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Therapeutic hypothermia and acute brain injury
NEUROINTENSIVE CARE
Therapeutic hypothermia and acute brain injury
Learning objectives After reading this article, you should be able to: C list the potential mechanisms of hypothermia induced neuroprotection C identify best practice recommendation for target temperature management C determine the potential complications from hypothermia C appraise the evidence for hypothermia and acute brain injury
Jagdish Sokhi Ugan Reddy
Abstract Secondary brain injury has devastating effects on morbidity, mortality and good functional outcomes. Neuroprotection is multimodal, with decades of preclinical and small clinical studies showing the benefits of therapeutic hypothermia. The basic scientific principles have merit, yet large randomized controlled trials fail to show a clear benefit. This article will review the basic science the practical aspects of delivering targeted temperature management and evaluate the evidence behind its use for acute brain injuries. With a lack of high-quality evidence for hypothermia, recent consensus statements are shifting the paradigm away from hypothermia to the maintenance of normothermia and prevention of pyrexia.
The potential benefits of therapeutic hypothermia (TH) have been recognized for decades; however, despite a strong scientific rationale and promising pre-clinical trials, TH has translated poorly into improved clinical outcomes. In this article, we will explore the basis for TH, including the scientific principles, complications, practical aspects and the evidence for its use in various clinical conditions. Target temperature management (TTM) has superseded TH in terms of nomenclature. TTM is difficult to define, but it is an active treatment aimed at maintaining a patient’s core body temperature at a pre-determined value, to reduce morbidity and improve neurological outcomes. The target can be either hypothermia (<36 C) or normothermia (37 C 0.5 C).
there is significant ischaemia, which is not promptly treated then irreversible brain damage occurs, culminating in cellular dysfunction and necrosis. The pathophysiology involves primary cellular energy failure, depolarization of cell membranes, release of excitatory amino acids and excessive cytosolic calcium.1 Interest in the potential neuroprotective benefits of hypothermia comes from several case reports of patients exposed to profound hypothermia. These patients had suffered out of hospital cardiac arrests (OOHCA), with prolonged ‘down times’, but made ‘miraculous’ neurological recoveries. Once such case published by Gilbert et al. (Lancet 2000), involved a skier who was successfully resuscitated after an OOHCA, with a core temperature measured at 13.7 C, without significant neurological disability. The patient went on to become a doctor! It was believed that the inadvertent hypothermia provided a significant degree of neurological protection. This is potentially achieved through: reduction in cerebral metabolic requirement oxygen (CMRO2) by approximately 7% per 1 C, below core body temperature reduction of intracranial pressure (ICP) and therefore maintenance of the cerebral perfusion pressure (CPP) by cerebral vasoconstriction reduction in vascular permeability and consequently less cerebral oedema suppression of the inflammatory cascade reduction in the release of excitatory mediators reduction in neuronal apoptosis by inhibition of caspase activity reduction in free radical formation.2 TTM is not without complications. The greater the degree of hypothermia, the more significant the side effects. Table 1 highlights the potential consequences for each organ system.
Pathophysiology
Practical aspects
Cerebral ischaemia is characterized by a failure in the supply of oxygen and nutrients to match the cerebral metabolic demand. If
The methods of cooling can be divided into: pharmacological e paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) non-pharmacological external e blankets (circulating air or water), ice packs internal e cold intravenous (IV) fluids, endovascular cooling IV lines, extracorporeal circuits. There are essentially three stages of TTM. Induction, normally performed at the point of admission, maintenance and rewarming, commonly performed in the intensive care. Because
Keywords Acute ischaemic stroke; hypoxic-ischaemic encephalopathy; induced normothermia; intracranial haemorrhage; intracranial pressure; subarachnoid haemorrhage; targeted temperature management; therapeutic hypothermia; traumatic brain injury Royal College of Anaesthetists CPD Matrix: 1H02, 2F01, 3F00
Introduction
Jagdish Sokhi MBBS BMedSci MRCP FRCA FFICM is a Specialty Registrar in Anaesthesia and Critical Care, London, UK. Conflicts of interest: none. Ugan Reddy BSc MBChB FRCA FFICM is a Consultant in Neuroanaesthesia and Neurocritical Care at The National Hospital for Neurology and Neurosurgery, London¸, UK. Conflicts of interest: none.
