Opinion
VIEWPOINT
Robert C. Tasker, MBBS, MD Department of Anesthesia, Perioperative and Pain Medicine, Division of Critical Care Medicine, Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts; and Harvard Medical School, Boston, Massachusetts. David K. Menon, MD, PhD Division of Anaesthesia, Clinical School, University of Cambridge, Cambridge, United Kingdom; and Addenbrooke’s Hospital, Cambridge, United Kingdom.
Corresponding Author: Robert C. Tasker, MBBS, MD, Division of Critical Care Medicine, Bader 621, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (robert.tasker @childrens.harvard .edu).
Critical Care and the Brain Critical care is always about the brain. This statement is obvious when the primary problem is neurologic emergencies. However, even when the primary pathology necessitating intensive care unit (ICU) treatment lies outside the brain, the eventual aim of care is preserving cerebral function. Thus, regardless of whether the proximate cause for ICU admission is neurologic insult or systemic illness, there is increasing recognition of the longterm effects of these conditions and their treatment on recovery of brain function and functional outcomes over the long term.
Acute Neurologic Emergencies and Rescuing the Injured Brain “Neurocritical care” of emergency medical, neurologic, and neurosurgical conditions has matured to the point of established and newly reviewed professional guidelines.1 The field has been responsible for bringing tools traditionally found in experimental laboratories to the bedside. The most advanced neurosciences ICUs are now, in effect, clinical laboratories that integrate into patient care brain oximetry, cerebral microdialysis, brain cortical and depth electrodes, and continuous surface electroencephalography. These bedside techniques are supplemented by advanced neuroimaging of initial injury, regional pathophysiology, and tissue outcome, using both magnetic resonance imaging and isotope-based techniques such as positron emission tomography. Together, these
This failure to separate harms from benefits of individual interventions has triggered a new approach to clinical research and management, with a focus on identifying clinical phenotypes, for example, dividing groups of patients with TBI into more homogeneous subsets according to presentation, mechanism, and treatment responsiveness. Such stratification could allow better matching of patient to individual therapies or to the intensity and timing of more burdensome interventions. The substantial sample sizes needed to underpin such an approach have triggered large international collaborations such as the International TBI Research Initiative, which will recruit more than 10 000 patients. Inherent to this individualization of therapies is also the recognition of complexity in patient physiology. Classic among these are the brain-heart-lung interactions that account for neurogenic pulmonary edema and stress-induced cardiomyopathy (takotsubo). Conversely, the traumatized brain is exquisitely sensitive to physiological insults, and attempts to optimize cardiopulmonary physiology for brain protection in these settings often involve interventions that have undesirable consequences for extracranial critical illness, such as targeting cerebral perfusion pressure and the development of acute lung injury and edema.
Brain Dysfunction in the Critically Ill
Many extracranial illnesses that necessitate critical care trigger well-recognized encephalopathies mediated by a range of mechanisms, including oxygen and substrate deficiency leading to energy failure, neuroinflammation, neuThe most salutary lesson of intensive care rochemical modulation by disease and over the last decade—the minimization drugs, immune responses against neuof iatrogenic harm—perhaps applies more ral epitopes, neuronal and astrocyte toxins or hypercapnia, and osmotic cell to the brain than any other organ…. swelling or vasogenic edema. There are also instances when clinicians have to approaches have elucidated pathophysiology and validated clinical biomarkers of injury, such as posthypoxic contend with the physiological limits of homeostasis edema and restricted diffusion. Such detailed charac- and the consequences that these may have on the terization is a rare opportunity in critical care, perhaps brain. Here, the issue is human life at the extremes and not available in any other context, and might be understanding of survival biology. For example, in the expected to deliver steady improvements in therapy patient undergoing mechanical ventilation with high mean airway pressure for acute respiratory distress and hence outcome. However, the available evidence suggests other- syndrome and exhibiting hypoxemia and elevated cenwise. Erythropoietin,2 progesterone,3 and therapeutic tral venous pressure, 3 key questions about brain tishypothermia have recently joined the long list of experi- sue oxygen delivery and carbon dioxide removal arise. mentally effective neuroprotective agents that have How low can the hemoglobin concentration go? How failed to achieve clinical translation, and clinicians re- high can permissive hypercapnia be? How low can the main unable to document the benefits of many inter- oxygen-hemoglobin saturation go? These are not new ventions in common clinical use—even monitoring of in- questions; they have been topical for high-altitude tracranial pressure after traumatic brain injury (TBI). mountaineers, submariners, and aviators for decades. These results are puzzling, because protocols that inte- What is new, however, is a realization of the congrugrate these clinical options appear to improve out- ence between what is done in the ICU and what human physiology has contended with and adapted to comes in nonrandomized evaluations.
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(Reprinted) JAMA February 23, 2016 Volume 315, Number 8
Copyright 2016 American Medical Association. All rights reserved.
