hours post cardiac arrest and under mild hypothermia and the second after 1 day under normothermic conditions (143). A deterioration of auditory discrimination between the two sets of recordings had a 100% positive predictive value for non-survival. Tracking auditory discrimination in comatose patients over time could provide new insight into the chances of awakening in a quantitative and automatic fashion during early stages of coma. Traumatic brain injury Following TBI, bilaterally absent cortical SSEP responses in the presence of intact peripheral and spinal potentials is associated with poor outcome (144). In a review of studies (n = 44) addressing the prediction of outcome after severe brain injury using SSEPs, the positive likelihood ratio, positive predictive value and sensitivity for normal SEPs predicting favourable outcome were 4.04, 71.2%, and 59.0% respectively, and 11.41, 98.5%, and 46.2% respectively
for bilaterally absent SEPs predicting unfavourable outcome ( 144). The false-positive rate of bilaterally absent SEPs for the prediction of poor outcome was less than 0.5%. Serial EPs may allow early detection of the onset of recovery after TBI. For example, reduction of latency or normalization of amplitude may occur earlier than clinical signs of recovery (Figure14.9) (124,145). Moreover, serial EPs can provide early warning of the development of secondary brain injury including haematoma enlargement, increased ICP, brainstem herniation, and cerebral ischaemia ( 146,147). Poor long-term functional outcome (death or vegetative state at 2 years) has been reported in comatose patients with traumatic brainstem lesions and absent N20s who did not recover consciousness within 48 hours of the injury ( 148), although it must be remembered that recovery of the N20 does not necessarily equate to recovery of brain function. Prolongation or absent CCT is associated with poor 1-year cognitive and behavioural function after TBI (149). Although rare, reappearance of previously absent bilateral SSEPs may occur after TBI and has been describedin some patients with good outcome after infratentorial haemorrhage or following hemicraniectomy (150).
Click to view larger Download figure as PowerPoint slide Fig. 14.9. Recovery of somatosensory evoked potential (SSEP) after TBI. This 14-year-old boy was admitted in a deep coma (GCS score 3) with severe diffuse axonal injury associated with elevated intracranial pressure. GCS score improved on day 13 post TBI but he did not move his left side purposefully until day 26. The initial median nerve SSEP was severely abnormal. Left cortical recordings were absent, and right hemispheric responses were prolonged with severely decreased amplitude. For the left cortical projections, the first indication of recovery was documented with somatosensory evoked potentials on day 10. Over the next few days, these somatosensory evoked potential findings improved. Twenty-three days after injury, latencies of the right cortical projection were within normal limits, whereas amplitudes remained reduced. One year after the accident, he suffered from minimal residual speech impairment and has returned fully to his former activities. Ischaemic and haemorrhagic stroke The role of EPs in outcome prediction after AIS and intracerebral haemorrhage (ICH) is limited and less well studied than after TBI or coma from toxic or metabolic causes. Although several EP observations can be associated with the
anatomical location of a stroke, EP is rarely used clinically to guide clinical management. BAEPs obtained within 24 hours of malignant MCA territory stroke may identify patients at risk of malignant oedema ( 151). Recovery of motor function after putaminal or thalamic ICH generally parallels normalization of SSEP components ( 152) but SSEPs do not provide the same predictive accuracy of poor outcome in coma from other neurological injuries. BAEP and SSEP abnormalities are observed in SAH patients with poor functional outcome ( 147,153) and as in other pathologies bilaterally absent cortical potentials carry a dismal prognosis (147). Brain death In a review of different international practice parameters and guidelines for determining brain death, it was reported that there is a lack of consensus on the exact criteria for defining brain death due to differences in cultural perceptions and beliefs, but about 40% recommended some confirmatory testing ( 154). Many practice parameters and guidelines accept EPs as one option for a confirmatory test (154) but the American Academy of Neurology’s recently updated guidelines on the determination of brain death do not include SSEPs as a recommended ancillary test ( 155). On serial examination, patients evolving to brain death lose subcortical SSEPs and all BAEP responses, and loss of median nerve SSEP non-cephalic P14, and its cephalic referenced reflection N14 as well as the N18, is seen in brain death (156,157). However, the disadvantages of relying on SSEPs or BAEPs for the confirmation of brain death are multiple, including the fact that they cannot be interpreted by all clinicians and, most importantly, that there is a likelihood of false-positive and false-negative results. Spinal cord injury After spinal cord injury (SCI) SSEPs can assist in localizing the level of injury and in determining prognosis for functional outcome. Latencies and amplitudes of tibial SSEPs change over time after SCI and the early presence of a tibial SSEP is associated with a favourable functional and neurological outcome ( 158). Median and ulnar SSEP are valuable to indicate the level of injury, degree of sensory impairment, and to predict the outcome of hand function even in unconscious patients (159). SSEPs and MEPs have similar significance in predicting functional outcome of ambulatory capacity, hand and bladder function, as clinical examination (160). The electromyogram (EMG), neurographic, and reflex recordings of acute SCI patients with spinal shock are more sensitive than clinical examination in assessing associated damage of peripheral motor pathways and allow the possibility of predicting the development of muscle tone or muscle atrophy ( 161). Event-related potentials Event-related potentials (ERPs) are long-latency potentials visualized by applying signal-averaging techniques to the EEG and are thought to reflect more complex cognitive processing of stimuli. Examples of ERPs include P300, N100, and mismatch negativity (MMN). The N100 is thought to represent attention ( 162), the P300is elicited by a rare taskrelated stimulus, and the MMN by an ‘oddball’ sound in a sequence of sounds ( 163). A meta-analysis compared the predictive ability of late-stage EPs for awakening from coma due to ischaemia, haemorrhage, trauma, anoxic injury, and metabolic aetiologies, and the presence of an N100 had a sensitivity of 71% and specificity of 57% for good outcome across several studies (164). The MMN had a sensitivity of 38% and specificity of 91% for good outcome and P300 a sensitivity of 62% and specificity of 77%. MMN has a relatively high specificity for recovery of wakefulness, particularly after anoxic injury. Fischer and colleagues found it to be the most powerful prognostic indicator for awakening from coma and used it as the initial criterion to develop a decision tree for prognostication after cardiac arrest (165).
Top Previous Electromyography and nerve conduction studies In addition to a focused clinical history and neurological examination, electrodiagnostic test, such as EMG and nerve conduction velocity studies (NCSs), may assist in the diagnosis and prognosis of patients with neuromuscular disease (see Chapter22). Some basic terminologies for understanding EMG and NCS are important. These are discussed briefly in the following sections but for a detailed description the reader is referred elsewhere ( 166).
Nerve conduction studies NCSs can be motor, sensory, or mixed. Motor conduction responses are recorded in millivolts and sensory or mixed studies in microvolts. The active recording electrode, also known as G1, is placed on the centre of a muscle belly over the motor endplate and the reference electrode (G2) distally over the tendon. The stimulating electrode is placed over the nerve that supplies the muscle with the cathode closest to the recording electrode. The latency is recorded as the time from the stimulus to the initial compound muscle action potential (CMAP) deflection from baseline, and the amplitude from the baseline to the negative peak of the CMAP. Motor conduction velocity can be calculated after two sites, one distal and one proximal, have been stimulated. The CMAP is a biphasic potential with an initial negativity. Ring recording electrodes are used for sensory nerve conduction studies. A sensory nerve action potential (SNAP), a compound potential representing a summation of all sensory fibre action potentials, is recorded. Similar to motor studies, latency, amplitude, duration, and conduction velocity is recorded for each SNAP. In patients with neuropathic lesions and axonal loss, the primary abnormalities are a reduction in the amplitude of the SNAP, CMAP, or both. Conduction velocities and latencies may be normal as long as the largest and fastest conducting axons remain intact. Myelin is essential for salutatory conduction so in patients with demyelinating lesions there will be marked slowing in conduction velocities and prolongation of distal latencies. Essentially any motor, sensory or mixed nerve conduction velocity slower than 35 m/s in the arms or 30 m/s in the legs signifies unequivocal demyelination. Conduction blocks are also seen in acquired demyelination where there is also a reduction in the CMAP amplitude depending on the site of stimulation and the conduction block. In myopathies, SNAPs and CMAPs will usually be normal. There are additional reflexes and potentials that can be recorded during NCSs including the late responses of the F-wave and Hreflex. The F wave is the second of two voltage changes observed after electrical stimulation is applied above the distal region of a nerve and the H-reflex (Hoffmann’s reflex) a reaction of muscles after electrical stimulation of innervating sensory fibres. Temporal dispersion occurs as individual nerve fibres fire at slightly different times and is normally more prominent at proximal stimulation sites because slower fibres progressively lag behind faster fibres.
Electromyogram The motor unit comprises a motor nerve and all the muscles fibres that it innervates. It acts as a single functional unit with all the fibres contracting synchronously. Each muscle fibre produces an action potential and the summation of the individual potentials within the motor unit is the motor unit action potential (MUAP). EMG evaluates the electrophysiological activity from multiple motor units. A concentric needle electrode is used to measure the EMG. The shaft of the needle serves as the reference electrode and the active electrode runs as a very small wire through the centre of the needle. Once the appropriate muscle is identified using anatomical landmarks, the first part of the examination assesses insertional and spontaneous activity at rest. Increased insertional muscle activity is defined as any electrical activity other than endplate potentials that lasts longer than 300 milliseconds after brief needle movement. Spontaneous activity is any activity at rest that lasts longer than 3 seconds. Next, MUAPs are recorded during minimal activation or contraction of the muscle and assessed for duration, amplitude, and number of phases. Recruitment and activation refers to the change in the frequency and number of firing MUAPs as the patient slowly increases force and tries to maximally contract the muscle under examination. Activation is the ability to fire the available MUAPs faster and recruitment refers to the ability to ‘recruit’ more MUAPs as the strength of muscle contraction increases. MUAPs are abnormal in different types of myopathy (see Chapter22).
Electrodiagnostics in the intensive care unit There are several indications for EMG and NCS are useful in the ICU. These include the following:
◆Rapidly progressive ascending or descending weakness, with or without sensory signs/symptoms, and impending respiratory failure. ◆The diagnosis of critical illness polymyoneuropathy. ◆Difficulty in weaning mechanical ventilator despite improvement of underlying systemic illness. ◆Patients with known diagnoses of myasthenia gravis or other neuromuscular disease presenting with an acute exacerbation
◆A ‘train of 4’ technique, using a peripheral nerve stimulator, can be used to monitor the depth of neuromuscular blockade in patients receiving neuromuscular blocking agents to facilitate ventilation in severe ARDS or to prevent shivering during therapeutic hypothermia (167). The minimal current intensity (MCI) for recording a train of four responses is documented and then the responses are recorded at different current strengths, for example, 20, 40, 60, and 80 mA. Depending on the underlying indication for neuromuscular blockade, a target train of 4 is chosen. 0 out of 4 represents the most profound degree of neuromuscular block, 3 out of 4 the weakest, and 4 out of 4 indicates no blockade although some receptors may still be blocked.
Limitations There are several limitations to performing EMGs and NCSs in critically ill patients including frequent occurrences of electrical interference, electrode contact problems associated with peripheral oedema and cool extremities due to the use of vasopressors, limited patient cooperation, reduced access to sites for electric stimulation and recording because of catheters and dressings, and the use of therapeutic anticoagulation. Patients with neuromuscular emergencies are often intubated and sedated which makes EMG limited to the study of insertional activity. These difficulties can be overcome to some extent. For example, hot packs can be used for warming cool limbs and electrical interference can be minimized by using an isolated electrical outlet although this is often insufficient on its own. Increasing the low-frequency filter during needle examination may allow identification of fibrillation potentials. Sound can also be used to identify fibrillation potentials and small, polyphasic motor unit potentials even if they are hidden within an electrical artefact. A 50 Hz artefact may particularly interfere with F-wave recordings and sensory responses, although signal averaging may help overcome these problems. Fortunately, motor nerve conduction studies are usually less affected. Attention to electrical safety is also crucially important in the ICU. Proper grounding is essential and stimulation in a region of fluid spills should be avoided to prevent current leak. Patients with external pacemakers cannot undergo NCSs and although those with implanted pacemakers can be studied it is prudent to avoid repetitive stimulation. A better yield is obtained if EMG recording is performed in patients who are minimally sedated and able to cooperate, so timing the study when a patient can tolerate minimal or no sedation safely may facilitate a diagnostic recording.
Indications There are several conditions in which EMG and NCSs offer a high diagnostic yield (see also Chapter22) (166). Acute axonal and demyelinating polyneuropathies Patients with clinical features suggestive of an acute polyneuropathy cannot be diagnosed solely on the basis of clinical features. Electrodiagnostic tests are required to classify these disorders into axonal and demyelinating variants which is important both for management and prognosis. The incidence of acute polyneuropathy variants is variably reported depending on many factors including clinical definitions, underlying triggering factors, and also on the electrophysiological criteria used to confirm the diagnosis and whether this was based on single or serial studies (168). In Ho’s criteria for diagnosing Guillain–Barré syndrome, evidence of ‘unequivocal temporal dispersion’ was included among the parameters to assess demyelination (169), but Hadden and colleagues replaced this with conduction block defined as a proximal CMAP:distal CMAP amplitude ratio less than 0.5 ( 170). Acute motor and sensory axonal neuropathy is diagnosed by the absence of demyelinating features, as in Ho’s criteria, and reduction of SNAP amplitude to lower than 50% of the lower limit of normal in at least two nerves ( 168). Myasthenic syndromes Acute neuromuscular weakness from a variety of causes can lead to respiratory failure. In patients presenting for the first time, electrodiagnostic studies with repetitive nerve stimulation and single-fibre EMG are important for diagnosis and management (171). Critical illness myopathy and neuropathy EMGs and NCSs are the gold standard for diagnosing critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), although some authors suggest that the diagnosis can also be made clinically ( 172,173). CIM is more difficult to diagnose than CIP because diagnostic EMG findings require patient cooperation ( 173). CIP is usually an acute axonal polyneuropathy which can be sensory, motor, or both ( 174).
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Neuroimaging Chapter: Neuroimaging Author(s): Yanrong Zhang , Peter Komlosi , Mingxing Xie , and Max Wintermark DOI: 10.1093/med/9780198739555.003.0015 Neuroimaging is a critical tool in the management of patients in the neurocritical care unit (NCCU). It is used to diagnose, monitor, and guide treatment for a variety of conditions, and may assist in prognosis. This chapter will review the imaging modalities available during the management of critically ill neurological patients, and discuss the typical imaging features of the most common pathological conditions encountered during neurocritical care.
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Structural imaging modalities Computed tomography (CT) and magnetic resonance imaging (MRI) are routine imaging tools used to identify structural lesions in neurological patients.
Non-contrast computed tomography Owing to its non-invasiveness, speed of data acquisition, and ease of access, non-contrast computed tomography (NCCT) is the preferred imaging modality for the initial evaluation of many intracranial lesions, especially in the acute setting of traumatic brain injury (TBI), acute ischaemic stroke (AIS), and subarachnoid haemorrhage (SAH), and also for patients on the NCCU who require prompt identification of potential surgically remedial lesions, such as acute haemorrhage or herniation, in whom timely surgical intervention is associated with improved outcome (1). Many patients may be unstable or agitated, so the rapid imaging times of NCCT are crucial. Modern CT scanners are able to acquire volumetric data, improving the evaluation of intracranial and spinal structures in reconstructed three-dimensional (3D) images. The principal disadvantage of NCCT is the use of ionizing radiation, although technological CT advancements such as dose modulation have effectively reduced the amount of radiation exposure. It is also limited in the assessment of lesions in the middle and posterior cranial fossas where ‘beamhardening’ artefacts from thick surrounding bone structures obscure the brain tissue images.
Magnetic resonance imaging Clinical MRI is based on the relaxation properties of the hydrogen nuclei of water molecules following excitement by radiofrequency waves. The hydrogen nuclei (protons) of body tissue water become aligned with the direction of the magnetic field inside a magnetic resonance (MR) scanner. A radio frequency is briefly turned on, and this is absorbed and flips the spin of the protons in the magnetic field. After the electromagnetic field is turned off, the spin of the protons relaxes back to the original states and they become realigned with the static magnetic field. As protons relax back to their original states, they re-emit energy at the same radiofrequency and this is detected by a receiving coil in the scanner. MRI produces particularly good images of soft tissue, and greater contrast between different tissue types than NCCT. By varying the manner in which images are obtained, the soft tissue contrast of the visualized anatomical structures can be altered (Table15.1). On T1-weighted images, water and fluid-containing tissues are dark and fat-containing tissues bright, whereas on T2-weighted images water and fluid-containing tissues are bright. T1-weighted images are
therefore best suited to imaging anatomy and T2 tissue oedema. MRI thus has the potential to provide much more information on tissue status than CT, but there are many factors that limit its use in critically ill patients including long scan duration and MR-related safety issues (see later) (2,3). Table 15.1Signal changes displayed in computed tomography and magnetic resonance imaging sequences in different pathological conditions
Conditions
CT density
DWI intensity
T1 intensity
T2 intensity
GRE/SWI intensity
Acute ischaemic stroke
≅
↑
≅
≅
≅
Subacute ischaemic stroke
↓
↑
↓
↑
≅
Chronic ischaemic stroke
↓↓
↑ or ↓
↓
↑
≅
Hyperacute haemorrhage
≅
≅
≅
↑
↓
Acute haemorrhage
↑
↓
↑
↓
↓
Subacute haemorrhage
≅
↓
↑
↑
↓
Chronic haemorrhage
↓
↓
↑
↓
↓
Traumatic axonal injury
≅
↑
≅
≅
↓ in haemorrhagic cases
Epilepsy
≅
↑
≅
≅
≅
DWI, diffusion weighted; GRE, gradient-echo; SWI, susceptibility weighted images. There are several distinct MRI sequences that can be used to enhance image acquisition.