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
1
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019
NEUROINTENSIVE CARE
scale 0e3) is approximately 2%. After return of spontaneous circulation (ROSC), neurological injury was the single biggest cause of disability. In 2002, the hypothermia after cardiac arrest (HACA) trial was one of the first trials designed to assess whether hypothermia provided neurological protection. The results published in the NEJM demonstrated that hypothermia (initiated 4e6 hours post cardiac arrest) and maintained at 33 C for 24 hours, improved survival, numbers needed to treat (NNT 7) and neurological outcomes (NNT 6). ‘Cooling’ after cardiac arrests with an initial shockable rhythm became commonplace, and guidance was eventually extended to cover all rhythms, and both in and out of hospital cardiac arrests. However in 2013, the TTM trial (2013 NEJM) with nearly 1000 patients, showed no difference in neurological outcome or survival in patients cooled to 33 C versus 36 C for 36 hours. Following this, most UK intensive care units have elected to use 36 C as the target temperature, for a minimum of 24 hours, provided there are no significant side effects.
Consequences of hypothermia System
Effects
Cardiovascular
Reduction in cardiac output (CO) Increase in systemic vascular resistance (SVR) Bradyarrhythmias e atrial fibrillation (AF), and if severe (<30 C) ventricular fibrillation (VF) ECG changes e prolonged PR, widening QRS, J waves/Osborne Reduction in minute ventilation (MV) Increased risk of pneumonia/ventilation associated pneumonia (VAP) Increased solubility of carbon dioxide leading to respiratory alkalosis Insulin resistance Reduced peristalsis Delayed gastric emptying Reduced liver metabolism, including drugs Metabolic acidosis lactaemia ‘Cold diuresis’ Electrolyte disturbances Impaired innate immune system cell function Shivering Coagulopathy Impaired platelet function
Respiratory
Gastrointestinal
Renal Infection Musculoskeletal Haematological
Newborn hypoxic ischaemic encephalopathy (HIE) HIE remains a significant cause of mortality and long-term morbidity. Data from various randomized clinical trials indicate that cooling is an effective therapy if initiated within 48 hours of birth. Both whole body cooling and selective head cooling (SHC) have been successfully implemented, with a preference towards using SHC.4 The trials included infants born at 36 weeks of gestation with evolving moderate to severe HIE. The temperature targeted was 34.5 C 0.5 C within the first 6 hours of life for 48 e72 hours.4 Complications were primarily cardiovascular, thrombocytopenia and local effects of the skin such as erythema or skin hardening. The American Heart Association’s 2010 neonatal resuscitation guidelines recommend TTM in infants born at 36 weeks of gestation with evolving moderate to severe hypoxic-ischaemic encephalopathy. Further trials are needed to assess if the benefits would apply to infants below <35 weeks and if starting cooling after 6 hours is beneficial.