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749
Opinion Viewpoint
in different environments on the planet. For example, a recent description of cerebral injuries in patients with acute respiratory distress syndrome showed multiple microhemorrhages predominantly in the splenium of the corpus callosum.4 This pattern of brain injury resembles neuropathological findings in individuals with high-altitude cerebral edema.
Functional Status After Critical Illness Critical illness leaves ICU survivors with a burden of disability, and evidence has emerged that, in both adult and pediatric patients, such disability includes the brain. Patients are at risk of developing early delirium, general anxiety, depression, and delusional memories; late posttraumatic stress disorder; eventual reduced neuropsychological function, disability, or cognitive decline; and, in the older population, frailty—a multidimensional syndrome characterized by loss of physiologic reserve and vulnerability to poor outcomes. Examples of these adverse outcomes have been illustrated by recent large critical care–based studies. A recent study of 420 critically ill adult patients receiving mechanical ventilation found that 226 (54%) had delirium, and this finding was associated with longer duration of ventilation and hospitalization.5 In the pediatric critical care literature there is less talk of delirium; rather, the focus is on sedative/hypnotic drug withdrawal, which, based on the available instruments to make this diagnosis, may well represent the same phenomenon as delirium in adults. If this assumption is true, the recently reported RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) study in 2449 pediatric patients is of interest; 68% of those in each group developed “iatrogenic withdrawal.”6 Both adult and pediatric ICU survivors show significant morbidity in the year after ICU discharge. The involvement of the brain in this post-ICU syndrome is well illustrated by the BRAIN-ICU (Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors) study.7 Among 821 adult patients with respiratory failure or shock in the medical or surgical ICU, a longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. Delirium developed in 74% during the hospital stay. At ARTICLE INFORMATION Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tasker reported receiving grants from the National Institutes of Health. Dr Menon reported receiving grants from the National Institute for Health Research and the European Union. REFERENCES 1. Miller CM, Pineda J, Corry M, Brophy G, Smith WS. Emergency neurologic life support (ENLS): evolution of management in the first hour of a neurological emergency. Neurocrit Care. 2015; 23(suppl 2):1-4. 2. Robertson CS, Hannay HJ, Yamal JM, et al; Epo Severe TBI Trial Investigators. Effect of
750
3 months, 26% had scores similar to those reported for patients with mild Alzheimer disease. At 1 year, such deficits occurred in 24% of all patients with assessments at 12 months. It is also important to acknowledge that none of the currently available therapies are risk free. Indeed, the most salutary lesson of intensive care over the last decade—the minimization of iatrogenic harm—perhaps applies more to the brain than any other organ, and oversedation may play a substantial role in contributing to worse neurologic outcomes.
Neurocritical Care vs General Critical Care Despite the continued failure to demonstrate benefit from brainspecific therapies in neurologic and neurosurgical emergencies, the continued use of neurocritical care protocols that optimize physiology1 remain increasingly important. The pervasiveness of acute brain dysfunction in extracranial critical illness means that these approaches are just as relevant in the wider ICU population. Put bluntly, all ICU patients have a vulnerable brain, and the recent literature shows that ICU survivors experience a significant burden of acute brain dysfunction, delirium, and later cognitive and neuropsychological deficits after admission for medical and surgical intensive care, irrespective of age. The last 20 years have seen the development of specialist expertise in the critical care of acute neurologic and neurosurgical disease. Neurocritical care units that make use of systematic protocols may make clinical practice more efficient. However, although the outcome benefits of such specialist units have been suggested by historical comparisons,8 these are not easy to prove in prospective comparative effectiveness research studies. One inference is that labels may be less important than expertise—and the ability to implement best practice can exist in more than one organizational context. A second inference is that expertise gained in supporting the at-risk brain may also be ready for use in extracranial disease. Perhaps it is now time to talk about brain-oriented intensive/critical care for all patients as a unifying concept for critical illness, and cross-fertilization between specialists and generalists who have a different perspective of the same issues.
erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312(1):36-47. 3. Skolnick BE, Maas AI, Narayan RK, et al; SYNAPSE Trial Investigators. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467-2476. 4. Riech S, Kallenberg K, Moerer O, et al. The pattern of brain microhemorrhages after severe lung failure resembles the one seen in high-altitude cerebral edema. Crit Care Med. 2015; 43(9):e386-e389. 5. Mehta S, Cook D, Devlin JW, et al; SLEAP Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. Crit Care Med. 2015;43(3):557-566.
6. Curley MA, Wypij D, Watson RS, et al; RESTORE Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379-389. 7. Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306-1316. 8. Pineda JA, Leonard JR, Mazotas IG, et al. Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: a retrospective cohort study. Lancet Neurol. 2013;12(1):45-52.
JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Pittsburgh User on 02/22/2016
jama.com
VIEWPOINT
Robert C. Tasker, MBBS, MD Department of Anesthesia, Perioperative and Pain Medicine, Division of Critical Care Medicine, Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts; and Harvard Medical School, Boston, Massachusetts. David K. Menon, MD, PhD Division of Anaesthesia, Clinical School, University of Cambridge, Cambridge, United Kingdom; and Addenbrooke’s Hospital, Cambridge, United Kingdom.
Corresponding Author: Robert C. Tasker, MBBS, MD, Division of Critical Care Medicine, Bader 621, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (robert.tasker @childrens.harvard .edu).
Critical Care and the Brain Critical care is always about the brain. This statement is obvious when the primary problem is neurologic emergencies. However, even when the primary pathology necessitating intensive care unit (ICU) treatment lies outside the brain, the eventual aim of care is preserving cerebral function. Thus, regardless of whether the proximate cause for ICU admission is neurologic insult or systemic illness, there is increasing recognition of the longterm effects of these conditions and their treatment on recovery of brain function and functional outcomes over the long term.
Acute Neurologic Emergencies and Rescuing the Injured Brain “Neurocritical care” of emergency medical, neurologic, and neurosurgical conditions has matured to the point of established and newly reviewed professional guidelines.1 The field has been responsible for bringing tools traditionally found in experimental laboratories to the bedside. The most advanced neurosciences ICUs are now, in effect, clinical laboratories that integrate into patient care brain oximetry, cerebral microdialysis, brain cortical and depth electrodes, and continuous surface electroencephalography. These bedside techniques are supplemented by advanced neuroimaging of initial injury, regional pathophysiology, and tissue outcome, using both magnetic resonance imaging and isotope-based techniques such as positron emission tomography. Together, these
This failure to separate harms from benefits of individual interventions has triggered a new approach to clinical research and management, with a focus on identifying clinical phenotypes, for example, dividing groups of patients with TBI into more homogeneous subsets according to presentation, mechanism, and treatment responsiveness. Such stratification could allow better matching of patient to individual therapies or to the intensity and timing of more burdensome interventions. The substantial sample sizes needed to underpin such an approach have triggered large international collaborations such as the International TBI Research Initiative, which will recruit more than 10 000 patients. Inherent to this individualization of therapies is also the recognition of complexity in patient physiology. Classic among these are the brain-heart-lung interactions that account for neurogenic pulmonary edema and stress-induced cardiomyopathy (takotsubo). Conversely, the traumatized brain is exquisitely sensitive to physiological insults, and attempts to optimize cardiopulmonary physiology for brain protection in these settings often involve interventions that have undesirable consequences for extracranial critical illness, such as targeting cerebral perfusion pressure and the development of acute lung injury and edema.
Brain Dysfunction in the Critically Ill
Many extracranial illnesses that necessitate critical care trigger well-recognized encephalopathies mediated by a range of mechanisms, including oxygen and substrate deficiency leading to energy failure, neuroinflammation, neuThe most salutary lesson of intensive care rochemical modulation by disease and over the last decade—the minimization drugs, immune responses against neuof iatrogenic harm—perhaps applies more ral epitopes, neuronal and astrocyte toxins or hypercapnia, and osmotic cell to the brain than any other organ…. swelling or vasogenic edema. There are also instances when clinicians have to approaches have elucidated pathophysiology and validated clinical biomarkers of injury, such as posthypoxic contend with the physiological limits of homeostasis edema and restricted diffusion. Such detailed charac- and the consequences that these may have on the terization is a rare opportunity in critical care, perhaps brain. Here, the issue is human life at the extremes and not available in any other context, and might be understanding of survival biology. For example, in the expected to deliver steady improvements in therapy patient undergoing mechanical ventilation with high mean airway pressure for acute respiratory distress and hence outcome. However, the available evidence suggests other- syndrome and exhibiting hypoxemia and elevated cenwise. Erythropoietin,2 progesterone,3 and therapeutic tral venous pressure, 3 key questions about brain tishypothermia have recently joined the long list of experi- sue oxygen delivery and carbon dioxide removal arise. mentally effective neuroprotective agents that have How low can the hemoglobin concentration go? How failed to achieve clinical translation, and clinicians re- high can permissive hypercapnia be? How low can the main unable to document the benefits of many inter- oxygen-hemoglobin saturation go? These are not new ventions in common clinical use—even monitoring of in- questions; they have been topical for high-altitude tracranial pressure after traumatic brain injury (TBI). mountaineers, submariners, and aviators for decades. These results are puzzling, because protocols that inte- What is new, however, is a realization of the congrugrate these clinical options appear to improve out- ence between what is done in the ICU and what human physiology has contended with and adapted to comes in nonrandomized evaluations.
jama.com
(Reprinted) JAMA February 23, 2016 Volume 315, Number 8
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Pittsburgh User on 02/22/2016
749
Opinion Viewpoint
in different environments on the planet. For example, a recent description of cerebral injuries in patients with acute respiratory distress syndrome showed multiple microhemorrhages predominantly in the splenium of the corpus callosum.4 This pattern of brain injury resembles neuropathological findings in individuals with high-altitude cerebral edema.