Fluid-attenuated inversion recovery Fluid-attenuated inversion recovery (FLAIR) is an MRI sequence used to null the signal from fluids so that cerebrospinal fluid (CSF) is suppressed during brain imaging, making periventricular and subcortical T2 bright lesions more conspicuous. On FLAIR images, focal bright grey matter (e.g. contusions) and white matter abnormalities (e.g. diffuse axonal injury involving the fornix and corpus callosum) are more easily appreciated against the adjacent ‘nulled’ (dark) CSF-filled ventricles and subarachnoid spaces (4,5). FLAIR also has increased sensitivity for the presence of acute or subacute SAH, which appears as bright signals within the sulci and cisterns (6,7).
Gradient-echo Gradient-echo (GRE) T2*-weighted images, and their most modern counterpart, susceptibility-weighted images (SWI), are very sensitive for the detection of intracranial blood (8,9,10).
Diffusion-weighted imaging
Diffusion-weighted imaging (DWI) explores the random motion of water molecules in the body, and the rate of water diffusion of tissue at specific locations is reflected by the intensity of each image voxel. On clinical MR scanners, the diffusion sensitivity is easily varied by changing the parameter known as the b value; generally the larger the b value the greater the degree of signal attenuation from water molecules. To enable meaningful interpretation, DWI is typically performed using at least two b values. Because the movement of water molecules is the reflection of the surrounding cellular environment, DWI reveals early pathological abnormalities. For example, in the acute phase after AIS, cytotoxic oedema results in ‘restricted’ diffusion of water which appears ‘bright’ on DWI. This ‘restricted’ diffusion must not beconfused with ‘T2 shine through’, which occurs when a bright, usually chronic, lesion on T2 imaging also appears bright on DWI. Confusion between these can be avoided by obtaining apparent diffusion coefficient (ADC) maps, which are based on quantitative differences of tissue diffusion independent of T2 effects. An area of infarction after AIS is thus typically ‘bright’ on DWI and ‘dark’ on ADC. DWI becomes positive in stroke patients within 5–10 minutes of symptom onset, whereas CT often does not detect changes of acute ischaemia/infarction for up to 4–6 hours. DWI can also be used to assess the connectivity of white matter axons in the central nervous system. In an isotropic medium such as water inside a glass, water molecules move randomly in all directions because of turbulence and Brownian motion, but in biological tissues diffusion is anisotropic. For example, water molecules inside a neuronal axon move principally along the axis of the neural fibre, but have a low probability of crossing the myelin membrane. This property is exploited in a variant of DWI called diffusion tensor imaging (DTI) which can be used to examine the connectivity of different regions in the brain (tractography) (11,12), or areas of neural degeneration and demyelination in diseases like multiple sclerosis (13,14,15).
Safety issues There are many factors that interfere with the routine use of MRI in critically ill patients. These include the relatively long image acquisition times, interference from metallic implants (pacemakers, defibrillators, cochlear implants), and the requirement for specialized, MRI-compatible, monitoring equipment (2,3). The MRI environment is hazardous because of the static magnetic field and risk of radiofrequency heating. Ferromagnetic objects are pulled towards the centre of the magnet, risking injury to patients. Pacemakers or hearing implants may also be dislodged or inactivated. Therefore, a safety check for metallic foreign bodies, implantable devices, equipment, and other contraindications should always be undertaken prior to MRI. The reader is directed elsewhere for detailed discussion of MRI safety issues (16).
Angiography Digital subtraction angiography (DSA) is the established diagnostic tool for imaging intracranial and cervical vessels, but the non-invasive modalities of CT angiography (CTA) and MR angiography (MRA) are increasingly used alternatives.
Digital subtraction angiography DSA utilizes computerized X-ray imaging equipment for image acquisition, and subtraction of the images acquired prior to injection of iodinated contrast agent injection from the subsequent images after contrast. In this way, the bony or dense soft tissue images are removed. Although DSA is considered the gold standard for the evaluation of cerebrovascular diseases, it is an invasive procedure with an associated procedural risk. The rate of neurological complications ranges from 0.3% to 1.3%, of which 0.07–0.5% are permanent (17,18,19,20). The vast majority are minor and transient (e.g. groin haematomas, femoral artery injury, and minor allergic reactions), although more severe complications, such as cerebral infarction, seizure, and death can occur. Spinal angiography imposes the same risks as cerebral angiography, and increases the risk of cord infarction due to spinal artery embolus. Therefore, it should only be performed when a vascular malformation is displayed by another imaging technology or in a patient with SAH and normal pan-cerebral angiographic findings in whom a spinal source is strongly suspected (20).
With the rapid progress of CTA and MRA, DSA is now rarely used for initial diagnostic purposes and reserved for endovascular interventions to treat cerebral aneurysms and other cerebrovascular malformations, or to recannulate a stenosed or occluded artery.
Computed tomography angiography Using multidetector-row computed tomography (MDCT) technology, CTA can assess the entire vasculature from the aortic arch to the circle of Willis quickly in a single data acquisition with excellent 3D spatial resolution. The acquisition time is typically less than 10 seconds, that is, within a single breath-hold during injection of intravenous contrast. Multiplanar reformatted images, maximum intensity projection images (MIP), and 3D reconstructions of axial CTA source images provide images comparable, or even superior, to those obtained with conventional DSA (Figures15.1and15.2) (21,22).
Click to view larger Download figure as PowerPoint slide Fig. 15.1. A 45-year-old patient was admitted with thunderclap headache, nausea, and vomiting. Non-contrast computed tomography (NCT) brain scan demonstrated diffuse subarachnoid haemorrhage (arrowheads), and bilateral enlargement of the ventricles. Computed tomographic angiography (CTA) and digital subtraction angiography (DSA) identified a ruptured saccular aneurysm at the right pericallosal-calloso-marginal bifurcation (arrows).
Click to view larger Download figure as PowerPoint slide Fig. 15.2. A 40-year-old patient underwent coiling for a ruptured anterior communicating artery aneurysm and 5 days later experienced new symptoms of apathy and altered mental state. Non-contrast computed tomography (NCT) scan of the brain demonstrated extensive residual subarachnoid haemorrhage, as well as an area of loss of the grey–white matter differentiation (white arrowheads) in the left frontal lobe. Perfusion-CT demonstrated increased mean transit time (MTT) and decreased cerebral blood flow (CBF) (arrowheads), suggestive of vasospasm in this area and also in the right frontal lobe. CT angiography (CTA) and digital subtraction angiography (DSA) confirmed the suspicion of moderate vasospasm in both A2 and A3 segments of the anterior cerebral arteries (white arrows). The advantages of CTA lie in the short imaging time, wide availability, logistical ease of imaging critically ill patients, fewer artefacts relative to MRA, availability of extra-luminal information not available with DSA, and excellent sensitivity for intracranial aneurysms. On the other hand, CTA does not provide the dynamic, real-time information of DSA. The increased usage of MDCT technology has led to a significantly increased radiation dose to patients, andneuroradiologists now apply techniques to reduce the dose associated with neuro-CT imaging protocols (23). In addition, the use of X-ray contrast agent is associated with a risk of allergic reaction and acute kidney injury. As a result, CTA should be used with caution in patients with renal disease or diabetes.
Magnetic resonance angiography
MRA can be performed using one of three techniques—time-of- flight (TOF), phase-contrast, and contrast-enhanced. Contrast- enhanced MRA uses a contrast agent which changes the relaxation time of blood whereas TOF and phasecontrast techniques exploit two MRI in-flow effects, saturation and phase effects, which differentiate flowing blood from static tissue. TOF MRA is the most widely used technique, and two-dimensional TOF MRA is sensitive to slow velocity blood flow and therefore recommended for venous evaluation. On the other hand, 3D TOF works well for high arterial flow areas such as the circle of Willis. There are several advantages of MRA over DSA and CTA including no exposure to ionizing radiation and, in the case of TOF MRA, no contrast material. Disadvantages of MRA include the relatively long scanning time compared to CTA, its somewhat limited spatial resolution for small aneurysms, and overestimation of the degree of stenosis because of signal loss immediately distal to a stenosis on TOF MRA (24).
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Functional imaging modalities As technology advances, functional CT and MRI techniques are becoming more widely used in clinical practice.
Perfusion computed tomography Perfusion CT (PCT) consists of continuous scanning of a region of interest in the brain during the injection of a bolus of contrast medium as it washes in and washes out through the cerebralvasculature. There is a linear relationship between contrast agent concentration and X-ray attenuation, with the contrast agent causing a transient increase in attenuation proportional to the amount of contrast agent in the region of interest. PCT data are analysed utilizing mathematical models and custom software to calculate quantitative values of several variables describing cerebral perfusion (25,26,27,28):
◆The mean transit time (MTT) is the time taken for a theoretical instantaneous bolus of iodinated contrast to cross the capillary network in each voxel of the brain. ◆The cerebral blood volume (CBV) indicates the volume of blood per unit of brain mass (normal range in grey matter: 4–6 mL/100 g), and the CBV map is calculated from the area under the time–density curves. ◆Cerebral blood flow (CBF) indicates the volume of blood flow flowing per unit of brain mass per minute (normal range in grey matter: 60–80 mL/100 g/min), and the relationship between CBF and CBV is expressed by the equation:
CBF=CBVMTT The main advantages of PCT are its wide availability and quantitative accuracy (25,28). It has multiple applications in the NCCU. PCT is able to differentiate the reversible ischaemic penumbra and irreversible infarct core after AIS (Figure15.3) (25,29) and, after SAH, can diagnose and quantify the severity of cerebral vasospasm (30). In patients with TBI, PCT can be used for the early diagnosis of contusions and also to assess cerebral vascular autoregulation and guide treatment of brain oedema (31,32).
Click to view larger Download figure as PowerPoint slide Fig. 15.3. A 67-year-old patient was admitted to the emergency department with a left hemiparesis. The non-contrast head CT scan (NCT) showed patchy areas of hypodensity and blurry grey–white matter junctions in the right middle cerebral artery territory. The perfusion CT scan (PCT) demonstrated delayed mean transit time (MTT) (arrowheads), decreased cerebral blood flow (CBF), and decreased cerebral blood volume (CBV). The lesion was ‘bright’ on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MR sequences, and ‘dark’ on apparent diffusion coefficient (ADC) maps, consistent with an acute infarction. Digital subtraction angiography (DSA) identified an occlusion at the right M1 bifurcation (arrow) as the cause of the infarction.
Perfusion-weighted magnetic resonance imaging MRI can also be used to assess brain perfusion. Perfusion-weighted imaging (PWI) monitors the passage of a contrast agent bolus through brain capillaries as a transient loss of signal because of the susceptibility (T2*) effects of the contrast agent. A haemodynamic time–signal intensity curve is produced, and MTT, CBF, and CBV perfusion maps subsequently calculated using the same principles as for PCT. The T1-weighted signal of the contrast material can also be used to assess the permeability of the blood–brain barrier (33). Arterial spin labelling (ASL) is an MRI technique that uses the blood signal as an endogenous tracer and can therefore be used to assess cerebral perfusion without the need for exogenous tracers. Because of its non-invasiveness, ASL can be repeated over time and therefore used to track changes in CBF during disease progression or treatment interventions. Importantly, ASL yields an absolute measure of CBF and change in flow is expressed in physiologically meaningful units rather than as a percentage change from baseline (34,35,36,37). However, because of the large amount of processing involved, this method largely remains a research tool.
PWI is often used in combination with DWI in stroke patients to assess the infarct core and ischaemic penumbra. The DWI abnormality represents the infarct core, and the DWI–PWI mismatch, that is, the area that is abnormal on PWI but not yet abnormal on DWI, the ischaemic penumbra (Figure15.4) (38).
Click to view larger Download figure as PowerPoint slide Fig. 15.4. Diffusion-weighted imaging (DWI) of a 70-year-old patient with aphasia and right hemiplegia showed reduced diffusion in the left frontal lobe (arrow), reflecting irreversibly damaged infarct core. The T2-weighted images show a faint increased corresponding signal indicating that the infarct is acute. Mean transit time (MTT) maps calculated from the perfusion-weighted imaging (PWI) show an area of hypoperfusion (arrowheads) that is larger than the infarct core on DWI. This PWI/DWI ‘mismatch’ represents the ischaemic penumbra. Magnetic resonance angiography (MRA) displays an occlusion of the left middle cerebral artery (arrow).
Single-positron emission computed tomography imaging In single-positron emission computed tomography (SPECT) perfusion studies, the radioisotope technetium-99m is attached to a delivery compound, either hexamethylpropyleneamine oxime (HMPAO) or ethyl cysteinate dimer (ECD). After intravenous injection it crosses the blood–brain barrier and is taken up by the neuronal and glial cells where it remains trapped for several hours. Imaging can thus be performed anytime within a few hours after injection (39). SPECT imaging of brain perfusion can be used at the bedside and is feasible in children. One specific indication for SPECT is in the investigation of seizures. Because SPECT uses a retention tracer for measurement of cerebral perfusion, the radiopharmaceutical can be administered at the moment of the seizure and imaging performed later, after stabilization of the patient, to identify the active epileptic focus (40). Ictal SPECT studies, complemented by interictal investigations (Figure15.5) and co-registered with CT or MRI anatomical images are indicated in focal epilepsy for the localization of the epileptic focus before epilepsy surgery. SPECT perfusion can also be used in patients with acute and chronic cerebrovascular diseases (41).
Click to view larger Download figure as PowerPoint slide Fig. 15.5. A 28-year-old female with intractable epilepsy was admitted to hospital for presurgical evaluation. T2weighted imaging showed an abnormal area of deeply infolded cortex extending from the posterior aspect of the insular cortex deep into the right parietal lobe and lined by abnormally lobulated grey matter. It extends to the body of the right lateral ventricle and protruding into it (star). The interictal positron emission tomography (PET) scan shows increased metabolic activity (brighter signal) in the right frontal lobe and posterior right parietal lobe (arrowheads). The interictal single-positron emission computed tomography (SPECT) scan shows three areas of decreased radioisotope uptake (lighter grey)—two in the right parietal lobe and one in right temporal lobe (arrows). These same areas showed increased uptake (darker grey) on the ictal SPECT, indicating that these are the likely sites of the seizure focus. Top Previous
Application of neuroimaging techniques in neurocritical care Neuroimaging plays a key role in the management of critically ill neurological patients. This section will outline the typical imaging features of the most common conditions encountered on the NCCU.
Cerebral oedema Cerebral oedema results from a pathological increase in the total amount of brain water content, and consequent increase in brainvolume. There are three types of brain oedema—cytotoxic, vasogenic, and interstitial. Cytotoxic oedema is characterized by an increase in intracellular water content and caused by an energy depletion that results in an imbalance of neurotransmitters and failure of active ion-pumps that normally maintain cellular homeostasis. Ischaemia and profound metabolic derangements are the most common causes of cytotoxic oedema which involves both grey matter and white matter. Vasogenic oedema on the other hand results from disruption of the blood–brain barrier, leading to extravasation of fluid from the intravascular into the extravascular and extracellular spaces. It is
primarily associated with tumours, inflammatory lesions, traumatic tissue damage, and haemorrhage, and predominantly involves the white matter. Interstitial oedema results from obstructive hydrocephalus in which there is an increase in trans-ependymal flow of CSF from the intraventricular compartment to the brain parenchyma, leading to CSF infiltration of the extracellular space of the periventricular white matter. CT is poor at differentiating different types of brain oedema because it displays any water content increase as an abnormal dark area. MRI however shows oedema as dark on T1-weighted sequences and bright on T2-weighted and FLAIR sequences. On DWI, cytotoxic oedema is bright because of the diffusion restriction, whereas vasogenic oedema appears grey or dark. Contrast-enhanced CT/MRI is helpful to delineate the oedema and reveal BBB leakage in vasogenic oedema (42).
Intracranial mass effect Intracranial mass effect results from a large tumour, haemorrhage, or severe oedema sufficient to cause displacement and distortion of normal brain structures. This is manifest as sulcal effacement, midline shift, obstructive hydrocephalus, and herniation (Figure15.6). The displacement of brain tissue can compress blood vessels, cranial nerves, and vital structures of the brainstem (medullary respiratory and cardiac rhythm centres), and may lead to infarction and death.