Table 1
of the multiple options available, including different methods, devices and protocols in place, practice can be highly variable. In 2018, a consensus of recommendations was published in the British Journal of Anaesthesia, to help standardize practice. The following recommendations were made: Core temperature should be measured continuously in patients with neurological injury. The optimal site is still debatable. TTM should be initiated if a patient’s temperature exceeds 37.5 C and infection is excluded, and within 1 hour if pharmacological treatment has not succeeded. TTM should continue for as long as there is potential for secondary brain injury with a target temperature of 37 C 0.5 C Shivering, one of the most common side effects should be actively managed, as it causes increased cerebral and metabolic stress, by as much as 100%. It also has deleterious effects on ICP and myocardial oxygenation. All acute brain injuries, regardless of aetiology should be managed using a single protocol for neurogenic fever. Rewarming should occur at 0.25 C per hour.3
Primary neurological injuries Traumatic brain injury (TBI) Minimizing secondary brain injury is the main priority for neurocritical care. Secondary brain injury is multifactorial in origin, including ischaemia, reperfusion, inflammation, metabolic or cellular dysfunction, and raised ICP. Hypothermia, with a core temperature of <35.5 C, consistently provides neuroprotection by reducing the aforementioned processes.5 Despite promising preclinical trials, the first major phase III clinical trials (National Acute Brain Injury Study I and II) failed to show a benefit. To answer this question a large multicentre randomized control trial (RCT) was necessary. EUROTHERM3235 was a large RCT comparing hypothermia (32 Ce35 C) to standard care in those with TBI. Primary outcomes included major disability at 6 months. Inclusion criteria was closed TBI and an ICP >20 mmHg for greater than 5 minutes after initial treatment (stage 1) failed to control ICP. Hypothermia was continued >48 hours and until ICP was controlled. Recruitment was stopped early due to a higher mortality in the
Clinical uses of TTM Cardiac arrest Despite multiple advances in the management of cardiac arrest, outcomes remain poor. In 2018, the UK-based PARAMEDIC trial, published in the New England Journal of Medicine (NEJM ), showed a 3-month survival of less than 3% and those with favourable neurological outcomes (modified Rankin Scale (mRS)
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
2
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019
NEUROINTENSIVE CARE
It is worth noting that results cannot be applied to neurocritical care unit or those with poor grade SAH. There are small case series for these patient groups that report reduced vasospasm, delayed cerebral ischaemia and intracranial hypertension with hypothermia.
hypothermia group. The odds ratio was 1.53 in the hypothermia group when comparing extended Glasgow outcome scale versus standard care (95% confidence interval, 1.02 to 2.30; P ¼ 0.04).6 In 2018, another multicentre RCT, entitled the ‘effects of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe TBI (POLAR)’, demonstrated no difference at 6 months in neurological outcomes in those with blunt TBI, but there was an increased rate of complications in the hypothermia group.7 In 2017, a Cochrane systematic review, which pooled 37 eligible trials with over 3000 patients, concluded ‘there remains no high quality evidence that hypothermia is beneficial in the treatment of people with TBI.’
Conclusion Fever is a common phenomenon in neurocritical care patients and is associated with poorer functional outcomes.10 In those with fever up to 50% will be due to an infective cause and therefore early diagnosis and treatment of sepsis is vital. Potentially, by preventing fevers, targeted temperature management has its beneficial effects. However, owing to the lack of grade I evidence for hypothermia in acute brain injuries, and the known detrimental effects of hyperthermia, current practice is adopting TTM to maintain normothermia in response to the first neurogenic fever. A
Acute ischaemic stroke (AIS) Acute treatment involves thrombolysis, with or without mechanical thrombectomy, to minimize infract size. This is followed by antiplatelet agents and cardiovascular secondary prevention. Minimizing the infarct size is important, with preclinical data suggesting this is possible with hypothermia. The ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2), which utilized intravascular cooling post thrombolysis, was stopped early and only recruited 120 of the expected 1600 patients. The results showed no difference in mortality, functional outcomes and adverse effects of hypothermia. There was a non-significant trend towards an increased risk of pneumonia associated with hypothermia. The effect of cooling on thrombolysis (rtPA) is negligible.8 The therapeutic hypothermia for acute ischaemia stroke (EuroHYP-1), was supposed to be the largest (1500 patients), pan-European phase III RCT. The primary endpoint was functional outcomes at three months in conscious stroke patients. Unfortunately, only 98 patients were recruited and the trial was stopped early due to slow recruitment. Of those in the hypothermia group, only 31% (15/49) achieved the predefined cooling targets, highlighting how difficult the practical aspects of TTM are to initiate. Although the numbers were significantly lower than intended, there was no difference in the primary outcome.9
REFERENCES 1 Kunz A, Dirnagl U, Mergenthaler P. Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol 2010; 24: 495e509. 2 Yenari MA, Han HS. Neuroprotective mechanism of hypothermia in brain ischaemia. Nat Rev Neurosci 2012; 13: 267e78. 3 Andrews PJD, Verma V, Healy M, et al. Targeted temperature management in patients with intracranial haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: consensus recommendations. British Jounral of anaesthesia 2018; 121: 768e75. 4 Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663e70. 5 Chol HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury- mechanism and practical aspects. Nat Rev Neurol 2012; 8: 214e22. 6 Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for Intracranial hypertension after traumatic brain inury. N Engl J Med 2015; 373: 2403e12. 7 Cooper DJ, Nichol AD, Bailey M, et al. Effects if early sustained prophylactic hypothermia on neurological outcomes among patients with severe traumatic brain injury. The POLAR randomised clinical trial. J Am Med Assoc 2018; 320: 2211e20. 8 Lyden P, Hemmen T. Grotta J et al. Results of the ICTuS 2 trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 2016; 47: 2888e95. 9 Van der Worp HB, Macleod MR, Bath PM, et al. EuroHYP-1: European multicenter randomised, phase III clinical trail of therapeutic hypothermia plus best medical treatment alone for acute ischaemic stroke. European Stroke journal 2019; 0: 1e9. 10 Madden LK, Hill M, May TL, et al. The implementation of targeted temperature management: an evidence based guideline from the neurocritical care society. Neurocrit care 2017; 27: 468e87.
