By Halinder S. Mangat, MD
Assistant Professor of Clinical Neurology,
Weill Cornell Medical College

Dr. Mangat reports no financial relationships relevant to this field of study.

Synopsis: Hypothermia therapy is effective after severe traumatic brain injury for patients ages 50 years and younger. However, mortality was increased in patients treated with hypothermia who had diffuse injury with swelling on CT.

Source: Suehiro E, et al. Diverse effects of hypothermia in patients with severe traumatic brain injury based on the computed tomography classification of the Traumatic Coma Data Bank. J Neurotrauma 2015;32:353-358.

The authors studied the effect of hypothermia after severe traumatic brain injury (TBI) in a secondary analysis of data collected from 2002-2008 in a prospective, randomized trial of 135 patients with severe TBI. They utilized CT classification of brain injury based on the Traumatic Coma Data Bank (TCDB) to identify subgroups that might derive benefit.1 Although patients undergoing therapeutic hypothermia were targeted to 32º-34º C, patients in the fever-control group were cooled to 35.5º-37º C. Cooling was initiated within 2 hours after TBI and maintained for at least 72 hours. Sedation, analgesia, and paralytics were used for the temperature-control phase. Primary outcomes were the Glasgow Outcome Scale (GOS) and mortality at 6 months after injury.

Results showed that patients 50 years of age with evacuated mass lesions who underwent therapeutic hypothermia had a greater chance of having a favorable outcome than those who only had fever control (77.8% vs 33.3%), whereas patients with diffuse injury and swelling had higher mortality with therapeutic hypothermia.

Commentary

The authors conducted a secondary analysis of a prospective trial utilizing the TCDB CT classification to study the benefits of hypothermia. The results are consistent with those from previous small studies.2,3 Although the results in earlier studies were suggestive of these findings, in this study cohort, they are statistically significant. However, these are still preliminary data and the study was not adequately powered to make firm conclusions regarding treatment recommendations. The conclusions need to be fully validated in a larger prospective cohort. Although these data are encouraging, this is by no means the first study showing encouraging benefits of hypothermia after TBI. The authors have also included patients with “moderate disability” as a good outcome, and this may not stand scrutiny in a larger cohort with a more rigid definition of “good outcomes.” Age > 45 years was previously shown to be associated with poor outcome after hypothermia.4 Although the current study enrolled patients up to 69 years of age, data are only reported for those 50 years or less. No reasons are provided for failure to report the data on older patients.

The finding that patients with evacuated mass lesions had significant benefit may be related to an ischemia-reperfusion type of brain injury that follows formation and evacuation of a mass lesion, including deformation of midline structures. Hypothermia has been shown to be effective in this type of brain injury as evidenced by benefit of hypothermia in patients after cardiac arrest. The mechanism of injury in diffuse brain injury with edema is characterized by axonal injury and, hence, the difference in effect in this subgroup.

In this study, comparison is made between the effects of hypothermia and fever control. The target temperature for the latter group was 35.5º-37º C. Therefore, this is not merely fever-control but may be classified as mild hypothermia when temperature of 35.5º C is reached (as on day 3). With this temperature target, adverse effects of cooling can be experienced due to the target temperature’s proximity to the shivering threshold of 35.7º C.5 The use of paralytics and how shivering was controlled are not detailed. The occurrence of shivering may contribute to significantly increased oxygen consumption and may affect brain metabolism. Studies are underway to explore this; shivering effects should be kept in mind for the planning of future trials.

The choice of temperature target may be important since more recent data suggest that there is no added benefit of therapeutic hypothermia as compared to fever control alone (36º C) in improving outcomes after cardiac arrest: both mortality and cognitive impairment.6,7 However, the pathophysiology is not the same in cardiac arrest and TBI, and there may well be different results in patients with TBI. This underscores the importance of having a fever-control arm, in addition to a “no intervention” control arm, in future trials.

Although the evidence so far has suggested no benefit from hypothermia in patients suffering from severe TBI, these pilot data, along with data from subgroup analysis of previous trials, suggest a possible role for hypothermia in patients with surgical mass lesions. The design of future trials will be crucial to their success, to avoid adding to the existing list of negative Phase 3 trials in TBI. A widely accepted standard for classifying patients by imaging, as well as inclusion of patients 50 years of age, will help to clarify results.

References

  1. Suehiro E, et al. Diverse effects of hypothermia in patients with severe traumatic brain injury based on the computed tomography classification of the Traumatic Coma Data Bank. J Neurotrauma 2015;32:353-358.
  2. Clifton GL, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): A randomized trial. Lancet Neurol 2011;10:131-139.
  3. Clifton GL, et al. Early induction of hypothermia for evacuated intracranial hematomas: A post-hoc analysis of two clinical trials. J Neurosurg 2012;117:714-720.
  4. Clifton GL, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556-563.
  5. Mokhtarani M, et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth Analg 2001;93:1233-1239.
  6. Nielsen N, et al. Targeted temperature management at 33º C versus 36º C after cardiac arrest. N Engl J Med 2013;369:2197-2206.
  7. Lilja G, et al. Cognitive function in survivors of out-of-hospital cardiac arrest after targeted temperature management at 33º C versus 36º C. Circulation 2015;131:1340-1349.