For over 50 years, clinicians have used hypothermia to manage traumatic brain injury (TBI). In the last two decades numerous trials have assessed whether hypothermia is of benefit in patients. Mild to moderate hypothermia reduces the intracranial pressure (ICP). Randomized control trials for short-term hypothermia indicate no benefit in outcome after severe TBI, whereas longer-term hypothermia could be of benefit by reducing ICP. This article summarises current evidence and gives recommendations based upon the conclusions.
Key points
- •
Mild to moderate hypothermia reduces the intracranial pressure (ICP).
- •
Randomized control trials for short-term hypothermia indicate no benefit in outcome after severe traumatic brain injury.
- •
Longer-term hypothermia could be of benefit by reducing ICP, and ongoing studies may determine this.
Introduction
Introduction and History
The use of therapeutic hypothermia in clinical medicine has become widely established in the management of cardiac arrest and neonatal hypoxia, whereas the body of evidence in stroke, spinal cord injury, and traumatic brain injury (TBI) remains an ongoing area of active research and discussion. Some of the original laboratory studies for TBI used crude methods of cooling, and to temperatures regarded as extreme by current standards. For instance, Rosomoff induced a “closed head injury” in 2 groups of mongrel dogs either at normothermia or at 25°C body temperature, by pouring liquid air into a cylinder in contact with the dura. The hypothermic dogs survived 5 times longer than the normothermic dogs, and this was accompanied by reduced brain swelling. Again, in the laboratory, surface cooling of uninjured dogs to 28°C to 30°C led to a drop in the cerebrospinal fluid (CSF) pressure. Concurrently, several remarkable clinical studies reported instances of the effect of cooling in patients following TBI. Perhaps the first was by Fay, who described therapeutic cooling of the human brain after cerebral trauma as early as 1941, in which he cooled the brain using local irrigation of ice-cold fluids into the cranial vault or cooled systemically using a refrigeration blanket. Some anecdotes that he reported indicate serendipitous, yet remarkable improvement of the patient with cooling (for example, see page 254 of his seminal paper). Around the same time, in a cohort of 30 patients with severe TBI who were cooled, 17 of them survived, which was a large number in the 1950s. To determine the mechanisms that may underlie this improvement, in a controlled study in a small number of patients, the CSF pressure was reduced following hypothermia. These initial groundbreaking studies laid the foundation for hypothermia research in the context of severe TBI and now include the more recent and numerous preclinical mechanistic studies, along with early clinical and more recently larger randomized control trials (RCTs) in an effort to determine whether therapeutic hypothermia is of benefit following severe TBI.
Basic Science Studies
In rodent studies, following a lateral fluid percussion injury, rats undergoing induced hypothermia did better in terms of survival and behavior. The mechanisms by which this occurs in animal models are multifactorial but include the prevention of secondary brain injury by reducing the excitotoxic, oxidative, and inflammatory effect, by targeting ischemia-reperfusion, and by minimizing cortical depolarization. Hypothermia decreases cerebral metabolic rate and alters release of excitatory neurotransmitters following injury. Other mechanisms also include attenuated proinflammatory cytokines, reduced free radicals, and excitotoxic substances. Lowering the temperature after TBI has a protective effect on hypoxia-induced cell death. Hypothermia also prevents the disruption of the blood brain barrier following injury. Cooling induces a reduction in brain metabolism by 5% per 1°C reduction in core temperature, leading to vasoconstriction and reduced cerebral blood volume, hence a decrease in intracranial pressure (ICP). Moreover, after-injury hypothermia leads to a reduction of chemically induced seizures and spreading depolarizations, and this hypothermia-dependent reduction in seizures has also been reported clinically in TBI patients. Perhaps critically, if the rate of rewarming is too fast, the benefits of reducing the core temperature are lost. With this mechanistic knowledge of the benefits of hypothermia, numerous clinical studies have been undertaken to demonstrate if this treatment modality is ultimately of benefit in the severely injured TBI patient.