Intracerebral haemorrhage Preclinical data suggests hypothermia reduces oedema and blood brain barrier disruption following ICH. Perihaemorrhagic oedema may be an important factor affecting outcomes. With a lack of large RCTs identifying optimal temperature management in intracerebral haemorrhage, current expert consensus is ‘management of early fever may be reasonable’, and one should ‘consider hypothermia (35 Ce37 C) in those comatose patients with spontaneous ICH.’3 Subarachnoid haemorrhage (SAH) The largest randomized trial for SAH, entitled the Intraoperative Hypothermia for Aneurysm Surgery Trial (I-HAST) applied hypothermia in 1001 patients with good-grade SAH. The results, published in the NEJM in 2005, showed no significant difference in neurological outcome at 3 months post-surgery.
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
3
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019
Therapeutic hypothermia and acute brain injury
Learning objectives After reading this article, you should be able to: C list the potential mechanisms of hypothermia induced neuroprotection C identify best practice recommendation for target temperature management C determine the potential complications from hypothermia C appraise the evidence for hypothermia and acute brain injury
Jagdish Sokhi Ugan Reddy
Abstract Secondary brain injury has devastating effects on morbidity, mortality and good functional outcomes. Neuroprotection is multimodal, with decades of preclinical and small clinical studies showing the benefits of therapeutic hypothermia. The basic scientific principles have merit, yet large randomized controlled trials fail to show a clear benefit. This article will review the basic science the practical aspects of delivering targeted temperature management and evaluate the evidence behind its use for acute brain injuries. With a lack of high-quality evidence for hypothermia, recent consensus statements are shifting the paradigm away from hypothermia to the maintenance of normothermia and prevention of pyrexia.
The potential benefits of therapeutic hypothermia (TH) have been recognized for decades; however, despite a strong scientific rationale and promising pre-clinical trials, TH has translated poorly into improved clinical outcomes. In this article, we will explore the basis for TH, including the scientific principles, complications, practical aspects and the evidence for its use in various clinical conditions. Target temperature management (TTM) has superseded TH in terms of nomenclature. TTM is difficult to define, but it is an active treatment aimed at maintaining a patient’s core body temperature at a pre-determined value, to reduce morbidity and improve neurological outcomes. The target can be either hypothermia (<36 C) or normothermia (37 C 0.5 C).