Functional Status After Critical Illness Critical illness leaves ICU survivors with a burden of disability, and evidence has emerged that, in both adult and pediatric patients, such disability includes the brain. Patients are at risk of developing early delirium, general anxiety, depression, and delusional memories; late posttraumatic stress disorder; eventual reduced neuropsychological function, disability, or cognitive decline; and, in the older population, frailty—a multidimensional syndrome characterized by loss of physiologic reserve and vulnerability to poor outcomes. Examples of these adverse outcomes have been illustrated by recent large critical care–based studies. A recent study of 420 critically ill adult patients receiving mechanical ventilation found that 226 (54%) had delirium, and this finding was associated with longer duration of ventilation and hospitalization.5 In the pediatric critical care literature there is less talk of delirium; rather, the focus is on sedative/hypnotic drug withdrawal, which, based on the available instruments to make this diagnosis, may well represent the same phenomenon as delirium in adults. If this assumption is true, the recently reported RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) study in 2449 pediatric patients is of interest; 68% of those in each group developed “iatrogenic withdrawal.”6 Both adult and pediatric ICU survivors show significant morbidity in the year after ICU discharge. The involvement of the brain in this post-ICU syndrome is well illustrated by the BRAIN-ICU (Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors) study.7 Among 821 adult patients with respiratory failure or shock in the medical or surgical ICU, a longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. Delirium developed in 74% during the hospital stay. At ARTICLE INFORMATION Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tasker reported receiving grants from the National Institutes of Health. Dr Menon reported receiving grants from the National Institute for Health Research and the European Union. REFERENCES 1. Miller CM, Pineda J, Corry M, Brophy G, Smith WS. Emergency neurologic life support (ENLS): evolution of management in the first hour of a neurological emergency. Neurocrit Care. 2015; 23(suppl 2):1-4. 2. Robertson CS, Hannay HJ, Yamal JM, et al; Epo Severe TBI Trial Investigators. Effect of
750
3 months, 26% had scores similar to those reported for patients with mild Alzheimer disease. At 1 year, such deficits occurred in 24% of all patients with assessments at 12 months. It is also important to acknowledge that none of the currently available therapies are risk free. Indeed, the most salutary lesson of intensive care over the last decade—the minimization of iatrogenic harm—perhaps applies more to the brain than any other organ, and oversedation may play a substantial role in contributing to worse neurologic outcomes.
Neurocritical Care vs General Critical Care Despite the continued failure to demonstrate benefit from brainspecific therapies in neurologic and neurosurgical emergencies, the continued use of neurocritical care protocols that optimize physiology1 remain increasingly important. The pervasiveness of acute brain dysfunction in extracranial critical illness means that these approaches are just as relevant in the wider ICU population. Put bluntly, all ICU patients have a vulnerable brain, and the recent literature shows that ICU survivors experience a significant burden of acute brain dysfunction, delirium, and later cognitive and neuropsychological deficits after admission for medical and surgical intensive care, irrespective of age. The last 20 years have seen the development of specialist expertise in the critical care of acute neurologic and neurosurgical disease. Neurocritical care units that make use of systematic protocols may make clinical practice more efficient. However, although the outcome benefits of such specialist units have been suggested by historical comparisons,8 these are not easy to prove in prospective comparative effectiveness research studies. One inference is that labels may be less important than expertise—and the ability to implement best practice can exist in more than one organizational context. A second inference is that expertise gained in supporting the at-risk brain may also be ready for use in extracranial disease. Perhaps it is now time to talk about brain-oriented intensive/critical care for all patients as a unifying concept for critical illness, and cross-fertilization between specialists and generalists who have a different perspective of the same issues.
erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312(1):36-47. 3. Skolnick BE, Maas AI, Narayan RK, et al; SYNAPSE Trial Investigators. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467-2476. 4. Riech S, Kallenberg K, Moerer O, et al. The pattern of brain microhemorrhages after severe lung failure resembles the one seen in high-altitude cerebral edema. Crit Care Med. 2015; 43(9):e386-e389. 5. Mehta S, Cook D, Devlin JW, et al; SLEAP Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. Crit Care Med. 2015;43(3):557-566.
6. Curley MA, Wypij D, Watson RS, et al; RESTORE Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA. 2015;313(4):379-389. 7. Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306-1316. 8. Pineda JA, Leonard JR, Mazotas IG, et al. Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: a retrospective cohort study. Lancet Neurol. 2013;12(1):45-52.
JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Pittsburgh User on 02/22/2016
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