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Hypothermia for Acute Brain Trauma
Abstract & Commentary
By Christoph P. Hofstetter, MD, PhD, and Roger Härtl, MD. Dr. Hofstetter is Neurosurgery Resident, Brain and Spine Center, Weill Cornell Medical College. Dr. Härtl is Leonard and Fleur Harlan Clinical Scholar in Neurological Surgery, Associate Professor, Neurological Surgery, Weill Cornell Medical College. Dr. Hofstetter reports no financial relationships relevant to this field of study. Dr. Härtl reports that he is a consultant for Synthes and Brainlab.
This article originally appeared in the April 2011 issue of Neurology Alert. It was edited by Matthew E. Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Interim Chair and Neurologist-in-Chief, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York Presbyterian Hospital, and Dr. Beal is Anne Parrish Titzel Professor, Department of Neurology and Neuroscience, Weill Cornell Medical Center. Drs. Fink and Beal report no financial relationships relevant to this field of study.
Synopsis: Therapeutic hypothermia does not result in improved outcomes in patients with traumatic brain injury.
Source: Clifton G, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): A randomised trial. Lancet Neurol 2011;10:131-139.
The first therapeutic use of hypothermia dates back to the battlefields during the French invasion of Russia in 1812. Then, Laron Larrey, the surgeon of Napoleon Bonaparte, used ice packs to numb injured limbs prior to amputation on the field. More than a hundred years later, first reports proposed a potential benefit of induced hypothermia on neurological outcome.1-4 However, given the undefined patient cohorts, variability of depth and duration of hypothermia treatment and the lack of control groups, the clinical value of these early series remained limited. In 1956, Rosomoff provided the first experimental evidence demonstrating neuroprotective properties of hypothermia.5 He showed that severe hypothermia (22-24 degrees) reduced the amount of infarcted brain tissue and improved neurological outcomes following occlusion of the middle cerebral artery in dogs.5 It is believed that beneficial effects of hypothermia on neurological outcome are due to reduction of free radical production,6 decrease of excitatory amino-acid release,7 and limitation of blood brain barrier disruption8 with concomitant decrease of brain edema.9
To date, the use of hypothermia for treatment of traumatic brain injury remains controversial.10 The Brain Trauma Foundation Guidelines from 2007 found level III evidence that prophylactic hypothermia was not significantly associated with decreased mortality when compared to normothermic controls.11 However, preliminary evidence suggested that better results could be achieved if the target temperature was maintained for > 48 hours. The National Acute Brain Injury Study: Hypothermia II (NABIS:HII) was initiated because an earlier multicenter trial of hypothermia for traumatic brain injury suggested a tendency toward better outcomes in patients who were hypothermic at the time of admission and continued to be cooled compared to patients maintained in normothermia (p = 0.09).12 Thus, the authors suggested that hypothermia may be more efficacious when initiated very early following the trauma. The current randomized, multicenter trial with very early hypothermia (NABIS:HII) included 97 patients with severe traumatic brain injury (GCS < 8) without life-threatening associated injuries and without pronounced hypotension. The target temperature was reached in 4.4 hours and patients were re-warmed 48 hours later. After an interim analysis, the study was terminated with the conclusion that hypothermia did not improve neurological outcome, defined as GSC at 6 months or reduce mortality. However, the conclusions are limited due to the premature termination of the study.
The current trial also reports an increased incidence of intracranial hypertension in patients treated with hypothermia. This occurrence was detected mainly during and following re-warming of patients treated with hypothermia. Rebound intracranial hypertension following short periods (2 days) of hypothermia has been reported in several studies.13-15 The pathophysiology underlying raised ICP in patients with traumatic brain injury has been studied in great detail. Cerebral swelling and brain edema peak at 48 hours after traumatic brain injury.16 Re-warming at this time may increase blood flow in the internal carotid arteries and exacerbate intracranial pressure.14 Thus, in the present clinical trial, patients treated with hypothermia required significantly more therapeutic interventions to control elevated ICP, compared to patients treated with normothermia. One of the interventions performed was hyperventilation, which reduces ICP by constriction of cerebral arteries leading to decreased cerebral blood flow17 and has been associated with poor outcome in patients with traumatic brain injury.18 This may have contributed to the tendency for worse outcome in patients with diffuse injuries treated with hypothermia. In a subgroup analysis, patients with craniotomies treated with hypothermia had better outcomes compared to patients with craniotomies in the normothermia cohort (p = 0.02). Although the finding that hypothermia may be beneficial for patients following craniotomy is intriguing, the numbers in this subgroup were too small to make any definite conclusions. Low patient numbers were due to the early termination of the study. Slow patient recruitment and financial constraints prompted the National Institutes of Health to perform the interim analysis after only 97 patients were recruited, instead of the 120 patients for which the protocol planned.
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