there is significant ischaemia, which is not promptly treated then irreversible brain damage occurs, culminating in cellular dysfunction and necrosis. The pathophysiology involves primary cellular energy failure, depolarization of cell membranes, release of excitatory amino acids and excessive cytosolic calcium.1 Interest in the potential neuroprotective benefits of hypothermia comes from several case reports of patients exposed to profound hypothermia. These patients had suffered out of hospital cardiac arrests (OOHCA), with prolonged ‘down times’, but made ‘miraculous’ neurological recoveries. Once such case published by Gilbert et al. (Lancet 2000), involved a skier who was successfully resuscitated after an OOHCA, with a core temperature measured at 13.7 C, without significant neurological disability. The patient went on to become a doctor! It was believed that the inadvertent hypothermia provided a significant degree of neurological protection. This is potentially achieved through: reduction in cerebral metabolic requirement oxygen (CMRO2) by approximately 7% per 1 C, below core body temperature reduction of intracranial pressure (ICP) and therefore maintenance of the cerebral perfusion pressure (CPP) by cerebral vasoconstriction reduction in vascular permeability and consequently less cerebral oedema suppression of the inflammatory cascade reduction in the release of excitatory mediators reduction in neuronal apoptosis by inhibition of caspase activity reduction in free radical formation.2 TTM is not without complications. The greater the degree of hypothermia, the more significant the side effects. Table 1 highlights the potential consequences for each organ system.
Pathophysiology
Practical aspects
Cerebral ischaemia is characterized by a failure in the supply of oxygen and nutrients to match the cerebral metabolic demand. If
The methods of cooling can be divided into: pharmacological e paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) non-pharmacological external e blankets (circulating air or water), ice packs internal e cold intravenous (IV) fluids, endovascular cooling IV lines, extracorporeal circuits. There are essentially three stages of TTM. Induction, normally performed at the point of admission, maintenance and rewarming, commonly performed in the intensive care. Because
Keywords Acute ischaemic stroke; hypoxic-ischaemic encephalopathy; induced normothermia; intracranial haemorrhage; intracranial pressure; subarachnoid haemorrhage; targeted temperature management; therapeutic hypothermia; traumatic brain injury Royal College of Anaesthetists CPD Matrix: 1H02, 2F01, 3F00
Introduction
Jagdish Sokhi MBBS BMedSci MRCP FRCA FFICM is a Specialty Registrar in Anaesthesia and Critical Care, London, UK. Conflicts of interest: none. Ugan Reddy BSc MBChB FRCA FFICM is a Consultant in Neuroanaesthesia and Neurocritical Care at The National Hospital for Neurology and Neurosurgery, London¸, UK. Conflicts of interest: none.
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
1
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019
NEUROINTENSIVE CARE
scale 0e3) is approximately 2%. After return of spontaneous circulation (ROSC), neurological injury was the single biggest cause of disability. In 2002, the hypothermia after cardiac arrest (HACA) trial was one of the first trials designed to assess whether hypothermia provided neurological protection. The results published in the NEJM demonstrated that hypothermia (initiated 4e6 hours post cardiac arrest) and maintained at 33 C for 24 hours, improved survival, numbers needed to treat (NNT 7) and neurological outcomes (NNT 6). ‘Cooling’ after cardiac arrests with an initial shockable rhythm became commonplace, and guidance was eventually extended to cover all rhythms, and both in and out of hospital cardiac arrests. However in 2013, the TTM trial (2013 NEJM) with nearly 1000 patients, showed no difference in neurological outcome or survival in patients cooled to 33 C versus 36 C for 36 hours. Following this, most UK intensive care units have elected to use 36 C as the target temperature, for a minimum of 24 hours, provided there are no significant side effects.
Consequences of hypothermia System
Effects
Cardiovascular
Reduction in cardiac output (CO) Increase in systemic vascular resistance (SVR) Bradyarrhythmias e atrial fibrillation (AF), and if severe (<30 C) ventricular fibrillation (VF) ECG changes e prolonged PR, widening QRS, J waves/Osborne Reduction in minute ventilation (MV) Increased risk of pneumonia/ventilation associated pneumonia (VAP) Increased solubility of carbon dioxide leading to respiratory alkalosis Insulin resistance Reduced peristalsis Delayed gastric emptying Reduced liver metabolism, including drugs Metabolic acidosis lactaemia ‘Cold diuresis’ Electrolyte disturbances Impaired innate immune system cell function Shivering Coagulopathy Impaired platelet function
Respiratory
Gastrointestinal
Renal Infection Musculoskeletal Haematological
Newborn hypoxic ischaemic encephalopathy (HIE) HIE remains a significant cause of mortality and long-term morbidity. Data from various randomized clinical trials indicate that cooling is an effective therapy if initiated within 48 hours of birth. Both whole body cooling and selective head cooling (SHC) have been successfully implemented, with a preference towards using SHC.4 The trials included infants born at 36 weeks of gestation with evolving moderate to severe HIE. The temperature targeted was 34.5 C 0.5 C within the first 6 hours of life for 48 e72 hours.4 Complications were primarily cardiovascular, thrombocytopenia and local effects of the skin such as erythema or skin hardening. The American Heart Association’s 2010 neonatal resuscitation guidelines recommend TTM in infants born at 36 weeks of gestation with evolving moderate to severe hypoxic-ischaemic encephalopathy. Further trials are needed to assess if the benefits would apply to infants below <35 weeks and if starting cooling after 6 hours is beneficial.