Click to view larger Download figure as PowerPoint slide Fig. 15.6. A 30-year-old patient was admitted with nausea and vomiting. A non-contrast head CT (NCT) showed a heterogeneous mass lesion cantered in the tectum of the midbrain (black arrowheads) and causing obstructive hydrocephalus with enlargement of the lateral (numbers 1 and 2) and third (number 3) ventricles. Corresponding findings were observed on the T2-weighted magnetic resonance images. The post-gadolinium T1-weighted images (contrast) demonstrated the mass to be enhancing in a multiseptated pattern (black arrowhead).
Brain herniation Different types of brain herniation can be encountered—subfalcine, transtentorial, and tonsillar.
Subfalcine herniation In subfalcine herniation the cingulate or supracingulate gyri are pushed beneath the falx. These changes are easily recognized on CT or MRI as deviation of the falx and extension of hemispheric structures across the midline. Midline shift is easily measured by imaging software, and its degree is a useful guide to clinical management and prognostication (43).
Transtentorial herniation Transtentorial herniation is usually caused by a supratentorial mass or severe oedema displacing the medial temporal lobe downward through the tentorial incisura. It may involve the uncus anteriorly, the parahippocampal or lingual gyri posteriorly, or both. CT and MRI may demonstrate widening of the ipsilateral ambient cistern and effacement of the contralateral ambient cistern (44,45). An ascending transtentorial herniation can also occur when an infratentorial mass pushes the pons, vermis, and adjacent portions of the cerebellar hemispheres upward through the incisura. CT and MRI display symmetrical effacement of the ambient cisterns and acute hydrocephalus from compression of the Sylvian aqueduct. An occipital lobe infarction may occur if the posterior cerebral artery is compressed between the temporal lobe and the crus cerebri (46).
Tonsillar herniation Tonsillar herniation occurs when the cerebral tonsils are forced through the foramen magnum into the cervical spinal canal, usually as a result of uncontrolled intracranial hypertension. Eventually the medulla is compressed leading to dysfunction and then failure of the vital respiratory and cardiac centres. Displacement of the cerebellar tonsils below the level of the foramen magnum is clearly seen on CT or MRI, although sagittal MR images display the tonsillar herniation most clearly (47).
Hydrocephalus Hydrocephalus is defined as the abnormal enlargement of the ventricles and is of two types—communicating and obstructive.
Communicating hydrocephalus In communicating hydrocephalus there is no obstruction between the ventricles and subarachnoid spaces. It results either from an overproduction of CSF (e.g. choroid plexus papilloma) or defective CSF absorption in conditions such as SAH, meningitis, and leptomeningeal carcinomatosis. The typical appearance of communicating hydrocephalus on CT and MRI is symmetrical expansion of all the ventricles with effacement of cerebral sulci. Because of the high pressure, CSF may leak from the ventricles into the brain leading to interstitial oedema that can be easily recognized on MRI.
Obstructive hydrocephalus In obstructive hydrocephalus, CSF flow is obstructed within the ventricular system or at the level of its outlets into the subarachnoid space. Therefore only the ventricles proximal to the obstruction are seen to be dilated on CT or MRI. Both modalities are useful in identifying the site of obstruction as well as its aetiology (Figure15.6). With relatively new MRI sequences, such as 3D constructive interference in the steady state (3D CISS), MRI can now scrutinize CSF flow at various sites (48).
Traumatic brain injury Imaging is critical both for the initial diagnosis and subsequent management of TBI (see Chapter17). Primary injuries, such as skull fractures, cortical contusions, haematomas, and traumatic axonal injury (TAI), result directly from the initial mechanical damage and are readily imaged using a variety of CT and MRI techniques (Figure15.7). For the diagnosis of TBI in the acute setting, NCCT is the modality of choice as it quickly and accurately identifies intracranial
haematomas that require urgent neurosurgical evacuation. CT with thin slices and 3D reconstructions is the preferred imaging modality to assess skull fractures. MRI has better diagnostic sensitivity for lesions such as TAI.
Click to view larger Download figure as PowerPoint slide Fig. 15.7. A 45-year-old patient had a transient cognitive disorder after traumatic brain injury. Non-contrast cranial CT (NCT) demonstrated a small haemorrhagic focus in the left dorsolateral midbrain and in the adjacent left upper vermis (arrows). This was confirmed on fluid-attenuated inversion recovery (FLAIR) magnetic resonance images, which also demonstrated several additional injuries in the brainstem and upper vermis (arrows). The NCT also shows a small amount of intraventricular blood and a punctate focus of haemorrhage at the right frontal grey–white matter junction (star) which is also visualized on gradient-echo (GRE) magnetic resonance images (star). Diffusion-weighted imaging (DWI) demonstrated restricted diffusion in the splenium of the corpus callosum (arrowhead), which appears dark on apparent diffusion coefficient (ADC) maps. All these features are typically encountered after haemorrhagic and nonhaemorrhagic traumatic axonal injury.
Extradural haematoma An extradural haematoma (EDH) is an abnormal blood accumulation between the dura mater and inner table of the skull, and is usually related to blunt trauma to the head, often to the temporal region. It may be associated with an overlying calvarial skull fracture. The source of haemorrhage is arterial in 85% of cases, but venous EDHs are occasionally seen in an occipital location secondary to traumatic laceration of venous sinuses (49). On NCCT, an EDH
appears as a biconvex, extra-axial, bright fluid collection(Figure15.8). EDHs do not typically cross cranial suture lines because the dura is tightly adherent to the inner table at these sites. However, they can extend from the right to the left or from the supratentorial to infratentorial space, in contrast to subdural haematomas (SDHs) which are limited by the falx and the tentorium. The presence of alternating crescent-shaped dark regions within an otherwise bright EDH (the ‘swirl’ sign) may represent areas of active (ongoing) bleeding (50).
Click to view larger Download figure as PowerPoint slide Fig. 15.8. Images of a 19-year-old patient involved in a high-speed motor vehicle accident. The admission noncontrast brain CT (NCT) demonstrated a small right frontal epidural haematoma (A and B arrowheads), which increased in size over a few hours (C and D arrowheads), before being surgically evacuated (E and F). A right parietal subgaleal haematoma was also present (A–D arrows).
Subdural haematoma SDHs may also be caused by brain trauma and usually have a venous origin. They often evolve rapidly and compress brain tissue, resulting in progressive neurological deterioration and death. On NCCT, an acute SDH appears as a crescent-shaped, bright, extra-axial fluid collection, which can extend along the falx and/or the tentorium. After a few days, SDHs become increasingly isodense to grey matter on CT, and this can make their detection difficult. A SDH can result from very minor head trauma and, under such circumstances, may progress unnoticed into a ‘chronic’ subdural haematoma (CSDH) which typically appears homogeneously dark relative to grey matter. The MRI appearance of an SDH is analogous to that on CT, with the age of the haematoma influencing the signal characteristics on T1- and T2-weighted images. MRI is more sensitive than CT in the detection of a small SDH, especially in the tentorial and interhemispheric locations (50).
Traumatic axonal injury TAI, also commonly referred to as diffuse axonal injury or shear injury, is characterized by widespread damage to the axons of the brainstem, parasagittal white matter of the cerebral cortex, corpus callosum, and at the grey–white matter junction of the cerebral cortex. The changes associated with TAI are thought to be responsible for the majority of global cognitive defects seen after TBI, particularly with regard to difficulties with memory and information processing (51). TAI is difficult to diagnose on CT because more than 80% are non-haemorrhagic (52). However, advanced MRI sequences (as opposed to conventional MRI) can detect haemorrhagic and non-haemorrhagic TAI lesions more sensitively. Haemorrhagic lesions demonstrate focal susceptibility and signal loss because of the paramagnetic effects of deoxyhaemoglobin on GRE and SWI (53). DWI and FLAIR can identify non-haemorrhagic lesions in the corpus callosum, at the grey–white matter interface and in the dorsolateral aspect of the brain stem (Figure15.7) (54,55). As previously discussed, DTI can provide information about brain microstructure by quantifying isotropic and anisotropic water diffusion. Water diffusion has a directional asymmetry (anisotropy) in organized tissues such as brain white matter (56).Where axons are aligned in white matter fibre tracts, diffusion along the axons is greater than that perpendicular to the axons but, when axonal injury occurs, diffusion anisotropy decreases (57). In this way disrupted axonal tracts can be imaged.
Subarachnoid haemorrhage SAH is the accumulation of blood in the space between the arachnoid membrane and pia mater surrounding the brain. Intracranial aneurysms are the cause of SAH in 85% of cases (see Chapter18) (58), but SAH can also occur secondary to trauma or intraparenchymal haemorrhage. Non-contrast cranial CT is the primary screening tool for patients in whom SAH is suspected (59). The sensitivity of CT for SAH is more than 95% in the first 12 hours after the ictus. Beyond 12 hours, normal CT findings do not rule out the diagnosis of acute SAH, and a lumbar puncture is indicated if there is a high index of clinical suspicion (60). Acute SAH appears as a bright filling of the subarachnoid spaces around the brain (sulci, ventricles, and cisterns) on NCCT (Figures15.1and15.2). After several days, the initial high-attenuation of blood and clot tends to decrease, and changes to an intermediate grey relative to normal brain parenchyma. The distribution of the subarachnoid blood load can help localize the ruptured aneurysm. For example, blood in the anterior interhemispheric fissure or the adjacent frontal lobe is highly suggestive of rupture of an anterior communicating artery aneurysm. CT also allows for some degree of prognostication because the blood load, and presence of localized clots in the subarachnoid space, are correlated with a higher incidence of delayed symptomatic arterial vasospasm (61).
In the first few days after the ictus, MRI with proton density and especially FLAIR images is as sensitive as NCCT in detecting SAH. However, later, when the subarachnoid brightness on CT scans decreases, MRI becomes better at detecting SAH, with FLAIR and T2* images being the most sensitive techniques (62,63).
Vascular imaging in SAH DSA is considered the gold standard for the identification of intracranial aneurysms and of aneurysm-related complications. It also represents a treatment modality as it permits coiling of ruptured and unruptured aneurysms, and endovascular treatment of vasospasm, including angioplasty and/or intra-arterial injection of vasodilators (64). CTA and MRA are now feasible alternatives to conventional angiography. CTA has 83–96% sensitivity and 97–100% specificity for aneurysm detection overall, although the sensitivity for smaller aneurysms is lower (40–91% for those < 3 mm diameter) (Figure15.1) (65,66,67). Similarly, MRA is highly sensitive and specific for the detection of intracranial aneurysms but, like CTA, has lower sensitivity for smaller (< 3 mm diameter) aneurysms (66,67). Cerebral vasospasm is a major cause of delayed neurologic morbidity after SAH. Vasospasm-related cerebral ischaemia occurs in 20–30% of patients (68), and is associated with a 1.5- to 3-fold increase in mortality in the first 2 weeks after SAH (69). Transcranial Doppler ultrasonography is a widely used technique for the detection of vasospasm, but has clear limitations (see Chapter10) (70). The standard for the anatomical demonstration of cerebral vasospasm is DSA, but CTA has emerged as a reliable and accurate alternative that offers the potential for rapid diagnosis and monitoring (71). The very rapid acquisition of CTA images is a major advantage in unstable patients. CTA can be supplemented with PCT to provide an accurate and non-invasive assessment of the haemodynamic effects of vasospasm (Figure15.2) (30,72,73), including quantification of CBF in the regions of interest (74).
Intraventricular haemorrhage Intraventricular haemorrhage is usually associated with other lesions such as intraparenchymal haematoma, SAH, or TAI and has a poor prognosis (75). Blood enters the ventricles from contiguous extension from a parenchymal haematoma, shearing of subependymal veins that line the ventricular cavities, or retrograde reflux of a SAH through the foramina of the fourth ventricle.
Intracerebral haemorrhage Intraparenchymal haematomas display five characteristic stages on CT and MRI—hyperacute (< 12 hours), acute (12 hours to 2 days), early subacute (2–7 days), late subacute (8 days to 1 month), and chronic (> 1 month to years) (76,77). A hyperacute intracerebral haematoma consists of a matrix of red blood cells (RBC), white blood cells, and platelet thrombi intermixed with protein-rich serum. Because RBCs retain intracellular oxygenated haemoglobin, which has a density equal to that of the adjacent normal brain parenchyma, the haemorrhage can be difficult to delineate on NCCT in the early stages. However, a hyperacute haematoma has T1-grey or dark and T2-bright appearance on MRI. CTA is often performed in the acute phase after intracerebral haemorrhage (ICH) to identify extravasation of intravenous contrast in the centre or edge of the haematoma, the so-called spot sign (see Chapter19). A positive spot sign suggests active bleeding and is predictive of early haematoma expansion and poor outcome compared to spot signnegative patients. After a few hours, the density of the haematoma increases with the extrusion of the serum, and vasogenic oedema develops in the adjacent brain tissue. This leads to developing brightness of the clot on NCCT, and a surrounding dark rim due to the serum and vasogenic oedema in the adjacent brain tissue. As the acute stage progresses, RBCs in the clot dehydrate and shrink, and the intracellular haemoglobin becomes progressively deoxygenated, so that the haematoma appears T1-grey or dark and T2-dark on MRI. During the subsequent early subacute phase of ICH, the intracellular deoxyhaemoglobin is gradually converted to methaemoglobin and released into the extracellular space in the late subacute stage. On CT, the haematoma therefore becomes isodense to adjacent brain parenchyma. Injection of contrast media can delineate the haematoma because its periphery may show enhancement due to the disruption of the BBB because of local inflammation. On
MRI, the haematoma is T1-bright and T2-dark in the early subacute stage, andT1- and T2-bright in the late subacute stage. In the final, chronic, stage of haematoma evolution, macrophages and astroglial cells surround the haematoma and slowly phagocytize it. Extracellular methaemoglobin is converted by, and stored within, macrophages as haemosiderin and ferritin. On NCCT, a small dark brain defect typically remains and sometimes residual bright calcifications. Occasionally, focal atrophy leads to enlargement of neighbouring sulci. On MRI, chronic haematomas appear as T1dark and T2-centrally bright surrounded by a rim of darkness (Figure15.9). The high sensitivity of T2*-GRE MR sequences for the susceptibility effects of paramagnetic and superparamagnetic substances increases the number of haemorrhagic lesions that can be identified (78). A major limitation of this modality is that it cannot estimate the age of the haematomas.
Click to view larger Download figure as PowerPoint slide Fig. 15.9. An 89-year-old patient was admitted with a left motor deficit and numbness. Within the right thalamus, T2weighted, fluid-attenuated inversion recovery (FLAIR), and gradient-echo (GRE) images showed a focus with increased T2 signal and a peripheral rim of low signal (black arrowhead). Diffusion-weighted imaging (DWI) also demonstrated a bright signal at the centre, corresponding to a dark signal on the apparent diffusion coefficient (ADC) map (black arrowhead). These findings are consistent with a chronic lacunar infarct with a haemorrhagic component.
Ischaemic stroke Neuroimaging plays a critical role in the diagnosis and acute management of AIS. Early imaging is used to differentiate between ischaemic and haemorrhagic strokes, exclude stroke mimics, confirm and localize the area of ischaemia and clot if present, differentiate infarct core and penumbra, and assess the risk of haemorrhagic transformation. NCCT is commonly used to rapidly exclude intracranial haemorrhage after stroke onset but, in the absence of haemorrhage, it may appear completely normal in the hyperacute phase. Early signs of brain infarction on NCCT include hyperdense arteries (see ‘Vascular imaging’), sulcal effacement, effacement of grey structures including the insular ribbon sign and disappearing basal ganglia sign, and, later in the evolution of the infarct, hypodensity. Compared with DWI, NCCT is insensitive (25%) for the detection of ischaemia in the first 3 hours after stroke onset, but its sensitivity increases in the first 6 hours to 40–60%. Despite this, NCCT remains the acute imaging modality most commonly used to rule out ICH and some stroke mimics that would obviate the need for recanalization therapy. Using GRE and other T2* sequences, MRI is equally sensitive to NCCT at excluding haemorrhage, but far more sensitive for the detection of non-haemorrhagic stroke mimics. Conventional T2-weighted and FLAIR images, in association with post-contrast T1-weighted images, identify non-haemorrhagic lesions such as tumours, metabolic disorders (e.g. hypoglycaemi), and seizure foci (79). DWI is the most sensitive method for the delineation of hyperacute ischaemia. The infarct core has restricted diffusion and this appears bright on DWI and dark on ADC maps. DWI is able to detect changes within minutes after the onset of ischaemia (80,81). Direct visualization of the infarct core and assessment of brain tissue viability is the main advantage of MR over CT in the assessment of AIS. Although signs of cerebral ischaemia on T2-weighted and FLAIR images are not visible until several hours post stroke, a ‘mismatch’ between positive DWI and negative FLAIR allows for the identification of patients within 3 hours of symptom onset with high specificity and positive predictive value (82,83).