Introduction
Introduction and History
The use of therapeutic hypothermia in clinical medicine has become widely established in the management of cardiac arrest and neonatal hypoxia, whereas the body of evidence in stroke, spinal cord injury, and traumatic brain injury (TBI) remains an ongoing area of active research and discussion. Some of the original laboratory studies for TBI used crude methods of cooling, and to temperatures regarded as extreme by current standards. For instance, Rosomoff induced a “closed head injury” in 2 groups of mongrel dogs either at normothermia or at 25°C body temperature, by pouring liquid air into a cylinder in contact with the dura. The hypothermic dogs survived 5 times longer than the normothermic dogs, and this was accompanied by reduced brain swelling. Again, in the laboratory, surface cooling of uninjured dogs to 28°C to 30°C led to a drop in the cerebrospinal fluid (CSF) pressure. Concurrently, several remarkable clinical studies reported instances of the effect of cooling in patients following TBI. Perhaps the first was by Fay, who described therapeutic cooling of the human brain after cerebral trauma as early as 1941, in which he cooled the brain using local irrigation of ice-cold fluids into the cranial vault or cooled systemically using a refrigeration blanket. Some anecdotes that he reported indicate serendipitous, yet remarkable improvement of the patient with cooling (for example, see page 254 of his seminal paper). Around the same time, in a cohort of 30 patients with severe TBI who were cooled, 17 of them survived, which was a large number in the 1950s. To determine the mechanisms that may underlie this improvement, in a controlled study in a small number of patients, the CSF pressure was reduced following hypothermia. These initial groundbreaking studies laid the foundation for hypothermia research in the context of severe TBI and now include the more recent and numerous preclinical mechanistic studies, along with early clinical and more recently larger randomized control trials (RCTs) in an effort to determine whether therapeutic hypothermia is of benefit following severe TBI.
Basic Science Studies
In rodent studies, following a lateral fluid percussion injury, rats undergoing induced hypothermia did better in terms of survival and behavior. The mechanisms by which this occurs in animal models are multifactorial but include the prevention of secondary brain injury by reducing the excitotoxic, oxidative, and inflammatory effect, by targeting ischemia-reperfusion, and by minimizing cortical depolarization. Hypothermia decreases cerebral metabolic rate and alters release of excitatory neurotransmitters following injury. Other mechanisms also include attenuated proinflammatory cytokines, reduced free radicals, and excitotoxic substances. Lowering the temperature after TBI has a protective effect on hypoxia-induced cell death. Hypothermia also prevents the disruption of the blood brain barrier following injury. Cooling induces a reduction in brain metabolism by 5% per 1°C reduction in core temperature, leading to vasoconstriction and reduced cerebral blood volume, hence a decrease in intracranial pressure (ICP). Moreover, after-injury hypothermia leads to a reduction of chemically induced seizures and spreading depolarizations, and this hypothermia-dependent reduction in seizures has also been reported clinically in TBI patients. Perhaps critically, if the rate of rewarming is too fast, the benefits of reducing the core temperature are lost. With this mechanistic knowledge of the benefits of hypothermia, numerous clinical studies have been undertaken to demonstrate if this treatment modality is ultimately of benefit in the severely injured TBI patient.
Treatment options
Literature Review
Overview of clinical trials
Clinical trials of hypothermia have 2 broad aims: first, to control the ICP, and second, to provide neuroprotection. As a consequence, the mortality and morbidity outcome determines whether the treatment regimen instigated is of clinical benefit. In general terms, ICP control has been more widely studied in the Far East, whereas primary neuroprotection has been the focus of western clinical trials. The initial western trials involved small patient numbers up to 80. In an early trial, with moderate hypothermia between 32°C and 33°C for 48 hours, a trend toward a better Glasgow Outcome Score (GOS) with a reduction in seizures was observed. In a similar trial, with the same target temperature but for 24 hours, the ICP and cerebral blood flow were lower, and a similar trend toward an improved outcome was observed. In a follow-up study, similar improvements in GOS were observed in patients with a Glasgow Coma Score (GCS) of between 5 and 7, but this difference in GOS was insignificant by 1 year. To evaluate the effect of mild hypothermia (34°C) on ICP in severely head-injured patients, Shiozaki and colleagues in Japan determined that ICP was significantly reduced and cerebral perfusion pressure was increased in those with hypothermia. Hypothermia was continued for at least 2 days, or until it was thought not to be effective. Similarly, reducing the temperature to 35°C resulted in ICP control and improved cerebral perfusion pressure (CPP) in TBI patients, while also reducing metabolism and energy expenditure but maintaining hemodynamic stability. In summary, these small studies were the foundation of larger RCTs to determine the efficacy of hypothermia in the TBI patient.