Table 1
of the multiple options available, including different methods, devices and protocols in place, practice can be highly variable. In 2018, a consensus of recommendations was published in the British Journal of Anaesthesia, to help standardize practice. The following recommendations were made: Core temperature should be measured continuously in patients with neurological injury. The optimal site is still debatable. TTM should be initiated if a patient’s temperature exceeds 37.5 C and infection is excluded, and within 1 hour if pharmacological treatment has not succeeded. TTM should continue for as long as there is potential for secondary brain injury with a target temperature of 37 C 0.5 C Shivering, one of the most common side effects should be actively managed, as it causes increased cerebral and metabolic stress, by as much as 100%. It also has deleterious effects on ICP and myocardial oxygenation. All acute brain injuries, regardless of aetiology should be managed using a single protocol for neurogenic fever. Rewarming should occur at 0.25 C per hour.3
Primary neurological injuries Traumatic brain injury (TBI) Minimizing secondary brain injury is the main priority for neurocritical care. Secondary brain injury is multifactorial in origin, including ischaemia, reperfusion, inflammation, metabolic or cellular dysfunction, and raised ICP. Hypothermia, with a core temperature of <35.5 C, consistently provides neuroprotection by reducing the aforementioned processes.5 Despite promising preclinical trials, the first major phase III clinical trials (National Acute Brain Injury Study I and II) failed to show a benefit. To answer this question a large multicentre randomized control trial (RCT) was necessary. EUROTHERM3235 was a large RCT comparing hypothermia (32 Ce35 C) to standard care in those with TBI. Primary outcomes included major disability at 6 months. Inclusion criteria was closed TBI and an ICP >20 mmHg for greater than 5 minutes after initial treatment (stage 1) failed to control ICP. Hypothermia was continued >48 hours and until ICP was controlled. Recruitment was stopped early due to a higher mortality in the
Clinical uses of TTM Cardiac arrest Despite multiple advances in the management of cardiac arrest, outcomes remain poor. In 2018, the UK-based PARAMEDIC trial, published in the New England Journal of Medicine (NEJM ), showed a 3-month survival of less than 3% and those with favourable neurological outcomes (modified Rankin Scale (mRS)
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
2
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019
NEUROINTENSIVE CARE
It is worth noting that results cannot be applied to neurocritical care unit or those with poor grade SAH. There are small case series for these patient groups that report reduced vasospasm, delayed cerebral ischaemia and intracranial hypertension with hypothermia.
hypothermia group. The odds ratio was 1.53 in the hypothermia group when comparing extended Glasgow outcome scale versus standard care (95% confidence interval, 1.02 to 2.30; P ¼ 0.04).6 In 2018, another multicentre RCT, entitled the ‘effects of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe TBI (POLAR)’, demonstrated no difference at 6 months in neurological outcomes in those with blunt TBI, but there was an increased rate of complications in the hypothermia group.7 In 2017, a Cochrane systematic review, which pooled 37 eligible trials with over 3000 patients, concluded ‘there remains no high quality evidence that hypothermia is beneficial in the treatment of people with TBI.’