Vascular imaging Vascular imaging in stroke is used to detect arterial thrombus and characterize collateral flow. The presence of a bright thrombus or embolus in the middle cerebral artery creates a linear brightness on NCCT, often called the ‘hyperdense artery sign’. It is seen in approximately one-third of AIS patients, and associated with poor radiological and clinical outcome. Similarly, because of the high concentration of deoxyhaemoglobin in the acute thrombus, T2*weighted images delineate intraluminal clots as areas of linearor dot-shaped dark signal. CTA demonstrates arterial abnormalities in up to 95% of patients with acute ischaemic infarcts, and evaluates the intra- and extracranial vasculature with a single injection of contrast, revealing the location of the clot as well as the extent of atherosclerotic disease (84). In the setting of AIS, CBF is compromised to the affected brain territory. The central core of tissue that dies immediately is often called the infarct core, and this is surrounded by an area of brain that is hypoperfused but still viable. It is this latter region of brain, often called the ischaemic penumbra, which is potentially salvageable by acute reperfusion therapy (see Chapter20). Intravenous tissue plasminogen activator (rt-PA) is approved for thrombolysis after AIS within a short time (0–4.5 hours) from symptom onset (85), but this narrow time window significantly limits its usage and fewer than 10% of AIS patients are applicable for such treatment (86). It has been suggested that intravenous rt-PA, or other reperfusion therapies, could be safely administered in an extended time window in selected patients with a sufficient volume of salvageable penumbra (87,88). MRI could be used to identify those suitable for later intervention and allow a much larger percentage of stroke patients to be safely treated. DWI reflects irreversibly damaged tissue whereas PWI demonstrates an overall area of hypoperfusion. The volumetric difference between these abnormal regions, called the PWI/DWI ‘mismatch’, represents the MR correlate of the ischaemic penumbra (Figure15.4). On the other hand, there is no difference in the PWI and DWI volumes (i.e. there is a PWI/DWI ‘match’) in patients with no penumbral (i.e. ‘salvageable’) tissue. The Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study showed that early reperfusion is associated with a more favourable clinical response in patients with a PWI/DWI mismatch profile, and that those without a mismatch do not benefit from reperfusion (38). The optimal definition of mismatch remains uncertain but, in many studies, is defined as a PWI lesion of at least 10 cm3or at least 120% of the DWI lesion volume (89,90). A subgroup analysis of the DEFUSE study demonstrated that a mismatch ratio of 2.6 provided the highest sensitivity (90%) and specificity (83%) for identifying patients in whom reperfusion is likely to be associated with a favourable clinical response (91).
To differentiate the infarct core from the penumbra, PCT imaging relies on the difference in cerebral autoregulation between these two regions. In the penumbra, where autoregulation is intact or only mildly impaired, MTT is prolonged because of arterial occlusion but CBV is maintained or increased because of compensatory vasodilatation and recruitment of collaterals. In the infarct core, where autoregulation is severely impaired, MTT is prolonged in association with a reduction in CBV (Figure15.3). By combining MTT and CBV, PCT has the ability to reliably identify reversible ischaemic penumbra and irreversible infarct core after AIS.
Haemorrhagic transformation Haemorrhagic transformation is a serious complication of AIS that is associated with an 11-fold increase in mortality (92). Combined data from six major stroke trials confirm that severe haemorrhage with significant mass effect occurs in around 5% of patients treated with rt-PA within 3 hours after symptom onset, and in up to 6% of those treated between 3 and 6 hours (93). However, haemorrhagic transformation is a multifactorial phenomenon, with damage to the blood–brain barrier and subsequent vascular leakage one of the contributing mechanisms (94). Although often triggered by reperfusion, it can occur spontaneously (95,96). Imaging can potentially be used to detect early blood– brain barrier damage and thereby identify patients who are more likely to develop haemorrhagic transformation after reperfusion. CT and MR both allow assessment of the integrity of the blood–brain barrier (97,98,99), and patients with abnormal barrier permeability are at increased risk of haemorrhagic transformation (98,99). Other imaging biomarkers associated with an increased risk of haemorrhagic transformation include CT hypodensity involving more than onethird of the middle cerebral artery territory, and a large volume of infarct on DWI (100).
Epilepsy Imaging plays an important role in the pre-surgical assessment of patients with refractory epilepsy. SPECT and positron emission tomography (PET) techniques can define seizure onset zone and outline resection margins in those in whom surgery is planned. In general, cerebral metabolism and CBF are markedly increased during an epileptic seizure and decreased in the interictal period (101). Ictal SPECT has substantially higher specificity and positive predictive value than interictal studies (102), with ictal hyperperfusion restricted to the ictal-onset zones unless the seizure propagates (Figure15.5). The accuracy of ictal SPECT analysis is enhanced when comparing ictal and interictal perfusion imaging data.18F-FDG-PET is routinely restricted to interictal studies, where it can provide useful localizing information with regards to the epileptogenic focus. The brain region with marked hypometabolism is considered to contain the epileptogenic zone, although this area tends to be larger than the actual seizure onset zone (103,104). The advantages of PET over SPECT include superior spatial resolution, and the potential for metabolic rather than blood-flow imaging (Figure15.5) (105). Epileptogenic lesions may also be visualized on structural imaging such as MRI, particularly using T1-weighted spoiled gradient recalled pulse sequences, T2, and FLAIR images. Contrast can be used to further delineate a lesion detected on non-contrast images, for example, in patients with a suspected brain tumour. MRI, SPECT, and PET image fusion allows direct correlation of the anatomical abnormalities identified on MRI with the metabolic and perfusion abnormalities detected on FDG-PET and SPECT respectively.
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Specific conditions
16 Postoperative care Nicolas Bruder and Lionel Velly 17 Traumatic brain injury Hayden White and Bala Venkatesh 18 Subarachnoid haemorrhage Pouya Tahsili-Fahadan and Michael N. Diringer 19 Intracerebral haemorrhage Candice Delcourt and Craig Anderson 20 Acute ischaemic stroke Barry M. Czeisler, Daniel Sahlein, and Stephan A. Mayer 21 Traumatic spinal cord injury Jefferson R. Wilson, Newton Cho, and Michael G. Fehlings 22 Neuromuscular disorders and acquired neuromuscular weakness Nicola Latronico and Nazzareno Fagoni 23 Status epilepticus in adults Jan Novy and Andrea O. Rossetti 24 Central nervous system infection and inflammation Erich Schmutzhard, Ronny Beer, Raimund Helbok, and Bettina Pfausler 25 Post-cardiac arrest syndrome Jerry P. Nolan 26 Disorders of consciousness Olivier Bodart, Aurore Thibaut, Steven Laureys, and Olivia Gosseries 27 Non-neurological complications of acquired brain injury Derek J. Roberts and David A. Zygun 28 Electrolyte and endocrine disturbances Adikarige Haritha Dulanka Silva, Antonio Belli, and Martin Smith 29 Brain death Jeanne Teitelbaum and Sam Shemie 30 Principles of organ donation Ivan Rocha Ferreira da Silva and Jennifer A. Frontera 31 Outcome after neurointensive care Lakshmi P. Chelluri and Jayaram Chelluri
Postoperative care
Chapter: Postoperative care Author(s):Nicolas Bruder and Lionel Velly DOI: 10.1093/med/9780198739555.003.0016 Postoperative complications are common after intracranial procedures. In a prospective study of 486 patients, 54.5% of the 431 who were extubated during the 4 hours following surgery suffered at least one complication (1). Nausea or vomiting occurred in 38% of patients, and respiratory, cardiovascular, and neurological complications in 2.8%, 6.7%, and 5.7% respectively. In retrospective studies, the overall major complication rates are variably reported between 13% and 27.5% (2). The 30-day mortality rate after intracranial tumour surgery is around 2.2% (3,4). Although the overall risk of perioperative death has decreased over the last decades, mortality is probably not the best outcome measure for quality of care after neurosurgery (4). In our institution during the years 2000–2001, in-hospital mortality was 2% but the frequency of postoperative complications in the first 48 hours after elective surgery was 14.4%, and major neurological events represented 45% of these complications (intracranial haemorrhage in 20% and seizures in 15%). Risk factors for mortality after intracranial tumour surgery include tumour type, age older than 60 years, and biopsy compared to craniotomy (3). The most frequent cause of early postoperative death relate to the tumour itself, but intracranial bleeding accounts for about one-third of perioperative mortality. The risks associated with other intracranial procedures are roughly similar to those for tumour surgery. For example, symptomatic haemorrhage occurs in 2.1% of patients after functional neurosurgery and results in permanent deficit or death in 1.1% (5).
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Indications for postoperative admission to neurointensive care The need for neurointensive care after neurosurgery is dependent on many factors, and varies for elective and emergency procedures.
Elective craniotomy The rationale for admitting patients to a neurocritical care unit (NCCU) after uncomplicated elective craniotomy is the relatively high rate of postoperative complications compared to other surgery types, and the need to recognize and treat intracranial complications as early as possible. The outcome after urgent reoperation for haemorrhage is independently associated with the Glasgow Coma Scale (GCS) score before reoperation and the time interval between primary surgery and reoperation (6). However, the identification of intracranial haemorrhage may be difficult in the first hours after craniotomy. Drowsiness or mild confusion may be the only early clinical signs and these may be interpreted as delayed anaesthetic recovery. Headaches and mild hemiparesis may also occur and, when temporary, can also be associated with anaesthesia recovery (7). Close clinical monitoring is mandatory and there should be a low index of suspicion, prompting an urgent computed tomography (CT) scan to confirm an intracranial complication before intracranial hypertension and cerebral herniation ensue. However, most elective patients do not need active intervention after the first 4 hours following craniotomy and only 15% need to stay in the NCCU for more than 24 hours (8,9). This is a problem for a busy NCCU where bed resources are often scarce, and other care locations are often chosen (see below) if the predicted risk of complications is low (Table 16.1). Risk factors for the development of postoperative complications include failure to extubate the trachea in the operating theatre, duration of surgery more than 4 hours, lateral positioning of the patient during surgery, Karnofsky performance scale score below 80, and intraoperative blood loss greater than 350
mL (10,11). Such factors should be considered when deciding which patients require admission to the NCCU after elective neurosurgery. Table 16.1 Indications for postoperative admission to different care locations NCCU
Major preoperative comorbidity Slow emergence after surgery Unexpected neurological deficit after surgery Massive intraoperative blood losses Posterior fossa surgery involving cranial nerves IX–XII Postoperative seizures Karnofsky index < 80
Intermediate care unit Posterior fossa surgery Preoperative midline shift > 5 mm (CT scan) Duration of surgery > 4 h Age > 70 years Severe postoperative pain Recurrent postoperative nausea and vomiting Hypothermia < 35.5°C at extubation Severe postoperative arterial hypertension Postoperative hypoxaemia Blood loss > 350 mL
Ward
Small supratentorial tumour without complication Grade 0 aneurysm Intracranial biopsy without complication Surgery not involving the brain CSF shunt placement Uncomplicated transsphenoidal surgery
In the absence of risk factors and with meticulous neurological monitoring in the recovery room for 4–6 hours, some centres admit postoperative craniotomy patients to a regular neurosurgical ward with good results (12). However, this practice has been validated only in a small number of patients and the financial and personal cost of one undetected major complication is likely to far outweigh the resource benefits of bypassing the NCCU. Most postoperative intracranial haemorrhages occur in the first 6 hours following surgery (13,14), so if intracranial procedures are planned for the morning, prolonged monitoring in the recovery room (or NCCU) prior to return to the ward is feasible. Another solution is the development of intermediate care units, appropriately staffed to perform frequent clinical checks but without the extended monitoring and life support capabilities available in the NCCU. It is only possible to avoid admission to the NCCU if rapid emergence and tracheal extubation are possible at the end of surgery. Although this practice is widely recommended, a survey of German neuroanaesthetists revealed that only 61% of patients with brain tumours were managed without postoperative ventilation in the 1990s (15). However, there was a trend towards earlier extubation from 1991 to 1997 and, with the developments in neuroanaesthesia, this trend is likely to have continued since then. In summary, the indication for postoperative intensive care after elective intracranial surgery varies between neurosurgical centres and depends on NCCU capacity, nurse staffing, and competency levels in other clinical areas, as well as intraoperative anaesthesia and surgical management.
Emergency procedures There is little doubt that the majority of emergency neurosurgical procedures require postoperative management in the NCCU. Emergency neurosurgery is indicated most frequently for trauma patients or to treat intracranial hypertension and impending brain herniation and, less frequently, to clip an intracranial aneurysm, excise an arteriovenous malformation, treat pituitary apoplexy, or remove a brain abscess or subdural empyema. After serious head trauma, the benefit of direct transportation to an institution with a neurosurgical unit compared to the nearest hospital is strongly recommended (16), but this can be a challenge for busy neurosurgical centres with limited NCCU beds. Our policy is to admit patients and perform surgery whenever it is indicated, sometimes by
admitting the patient directly into the operating theatre (after the CT scan) if the NCCU is full. This ensures timely surgical intervention and allows time to identify a bed, or in extreme circumstances to transfer the patient to another facility after post-surgery stabilization.
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General care after craniotomy Frequent neurological observations undertaken by a trained nurse are mandatory after intracranial neurosurgery irrespective of the care location. In addition, several treatments are needed to prevent postoperative complications or treat side effects of surgery and anaesthesia (Table 16.2). Table 16.2 Corticosteroids comparison table (potency of anti-inflammatory and mineralocorticoid effect is relative to hydrocortisone) Drug
Short acting Hydrocortisone Intermediate acting Prednisolone Prednisolone Methylprednisolon e Long acting Dexamethasone Betamethasone Mineralocorticoid Fludrocortisone Aldosterone
Equivalent glucocorticoid dose (mg)
Route of administration
Potency relative to hydrocortisone AntiMineralocorticoi inflammator d y
Duration of action (hours)
20
IM, IV, PO
1
1
8–12
5 5 4
PO PO IM, IV, PO
4 4 5
0.8 0.8 0.5
12–36 12–36 12–36
0.75 0.6
IM, IV, PO IM, PO
30 30
0 0
36–54 36–54
0 0
PO PO
15 0
150 400
24–36 –
Modified from Adrenal cortical steroids. In Drug Facts and Comparisons, 2015 edition. Clinical Drug Information, 2014.
Postoperative pain, nausea, and vomiting Although craniotomy is less painful than other major surgical procedures such as thoracic, abdominal, and orthopaedic surgery (17), post-craniotomy pain is often moderate or severe, and frequently underestimated and inadequately treated (18). Pain scores decrease from the first to the second postoperative day and pain is more severe after infratentorial than supratentorial surgery. The increasing use of remifentanil during anaesthesia for craniotomy means that postoperative analgesia requirements must be anticipated before awakening. Scalp nerve blocks or wound infiltrations with local anaesthesia provide effective early postoperative analgesia, but pain reappears a few hours after the end of surgery (19,20,21). Importantly, the duration of the analgesic effect of scalp infiltration placed before surgery may be too short to provide long-lasting postoperative analgesia. Paracetamol (acetaminophen) alone does not provide adequate pain relief and should be used in combination with other analgesics including opioids in the early postoperative period (22). Tramadol is effective after craniotomy, does not affect intracranial pressure (ICP) or cerebral perfusion pressure (CPP) (23), but may increase the frequency of nausea
and vomiting and induce somnolence (24). Nefopam has anti-shivering and analgesic properties but has been associated with convulsions (25) despite having strong anticonvulsant properties in experimental studies (26). Patient-controlled opioid analgesia is effective and safe after craniotomy, although the adverse effects of opioids in neurosurgical patients, including somnolence, retention of CO 2, and increased ICP, may limit its use (27). Nonsteroidal anti-inflammatory drugs (NSAIDs) are rarely used early after craniotomy because they inhibit platelet aggregation and might thereby increase the risk of postoperative bleeding. There are also concerns about the wellknown upper gastrointestinal side effects, particularly in patients concurrently receiving corticosteroids. However, there are no data demonstrating adverse consequences of NSAIDs after craniotomy and they can probably be used safely in selected patients. Nausea occurs in 50% of patients after craniotomy and vomiting in approximately 40% (1,28,29). Emesis is more frequent after infratentorial surgery and in women. Prophylaxis for postoperative nausea and vomiting is often indicated. Ondansetron is safe and has few side effects, but is only partially effective (28,29,30). Droperidol is more effective than ondansetron and does not induce sedation at doses of 1 mg or less (28). Repeated doses of droperidol may be sedative so the combination of droperidol (< 1 mg) and ondansetron is often used. Corticosteroids are also effective in the prevention of postoperative nausea and vomiting (31).
