Experimental Brain Trauma

Renewed interest in the application of modest levels of brain hypothermia in experimental models of TBI occurred in the 1990s. This renewed interest followed mainly from the cerebral ischemia literature, which showed for the first time that relatively small variations in brain temperature critically determine the vulnerability of hippocampal neurons to a transient ischemic insult.²⁰ Clifton and colleagues first reported that modest hypothermia before and after TBI improved beam walking in a rat model of fluid percussion brain injury.² In that study, hypothermia of 30° C significantly reduced mortality rates, as well as attenuated deficits in beam balance and body weight loss in comparison to normothermic treatment. The effect of hypothermia (30° C) for 1 hour after injury on behavioral outcome was also evaluated by Lyeth and colleagues, who reported evidence of improved behavioral outcome.⁶ Dietrich and colleagues in 1994 showed that posttraumatic hypothermia (30° C) initiated 5 minutes after parasagittal fluid percussion brain injury significantly reduced overall contusion volume and preserved the survival of pericontusional cortical neurons.³ In addition to fluid percussion brain injury, hypothermia was also tested in other models of brain injury, including the controlled cortical impact and diffuse injury models.^4,7 In a study by Dixon and colleagues, posttraumatic hypothermia reduced overall contusion volume in a controlled cortical impact injury model.⁴ In other studies, posttraumatic hypothermia reduced sensory, motor, and cognitive deficits relative to normothermic animals.^1,6 In terms of the treatment window for hypothermia, Markgraf and colleagues reported improved neurological outcome if hypothermia (3 hours at 30°C) was initiated 60 minutes but not 90 minutes after cortical impact injury.⁸ Thus, data from multiple laboratories using different TBI models show that hypothermia protects against behavioral and neuropathologic deficits if treatment is initiated fairly early after injury.

Posttraumatic hypothermia has also been shown to reduce the extent of axonal damage in models of TBI.^5,38–40 In one study, the use of preinjury or early posttraumatic hypothermia of relatively brief duration (60 minutes) provided significant axonal protection in the brain’s major projection systems.⁵ A well-known marker of axonal injury, amyloid precursor protein immunoreactive axonal profiles, was significantly reduced in traumatized animals treated with hypothermia. Because of the importance of diffuse axonal injury in the functional consequences of TBI,⁴¹ these findings emphasize the potential usefulness of this therapy in head-injury patients.

Rewarming Phase

Experimental data have emphasized that the rate of rewarming after a hypothermic period is critical in whether hypothermic protection is demonstrated. In a study in which axonal pathology was targeted for hypothermic intervention, Suerhio and Povlishock reported an exacerbation of traumatically induced axonal injury by rapid post-hypothermic rewarming.⁴² In contrast, posttraumatic hypothermia followed by a slow rewarming period was reported to protect the injured axons. In a related study, Matsushita and colleagues showed that posttraumatic hypothermia combined with slow rewarming was neuroprotective in a model of TBI complicated by a secondary hypoxic insult.⁴³ The modest hypothermia induced in this complicated TBI model with slow but not rapid rewarming significantly reduced overall contusion volume in comparison to normothermic animals. These studies emphasize the importance of the rewarming phase when considering both the experimental and the clinical use of modest hypothermia.

The Importance of Gender

Gender may play an important role in the response of the brain to a variety of insults, including cerebral ischemia and trauma.^44–49 Recently, the significance of gender has been reported after experimental TBI, with female animals showing smaller contusion volumes than corresponding traumatized male animals.⁴⁷ The importance of endogenous sex hormones on this gender difference in vulnerability was also shown in this study; ovariectomized rats did not appear to be protected against TBI, whereas corresponding intact females did. Because of this potentially important gender factor in terms of therapeutic interventions, recent studies have determined whether gender also plays a role in the beneficial effects of modest hypothermia. In a study by Suzuki and colleagues, the importance of gender on the consequences of posttraumatic hypothermia after fluid percussion brain injury was assessed.⁴⁸ Importantly, posttraumatic hypothermia (4 hours at 33° C) did not affect the short-term histologic outcome in intact female rats but significantly reduced contusion volume in ovariectomized rats (Fig. 329-1). In another study, the consequences of posttraumatic hyperthermia were found to be more severe in ovariectomized rats than in intact female or male animals.⁴⁹ These data and others emphasize the potential importance of gender in both the beneficial effects of hypothermic therapy and the detrimental consequences of secondary injury mechanisms such as reactive hyperthermia in the TBI patient population.

