Current Concepts of Hypothermia in Traumatic Brain Injury

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CHAPTER 329 Current Concepts of Hypothermia in Traumatic Brain Injury

This chapter reviews evidence for the use of therapeutic hypothermia in the treatment of traumatic brain injury (TBI). During the past decade, encouraging results have been reported in clinically relevant animal models of TBI; specifically, it has been shown that modest levels of cooling for various periods after trauma can improve behavioral and histologic outcomes in a number of laboratory settings.¹^–⁸ Importantly, some of these results have been successfully translated to the clinic, and multiple clinical studies have reported the beneficial effects of mild cooling in head-injured patients.⁹^–¹⁸

The results accumulated from many experimental and clinical studies indicate that hypothermic therapy may have a place in the standard care of severely head injured patients. However, controversies still exist regarding the efficacy of hypothermia, as well as the mechanisms by which cooling may protect the brain.¹⁹ Thus, there is a continued need to investigate the usefulness of mild cooling in both animal models and patients with severe TBI.

In reviewing the published data on the use of hypothermia, it is clear that relatively small variations in pretraumatic or posttraumatic brain temperature can critically alter the cellular, biochemical, and molecular responses of the brain to injury.²⁰^–²⁹ Thus, laboratory investigations have reported that this treatment affects multiple pathologic mechanisms thought to be important in trauma-induced cell death and the development of functional deficits. Indeed, one of the advantages of hypothermia is that cooling targets several of the major injury mechanisms believed to be important in the pathophysiology of TBI.

In addition to the importance of mild reductions in temperature on outcome after trauma, experimental and clinical investigations have emphasized the potentially detrimental effects of mild fever and brain hyperthermia on outcome after trauma.³⁰^–³⁵ Experimental studies first demonstrated the detrimental effects of mild hyperthermia in animal models of TBI and emphasized the importance of maintaining normothermia in head-injured patients.³⁰ Most recently, clinical studies have also reported that patients experiencing periods of hyperthermia in the intensive care unit may demonstrate worse outcomes after various neurological injuries.^33,³⁴ Because at the current time no therapeutic interventions have been successfully translated to head-injured patients that significantly improve functional outcome,^36,³⁷ it is important that treatment strategies including therapeutic hypothermia and the inhibition of reactive hyperthermia continue to be discussed and evaluated in the experimental and clinical TBI literature.

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