Corticosteroids The oedema surrounding brain tumours is mainly vasogenic, and corticosteroids dramatically reduce oedema associated with malignant glioma or brain metastasis. This effect has been known since 1961 (32) and, more recently, diffusion tensor magnetic resonance imaging studies confirm localized decreased water content in the white matter surrounding brain tumours a few days after corticosteroid use (33). A plateau effect is observed after 4–6 days of treatment. Corticosteroids have no effect on cytotoxic or interstitial oedema and should not be used in cerebral ischaemia or after brain trauma (34). Side effects of corticosteroids are frequent, and toxicity has been related to cumulative dose as well as duration of treatment. Hyperglycaemia is the most common complication of steroid use but psychoses can be problematic and are often overlooked or mistakenly presumed to be related to the primary neurological pathology. The administration of corticosteroids should be reviewed regularly in the postoperative period, and high doses tapered rapidly over a few days. Dexamethasone is the most commonly prescribed corticosteroid for the management of cerebral oedema and has low mineralocorticoid activity. The initial dexamethasone regimen is a bolus dose of 10 mg followed by 4 mg every 6 hours (35), although daily doses of 4–8 mg are usually appropriate (36). Other corticosteroids, for example, methylprednisolone, may also be used but each has specific potencies and anti-inflammatory and mineralocorticoid actions (Table 16.3). Dexamethasone is approximately six times more potent than methylprednisolone. Table 16.3 Treatments after intracranial tumour surgery Analgesics
Paracetamol 1 g/6 h + tramadol 100 mg/6–8 h ± nefopam or NSAID Persistent pain: opioid PCA
Corticosteroids
Dexamethason e Day 1: 12 mg/6 h Day 2: 6 mg/6 h + PPI
Antiepileptics
Thromboprophyl axis Levetiracetam Consider IPC in all 500 mg/8h patients or phenytoin LMWH 100 mg/8 h the or continue morning other after preoperative surgery drug (after CT scan)
Other
Antibiotic prophylaxis Hormonal treatment after pituitary surgery or craniophar yngioma
IPC, intermittent pneumatic calf compression; LMWH, low molecular weight heparin; NSAID, non-steroidal antiinflammatory drugs; PCA, patient-controlled analgesia; PPI, proton pump inhibitor.
Prophylactic anticonvulsants The prophylactic use of antiepileptic drugs after intracerebral surgery is controversial. Their effects on the prevalence of seizures are unclear (37), and they have important and potentially serious side effects (38,39). In 2000, a consensus statement from the Quality Standards Subcommittee of the American Academy of Neurology recommended that prophylactic antiepileptic drugs should not be used routinely in patients with brain tumours and that, if they are, the drug should be stopped in the first week after surgery if the patient remains seizure free (40). However, there is considerable disparity between guidelines and management strategies pursued by neurologists, neurosurgeons, and neuroanaesthetists. In 2005, a clinical practice survey showed that 70% of neurosurgeons routinely used prophylactic antiepileptic drugs in patients undergoing brain tumour resection (41). Two meta-analyses concluded that prophylactic anticonvulsants are not superior to placebo (no prophylaxis) in the prevention of a post-craniotomy seizure in patients with brain tumours, but are associated with a higher risk of other adverse effects (42,43). Milligan and colleagues compared the efficacy and tolerability of prophylactic levetiracetam with phenytoin after supratentorial surgery (44) and found no difference in efficacy but fewer adverse effects with levetiracetam. The duration of prophylactic therapy in patients without preoperative seizures should be restricted to the first postoperative week (45). Seizures have been reported after posterior fossa surgery but a preventive treatment is seldom required (46). Chronic antiepileptic treatments in known epileptics should be administered as early as possible in the postoperative period.
Thromboprophylaxis The risk of venous thromboembolism (VTE) is high after intracranial surgery. Without prophylaxis, the frequency of ultrasonography- or venography-confirmed deep vein thrombosis (DVT) is 20–35% and 2.3–6% for symptomatic events (47). Malignant tumour, prolonged surgery, hemiparesis, and advanced age are risk factors for VTE. The value of both mechanical methods of prophylaxis against DVT, such as intermittent pneumatic compression (IPC) of the calves, and low-molecular-weight heparin (LMWH) or low dose unfractionated heparin (UFH) have been demonstrated. Compression stockings are probably not effective alone (48), but are usually used in combination with IPC. LMWH or IPC decrease the risk of DVT by at least 50%, and at least one method should be employed routinely after intracranial surgery (49). The combination of LMWH and IPC is highly effective (50) but, in large trials, low-dose heparin or LMWH increased the rate of symptomatic haemorrhage (49,51). The potential benefits of heparin must therefore be weighed against the risk of intracranial haemorrhage. For this reason, IPC alone is usually recommended in the early period after craniotomy. In patients at high risk of developing VTE (see above), heparin is indicated when adequate haemostasis has been established. Otherwise, the optimal delay between surgery and anticoagulation has not been determined. Mechanical prophylaxis (IPC) should be started at the time of surgery and, in our practice, LMWH or UFH treatment is started on the morning after surgery following a cranial CT scan to rule out intracranial bleeding. In some centres, UFH is preferred to LMWH because heparin can be reversed by protamine, but this benefit is unclear and many centres use LMWH without adverse effects.
Antibiotics Antibiotic prophylaxis is recommended during intracranial surgery as it halves the rate of postoperative infection (52,53). The optimal duration of treatment is unknown but should be less than 24 hours to avoid the development
and selection of antibiotic-resistant microorganisms. It is common practice to continue antibiotic prophylaxis in the first few hours after surgery. A first-generation cephalosporin (cefazolin) is usually recommended.
Hormone replacement Hormone support may be necessary after pituitary or craniopharyngioma surgery. Postoperative thyroid replacement therapy is never an emergency because the half-life of thyroid hormone is several days. Cortisol replacement may be needed after the surgical treatment of Cushing’s disease, and is mandatory in patients with preoperative adrenal insufficiency. Hydrocortisone 50 mg 6-hourly is sufficient to prevent relative adrenal insufficiency in the first 24 hours after surgery. Cranial diabetes insipidus (CDI) is characterized by polyuria and polydipsia, but the signs of polydipsia are absent in sedated postoperative patients (see Chapter 28). CDI may rapidly induce dehydration and hypernatraemia if not diagnosed and treated early. Monitoring urine output and specific gravity or osmolarity is mandatory when there is a risk of CDI. Increased diuresis from intraoperative fluids or residual effects of mannitol can occur, but is usually limited to the early postoperative period, does not induce hypernatraemia and should not be mistaken for CDI. In the context of pituitary surgery, urine output above 250 mL/hour for more than 2 hours and a specific gravity less than 1.005 (urine osmolality < 300 mOsm/kg) is an indication to administer desmopressin (DDAVP) by the oral, nasal, intravenous, or subcutaneous route. In postoperative patients, intravenous administration, in doses of 1–4 mcg as required, is preferred. Oral water intake guided by thirst is an effective and safe way of managing fluid replacement in the majority of awake patients, but intravenous hypotonic fluid replacement may be necessary to limit hypernatraemia in those unable to take oral fluids. Rapid reduction of plasma osmolality may promote cerebral oedema and should be avoided.
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Monitoring strategies Although clinical neurological examination is the mainstay of monitoring postoperative neurosurgical patients, careful attention to systemic and cerebral physiological homeostasis mandates additional monitoring.
Clinical monitoring The best neurological monitor is repeated clinical examination by a trained observer. Neurological worsening may cause either a focal neurological deficit (motor, speech, or visual deficits) or a decrease in conscious level. Several scores have been described to assess neurological status (54). The Glasgow Coma Scale (GCS), although not validated for postoperative patients, is simple to use and well known by nurses and physicians, explaining its widespread use. The GCS score relies on the best global response and therefore cannot detect focal deficits, so focal neurological status (limb power and pupil responses) must also be documented. As well as monitoring for general neurological changes, attention should also be given to monitoring for procedure-specific deficits. For example, speech deficits after surgery of the left temporal lobe or swallowing disorders after surgery of the cerebropontine angle are deficits of concern after these specific procedures, and clinical monitoring must focus on these in addition to the GCS. A decrease in consciousness is the most common clinical sign of postoperative intracranial haemorrhage (see ‘Intracranial haemorrhage’). However, even small doses of narcotics or hypnotics may exacerbate or unmask focal neurological deficits and decrease consciousness, and may lead to unnecessary brain imaging (7,55).
Haemodynamic monitoring
Hypoxaemia and hypotension are associated with a significant increase in morbidity and mortality after traumatic brain injury (TBI) (56), and this probably also holds true for other brain injury types including the postoperative brain. It is also likely that severe postoperative hypertension may increase the risk of brain haemorrhage, especially shortly after a procedure when the process of fragile surgical haemostasis is ongoing (13). Therefore, continuous arterial blood pressure monitoring is common practice in the postoperative period after neurosurgery, and should be available until blood pressure is stable or intervention to control it is no longer required. Continuous electrocardiography is mandatory to detect arrhythmias, especially after epilepsy surgery or subarachnoid haemorrhage (SAH) (57,58). Cardiac output monitoring may be necessary in specific situations including pre-existing cardiac failure, SAH-induced cardiomyopathy, and when complex haemodynamic management is required after massive blood losses and sepsis. Echocardiography should also be available to quantify ventricular systolic function if required.
Respiratory monitoring Oxygen saturation measurement using pulse oximetry is indicated for all postoperative patients. The arterial partial pressure of CO2 (PaCO2) is a major determinant of cerebral blood flow (CBF) and patients with low intracranial compliance have a significant risk of developing raised ICP during hypercapnia. Blood gas analysis should be performed on admission of neurosurgical patients to the NCCU or recovery room. Administration of opioids or sedatives may lead to an increase in PaCO 2 and explain some temporally related neurological changes. Similarly, it seems reasonable to monitor end-tidal CO2 (ETCO2) in all ventilated neurosurgical patients. Although the gradient between PaCO2 and ETCO2 may vary over time (59), large variations in ETCO2 always indicate a change in PaCO2, and this may go undetected without ETCO2 monitoring.
Intracranial monitoring Except after SAH and TBI, ICP is rarely routinely monitored in elective postoperative craniotomy patients. In a retrospective study of 514 patients with ICP monitoring after elective supratentorial and infratentorial surgery, 17% had an increase in ICP and this was associated with clinical deterioration in 53% (60). Risk factors for postoperative ICP elevation included resection of glioblastoma, repeat surgery, and surgery lasting more than 6 hours. In a 2012 randomized study after TBI, care based on ICP monitoring was not superior to care based on imaging and clinical examination (61), confirming the results of a previous non-randomized study (62). Such findings do not mean that ICP is not useful in selected patients, but rather that the routine use of ICP monitoring, especially in the postoperative period, is probably not indicated. Conversely, ICP monitoring should be undertaken when clinical examination is unreliable because of sedation or coma, or when there are signs of intracranial hypertension or oedema on brain CT scan or intraoperatively. In this case, ICP monitoring is the only way to measure CPP continuously in order to identify and treat cerebral hypoperfusion. Transcranial Doppler sonography (TCD) of the middle cerebral artery allows real-time estimation of cerebral perfusion and CO2 reactivity (see Chapter 10). A low diastolic CBF velocity or a high pulsatility index on TCD suggests a low CPP (Figure 16.1). In this situation, physiological factors that alter CBF, such as hypocapnia, hypotension, and high ICP, should be checked and corrected. The effect of treatments on the cerebral circulation can be followed on successive TCD recordings or with continuous TCD monitoring over a few hours using a specially designed TCD probe fixation. In situations of zero diastolic flow, ICP is approximately equal to or is greater than the diastolic arterial pressure. Conversely, high blood flow velocity may indicate cerebral vasospasm, although it has rarely been reported after elective neurosurgery (Table 16.4). Case reports suggest that vasospasm be more frequent after amygdalohippocampectomy for epilepsy surgery (63) or pituitary surgery (64), but it has rarely been reported after uncomplicated tumour surgery (65). Blood flow velocity can also be increased in the postoperative period because of haemodilution, and should not be mistaken for vasospasm (66). Neurological symptoms due to vasospasm may appear as early as 2 days after surgery, and the time course of TCD flow velocity acceleration parallels the
development of angiographic vasospasm. If the patient develops symptoms compatible with cerebral vasospasm, immediate cerebral angiography should be performed in order to diagnose and treat this complication appropriately.
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Fig. 16.1 Transcranial Doppler (TCD) sonography to assess cerebral haemodynamics. CT scan (right of panel) showing postoperative frontal haemorrhage and TCD recording showing low velocities (V) and high pulsatility index (PI) suggesting elevated intracranial pressure and low cerebral perfusion pressure (low trace). A normal TCD trace is shown upper left panel. (See Chapter 10 for further discussion of TCD.) Table 16.4 Assessment of cerebral blood flow at the bedside using TCD and SjO 2 and suspected intracranial haemodynamic situation SjO2
CBF
PI
CBFV low
< 55% 55–75% > 75%
Low Adequate Brain ischaemia
CBFV high
< 55% 55–75%
Low Adequate
Suspected situation: recommendation
> 1.2 < 1.2
Low CPP, high ICP: monitor ICP Low CPP, low CO2: therapeutic trial Normal Ischaemic lesion: CT scan
Cerebral vasospasm: CT angiography Normal or impending vasospasm:
> 75%
High
repeat TCD Hyperaemia: check blood pressure, CO2
CBFV, cerebral blood flow velocity; CO2, arterial carbon dioxide partial pressure; PI, pulsatility index; TCD, transcranial Doppler. Jugular venous bulb oxygen saturation (SjO2), or the arteriojugular difference in oxygen content (AJDO 2), provides information about the balance between brain oxygen demand and supply, and may be useful in distinguishing between cerebral hyperaemia and vasospasm (see Chapter 11). During periods of constant cerebral metabolic rate, changes in CBF parallel changes in SjO2. SjO2 below 50% indicates relative hypoperfusion and, in the absence of anaemia, SjO2 above 75% suggests relative or absolute hyperaemia (Table 16.4). Thus, the combination of high blood flow velocity and low SjO2 strongly suggests diffuse cerebral vasospasm, although a normal SjO 2 value does not rule out focal cerebral ischaemia.
Blood glucose monitoring Hyperglycaemia has been consistently associated with poor outcome in neurosurgical patients (67,68,69). Routine glucose monitoring and glycaemic control are indicated in the postoperative period but the targets for glycaemic control remain a matter of debate. One randomized study in elective and emergency neurosurgical patients demonstrated shorter NCCU stay and reduced infection rates with tight glycaemic control, but more frequent episodes of hypoglycaemia (70). Studies in brain trauma patients have demonstrated reduced brain glucose availability and increased brain energy crisis with tight glycaemic control (71,72) and, after acute ischaemic stroke, intensive insulin therapy has been associated with larger infarct size (73). Therefore, both hyperglycaemia and low blood glucose should be avoided in neurosurgical patients justifying systematic blood glucose monitoring and maintenance of blood sugar between 5.0 and 10 mmol/L (90 and 180 mg/dL).
Electroencephalography Epilepsy is a frequent complication of neurosurgery. Seizures may be clinically evident in some patients and an electroencephalogram (EEG) is needed only to monitor the effectiveness of antiepileptic treatment. However, drowsiness or coma may be due to non-convulsive epilepsy or non-convulsive status epilepticus (NCSE) and these conditions can only be detected with EEG monitoring. In a study of 236 patients with coma and no overt clinical seizure activity, EEG monitoring demonstrated NCSE in 8% (74). In the postoperative period, NCSE is a well-identified cause of coma after various surgical procedures (75,76,77). Standard single EEG examination may miss the typical features of epilepsy due to intermittent epileptic discharges or difficulties in recognizing a specific pattern such as rhythmic delta waves, for example. When imaging does not identify a cause for a decrease in consciousness in the postoperative period, continuous EEG monitoring (i.e. over several hours or more) should be obtained to rule out NCSE.
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Haemodynamic management Because of the link between the brain and cardiovascular system, hypertension, hypotension, arrhythmias, myocardial failure, and neurogenic pulmonary oedema are common in neurosurgical patients (see Chapter 27) (78,79,80). Myocardial damage is especially frequent after SAH, and neurogenic pulmonary oedema may occur after TBI, stroke, and intracranial hypertension (81,82,83,84). Haemodynamic management may be difficult after
neurosurgical emergencies and complex neurosurgical procedures, particularly in the presence of intracranial hypertension, and invasive haemodynamic monitoring is mandatory. Echocardiography may also be of assistance because treatment may be different depending on the presence or absence of neurogenic myocardial dysfunction. Two studies in SAH patients have suggested improved outcome with cardiac output monitoring and goal-directed therapy (85,86).