FIGURE 329-1 Hematoxylin and eosin–stained paraffin sections 3 days after traumatic brain injury. Contusion areas are outlined. A, Normothermic male animal with a large cortical contusion. C, cortex; E, external capsule; H, hippocampus. B, Hypothermic male animal exhibiting a smaller contusion area than the normothermic male. C and D, Both normothermic and hypothermic female animals, respectively, have smaller contusion areas relative to normothermic males. E, Ovariectomized normothermic animal with a contusion similar in size to that of the normothermic male. F, Hypothermic ovariectomized animal with a decrease in contusion area. All figures are 40×.

(Reprinted from Suzuki T, Bramlett HM, Dietrich WD. The importance of gender on the beneficial effects of posttraumatic hypothermia. Exp Neurol. 2003;184:1017-1026, with permission from Elsevier.)

Mechanisms of Hypothermic Protection

In early studies, profound brain cooling was reported to decrease O₂ consumption and CO₂ production, as well as other indicators of metabolism.^50,51 Thus, the beneficial effects of hypothermic therapy were thought to primarily involve metabolic and energy demands. However, investigative studies over the past decade have shown that mild variations in temperature have profound effects on many injury mechanisms thought to be responsible for irreversible neuronal death and secondary injury mechanisms.⁵² In this regard, variations in ischemic brain injury or TBI have been shown to affect hemodynamic events, excitotoxicity, calcium-dependent intercellular signaling, inflammation and edema, apoptosis, and molecular changes in the postinjured brain. In the area of excitotoxicity, early studies showed that mild hypothermia reduced extracellular levels of the excitatory amino acid glutamate, as well as other neurotransmitters, after brain injury.^24,53–55 In addition to hypothermia affecting neuronal vulnerability, mild cooling was also shown to protect against blood-brain barrier permeability after ischemia and trauma.^56–58 A major mechanism by which hypothermia may confer protection is by reducing deleterious inflammatory events and trauma-induced increases in a number of proinflammatory cytokines that appear to represent important secondary injury mechanisms.^{21,25,26,35,57–62}

Apoptotic cell death has now been shown to also participate in the vulnerability of different cell types after trauma.⁶³ Recent studies have demonstrated that posttraumatic hypothermia can reduce levels of caspase-3, an important initiator of apoptotic cell death, as well as reduce release of cytochrome c.²⁷ The molecular mechanisms regulating these cellular events after trauma have also recently been shown to be temperature sensitive.⁶⁴ In a recent study, hypothermic therapy was shown to selectively reduce specific inflammatory genes believed to be important in secondary injury processes.⁶⁴ Thus, the ability of posttraumatic temperature to affect the acute and more delayed biochemical and genetic responses to injury has expanded our understanding of the complexity of the consequences that temperature may have on pathophysiology and recovery after brain injury.

Clinical Studies

In the early 1960s, profound levels of hypothermia were used in a number of centers as part of the routine treatment of severe TBI.^50,65 By the end of the 1970s, however, the use of hypothermia to treat TBI patients was mainly discontinued because of a number of reasons, including serious side effects such as infectious complications, cardiovascular incidents, and the general difficulty in cooling patients. In addition, laboratory work was just clarifying injury mechanisms that could be targeted with new pharmacologic agents, including barbiturates.