Conclusion Fever is a common phenomenon in neurocritical care patients and is associated with poorer functional outcomes.10 In those with fever up to 50% will be due to an infective cause and therefore early diagnosis and treatment of sepsis is vital. Potentially, by preventing fevers, targeted temperature management has its beneficial effects. However, owing to the lack of grade I evidence for hypothermia in acute brain injuries, and the known detrimental effects of hyperthermia, current practice is adopting TTM to maintain normothermia in response to the first neurogenic fever. A
Acute ischaemic stroke (AIS) Acute treatment involves thrombolysis, with or without mechanical thrombectomy, to minimize infract size. This is followed by antiplatelet agents and cardiovascular secondary prevention. Minimizing the infarct size is important, with preclinical data suggesting this is possible with hypothermia. The ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2), which utilized intravascular cooling post thrombolysis, was stopped early and only recruited 120 of the expected 1600 patients. The results showed no difference in mortality, functional outcomes and adverse effects of hypothermia. There was a non-significant trend towards an increased risk of pneumonia associated with hypothermia. The effect of cooling on thrombolysis (rtPA) is negligible.8 The therapeutic hypothermia for acute ischaemia stroke (EuroHYP-1), was supposed to be the largest (1500 patients), pan-European phase III RCT. The primary endpoint was functional outcomes at three months in conscious stroke patients. Unfortunately, only 98 patients were recruited and the trial was stopped early due to slow recruitment. Of those in the hypothermia group, only 31% (15/49) achieved the predefined cooling targets, highlighting how difficult the practical aspects of TTM are to initiate. Although the numbers were significantly lower than intended, there was no difference in the primary outcome.9
REFERENCES 1 Kunz A, Dirnagl U, Mergenthaler P. Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol 2010; 24: 495e509. 2 Yenari MA, Han HS. Neuroprotective mechanism of hypothermia in brain ischaemia. Nat Rev Neurosci 2012; 13: 267e78. 3 Andrews PJD, Verma V, Healy M, et al. Targeted temperature management in patients with intracranial haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: consensus recommendations. British Jounral of anaesthesia 2018; 121: 768e75. 4 Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663e70. 5 Chol HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury- mechanism and practical aspects. Nat Rev Neurol 2012; 8: 214e22. 6 Andrews PJD, Sinclair HL, Rodriguez A, et al. Hypothermia for Intracranial hypertension after traumatic brain inury. N Engl J Med 2015; 373: 2403e12. 7 Cooper DJ, Nichol AD, Bailey M, et al. Effects if early sustained prophylactic hypothermia on neurological outcomes among patients with severe traumatic brain injury. The POLAR randomised clinical trial. J Am Med Assoc 2018; 320: 2211e20. 8 Lyden P, Hemmen T. Grotta J et al. Results of the ICTuS 2 trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 2016; 47: 2888e95. 9 Van der Worp HB, Macleod MR, Bath PM, et al. EuroHYP-1: European multicenter randomised, phase III clinical trail of therapeutic hypothermia plus best medical treatment alone for acute ischaemic stroke. European Stroke journal 2019; 0: 1e9. 10 Madden LK, Hill M, May TL, et al. The implementation of targeted temperature management: an evidence based guideline from the neurocritical care society. Neurocrit care 2017; 27: 468e87.
Intracerebral haemorrhage Preclinical data suggests hypothermia reduces oedema and blood brain barrier disruption following ICH. Perihaemorrhagic oedema may be an important factor affecting outcomes. With a lack of large RCTs identifying optimal temperature management in intracerebral haemorrhage, current expert consensus is ‘management of early fever may be reasonable’, and one should ‘consider hypothermia (35 Ce37 C) in those comatose patients with spontaneous ICH.’3 Subarachnoid haemorrhage (SAH) The largest randomized trial for SAH, entitled the Intraoperative Hypothermia for Aneurysm Surgery Trial (I-HAST) applied hypothermia in 1001 patients with good-grade SAH. The results, published in the NEJM in 2005, showed no significant difference in neurological outcome at 3 months post-surgery.
ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx
3
Ó 2019 Published by Elsevier Ltd.
Please cite this article as: Sokhi J, Reddy U, Therapeutic hypothermia and acute brain injury, Anaesthesia and intensive care medicine, https:// doi.org/10.1016/j.mpaic.2019.10.019