Hypertension Hypertension is common after craniotomy (87) and likely to be related to sympathetic stimulation and release of epinephrine (adrenaline) and norepinephrine (noradrenaline). Continuing sedation into the postoperative period does not attenuate this response (88). Hypertension after craniotomy may lead to cerebral oedema and haemorrhage (89,90). A strong association between postoperative hypertension (> 160 mmHg) and intracranial bleeding has been reported (13) and, despite absence of evidence of causality, it seems wise to maintain postoperative blood pressure below 160 mmHg to reduce the risk of intracranial haemorrhage. In addition, it has been demonstrated that intensive blood pressure reduction after acute intracerebral haemorrhage (systolic blood pressure between 130 and 140 mmHg) can attenuate haematoma growth (91). The early administration of an antihypertensive agent is sometimes required to prevent or limit the rise in blood pressure associated with awakening and tracheal extubation, and labetalol (0.15 mg/kg, as needed), esmolol (1 mg/kg bolus followed with an infusion of 0.2 mg/kg/min), urapidil (0.15 mg/kg, as needed) or nicardipine (0.5 to 1 mg bolus) may be used. After extubation, blood pressure returns toward normal values in 30–60 minutes in most patients. In normotensive patients, a secondary rise in blood pressure may be the first sign of an intracerebral complication. Early intracranial hypertension has been reported in 18% of patients after elective supratentorial surgery (60), and is significantly associated with clinical deterioration possibly because cerebral hyperaemia combined with systemic hypertension may explain or aggravate cerebral oedema (92). Esmolol, a short-acting beta blocker, has the advantage of limiting the postoperative rise in blood pressure and the cerebral hyperaemic response (93). Intracranial hypertension is more common after craniotomy for ruptured intracranial aneurysms than for other indications. In one study, it was observed in 54% of 433 SAH patients overall (94) and, although more common in poor-grade patients (64%), high ICP occurred postoperatively in 48% of patients with a good clinical grade. The ICP response to treatment was strongly related to patient outcome.
Hypotension Arterial hypotension is an uncommon complication after intracranial surgery but it is important to recognize and treat it rapidly to avoid cerebral hypoperfusion and ischaemia. Hypotension is most often related to hypovolaemia as a result of urinary losses due to the infusion of mannitol or underestimation of intraoperative blood loss. If hypovolaemia is suspected it is reasonable to test the response to a small fluid challenge with 250 mL of isotonic crystalloid over 10–20 minutes (see Chapter 5). CDI may lead to profound volume loss after pituitary surgery if not diagnosed and treated early. Adrenal insufficiency may also occur after pituitary surgery or in patients on chronic corticosteroid treatment. Less frequently, myocardial ischaemia may progress to heart failure in patients with coronary artery disease and, if suspected, an electrocardiogram and plasma troponin-I should be obtained. Early postoperative pulmonary embolism should always be considered in cases of refractory hypotension, and the diagnosis may be suspected based on electrocardiographic, arterial blood gases, and chest X-ray findings. Echocardiography is easy to obtain at the bedside and is always positive after massive pulmonary embolism, but may be negative in small embolism. Helical pulmonary CT scanning has the highest sensitivity and specificity to confirm the diagnosis of pulmonary embolism.
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Management of common complications There are many complications that can arise in the postoperative period and some, such as intracranial haemorrhage, require immediate intervention. Early post-procedural neurological evaluation and timely investigations (see earlier sections) when indicated allow early identification of intracranial complications. An algorithm summarizing the approach to a new postoperative neurological deficit is shown in Figure 16.2.
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Fig. 16.2 Management algorithm to investigate new postoperative neurological deficits. EEG, electroencephalography; SjO2, jugular venous bulb oxygen saturation; TCD, transcranial Doppler.
Intracranial haemorrhage The most feared complication after neurosurgery is intracranial haemorrhage (Figure 16.3). Its reported incidence varies greatly depending on the definition (95). In large retrospective studies, the incidence of intracranial haemorrhage causing clinical deterioration or requiring surgery varies between 0.8% and 2.2% (Table 16.5) (3,13,14,96,97,98). Approximately 40–60% of such bleeding episodes are intracerebral haematomas (97,98), and the outcome is frequently poor. Most intracranial bleeding occurs within the first 6 hours after surgery (13,14), and risk factors for postoperative bleeding include cerebral amyloid angiopathy, platelet count below 10 9/L, factor XIII and other clotting factor deficiencies, and preoperative treatment with antiplatelet agents or anticoagulants (95). The risk of postoperative haemorrhage also depends on the surgical procedure (Table 16.6). As discussed earlier, postoperative hypertension is probably the most important and modifiable risk factor for intracerebral haemorrhage, and may in some cases be related to the hyperaemic response during awakening and extubation (92). Although prospective studies proving efficacy are lacking, retrospective studies (13) indicate that postoperative blood pressure control may reduce the risk of postoperative haemorrhage (93). Cerebral bleeding remote from the surgical area is a rare but well-described complication, and is most frequently located in the cerebellum. Remote cerebellar haemorrhage is thought to be related to cerebrospinal fluid (CSF) loss during surgery, intracranial hypotension, cerebellar sag and stretching, or transient occlusion of cerebellar veins leading to venous infarction (99,100). It may also occur after spinal surgery. Cerebellar haemorrhage is frequently asymptomatic but may lead to clinical deterioration requiring surgical evacuation.
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Fig. 16.3 CT scans showing postoperative intracranial haemorrhage. On the left panel, the patient suffered an extradural haematoma after removal of a frontal tumour. The patient was asymptomatic and the haematoma was revealed by a systematic postoperative CT scan the morning after surgery. On the right panel, an intracerebral haemorrhage occurred due to venous infarction after meningioma surgery. Table 16.5 Rates of intracranial haemorrhage after craniotomy in large (>1000 patients) retrospective studies Study Fukamachi et al., 1985 (96) Kalfas and Little, 1988 (97) Palmer et al., 1994 (98) Taylor et al., 1995 (14) Basali et al., 2000 (13) Lassen et al., 2011 (3)
Criteria CD Surgical evacuation CD CD Surgical evacuation
Complication/total (%) 42/1074 (3.9%) 40/4992 (0.8%) 71/6668 (1.1%) 50/2305 (2.2%) 86/11214 (0.77%) 54/2630 (2.1%)
Outcome Death 11; poor 7 Death 22 Death 9 ? Death 21
CD, clinical deterioration; poor, poor neurologic outcome. Data from various studies (see References). Table 16.6 Risk factors for postoperative intracranial haemorrhage Procedure Large intracerebral tumour (> 30 mL) Hypervascular tumour Large arterial-venous malformation resection Carotid or intracranial artery angioplasty Thrombolysis for stroke
Patient risk factor Uncontrolled arterial hypertension Coagulation disorders Disorders of haemostasis (low platelet count) Cerebral amyloid angiopathy Treatment with antiplatelet agents
Regular neurological monitoring is the best way to detect intracranial bleeding early, and this is the reason why short-acting anaesthetic agents should be used and patients extubated as early as possible after surgery. As already noted, even small doses of hypnotics and narcotics may worsen mild neurological deficits and impair neurological assessment (7,55). Conversely, inadequately treated pain may predispose to systemic hypertension and the abovenoted risk of intracranial haemorrhage. Not all patients can be awakened and extubated at the end of surgery. Reasons for delayed extubation include preoperative decreased consciousness, prolonged surgery, intraoperative complications (including bleeding and cerebral swelling) and end of surgery hypothermia (temperature < 35.5°C). In some patients, particularly if sedation will be continued for some time, postoperative ICP monitoring is indicated. Transcranial Doppler monitoring of middle cerebral artery blood flow velocity may be used to assess intracranial hypertension and impaired cerebral perfusion non-invasively by the demonstration of low diastolic velocity and high pulsatility index (Figure 16.1). Other non-invasive methods of assessing intracranial pressure, such as optic nerve sheath diameter, are discussed in Chapter 9. In all cases of unexpected neurological deficit, an urgent brain CT scan is mandatory to allow rapid diagnosis of intracranial complications and immediate treatment to avoid long-term sequelae. Symptomatic haemorrhage should to be evacuated as soon as possible after checking and correcting coagulation status, platelet count, and haemoglobin. After posterior fossa surgery, even small volume haemorrhage may cause significant neurological worsening and the decision to proceed to surgical evacuation can be difficult, although somnolence associated with even a small haemorrhage should prompt reoperation. Progression from coma to irreversible brainstem compression can be very rapid, particularly with posterior fossa haemorrhage. Some features such as duret haemorrhage (brainstem haemorrhage associated with herniation) may occur before obvious signs of clinical deterioration and should prompt urgent consideration of surgery.
Infection Neurosurgical site infections occur in approximately 4% of craniotomy cases (101), although the rate is variably reported in the literature (102,103,104,105). Reoperation to treat central nervous system infections is required in only 0.5% of patients (106). The frequency of meningitis is also low at 1.5–2%. The most important risk factors for postoperative infection and meningitis are postoperative CSF leak (103,104), surgical duration greater than 4 hours, emergency surgery, early reoperation, and Altemeier class (clean, clean-contaminated, contaminated, and dirty type of surgery) (107). Staphylococcus aureus and various Gram-negative bacteria are the most common pathogens associated with postoperative infections, although coagulase negative staphylococci, Propionibacterium acnes, and streptococci infections may also occur. The diagnosis of postoperative meningitis is often difficult because the usual clinical signs of fever, nuchal rigidity, headache, and decreased consciousness may be unreliable or appear late. Further, no CSF leucocyte count threshold is sensitive or specific enough for the diagnosis of postoperative meningitis and, although Gram staining is almost 100% specific, it has a very low sensitivity (108). A CSF serum to glucose ratio lower than 0.4 has a high sensitivity and specificity for the diagnosis of bacterial meningitis, but even extreme low glucose is not always confirmatory (109). CSF lactate greater than 4 mmol/L is highly sensitive and specific for the differentiation between bacterial and viral meningitis (110). CSF lactate may also differentiate bacterial from aseptic meningitis, although studies have reported mixed sensitivities and specificities (111). Among cytokines, CSF interleukin 1 beta seems to be the best biochemical marker of infection (112) but is not routinely performed in clinical practice. When bacteriological cultures are negative, a combination of clinical and biochemical markers is the best indicator for antibiotic treatment.
Epilepsy Supratentorial craniotomy is associated with a relatively high risk of postoperative seizure. Depending on the indications for surgery (Table 16.7), about 15–20% of patients have at least one seizure in the postoperative period (113,114). The majority are partial seizures, either simple partial (focal motor or sensory phenomena without alteration of consciousness), complex partial (with alteration of consciousness), or partial with secondary generalization. Early seizures are likely to be related to surgical injury such as cerebral oedema, local inflammation, excitotoxic damage, oxidative stress, and impairment of neuronal metabolism (115). In addition to the direct risks that they bring to the recently operated brain, seizures may precipitate other serious complications, including intracranial haemorrhage, hypoxaemia, and pulmonary aspiration. Table 16.7 Risk of seizures after common neurosurgical interventions Incidence of postoperative seizure Intracranial abscess Arteriovenous malformation Intracerebral haematoma Cerebral aneurysm Meningioma Metastasis resection Suprasellar tumour Shunt
(%) 92% 50% 10–20% 7–40% 36% 20% 5% 22%
Reproduced with permission from Shaw MDM and Foy PM, ‘Epilepsy after Craniotomy and the Place of Prophylactic Anticonvulsant Drugs: Discussion Paper’, Journal of the Royal Society of Medicine, 84, 4, p. 3, Copyright © 1991 SAGE publications.
Late postoperative seizures represent actual epilepsy and may require long-term treatment (116). Several risk factors for late seizures have been described and include the nature of the primary intracranial disease (Table 16.7), severity of surgical insult, and pre-operative heraldic seizures (117). Both early and late seizures negatively affect neurological outcome and patients’ quality of life.
Tension pneumocephalus Pneumocephalus, or asymptomatic intracranial air, is a common occurrence after craniotomy (118,119). Significant amounts of intracranial air may persist for up to 14 days after surgery. Transformation of pneumocephalus into tension pneumocephalus (symptomatic intracranial air) is a rare complication (0.5–3%) after sitting craniotomy, and an exceptional complication after non-sitting craniotomy. It has been attributed to a diminution of brain volume, and several contributing factors have been implicated including the use of intraoperative mannitol or hyperventilation, gravitational effects of the sitting position, nitrous oxide anaesthesia, and the presence of a ventriculoperitoneal shunt. Tension pneumocephalus presents with deterioration of consciousness, focal neurological deficit, severe restlessness, and generalized convulsions, and may be a serious and life-threatening emergency. It is easily recognized on a CT scan (Figure 16.4). Two signs suggest increased tension of the subdural air (120)—a widened interhemispheric space between the tips of the frontal lobes (because subdural air under tension separates and compresses the frontal lobes) that mimics the silhouette of Mount Fuji (121), and the presence of multiple small air bubbles scattered through several cisterns (the ‘air bubble sign’) (122). Putatively, these air bubbles enter the subarachnoid space through a tear in the arachnoid membrane caused by increased tension of air in the subdural space.
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Fig. 16.4 CT scans showing postoperative pneumocephalus. (A) Postoperative axial brain CT scans from a patient after brain tumour resection with a postoperative focal deficit showing pneumocephalus in the resection cavity and left frontal horn. There is ex vacuo dilatation with a stable 7 mm rightward midline shift and effacement of the lateral ventricles. (B) Postoperative axial brain CT scans from a patient after surgical clipping of a pericallosal right anterior cerebral aneurysm, re-admitted to the ICU with acute left hemiparesis. Axial brain shows a tension pneumocephalus in the right frontal horn resulting in mass effect and effacement of the right frontal lobe sulci. Noted to have eschar on right craniotomy site with likely dehiscence and tracking of air from atmosphere into cranium. (C) Postoperative sagittal and axial CT scan from a 59-year-old patient’s bilateral chronic subdural haematomas demonstrating the ‘Mount Fuji sign’ with an accumulation of air in the bi-frontal subdural space. Tension pneumocephalus must be rapidly treated with 100% oxygen. A frontal burr hole to release trapped air under local or general anaesthesia is rarely indicated.
Electrolyte disorders Hyponatraemia is a frequent complication of neurosurgery and it is important to distinguish between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW) (Table 16.8). SIADH is associated with fluid volume expansion, whereas CSW is a fluid volume-contracted state involving renal loss of sodium. Hence, the treatment of patients with SIADH is fluid restriction whereas the treatment for patients with CSW is salt and water replacement (123). The reader is referred to Chapter 28 for a detailed discussion of the mechanisms and treatment of these conditions. Table 16.8 Clinical features of cerebral salt wasting (CSW) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) Clinical features Serum osmolality Urine osmolality Extracellular fluid volume Haematocrit Plasma albumin concentration Plasma blood urea nitrogen/creatinine Plasma potassium Plasma uric acid Treatment
CSW Decreased Inappropriately high Decreased Increased Increased Increased Normal or increased Normal or decreased Normal saline
SIADH Decreased Inappropriately high Increased Normal Normal Decreased Normal Decreased Fluid restriction
Determination of extracellular fluid volume is the main method to differentiate CSW from SIADH. Reprinted from Trends in Endocrinology & Metabolism, 14, 4, Palmer BF, ‘Hyponatremia in patients with central nervous system disease: SIADH versus CSW’, pp. 182–187, Copyright 2003, with permission from Elsevier. In severe hyponatraemia (serum sodium < 120 mmol/L) from whatever cause, sodium replacement with 3% NaCl (513 mmol/L) may be required. Symptomatic patients with severe confusion or coma may require a 1 mL/kg 3% (hypertonic) saline load over 3–4 hours. This can be given more rapidly (over 30 minutes) if the patient is actively seizing, bearing in mind the risks of over-rapid sodium correction (see Chapter 28). One mL/kg of 3% NaCl elevates serum sodium by approximately 1 mmol/L.
CDI is a common complication of pituitary surgery and can be transient or permanent. The inability to concentrate urine leaves the patient dehydrated and leads to metabolic abnormalities that can be life-threatening if not recognized and treated with an exogenous arginine vasopressin analogue in a timely manner. The reported incidence of postsurgical CDI varies from 1% to 67% (124), and factors affecting the likelihood of CDI include pituitary tumour size, adherence to surrounding structures, surgical approach, and pathology of pituitary lesion. Postoperative CDI is characterized by urine output greater than 4 mL/kg/h, low urine, and high serum osmolality in the absence of other causes of polyuria (Table 16.9). Once the diagnosis is established, a DDAVP infusion is commenced at 1–4 mcg every 8–24 hours aimed at decreasing the urine output to less than 2 mL/kg/h. Total maintenance fluids (intravenous and oral) should not exceed the insensible losses plus the obligatory urinary losses. Table 16.9 Clinical features of cranial diabetes insipidus Urine output of Serum Na Serum osmolality Urine osmolality Polyuria persisting
> 4 mL/kg/h > 145 mEq/L > 300 mOsm/kg < 300 mOsm/kg > 30 min
Other causes of polyuria must be ruled out (e.g. administration of mannitol, furosemide, osmotic contrast agents, hyperglycaemia, or excessive fluid administration).
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Conclusion The postoperative period after intracranial neurosurgery is critical. Patients should be carefully monitored and managed in an appropriate environment to identify and treat complications early. It is necessary to control blood pressure, minimize the risk of brain oedema, maintain water and electrolytes homeostasis, and prevent and treat pain. Early post-procedural neurological evaluation is the key to the detection of early intracranial complications. A brain CT scan should be obtained urgently in cases of unexpected neurological deterioration, but a normal CT scan does not rule out complications such as epilepsy, infection, brainstem compression, or increased ICP. The cause of neurological worsening is sometimes difficult to determine, and cooperation between neurosurgeons, neuroanaesthesiologists, and neurointensivists is critical for the optimal management of postoperative patients.