In the 1990s, because of the demonstration that more modest levels of hypothermia improved outcomes in clinically relevant models of TBI, attention was turned to the use of mild hypothermia in several clinical studies.^{11,12,16,18,66,67} In a study of 82 patients with severe head injury, Marion and colleagues (1993) first reported that 62% of patients in the hypothermia group had good outcomes 12 months after injury versus 38% of those in the normothermic group.¹¹

Jiang and colleagues investigated the effects of long-term (3 to 14 days) mild hypothermia therapy (33° C to 35° C) on outcome in 87 patients with severe TBI.⁶⁸ These investigators found that the rate of complications between the normothermic and hypothermic patients was not significantly different and that induced hypothermia markedly reduced intracranial pressure and inhibited hyperglycemia. The importance of cooling duration has been emphasized in both preclinical and clinical investigations. Although short periods of hypothermia may not provide long-term protection, longer periods of cooling appear to lead to improved outcome even months after the treatment has been terminated. Thus, in a recent study, Jiang and colleagues critically assessed the importance of the duration of hypothermia on behavioral outcome after severe TBI.¹⁶ Importantly, patients who were cooled for 5 days did significantly better than those that were cooled for only a 3-day period. Accordingly, future studies need to take into account the fact that in specific clinical cases, a prolonged cooling period may be necessary to achieve the best recovery after severe TBI.

Based on encouraging single-center studies summarized by Polderman in 2008 (Fig. 329-2),¹⁰ a multicenter trial was initiated to test the efficacy of modest hypothermia in a large number of patients.¹⁹ In that study, 392 adult patients with severe trauma were randomly assigned to treatment with hypothermia or normothermia. In contrast to previous clinical studies,^12,18 mortality was reported to be no different in the normothermic and hypothermic groups, and beneficial effects on outcome were not observed. It should be emphasized that several important limitations of this multicenter trial have been identified, including inconsistencies in patient care between the different investigative sites and delay in initiating the hypothermic therapy.⁶⁹

FIGURE 329-2 Clinical trials assessing the effects of hypothermia on neurological outcome in patients with traumatic brain injury and intracranial hypertension.

(Reprinted from Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008;371:1955-1969, with permission from Elsevier.)

A new meta-analysis of hypothermia clinical trials was recently reported in the third edition of the guidelines for the management of severe TBI in 2007.⁷⁰ This analysis included 354 patients assigned to hypothermia groups and 340 patients assigned to normothermia groups from six clinical trials for which sufficient data were available.^{11,18,68,69,71,72} Although the risk for mortality was not significantly different between the hypothermic and normothermic groups, hypothermia was associated with a 46% increased chance of a good outcome. Currently, although hypothermic treatment is an experimental therapy and not considered a standard of care for patients with severe TBI, it may be considered an option for patients with refractory intracranial hypertension by clinicians experienced in its use. Finally, based on prospective results from the published multicenter trial on hypothermic treatment, a new hypothermia clinical trial focusing on adult patients younger than 45 years with severe TBI has been initiated. This trial emphasizes early cooling and more consistent management of the patients from various centers. A demonstration that hypothermia provides clinically relevant benefits in a large multicenter trial will be critical for successful translation of this experimental therapy to large numbers of severely injured patients.

Methods of Cooling

Recent technical advances in the development of cooling devices have improved the ability to induce modest hypothermia quickly in patients, as well as to maintain cooling levels for several days within relatively restricted ranges.^73–81 In addition, these new approaches allow one to rigorously control the rewarming phase, which now appears to be so critical in hypothermic treatments. Although selective head cooling methodologies have been attempted in some patient populations, whole-body cooling is currently being tested in a number of clinical studies involving patients with neurological insults. In pediatric patients, for example, selective head cooling may be most advantageous to limit the potential adverse effects of systemic hypothermia.