Short-term hypothermia
With the small case control studies suggesting a benefit of hypothermia in the severely injured TBI patient, the argument for larger RCTs for short-term hypothermia led to several trials in both adult and pediatric populations. The National Acute Brain Injury: Hypothermia (NABIS:H) study was an RCT that had the premise of a neuroprotective strategy so the patients in the treatment group were cooled for 48 hours after injury. The target temperature was 33°C, and the patients were rewarmed at 48 hours irrespective of their ICP. There was no difference in outcome (GOS at 6 months) between the cooled and normothermic groups, although there were significant intercenter differences. The most experienced centers had greater success, using faster cooling times from injury and avoiding hypotension and hypovolemia in the hypothermia group. With these differences between centers, NABIS:H II attempted to address the criticisms of NABIS:H. There were 6 dedicated centers, where patients were rapidly cooled using ice saline within 4 hours of injury. Again, the target temperature was 33°C with rewarming after 48 hours, and the primary outcome was the GOS at 6 months. The trial was terminated early because there was no difference to the null hypothesis, and these 2 studies have been interpreted to suggest that short-term hypothermia does not improve outcome nor provide neuroprotection in TBI. Interestingly, the hypothermia group had more patients with raised ICP and may be in part due to rebound ICP problems because hypothermia was only 48 hours, with ICP problems usually occurring after this during the at-risk swelling phase. Subgroup analysis of the surgical group in which patients had evacuation of an intracerebral hematoma suggested that hypothermia was of benefit, although the number of patients was small (28 surgical cases in which 15 had hypothermia therapy and did better overall as a cohort). A similar RCT from Japan instigated hypothermia for 48 hours before rewarming over 3 days in severe TBI patients. Importantly, all patients in the study had ICPs that were low (less than 25 mm Hg) before randomization. Again there was no difference in clinical outcome at 3 months between the hypothermic and normothermic groups. In the pediatric population, the instigation of short-term hypothermia again demonstrates no benefit. For example, the Cool Kids trial in which hypothermia (32°C–33°C) for 48 to 72 hours followed by slow rewarming was stopped early due to absence of any trend toward treatment benefit when looking at the 3-month pediatric GOS. Similarly, an even shorter cooling period of 24 hours to 33°C in the pediatric TBI population demonstrated no improvement in the Pediatric Cerebral Performance Score at 6 months, and in fact, showed a trend toward an increase in mortality with hypothermia. Clearly, based on these trials, the argument for short-term hypothermia was not justified, and therefore, attention was focused toward extending the length of hypothermia beyond the 48-hour time period.
Long-term hypothermia
A recently published trial, Eurotherm 3235, examined the hypothesis that titrated hypothermia treatments raised ICP in TBI patients and demonstrated a decrease in the ICP with hypothermia, but was closed for recruitment early. The trial results demonstrated that hypothermia, a stage 2 treatment in the tiered management of a severe head injury patient, was associated with worse outcomes in terms of GOS-E compared with patients in which hypothermia was not instigated. Critically, in this study, hypothermia was used instead of other stage 2 measures such as osmotherapy, which were only introduced if hypothermia failed to control ICP greater than 20 mm Hg. Also in this trial, hypothermia was maximal at day 3, after which the patients were warmed back to normothermia, and half the patients went to stage 3 treatment with either thiopentone coma or decompressive craniectomy. A similar Japanese trial, the B-HYPO study, where patients were cooled for 3 days to 32 to 34°C before rewarming, was again stopped early due to no observable difference in the GOS at 6 months. Rather than using medium-term hypothermia for the immediate benefits of neuroprotection, longer periods of hypothermia, beyond 3 days, improved ICP control. In the severe TBI cohort with a GCS of 8 or less, hypothermia to 33°C to 35°C for between 3 and 14 days led to decreased mortality compared with the normothermic control group. This decrease in mortality may have been because the long-term hypothermia reduced the ICP and swelling during the critical swelling phase. The same group compared short-term (2 days) versus long-term (average of 5 days) hypothermia in patients with TBI with mass effect and midline shift. The outcomes were improved in the patients with prolonged hypothermia, and they also observed that rebound intracranial hypertension often occurs with shorter periods of hypothermia. Currently, an ongoing trial may add to the evidence to demonstrate benefit in long-term cooling. The POLAR-RCT ( NCT00987688 ) is an Australasian trial to determine if early prophylactic sustained hypothermia has outcome benefit; patients will be cooled for between 3 and 7 days to 33°C. Similarly, the LTH-1 trial ( NCT01886222 ) is a Chinese study to determine if cooling to 34°C to 35°C for between 5 and 14 days leads to improved GOS at 6 months. With longer periods of hypothermia, cytotoxic edema and intracellular cascades of neurotoxicity may be attenuated. Cerebral edema peaks between 3 to 5 days; therefore, the long-term hypothermia may overcome the rebound intracranial hypertension observed in the short-term cooling studies.