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Traumatic brain injury Chapter:Traumatic brain injury Author(s):Hayden White and Bala Venkatesh DOI:10.1093/med/9780198739555.003.0017 Traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external mechanical force from direct impact, acceleration or deceleration forces, blast waves, or penetrating trauma. The term head injury, although used interchangeably with TBI, may also refer to trauma to other parts of the head such as the scalp and the skull. TBI remains the most common cause of trauma-related death and disability, disproportionately affecting young individuals (1) with the majority being male. Globally, the incidence of TBI is rising, largely from increasing motor vehicle use in low-income countries. Importantly, the cost to all societies in emotional, social, and financial terms is substantial as the disabling effects of the original injury may persist for many years. A further disturbing trend is the increasing age of patients suffering TBI, most likely related to increasing falls in the elderly (see Table 17.1) (2,3). Table 17.1 Increasing age of patients in TBI studies
Traumatic Coma Data Bank UK four-centre study European Brain Injury Consortium Core Data Survey Rotterdam cohort study Austrian Severe TBI study TBI outcomes in Australia and NZ
Year of study 1984– 1987 1986– 1988 1995 1999– 2003 1999– 2004 2000– 2001
n 74 6 98 8 84 7 77 4 41 5 63 5
Median age (years) 25
Proportion aged > 50 years 15%
29
27%
38
33%
42
39%
48
45%
42
45%
Reprinted from The Lancet Neurology, 7, 8, Maas AI et al., ‘Moderate and severe traumatic brain injury in adults’, pp. 728–741, copyright 2008, with permission from Elsevier. Over the last 40 years, a number of epidemiological studies have described the causes and outcomes of TBI in developed countries (4,5,6). All-cause mortality from severe TBI has remained consistent at approximately 30–35% over the last 20 years (4,7,8). Of patients who survive the initial injury and reach a healthcare system but subsequently die, the mortality attributable directly to the TBI is approximately 90%. Despite advances in critical care, resuscitation, and imaging techniques, the management of severe TBI continues to pose a challenge to intensivists. TBI remains a major global health problem with 12-month mortality of about 35% and poor neurological outcome in 55–60% of survivors (4,7).
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Classification Several systems have been used to classify TBI and are based on either the severity of injury, mechanism of injury, pathophysiology, or pathoanatomical location (9). The classification based on injury severity is the most commonly used in clinical practice for triage, direction of targeted therapies, and for research purposes. This is based on the Glasgow Coma Scale (GCS) score at the scene. A GCS score of 3–8 defines severe TBI, 9–13 moderate TBI, and 14–15 mild TBI. Classifications based on clinical scoring systems such as the GCS have limitations. They do not take account of the impact of sedation, hypoxaemia, and circulatory instability on the score, nor other potentially confounding factors such as the age, presence of other injuries, and general physiological status. TBI has also been classified according to its pathophysiological basis and the evolution of the injury over time which has given rise to the concepts of primary and secondary injury. Primary injury refers to the brain damage sustained at the time of the injury and can be in the form of a contusion, haematoma, diffuse axonal injury, and neuronal damage from mediator release and altered blood–brain barrier (BBB) permeability. Secondary injury refers to pathophysiological processes which occur from the moment of the primary injury and continue into the post injury phase, and can exacerbate brain damage. Secondary injury can occur at any time after the initial injury including during resuscitation, transport, and in the intensive care unit (ICU). A number of secondary physiological insults that can cause secondary brain injury have been described but the most common are hypoxia and hypotension. Classification of TBI based on the physical mechanism of injury relies on knowledge of the forces applied and their directions. They have utility in modelling injuries and their prevention, but do not have a significant impact on clinical management. A pathoanatomical approach has been used to classify head injury according to the location and type of the injury (Figure 17.1), and the advent of computed tomography (CT) scanning facilitated more precise classification. The sixcategory Marshall scoring system is an example (10). This is a descriptive system of CT classification which focuses on the presence or absence of a mass lesion, and differentiates diffuse injuries by signs of increased intracranial pressure (ICP) including compression of basal cisterns and midline shift (Table 17.2). CT classification methods are useful for diagnosis, targeted patient management, outcome prognostication, and standardized enrolment into research trials.
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Fig. 17.1 Cranial computed tomography scans showing some consequences of brain trauma. (A) Large left-sided occipitoparietal extradural haematoma. Note the classic convex nature of the haematoma. There is also a fracture in the temporoparietal region, marked cerebral oedema, midline shift with subfalcine herniation, and intracranial air. (B) Right-sided acute subdural haematoma. The high density suggests a recent bleed. There is midline shift with ipsilateral loss of Sylvian fissure and sulci. (C) Severe TBI complicated by intracranial haematoma requiring craniotomy. Note the intraventricular catheter.
Table 17.2 Marshall CT classification of TBI Structural damage Diffuse injury I Diffuse injury II Diffuse injury III (swelling) Diffuse injury IV (shift) Evacuated mass lesion Non-evacuated mass lesion
Definition No visible pathology Cisterns present, midline shift 0–5 mm and/or lesion densities present or no mass lesion > 25 mL Cisterns compressed or absent with midline shift 0–5 mm or no mass lesion > 25 mL Midline shift > 5 mm, no mass lesion > 25 mL Any lesion surgically evacuated High or mixed-density lesion > 25 mL, not surgically evacuated
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Resuscitation and transfer It is essential that there is coordinated teamwork and an organized approach to ensure prompt attention to clinical assessment and management after TBI. Retrieval systems, including road and air ambulances, play a major role in this process. Airway protection together with stabilization of the neck and cardiopulmonary systems are integral initial steps to minimize further neurological damage by preventing secondary insults.
Monitoring Prior to transfer to the ICU, optimizing perfusion and oxygenation at the scene of the injury and in the emergency department are critical. Monitoring haemoglobin oxygen saturation with a pulse oximeter (SpO 2) and blood pressure using a reliable non-invasive or preferably an invasive method to facilitate continuous recordings are essential.
Prevention of hypoxia and hypotension The impetus for cerebral haemodynamic monitoring in neurotrauma first arose from the original ‘talk and die’ studies which described a group of head-injured patients who talked and then subsequently died (11,12,13). At necropsy, hypoxic or ischaemic brain damage was observed in a variable proportion of these patients, raising the possibility that post-trauma systemic or cerebral hypoxia might have contributed to their death. The concepts of primary and secondary brain injury were thus developed as outlined earlier. However, the differentiation between primary and secondary injury is somewhat artificial and it is now appreciated that there is temporal overlap between the two (Figure 17.2).
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Fig. 17.2 Evolution of the injury and repair processes after brain trauma. A current model of the effects of impact on the brain showing three overlapping and inter-related processes. Reprinted from The Lancet, 306, 7931, Reilly PL et al., ‘Patients with head injury who talk and die’, pp. 375–377, Copyright 1975, with permission from Elsevier. The principal secondary insults causing secondary brain injury are hypoxia and hypotension. Data from the studies of Bouma et al. and Jaggi et al. demonstrated an inverse correlation between cerebral blood flow and neurological outcome after neurotrauma (14,15), and those from the Traumatic Coma Data Bank the importance of hypoxia and hypotension in determining outcome (16). Improved understanding of the pathophysiology of TBI influenced clinical practice in two ways. First, a plethora of monitoring modalities was developed for evaluating cerebral haemodynamics and oxygenation. Second, the concept of ‘driving’ oxygenated blood through a swollen brain to minimize the risk of cerebral hypoxia/ischaemia became the cornerstone of therapy in patients with severe TBI. The critical circulatory and oxygenation thresholds to prevent secondary injury to the brain are unknown but data from the Traumatic Coma Data Bank point to the importance of maintaining a systolic blood pressure (SBP) greater than
90 mmHg and SpO2 greater than 90%. In a cohort of 717 patients with severe TBI, Chesnut et al. demonstrated that hypotension (defined as SBP < 90 mmHg) was an independent predictor of outcome and that a single episode of hypotension was associated with a marked increase in morbidity and mortality (16). Similarly, episodes of arterial desaturation (SpO2 < 90%) were also associated with significant increases in morbidity and mortality, and the presence of hypotension and hypoxaemia simultaneously had an additive effect on poor outcome. Other published studies also support the crucial significance of avoiding hypotension and hypoxaemia, and these are summarized in Table 17.3 (16,17,136,137,138,139,140,141,142,143). Table 17.3 Summary of studies outlining the relationship between hypoxia and hypotension and poor neurological outcome Authors
Year of publication 1981
Sampl e size 190
Main findings
1992
600
1993
717
1995
177
2001
107
Jeremitsky et al. (17) Chi et al. (140) McHugh et al. (141)
2003
81
2006
150
Hypoxia and hypotension have independent and additive adverse effects on outcome Early hypotension was associated with a doubling of mortality (55% vs 27%). If shock was present on admission, the mortality was 65% Jugular venous desaturation (SjvO2 < 50%) was associated with poor neurological outcome Increases in number of hypotensive episodes increased the odds ratio for death. Hypotension, but not hypoxia, occurring in the initial phase of resuscitation is significantly (P = 0.009) associated with increased mortality following brain injury Hypoxia was significantly associated with longer intensive care unit length of stay. Hypotension was independently related to mortality Prehospital hypoxia increased the odds ratio for mortality after TBI
2007
6629
Franschmann et al. (142) Oddo et al. (143)
2011
339
2011
103
Jeffreys and Jones (136) Gentleman (137) Chestnut et al. (16) Robertson et al. (138) Manley et al. (139)
Respiratory failure was a common avoidable factor contributing to death
Prehospital hypoxia and hypotension were strongly associated with a poorer outcome (odds ratios of 2.1 95% CI (1.7–2.6) and 2.7 95% CI (2.1– 3.4) respectively) Hypotension was associated with an increased odds ratio (3.5) for poor neurological outcome. Brain tissue hypoxia was associated with poor CNS outcome
Data from various studies (see References). Because hypoxia (PaO2 < 8.0 kPa, < 60 mmHg) is generally considered deleterious, it has been suggested that early intubation and ventilation may be beneficial after severe TBI (16,17). However, data from studies investigating the benefits of pre-hospital intubation are conflicting. One randomized controlled trial reported improved functional outcome with pre-hospital intubation and mechanical ventilation, whereas others have demonstrated adverse outcomes that have been attributed to longer field times, misplaced tracheal tubes and overly aggressive hyperventilation (18). Concern that hypercapnia may lead to cerebral oedema prompted the use of hyperventilation in earlier guidelines, but it is now accepted that aggressive hyperventilation (PaCO 2 < 4.0 kPa (< 30 mmHg)) can lead to severe cerebral ischaemia because of PaCO 2-related reductions in cerebral blood flow (CBF) in the early postinjury period (19). Hyperventilation should therefore only be used in the setting of impending cerebral herniation (20,21,22).
Resuscitation The resuscitation of patients with severe TBI should follow standard Advanced Trauma Life Support (ATLS) guidelines, including airway protection, stabilization of the neck, and maintenance of cardiopulmonary stability. Primary and secondary surveys should also be carried out according to ATLS guidelines. A few key principles are particularly important:
◆ There is a 5% incidence of associated cervical spine injury in patients with moderate and severe TBI, and a thorough radiological assessment must be undertaken to exclude bony injury to the cervical spine (23). Until the spine is cleared, all patients must be assumed to have an unstable cervical spine and appropriate precautions undertaken (see Chapter 21). ◆ The Brain Trauma Foundation (BTF) recommends avoidance of hypoxia defined as SpO 2 less than 90% (level III recommendation) and hypotension defined as SBP lower than 90mm Hg (level II recommendation) (24). ◆ In intubated patients, hypocapnia (PCO 2 < 4.0 kPa ( 70 mmHg) and low (< 50 mmHg) CPP and more research is necessary to clarify the utility of cerebral microdialysis in directing CPP-guided management. Intracranial pressure Being encased in a fixed structure the brain is subject to the principles espoused by Munro (1783) and Kellie (1824) who noted that brain tissue is nearly incompressible and that any change in the volume of individual intracranial contents (brain, blood, and CSF) must occur at the expense of the volume of another element and will ultimately lead to an increase in ICP (73). The relationship between ICP and intracranial volume is described by a non-linear pressure volume curve and, once the compensatory mechanisms (reduction in cerebral blood volume (CBV) or CSF) are exhausted, ICP rises rapidly until cessation of CBF ensues (see Chapter 7). A number of techniques exist for monitoring ICP but the two most common are an intraventricular catheter and intraparenchymal probe. Each has benefits and limitations (see Chapter 9). An intraventricular catheter is able to drain CSF for ICP control but has a high incidence of catheter-associated ventriculitis (6–11%) (74). Intraparenchymal catheters have a very low infection rate but are subject to drift of the zero reference point. ICP is not necessarily uniformly distributed and significant pressure gradients exist across the tentorial compartments in patients with intracranial hypertension. Furthermore, although raised ICP is associated with worse outcome, the use of ICP monitoring and management has not been shown to improve outcome (75). In a Dutch study, mortality rates were similar when ICP-guided therapy was compared with empirical management of TBI (76). Several other studies have come to similar conclusions although most are retrospective (77,78). A recent study by Chestnut and colleagues compared outcomes in two groups of patients with severe TBI admitted to ICUs in Bolivia and Ecuador (75). Patients were managed using a protocol for monitoring intraparenchymal ICP or a protocol in which treatment was based on imaging and clinical examination. The trial included 324 patients and no difference in outcome including functional status and 6-month mortality could be demonstrated. The ICP threshold for intervention is controversial and depends on age and clinical diagnosis. For TBI in adults, the BTF recommends the institution of therapy when ICP rises above 20–25 mmHg (79) although there are reports of patients suffering cerebral herniation at lower ICP. ICP monitoring may also be utilized as an indicator for repeat imaging or further intervention as sudden changes in ICP may represent a new or worsening intracranial event. Analysis of ICP waveforms provide information about brain compliance and Lundberg historically classified waves based on a time domain (see Chapter 9) (80). More recently, advanced computer modelling has demonstrated that ICP waveform analysis monitoring can be used to provide an indicator of global cerebral perfusion (81,82).
Cerebral perfusion- and intracranial pressure-based therapy
It is difficult to separate the influence of CPP- and ICP-based treatment of intracranial hypertension as the two are inter-related. There are those who advocate a predetermined CPP target irrespective of ICP and others who allow CPP to decrease as long as ICP is maintained. The BTF has lowered the recommended CPP target (from > 70 mmHg to 50–70 mmHg) over the past few years, and recent research suggests that there is a place for both approaches with treatment being individualized based on the autoregulatory state of the brain. CPP-based therapy Rosner and colleagues were among the first to study the effects of aggressive CPP management on outcome after TBI (56,57). They assumed that autoregulation was not absent but shifted to the right, and that a higher CPP was therefore necessary to maintain adequate CBF. Reflex cerebral vasoconstriction would then result in a reduction in ICP because of secondary reductions in intracranial blood volume and cerebral oedema. In this way they described a vasodilatory and vasoconstriction cascade in which a decrease in CPP stimulates cerebral autoregulatory vasodilatation and an increase in CBV and ICP (Figure 17.4). It was assumed that the effects of ICP therapies were transient, potentially toxic and should be used sparingly, and that treatment directed towards maintaining CPP as high as possible, and certainly greater than 70 mmHg, was preferable.
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Fig. 17.4 The physiological basis of cerebral perfusion pressure (CPP)-guided management. The CPP management strategy is based on the vasodilatory cascade described by Rosner et al. (83). Increasing blood pressure breaks the vasodilatory stimulus for intracranial hypertension. CBF, cerebral blood flow; CBV, cerebral blood volume; SBP, systolic blood pressure. Robertson CS, ‘Management of cerebral perfusion pressure after traumatic brain injury’, Anesthesiology 2001, 95, pp. 1513–1517; and Rosner S, Johnson A, ‘Cerebral perfusion pressure: management protocol and clinical results’, Journal of Neurosurgery 1995, 83, pp. 949–962.
