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This large, prospective, randomized, multi-institutional study was terminated early after interim analysis failed to demonstrate any significant improvement in survival or functional level in the group subjected to hypothermia. A total of 392 adult patients with severe closed head injury (Glascow Coma Scale score < 8, but > 3) were randomized to be managed with hypothermia (a body temperature of 33°C for 48 hours), initiated within 6 hours following injury, or normothermia. Hypothermia was continued for 48 hours and rewarming was allowed on the third day. Patients were excluded if they had another life-threatening organ injury, were hypoxemic or in persistent shock following initial resuscitation, were pregnant, or had any severe, preexisting organ disfunction. Patients presenting with hypothermia at entry that were randomized to the normothermia treatment arm were allowed to warm spontaneously, not actively rewarmed. The primary outcome measure was functional status at 6 months.
Surface cooling was used to achieve the desired body temperature. Patients were randomized on average 4 hours after injury, and achieved target temperature within 8.4 (± 3.0) hours following injury. Intracranial pressure (ICP) was measured in all patients, and elevations treated. Patients with ICP greater than 20 mm Hg were treated sequentially with vecuronium, ventricular drainage of CSF, hyperventilation (keeping the PaCO2 > 30 mm Hg), mannitol (keeping the osmolality about 315), and barbiturate coma. Cerebral perfusion pressure was maintained at more than 70 mm Hg, using vasopressors if necessary. Hydration was kept normal, as judged by renal function and urinary output, and all patients received enteral or parenteral nutrition beginning within 48 hours in the normothermic group and 72 hours in the hypothermia group. All patients received sedation with morphine (5-10 mg/h) and seizure prophylaxis with phenytoin. Vecuronium was used to prevent shivering in the hypothermia group, and also in the control group, if needed, to facilitate mechanical ventilation.
The two groups of patients were well matched for age (31 years), severity of neurologic injury, trauma score (28), and incidence of prehospital hypoxemia and hypotension. Hypothermia patients required more vasopressors for more hours, less vecuronium, more fluids, and experienced more days with complications compared to the normothermia patients. During the initial 3 days, the hypothermic group experienced a slightly lower mean arterial blood pressure (92 vs 95 mm Hg), had fewer patients with an ICP greater than 30 mm Hg, and had fewer patients requiring aggressive ICP treatment. On rewarming, these differences between the groups were reversed (probably due to hyperperfusion from rewarming in the treatment group).
Functional status was not different in the 2 patient groups when evaluated by blinded investigators at 6 months: 28% of the hypothermic patients and 27% of the normothermic patients were dead, and 57% of both groups were either severely disabled or dead. (Clifton GL, et al. N Engl J Med. 2001;344:556-563.)
Comment by Charles G. Durbin, Jr, MD, FCCM
The role of hypothermia in brain protection is not clear. This negative study follows several smaller trials which suggested better functional outcome from closed head injury at 3 and 6 months following injury when patients were treated with mild hypothermia for 48 hours following injury.1 This study was performed in a prospective, randomized fashion and the data were analyzed in an "intent to treat" fashion. Other treatment measures related to brain injury were standardized and applied according to protocols.
What is clear from this study is that mild hypothermia results in a lowering of blood pressure and ICP in brain injured patients. This is consistent with previous clinical work. It resulted in the need to use vasopressors in more patients and to administer larger volumes of fluids. There was less use of mannitol and muscle relaxants in the hypothermic patients. It is possible that these interventions, potentially adversely affecting outcome, balanced out any benefits and resulted in no difference between the two groups.
This paper raises several important issues. When the hypothermic patients were rewarmed on the third treatment day, a significant percentage of them experienced dramatically elevated ICPs, requiring aggressive treatment. It’s possible that continued hypothermia or more gradual warming may have benefited these unstable patients, and a longer period of hypothermia, or a patient-response directed arm of treatment, should be tested.
There were some patients in this study who presented with initial body temperatures less than 35°C. Among these patients, those who were randomized to the normothermic group were allowed to warm spontaneously. In previous studies, such patients were actively rewarmed; this may have been detrimental and contributed to a worse outcome in the normothermia group. In this study, patients initially randomized to the hypothermic group tended to experience a better outcome than those hypothermic patients treated in the normothermic group: 61% of the former had a poor outcome compared to 78% of those treated to normothermia (P < .09.) The effect of maintaining hypothermia in initially hypothermic patients merits study.
There are many questions remaining about the use of hypothermia in brain injured patients. This well-designed and executed study suggests that hypothermia induced to 33°C within 6 hours of injury and continued for 48-72 hours is unlikely to have a dramatic improvement in neurologic functional outcome. More studies of other protocols and in different subgroups of patients are necessary to fully identify any benefit or lack of benefit of this therapy. Hypothermia use was associated with a lower incidence and less severe elevations in ICP, but required more aggressive cardiovascular support to maintain cerebral perfusion pressure.
1. Clifton GL, et. al. Neurotrauma. 1993;10:263-277
2. Marion DW, et al. N Engl J Med. 1997;336:540-546.