Hypothermia in Traumatic Brain Injury

An increased in temperature increased cerebral metabolism, oxygen requirements, CBF and ICP. Fever has been demonstrated to increase brain injury in animal models. In patients with raised ICP, a raised temperature should therefore treated aggressively (using cooling blankets, cool water, cool intravenous fluids, fans and antipyretic medications) and any evidence of infection identified early and treated with appropriate antibiotics. Fever can make an existing neurological dysfunction more apparent and may worsen an ongoing dysfunction.

It is postulated that fever may worsen ischaemia by following mechanisms:
1. Neurotransmitter and oxygen free radical production.
2. BBB failure.
3. Damaging depolarizations in the ischaemic penumbra.
4. Impaired recovery energy metabolism
5. Cytoskeletal proteolysis

Hypothermia has been known to offer protection for years. First reported as a treatment for brain injury in the 1950s. Currently therapeutic hypothermia is used in post cardiac arrest in particular VF/VT arrest and is supported by two randomized clinical trials  (in Europe and Australia).

In traumatic brain injury, the mechanism of ICP reduction in hypothermia is unknown but may be due to reduction in intracranial blood volume secondary in cerebral vasoconstriction or to alteration in metabolism. Induced hypothermia has been a proposed treatment fo TBI based upon its potential to reduce ICP as well as to provide neuroprotection and prevent secondary brain injury.

At present, there is no evidence that hypothermia  therapy should be used as primary neuroprotective strategy  in patients with severe traumatic brain injury.

1. A systemic review of 12 randomized controlled trials of mild to moderate hypothermia (32-33C) following TBI noted a small but significant decrease in the risk of death or poor neurologic outcome among more than 500 patients treated with hypothermia. Outcomes were influenced however by depth and duration of hypothermia as well as rate of rewarming after discontinuation of hypothermia. Nonetheless, the evidence is not yet sufficient to recommend routine use of therapeutic hypothermia for TBI outside of research settings.
JAMA 2003.

2. Lack of effect of induction of hypothermia after acute brain injury. NEJM 2001. Clifton GL et al. This study which evaluated the efficacy of hypothermia in head injuries was halted after the enrolment of 392 patients because the treatment was ineffective. Cooling patients to 33C within 8 hours after injury and maintaining hypothermia for 48h were not effective in improving the clinical outcome at 6 months and patients older than 45 years of age had a poorer outcome.

3. NABIS H II Trial - Very early hypothermia induction in patients with sever brain injury (the National Acute Brain Injury Study Hypothermia II): a randomized trial.
Prof Guy L Clifton et al. The Lancet Neurology, Volume 10, issue 2, February 2011.

Background: The inconsistent effect of hypothermia treatment on severe brain injury trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury.

Methods: It was a randomized multicentre clinical trial of patients with severe brain injury who were enrolled within 2-5 hours of injury at 6 sites in US and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomized to hypothermia (cooled to 35C) or normothermia. After trauma assessment was completed, the hypothermia group were cooled to 33C for 48h and then gradually rewarmed. Primary outcome was the Glasgow outcome scale score at 6 months.

Findings: Enrolment occurred over 4 years and the trial was terminated early due to suggestion of futility. Follow-up was from June 2006 to December 2009. 232 patients were intially randomized a mean of 1.6h after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia froup and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35C for the 52 patients in the hypothermia group was 2.6h and to 33C was 4.4h. Outcome was poor (severe disability, vegetative state or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (RR 1.08, 95% CI 0.76-1.53; p=0.67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1.30, 95% CI 0.58-2.52; p=0.52).

Interpretation
This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.
Given the uncertainties surrounding its appropriate use, therapeutic hypothermia treatment should be limited to clinical trials or to patients with elevated ICP refractory to other therapies.