Rosner undertook a non-randomized study of 158 TBI patients in whom CPP was maintained above 70 mmHg (CPP as high as 90 mmHg was allowed in certain circumstances) by the combination of vasoconstrictors, mannitol, and CSF drainage (83). The mortality rate was 29% and there was a favourable recovery at 10.5 months in 59% of patients. ICP averaged 25 ± 12 mmHg and the mean CPP was 83 mmHg. These results compared favourably with those from the Traumatic Coma Data Bank, and the authors concluded that CPP should be maintained above 70 mm Hg at all costs. These findings were subsequently confirmed in a case series published by Young et al. who questioned whether an upper limit of intracranial pressure existed in patients with severe head injury if CPP is maintained (84). They reported four patients with ICP ranging from 36 to 50 mmHg who were managed with CPP at 60 mmHg or greater. On discharge, all were able to perform activities of daily living with minimal disability and the authors concluded that aggressive CPP therapy should be instituted and maintained even though apparently lethal ICP levels may be present. Subsequent studies have, however, questioned this approach. Robertson and colleagues undertook a study in 189 TBI patients and compared CPP-targeted therapy with a standard ICP-targeted management protocol (85). In the CPP-targeted group, CPP was maintained at greater than 70 mmHg and PaCO 2 around 4.7 kPa (35 mmHg), whereas in the ICP-targeted group ICP was controlled by hyperventilation to a target PaCO 2 of 3.3–4.0 kPa (25–30 mmHg) and CPP was allowed to fall to 50 mmHg. The frequency of reduced cerebral oxygenation (as assessed by jugular desaturation) was 2.5 times higher in the ICP-targeted group, suggesting that CPP-targeted therapy is more effective at maintaining adequate cerebral oxygen delivery, but there was no difference in neurological outcome between the groups. The CPP group had a significantly higher frequency of acute lung injury suggesting that the potential benefits of CPP-based therapy were offset by its complications (86). It was these findings that led the BTF to decrease their recommended CPP level from 70 to 60 mmHg. Several other studies have also questioned the use of aggressive CPP targets. Lang et al. noted a plateau in brain tissue oxygen tension at CPP between 70 and 90 mmHg (87), and Juul et al., examining patients enrolled in the Selfotel trial, failed to find an independent effect on neurological outcome of CPP higher than 60 mmHg (88). Balestreri et al. subsequently confirmed the dangers of excessively high or low CPP in a retrospective review of 429 patients with TBI (89). In summary it is evident that artificially increasing blood pressure to generate arbitrarily high CPP is not associated with improved outcomes and has potential to produce significant complications. ICP-based therapy As previously noted, an ICP threshold in the region of 20–25 mmHg has been adopted by the BTF because higher levels correlate with worse outcome (79). However, it is worth noting that no prospective study has been undertaken (or is likely to be undertaken) to prove that this is the correct threshold. With continuous ICP monitoring, waveforms can be analysed in the time domain according to the Lundberg classification (80) and these provide prognostic information (see Chapter 9). ‘A’ waves comprise a steep increase in ICP from baseline to above 40 mmHg and persist for up to 20 minutes, and are always pathological. ‘B’ waves probably reflect changes in vascular tone and consist of oscillations occurring at 0.5–2 waves/min increasing to approximately 20 mmHg above baseline. ‘C’ waves which were originally described as oscillations that occur with a frequency of 4–8/min, are of little pathological significance. Although intraventricular catheters allow drainage of CSF to control ICP, this effect can be limited in the presence of severe brain swelling because the CSF compartment collapses under pressure from oedematous brain. Traditional techniques to reduce ICP have revolved around the use of hyperosmolar therapy to shrink the brain. The ideal osmotic agent would establish a strong transendothelial osmotic gradient across the BBB. Mannitol has been the predominant osmotherapeutic agent for decades but has several limitations including osmotic diuresis leading to hypotension, adverse effects on the kidney and central nervous system including a rebound phenomenon leading to raised ICP (90). Other solutions, particularly hypertonic saline, have been investigated as substitutes.
Animal and human studies have demonstrated that hypertonic saline has clinically desirable physiological effects on CBF, ICP, and inflammatory responses after neurotrauma. Potential benefits include increases in CBF, MAP, and CPP, reduction in ICP, modulation of inflammation, and maintenance of BBB integrity. Studies have demonstrated consistent effectiveness in reducing and maintaining ICP during periods of intracranial hypertension (91,92), findings that have been confirmed by a recent meta-analysis (93). These benefits and the limited side effects have led many units to adopt hypertonic saline in preference to mannitol. However, despite good basic research, no large randomized controlled trials demonstrating improved outcome from hypertonic saline have been performed. Three randomized controlled trials examining pre-hospital boluses of hypertonic saline in TBI failed to demonstrate a benefit (39,94,95). Lund therapy Possibly the biggest advocates of ICP-based therapy are the Lund group in Sweden who utilize a unique approach to the management of TBI. The so-called Lund therapy is a theoretical approach to controlling ICP based on physiological and pathophysiological haemodynamic principles of brain volume and perfusion regulation (96). Lund therapy is based on the observation that BBB permeability increases after TBI thereby reducing the effectiveness of the brain’s normal volume-regulating mechanisms (96,97,98). Consequently, brain volume is controlled by forces other than the crystalloid transcapillary force control, such as capillary hydrostatic and plasma oncotic pressure. Enthusiasts of the Lund approach advocate prevention of cerebral oedema and intracranial hypertension while maintaining intravascular volume using colloid volume expanders. Some even recommend the use of antihypertensive treatment such as beta blockers, alpha-2 agonists, and angiotensin II antagonists to counteract the development of brain oedema. Crystalloids are largely avoided in the Lund approach in which 20% albumin is the main volume expander with haemoglobin level maintained above 12 g/dL to maintain cerebral oxygen delivery. Vasoconstrictors are avoided and CPP is allowed to fall to 50 mmHg in adults. Osmotherapy is generally avoided although mannitol and hypertonic saline can be used in the setting of impending brain herniation. Patients remain heavily sedated to reduce stress, and hypothermia is avoided until ICP is under control. CSF may be drained via a ventricular catheter as necessary. A recent small randomized controlled trial in 60 postoperative patients with brain trauma and SAH demonstrated lower mortality in the patients treated with ICP-targeted (modified Lund) therapy guided by cerebral microdialysis monitoring compared to those treated with CPP-based therapy (99). However, this study has a number of limitations including the inclusion of SAH and TBI patients in the same groups and exclusion from the analysis of TBI patients who did not require surgery. Furthermore, the target haemoglobin concentration of 12.5–14.0 g/dL is contrary to current recommendations. Interpretation of these data is therefore difficult and further research is necessary before a definitive assessment can be made. In a pros/cons debate, Sharma and Vavilala took issue with a number of the treatment measures advocated by proponents of the Lund concept (100,101,102). Despite various reports of improved neurological outcomes in patients with TBI subsequent to the adoption of a volume-targeted protocol, they noted that the Lund concept has not found significant support elsewhere in the world. Further, some individual components have proved detrimental to TBI outcomes and the Lund concept deemphasizes the treatment goal of CBF optimization via maintenance of adequate brain perfusion. The assumption that the BBB is disrupted and explains the onset of cerebral oedema has also been questioned because oedema may occur in areas of brain not subject to direct injury. Furthermore, oncotic pressure is less likely to influence cerebral oedema than serum sodium levels, and haemoglobin concentration greater than 10 g/dL has not been shown to benefit TBI patients. Moreover the SAFE-TBI study reported a worse neurological outcome in patients receiving colloids as opposed to crystalloids. Although autoregulation can be altered by TBI, these changes are patient specific and may vary regionally within the same patient. Thus there is concern that the antihypertensive therapy advocated by the Lund approach risks causing cerebral hypoperfusion and focal cerebral ischaemia. Finally, Lund therapy has tended to evolve over time with changes in individual components of the protocol making interpretation of previous studies difficult.
Summary Current protocols based on CPP and ICP targeted therapy have not been adequately scrutinized and are based on physiological principles and prejudice rather than strong scientific evidence. Further, TBI is a heterogeneous disease with pathophysiological processes that vary regionally and temporally and, as such, there is an increasingly strong argument for individualization of therapy (103,104). Thus it is likely that certain individuals may benefit from CPPbased management while others from ICP-based therapy. Howells et al. compared an ICP based protocol in Uppsala, Sweden with a CPP based protocol in Edinburgh, Scotland evaluating pressure reactivity as a guide to treatment of CPP (59). They concluded that ICP-orientated therapy led to better outcomes in pressure-passive patients, whereas hypertensive CPP therapy was superior in patients with intact autoregulation. It is therefore likely that neuromonitoring technologies will allow further refinement of treatment protocols, but whether this translates into improved outcomes remains to be seen. See Table 17.4. Table 17.4 Comparison of CPP management protocols Therapy Management of cerebral volume and perfusion (97,98)
Theoretical concept Disruption of BBB leads to leakage of fluid into cerebral tissue worsening ICH. CPP based therapy leads to increased hydrostatic pressure in the setting of deranged autoregulation and increased ICP.
Goals Reduction in capillary hydrostatic cerebral pressure with antihypertensive therapy. Maintenance of COP with 20% albumin. CPP 60–70 mmHg but as low as 50 mmHg as long as ICP normal
CPP based (56)
Autoregulation after TBI is shifted to the right and therefore a much higher CPP is required to maintain cerebral perfusion
Maintenance of CPP > 70 mmHg with a combination of volume replacement (albumin in the original study), vasopressors and mannitol. CPP could be raised to 80–90 mmHg if necessary
TBI leads to reduced cerebral oxygen extraction with consequent relative cerebral hyperperfusion. Optimizing hyperventilation improves oxygen extraction coupling with better ICP control
Ventilation is manipulated to optimize SjVO2 and ICP
CBF/oxygen extraction coupling (144)
Supporting evidence 11-patient non-randomized study comparing outcome with that predicted by injury, and 53-patient study comparing with historical controls. Both suggested a good outcome with Lund therapy but the lack of a randomized prospective study has limited the universal acceptance of this therapy
Non-randomized study of 158 patients comparing outcome to the Traumatic Coma Data Bank. Subsequent studies have suggested that there may be significant adverse effects associated with CPP > 70 mmHg Prospective randomized study with 178 patients and 175 controls. Groups matched by CT rather than randomization. Mortality rate in treatment group was 9% and 30% in control. There are no data comparing ICP and CPP during the study period. Previous studies suggest hyperventilation leads to worse outcome (although these were not guided by
SjVO2)
Data from various studies (see References).
Multiple trauma About 50% of patients with severe TBI have associated severe extracranial injuries (105). In a 2012 meta-analysis of three observational TBI studies, International Mission on Prognosis and Clinical Trial Design in TBI (IMPACT), the randomized controlled trial Corticosteroid Randomization After Significant Head Injury (CRASH), and the Trauma Audit and Research Network (TARN) trauma registry study, van Leeuwen et al. investigated the prognostic value of extracranial injuries on mortality after TBI (106). These authors concluded that, while extracranial injuries have an impact on outcome after TBI, this relationship depends on the severity of TBI (where the relationship is not as strong) and the time of inclusion in the study. The principles of management of TBI associated with multi-trauma are similar to those of an isolated brain trauma but there are a few important additional considerations:
◆ Hypotension secondary to haemorrhage from extracranial injuries is associated with worse outcome after TBI and therefore the basic principles of resuscitation must be vigorously applied. ◆ There is a higher incidence of associated cervical spine injury (about 5%) in patients with moderate and severe TBI and other trauma, and therefore a thorough radiological assessment must be undertaken to exclude injury to the cervical spine (23). Until the spine is cleared, all patients must be assumed to have an unstable cervical spine and appropriate precautions undertaken. ◆ In situations where a patient with severe TBI needs life-saving non-neurological surgery prior to neuroimaging, there are few data to guide the utility of prophylactic ICP during anaesthesia and surgery. The use of ICP monitoring in these circumstances is variable amongst neurosurgeons. ◆ Intra-abdominal hypertension resulting from bleeding and ileus can result in secondary increases in ICP (107). ◆ The presence of extracranial trauma such as unstable spinal, pelvic, or limb injuries has implications on the positioning of the patient during intensive care and this may impact management of the injured brain. For example, head-up positioning to control ICP may be impossible.
Current guidelines for the management of severe traumatic brain injury As TBI is the most common cause of death in young adults in First World countries (108,109) a number of organizations have created guidelines for the management of severe TBI. This has been challenging because there is little evidence to support many treatment strategies, and expert opinion varies widely. Even the need for ICP monitoring is questioned because of the lack of conclusive evidence for its benefits. The use of other invasive monitoring techniques, such as brain tissue oxygen tension and microdialysis, has led some institutions to modify basic therapies to respond to changes in these monitored variable rather than the traditional measures of ICP and CPP. This variability in treatment approaches makes standardization difficult and creates problems in the design of large multicentre interventional studies. Despite these limitations, a number of organizations have attempted to standardize treatment and influential guidelines have been published by the European Brain Injury Consortium (EBIC) and the BTF (24,34,40,49,68,79,110,111,112,113,114,115,116,117,118,119). The original BTF guidance was published in 1995 and updated in 2000 and 2007, whereas the 1997 EBIC guidance has yet to be updated. The two guidelines differ in a number of key areas and this can be partly explained by the different approaches taken by their authors. The EBIC guidelines were written in an effort to create some uniformity in the management of TBI between institutions, primarily to facilitate research. As such, they are largely based on expert opinion and tend to be fairly pragmatic. The BTF guidelines on the other hand are largely evidence based (although in many instances the evidence is not strong),
and their main message has been to highlight the lack of rigorous evidence upon which clinical management is based. Despite the differences, the two sets of guidance represent complementary rather than opposing views (120). Much of the emphasis is on preventing or minimizing secondary brain injury and thereby limiting the ultimate burden of brain injury (14,121). Their focus is therefore on the prevention or early treatment of secondary insults, particularly hypoxia and hypotension, which are causes of worsening cerebral ischaemia and secondary brain injury. The EBIC consortium took a pragmatic approach and did not insist on sophisticated levels of invasive monitoring, known not to be in general use. They describe minimal monitoring requirements during ICU management and recommend maintaining MAP at greater than 90 mmHg and SpO 2 higher than 95%. MAP should be managed with fluid resuscitation to euvolaemia and inotropes/vasopressors as necessary. In ventilated patients, the PaO 2 should be greater than 13.3 kPa (> 100 mmHg) and PaCO 2 4.0–4.7 kPa (30–35 mmHg). Early enteral feeding is advocated as is maintenance of normoglycaemia and normothermia. If ICP monitoring is available and evidence of intracranial hypertension present, treatment should be aimed at maintaining ICP below 20–25 mmHg and CPP between 60 and 70 mmHg. The EBIC guidance for achieving these targets includes the following:
◆ Sedation and analgesia. ◆ Ventilation to maintain PaCO2 4.0–4.7 kPa (30–35 mmHg). ◆ Vasopressors—although there is no evidence supporting a specific agent. ◆ Osmotherapy—using boluses of mannitol or hypertonic saline. ◆ Consideration of moderate hyperventilation (PaCO 2 < 4 kPa (< 30 mmHg)) with monitoring of cerebral oxygenation to minimize the risk of cerebral ischaemia, and possibly barbiturates, if the above therapies fail to control ICP and CPP. ◆ Decompressive craniotomy may be considered in exceptional circumstances. ◆ Steroids should be avoided and nimodipine is not advocated.
Despite dating from 1997, the EBIC guidance is still considered a standard of care in many units. The American Brain Injury Consortium, in their 2010 guidelines, largely replicated the EBIC statement with a few minor modifications (122). The third (2007) and most recent edition of the BTF guidance was produced following a systematic review of the literature to assess the influence of the use of the earlier (2000) guidelines on mortality and morbidity after TBI. The BTF guidelines are generally more structured than those from the EBIC, and levels of evidence are provided for each recommendation. Rather than providing an overarching approach to TBI, the BTF guidelines are divided into topics such as blood pressure, oxygenation, or hyperosmolar therapy (24,34,40,68,79,110,111,112,113,114,115,116,117,118,119). Most of the BTF guidance is supported by only level II or III evidence. In summary (as it appears in the document):
◆ Systolic blood pressure lower than 90 mmHg and PaO 2 less than 8.0 kPa (< 60 mmHg) should be avoided (level II). ◆ Oxygenation should be monitored and hypoxia (PaO 2 ≤ 60 mm Hg or SpO2 ≤ 90%) avoided (level III) ◆ Mannitol is the osmotic agent of choice for the management of intracranial hypertension (level II), but the current evidence base was insufficiently strong to make recommendations on the use, concentration and method of administration of hypertonic saline. ◆ Induced hypothermia does not improve mortality but may improve neurological outcome in survivors, although the evidence is weak (level III). ◆ Treatment for raised ICP should be initiated if the pressure exceeds 20 mmHg (level II). ◆ CPP should be maintained between 50 and 70 mmHg, although patients with intact autoregulation may tolerate higher CPP. Ancillary monitoring of cerebral oxygenation, blood flow and metabolism may be indicated to guide CPP management (level III). ◆ If brain oxygen monitoring is employed, jugular venous saturation lower than 50% and brain tissue oxygen tension of less than 2 kPa (< 15 mmHg) should be avoided. There is insufficient evidence to generate a target level for these measurements (level III)
◆ While barbiturates should not be used routinely, there is a role for the control of refractory intracranial hypertension (level II). ◆ Nutritional goals should be attained by day 7 (level II). ◆ Hyperventilation to PaCO2 less than 4.0 kPa (< 30 mmHg) should be avoided unless as a temporizing measure for acute reduction in ICP (level III). ◆ Steroids should be avoided (level I).
Many countries also produce their own guidelines. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) produces guidelines for a number of clinical conditions including TBI (123). These have recently (2014) been updated but only address issues related to transportation of injured patients, indications for CT scanning and information that should be provided for family members. Despite an overall improvement in outcome from TBI, the IMPACT study demonstrated a significant difference between centres (124). This reflects a number of factors but the lack of an internationally agreed evidence-based approach to TBI management is believed to be important. As such, more research is necessary to further define and tailor treatments to match th