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.

Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

“…In reference to potential therapeutic interventions, targeted temperature management and therapeutic hypothermia after moderate and severe TBI have been evaluated in multiple randomized controlled trials (RCTs) with inconsistent results [40,41]. In contrast, preclinical translational findings have been encouraging and have provided evidence that cooling the brain after TBI reduces secondary injury mechanisms that contribute to histopathological abnormalities and functional deficits [42].…”

High Quality Targeted Temperature Management (TTM) After Cardiac Arrest

“…Importantly, the significant improvement in the clinical management of cardiac arrest patients (including early coronary angioplasty, standardized hemodynamic and ventilatory targets, avoidance of early withdrawal of lifesustaining therapies) between the early trials [4,5] and the "TTM trial" [8] may in part explain the blunted effects of TTM at 33°C in this study. Finally, the enthusiastic results supporting the effectiveness of TTM in experimental cardiac arrest [12] may not be directly translated in humans because the animals used in these models do not have comorbidities and/or underlying cardiac disease; resuscitation is standardized and cooling is immediate; the brain size is smaller; and some measured outcomes only included histological lesions and/or biomarkers of brain injury, which cannot reflect "cognitive function" as assessed in human studies.…”

Selective Brain Cooling Reduces Motor Deficits Induced by Combined Traumatic Brain Injury, Hypoxemia and Hemorrhagic Shock

“…Extending the cooling duration beyond the acute phase might improve long-term outcomes. Clinically, TBI patients are often cooled for a period of 24 h, up to several days, after injury with the core temperature targeted at 33–36°C ( 33 ). Yet it is both technically and logistically challenging to reproduce these clinical paradigms in the laboratory.…”

“…The rate of rewarming following therapeutic hypothermia was suggested to be an important factor in its success or failure. Slow progressive rewarming optimizes the benefits of cooling whereas rapid active rewarming aggravates tissue damage leading to worse outcomes after TBI ( 31 , 33 , 41 ). In the current study, the animals were allowed to rewarm spontaneously, and it typically takes about 30 min for the rat brain to return back to baseline temperature.…”