Strategies that include surface cooling and the use of endovascular catheters appear to be advantageous in specific clinical conditions. The intravenous infusion of ice-cold fluids is a commonly used method to initiate early cooling, even in the out-of-hospital environment.^75,82,83 In situations in which a central line is not required, surface cooling may be satisfactory in inhibiting periods of reactive hyperthermia, as well as in producing a mild hypothermic state.⁸¹ In contrast, intravascular catheters may have the advantage of reducing temperature in some patient populations at a faster rate and may provide more critical control over the range of temperatures during a prolonged cooling period.^77–80 Whether surface or endovascular cooling is used will depend on the patient population being treated and the experience of the treating physician.

Pediatric Traumatic Brain Injury

The potential beneficial effects of modest hypothermia are also being evaluated in the pediatric patient population.^84–86 Preclinical data support the concept that modest hypothermia may be protective in models of pediatric TBI. Thus, some studies have been initiated to test the efficacy of cooling in the pediatric TBI population.^84–86 In particular, temperature regulation and the use of hypothermia in initial case studies of small numbers of patients provided encouraging results. However, a recently published phase III multicenter international study involving the use of moderate hypothermia (32.5° C for 24 hours) initiated within 8 hours in children and adolescents with severe TBI was reported to be negative.⁸⁶ Discussions in the published manuscript and scientific literature have suggested potential shortcomings of this study, including delay in the initiation of treatment, critical care management issues, and problems with the rewarming procedure. Thus, additional work is required to determine the efficacy of this treatment in this specific TBI patient population.

Posttraumatic Hyperthermia

A high percentage of patients with neurological injuries have periods of reactive hyperthermia at variable points in time after the primary injury.^{10,32–35,75–77} Experimental studies have emphasized the detrimental effects of posttraumatic hyperthermia in terms of mortality and morbidity after TBI.^30,35 Mechanistic studies have indicated that elevations in temperature after injury aggravate many of the pathologic mechanisms thought to participate in neuronal vulnerability and long-term behavioral deficits.^21,30,49,87 Recently, several clinical studies have emphasized the importance of fever in extending hospital stay and worsening neurological outcome in patients with different neurological insults, including brain trauma.^33,34,88,89 Another important observation is that dissociations between brain temperature and core temperature may occur in selected patients after head injury.^90–92 In some patients, central nervous system temperature may be 1° C or 2° C higher than that being registered from the bladder or other organs from which systemic temperature readings are being monitored.^90,91 Thus, it is critical that steps be aggressively taken to inhibit or at least minimize refractive hyperthermia.

Conclusion and Future Directions

The use of hypothermia as a treatment strategy to target neuronal injuries has a rich history. Within the last 15 years, however, progress has been made regarding the use of more modest levels of hypothermia in both experimental and clinical studies. These investigations have provided a solid foundation with which to continue to evaluate the use of hypothermia in various patient populations and to determine factors that are important in providing the best benefits of this therapy. Indeed, certain factors, including appropriate patient populations, injury severity, age, gender, and clinical management issues, appear to play a major role in determining the efficacy of this complicated yet exciting treatment paradigm. In addition, questions remain regarding the therapeutic window of this treatment, how long cooling should be continued, and factors related to the rewarming phase. Although single-site clinical studies have appeared to show safety as well as efficacy with modest hypothermia treatment in restricted TBI populations, multicenter phase III trials have yet to show benefits in large numbers of patients treated at different locations. Thus, the treatment remains experimental, and future studies must continue to evaluate how best to use this treatment strategy in severely injured patients.

Future studies will also continue to evaluate and determine what specific cooling devices work best for a particular patient population. The addition of antishivering agents and commonly used sedatives needs to be explored to provide the necessary comfort and safety to patients being cooled in an awake state. Because combination therapies are currently being discussed in the trauma literature, it will be important to determine what pharmacologic agents can be combined with mild cooling to potentially produce synergistic benefits to the patient. Only through continued investigations of this potentially important therapy and the design of well-controlled clinical trials will therapeutic hypothermia be successfully translated to the general TBI patient population.