Therapeutic Hypothermia for Severe Traumatic Brain Injury

Hypothermia has been recommended in the treatment of severe traumatic brain injury (TBI) since at least the 1800s.^{1 - 7} By the mid 1960s, moderate hypothermia (28°C-32°C) had become part of the routine treatment of patients with severe TBI in a number of centers worldwide.⁸ However, by the early 1980s, moderate hypothermia for TBI had fallen out of favor because of infectious complications associated with its prolonged and uncontrolled use.⁹ In contrast, hypothermia has remained an accepted treatment for refractory intracranial hypertension in both adults and children.¹⁰ In the 1990s, there was renewed interest in the application of mild (33°C-36°C) hypothermia in experimental incomplete cerebral ischemia and cardiac arrest.^{11 - 14} A favorable effect of hypothermia has been reported in more than 90% of the 40 reports published by numerous laboratories using experimental models of TBI.

Since 1992 more than 25 clinical studies have reported effects of therapeutic hypothermia on outcome of TBI, as well as its secondary injury mechanisms and complications after TBI.^{15 - 24} Several of these have been randomized controlled trials (RCTs). Much of the recent clinical work on therapeutic hypothermia in clinical TBI has been performed in Asia and Australia.^{17 - 24}

In this issue of THE JOURNAL, McIntyre and colleagues²⁵ report a systematic review of 12 trials of therapeutic hypothermia involving 1069 patients. The results demonstrate an overall beneficial effect of moderate or mild hypothermia (32°C -33°C) in severe TBI, with a 19% relative reduction in the risk of death and a 22% relative reduction in the risk of poor neurological outcome compared with normothermia. The data suggest favorable effects for hypothermia durations of 24 or 48 hours, or longer; a target temperature of 32°C to 33°C; and a duration of rewarming of 24 hours or less.

The findings of this systematic review also suggest that some patients may benefit most from a longer duration of cooling, that is, 48 hours or more. It is possible that when used for refractory intracranial hypertension after severe TBI, the optimal use of hypothermia may require titration to effect, rather than application of a single protocol to all patients.²⁰ In fact, beneficial effects on secondary injury mechanisms may have occurred in patients treated with mild or moderate hypothermia for greater than 48 hours, despite the established risks of complications from prolonged moderate hypothermia.^{9 ,14 ,18}

Given that slow rewarming has been found to be optimal in laboratory studies,²⁶ it is surprising that McIntyre et al found that more rapid rewarming, within a 24-hour period of discontinuing hypothermia, conferred greater clinical benefit. However, this finding may not contradict existing laboratory data, because those experiments compared rewarming intervals of minutes vs hours, rather than days. It is likely that patients who tolerate rewarming at a rate of 1°C every 4 hours experience no therapeutic benefit but would have only greater risk of complications with slower rewarming, which could be important because some studies have used rewarming rates as low as 1°C per day.¹⁸

However, systematic review of these clinical data has many limitations. For example, because the use of hypothermia cannot be blinded, single-center studies may be inherently biased. However, the recent positive results of clinical trials of the use of mild hypothermia after resuscitation from cardiopulmonary arrest in adults^{27 - 28} argues against this possibility.

Also, most patients in recent studies of therapeutic hypothermia in TBI and many of those included in the systematic review of McIntyre et al are from single-center trials. In these studies, cerebral perfusion pressure–targeted treatment was relatively homogeneous, hypothermia was often titrated to optimal depth or duration,^{15 ,17 - 24} and other aspects of care may have been delivered in a consistent fashion within that center. These factors may limit the generalizability of these findings.

The findings of McIntyre et al contrast with those of a multicenter RCT by Clifton et al,¹⁶ which failed to demonstrate a beneficial effect of hypothermia on outcome after severe TBI in adults. However, several important limitations in that trial were later identified.²⁹ For instance, although a cerebral perfusion pressure–targeted therapeutic protocol was used in the study, the means by which that therapeutic goal was achieved varied between centers and may have created an impossible challenge for therapeutic hypothermia, despite its consistent benefit in experimental models of TBI. Furthermore, the trial by Clifton et al had a long delay (mean 8.4 hours) in achieving target temperature using surface cooling and gastric lavage. However, the delay in reaching target temperature is substantial in most published clinical trials of hypothermia, even those included in the review of McIntyre et al.

