Therapeutic hypothermia and targeted temperature management for traumatic brain injury: Experimental and clinical experience

Abstract

Traumatic brain injury (TBI) is a worldwide medical problem, and currently, there are few therapeutic interventions that can protect the brain and improve functional outcomes in patients. Over the last several decades, experimental studies have investigated the pathophysiology of TBI and tested various pharmacological treatment interventions targeting specific mechanisms of secondary damage. Although many preclinical treatment studies have been encouraging, there remains a lack of successful translation to the clinic and no therapeutic treatments have shown benefit in phase 3 multicenter trials. Therapeutic hypothermia and targeted temperature management protocols over the last several decades have demonstrated successful reduction of secondary injury mechanisms and, in some selective cases, improved outcomes in specific TBI patient populations. However, the benefits of therapeutic hypothermia have not been demonstrated in multicenter randomized trials to significantly improve neurological outcomes. Although the exact reasons underlying the inability to translate therapeutic hypothermia into a larger clinical population are unknown, this failure may reflect the suboptimal use of this potentially powerful therapeutic in potentially treatable severe trauma patients. It is known that multiple factors including patient recruitment, clinical treatment variables, and cooling methodologies are all important in yielding beneficial effects. High-quality multicenter randomized controlled trials that incorporate these factors are required to maximize the benefits of this experimental therapy. This article therefore summarizes several factors that are important in enhancing the beneficial effects of therapeutic hypothermia in TBI. The current failures of hypothermic TBI clinical trials in terms of clinical protocol design, patient section, and other considerations are discussed and future directions are emphasized.

Keywords: Clinical trials; fever; pathophysiology; targeted temperature management; therapeutic hypothermia; traumatic brain injury.

Figure 1

Bar graph of mean + standard error of the mean number of cortical necrotic neurons per microscopic field (1.65 mm²) at seven coronal levels. Data taken from normothermic (clear bars) and posttraumatic hypothermic (black bars) rats. (*, significantly reduced compared to normothermia. Bar graph of mean + standard error of the mean contusion area from normothermic (clear bars) and posttraumatic hypothermia (black bars) rats at 6 coronal levels (*, significantly reduced compared to normothermia). Reprinted from Acta Neuropathologica, Posst-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat, Vol 87, 1994, pages 250-258, Dietrich WD, Alonso O, Busto R, Globus, MY and Ginsberg MD with permission of Springer

Figure 2

Clinical trials assessing the effects of hypothermia on neurological outcome in patients with traumatic brain injury and intracranial hypertension. Reprinted from The Lancet, Vol 371, Polderman KH, Induced hypothermia and fever control for prevention and treatment of neurological injuries, pages 1955-1969, 2008, with permission from Elsevier

Figure 3

Effects of temperature manipulations on water maze performance. Analysis of escape latency on day 4 of testing 2 weeks postinjury. Hyperthermic mild traumatic brain injury animals had significantly longer escape latencies as compared to sham animals or hyperthermic/normothermic mild traumatic brain injury animals. *P < 0.05, one-way ANOVA and Tukey's post hoc analysis. Reprinted from Experimental Neurology, Vol 263, Emergence of cognitive deficits afer mild traumatic brain injury due to hyperthermia, pages 254-262, 2015, with permission from Elsevier

Figure 4

HPI 201-induced hypothermia attenuates apoptosis. Activation of the apoptotic gene caspase-3 was detected in the traumatic brain injury (a and b). At 24 h posttraumatic brain injury, the caspase-3 levels declined to the sham control levels in the HPI 201 group. There was also an observed significant increase of the antiapoptotic gene Bcl-2 in HPI 201-treated animals (c). #P < 0.05 versus sham; *P < 0.05 versus saline. Mean ± standard error of the mean n = 6–8 per group. Reprinted from Experimental Neurology, Vol 267, Gu X, Wei ZZ, Espinera A, Lee JH, Ji X, Dix TA, and Yu SP, Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats, Pages 135-142, 2015, with permission from Elsevier