Hypothermia with surgical lesions
Following the NABIS:H trials, a pooled meta-analysis indicated a benefit for hypothermia in patients with a surgical hematoma or acute subdural hematoma requiring evacuation. The rationale may be due to a high proportion of acute subdural hematoma patients getting either cortical spreading depolarizations or hyperemia, and hence, cooling is able to target both. Consequently, the HOPES (HypOthermia for Patients requiring Evacuation of Subdural hematoma) trial is currently recruiting to determine if early cooling, regardless of timing of surgery, is of benefit in this specific subdural hematoma TBI population ( NCT02064959 ). Moreover, in a small randomized trial, cooling after a craniotomy for TBI led to a favorable outcome at 1 year.
Summary papers
With a large body of clinical evidence for the use of cooling in severe TBI, several systematic reviews and meta-analyses have pooled data in an attempt to clarify the evidence base for therapeutic hypothermia. Reviewing the effect of hypothermia on ICP, all but 1 of 15 studies demonstrated a decrease in ICP. Similarly, comparing 11 prospective RCTs, mild hypothermia was associated with lowering the ICP. In a review of 12 trials with more than 1000 patients, McIntyre and colleagues concluded that the evidence suggested a benefit of mild to moderate hypothermia in severe TBI with a reduction in risk of both death (relative reduction, RR 19%) and poor neurologic outcome (RR 22%). It also suggested that a longer period of cooling, greater than 48 hours, might be beneficial because 9 studies with short-term hypothermia had no difference in outcome, whereas 3 long-term hypothermia studies demonstrated benefit. A similar finding demonstrated better mortality outcome from 12 studies; however, if the 4 short-term studies (48 hours of cooling or less) were taken out, there was no difference in outcome ( Table 1 ).
Several further systematic reviews come to differing conclusions based on the selection of available evidence for the use of cooling in TBI. Several reviews do not support the use of hypothermia. This goes against the review by McIntyre and colleagues that states there is a benefit in the RR of hypothermia, even more so with prolonged hypothermia. In support of this later review, Crossley and colleagues analyzed 20 RCTs with almost 2000 patients, similarly concluding an RR reduction in both mortality and outcome. When accounting for studies with low bias, this RR was greater. Interestingly, the incidence of pneumonia, one of the recognized risks of hypothermia, was not significantly different. In summary, although the review articles do come to differing conclusions, when dissecting out longer-term hypothermia beyond 3 days, the evidence to support this becomes more convincing.
Guidelines
Based on the current evidence for the use of hypothermia in severe TBI, the Brain Trauma Foundation (BTF) guidelines from 2007 are the most widely used guide to management for TBI. The latest 2016 BTF recommendations are due to be published imminently, but the 2007 guidelines suggest not to use hypothermia as standard of care, but to be used by experienced clinicians. The information is based on 6 RCTs, the conclusion of which is that hypothermia in severe TBI is likely to have a favorable neurologic outcome and may have a chance of reducing mortality if hypothermia is maintained greater than 48 hours.
Based on the data, the BTF gives a level 3 recommendation:
- •
Hypothermia does not reduce mortality. Preliminary data suggest that it may if hypothermia is maintained for more than 48 hours.
- •
Hypothermia is associated with better GOS.
Following on from these BTF recommendations, the above evidence provides further points for consideration that include:
- •
The depth of hypothermia: The target temperature should be titrated against ICP; 35°C to 35.5°C treats raised ICP and maintains CPP, and there is no compromise of cardiac function. Temperatures lower than 35°C may reduce brain tissue oxygenation, but overall the target temperature will need to be individualized.
- •
The duration of hypothermia: This depends on the severity of injury. The duration should be greater than 48 hours and continue until the peak period of swelling and subsequent intracranial hypertension (3–5 days) subside.
- •
Rate of rewarming: Fast rewarming not only loses any benefit of hypothermia but makes things worse. Moreover, there is a rebound raised ICP if rewarming is too rapid. Therefore, a rate of rewarming no more than 0.1°C to 0.2°C per hour should be used.
- •
Mass lesions: Patients with a focal mass lesion following TBI may respond to hypothermia better than a more diffuse injury.
With the above considerations, future guidelines should incorporate hypothermia in a tiered system of ICP management of the severely injured TBI patient. These guidelines should ideally be part of a standardized treatment algorithm that includes clear protocols for inducing cooling. Boxes 1 and 2 demonstrate 2 examples of algorithms from 2 large level 1 trauma centers: Jackson Memorial Hospital, Miami, Florida, USA and Wessex Neurological Centre, Southampton, Hampshire, UK.
Related posts:
Traumatic Brain Injury
Concussion—Mild Traumatic Brain Injury
Cerebral Metabolism and the Role of Glucose Control in Acute Traumatic Brain Injury
Cerebral Edema in Traumatic Brain Injury
Past, Present, and Future of Traumatic Brain Injury Research
Role of Metabolomics in Traumatic Brain Injury Research
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