The positive results in clinical trials of mild hypothermia in cardiopulmonary arrest have contributed to renewed interest in the application of hypothermia across a variety of applications, including severe TBI. First, Bernard et al³⁰ reported that cooling can be rapidly initiated by the intravenous administration of 30 mL/kg of iced (4°C) crystalloid solution in patients who survived cardiac arrest and are comatose. This approach reduced core temperature by about 2°C over 30 minutes and was well tolerated even after cardiopulmonary arrest and resuscitation. Compelling data from other experimental models of cardiopulmonary arrest and TBI suggest that rapid cooling maximizes the benefits of mild or moderate hypothermia. This use of cold intravenous fluids may represent a logical strategy for future clinical trials for use of hypothermia in severe TBI. Sustaining the initial reduction could be achieved with either an intravenous catheter,³¹ veno-venous blood cooling,³² or possibly surface cooling.

Second, studies in experimental TBI have suggested that moderate levels of hypothermia are needed to control intracranial hypertension.^{13 - 14} However, recent clinical studies indicate that treatment with mild hypothermia is often successful at controlling intracranial pressure, even in many cases refractory to medical management. Tokutomi et al²² evaluated the effect of temperature level on intracranial pressure during cooling to 33°C in 31 adults with severe TBI and found that the decrease in intracranial pressure and improvement in cerebral cranial pressure was greatest at 35.5°C. Such a moderate level of titrated cooling, if effective, might reduce the risk of adverse effects. Further clinical investigation and application of titrated mild hypothermia in patients with severe TBI are needed.

Third, recent animal studies by Statler et al³³ suggest that creating a state of poikilothermia is essential to prevent deleterious consequences of stress during induction and maintenance of moderate hypothermia after experimental TBI. Sedatives, narcotics, and neuromuscular blockade are generally recommended. Preliminary work in an animal model of cardiopulmonary arrest³⁴ suggests that novel pharmacological agents may facilitate rapid cooling while minimizing the stress response. Optimal pharmacological adjuncts in mild and moderate hypothermia represent an important future area of research and clinical application. Hypothermia appears to have extremely powerful effects on some but not all secondary injury mechanisms,³⁵ and the combination of hypothermia and pharmacological therapies to prevent oxidative stress may be particularly promising.^{36 - 37}

Fourth, following severe TBI, patients with secondary insults, such as hypotension or hypoxemia, have consistently poor outcomes³⁸ but are routinely excluded from clinical trials, including those of hypothermia treatment.^{15 - 16} It will be important to examine mild or moderate hypothermia in this clinical setting, where the contribution of ischemic mechanisms of secondary damage would suggest added value of mild cooling after resuscitation.

Fifth, both the duration of the application of hypothermia necessary for optimal effect and the rate of rewarming remain unclear, and may not be the same for all cases. Recent work by Iida et al²⁴ raises the possibility of using the occurrence of hyperemia (detected by transcranial Doppler) as an early predictor of the development of intracranial hypertension during rewarming of patients with severe TBI. This preliminary report reinforces the important concept of using physiological or biochemical parameters, rather than using a single fixed regimen for all cases, to determine the optimal duration of hypothermia or rate of rewarming. It is not yet clear what the optimal parameters are, but the concept merits further study.

Finally, considerable laboratory evidence suggests that hyperthermia is deleterious after severe TBI, and thus should be avoided. Catheter-based cooling for continuous temperature control,^{31 - 32} has been found to be feasible in patients with a number of diagnoses in a neurointensive care unit.³¹

Several clinical trials in patients with severe TBI are now ongoing, including 2 pediatric trials and a new adult trial, as described by McIntyre et al.²⁵ Because surface cooling is generally slow and unreliable, future clinical investigation on the use of hypothermia in patients with severe TBI should consider the following: rapid induction of cooling via intravenous administration of cold crystalloid; rigorous maintenance of temperature control with intravascular cooling devices; initially targeting mild levels of hypothermia; subsequent titration of the level and duration of hypothermia to clinical, physiological, and biochemical effect; and thorough characterization of the consequences of various rewarming paradigms. Although mild or moderate hypothermia is an accepted therapy for refractory intracranial hypertension after TBI in both adults and children, whether it should be used as a first tier therapy and exactly how it compares with other second tier therapies are 2 key questions that remain to be determined in clinical trials. Additional investigation of hypothermia in experimental and clinical brain injury should define the mechanisms underlying its beneficial, and potential deleterious effects, and translate that knowledge into optimized combinations of hypothermia and novel pharmacological strategies.