In what may be the largest study to date of the effect of hypothermia instituted early in patients with traumatic brain injury, an international team of researchers from six countries found no advantage to cooling treatment.
“It will be hard to justify a further study unless major new evidence comes to light. At this stage, we cannot recommend hypothermia,” wrote Peter Cameron, MBBS, MD, the academic director of the Alfred Hospital Emergency and Trauma Centre in Melbourne, Australia, a professor of emergency and divisional health services research, and an author of the report. (JAMA. 2018;320:2211; http://bit.ly/2Tj4f9G.)
The multicenter, randomized trial took place in six countries and recruited 511 severe traumatic brain injury patients out-of-hospital and in emergency departments. Patients were followed for six months. A total of 266 patients were randomized to hypothermia and 245 to normothermic management. The hypothermia group was targeted to receive early hypothermia of 33°C to 35°C for at least 72 hours and as long as seven days if intracranial pressures were elevated. Rewarming was gradual. Temperature was managed in both groups for seven days. All other care was ceded to the treating physicians.
A total of 466 of the 511 patients completed the primary outcome evaluation (favorable neurologic outcomes or independent living with a Glasgow Outcome Scale-Extended Score of 5 to 8.) One-hundred-seventeen patients (48.8%) in the hypothermia group had favorable neurologic outcomes at six months and 111 (49%) in the normothermic group. Rates of pneumonia were 55 percent in the hypothermic group and 51.3 percent in the normothermic group. Rates of increased intracranial bleeding were 18.1 percent in the hypothermic group and 15.4 percent in the normothermic.
Death, a secondary outcome, occurred in 54 patients in the hypothermic group and in 44 patients in the normothermic group, a finding that did not achieve statistical significance. “Results were similar for time to death,” the authors wrote.
First author D. Jamie Cooper, MD, the director of the Australian and New Zealand Intensive Care Research Centre at Monash University in Melbourne, wrote in an email to EMN that the POLAR trial was definitive that prophylactic hypothermia for patients with severe traumatic brain injury (TBI) was of no benefit, even when the POLAR trial design gave hypothermia the best possible chance to improve patient outcomes. “These features included commencing hypothermia at the accident site when possible by paramedics or otherwise as early as possible in the ER,” he wrote. “Further, prophylactic hypothermia had complications of bradycardia, hypotension, increased pneumonia, and longer times in ICU.”
Ineffective and Even Harmful
Interest in hypothermia began more than a decade ago when animal studies showed that cooling the brain very shortly after traumatic brain injury led to improved function, wrote Dr. Cooper. Translating that benefit to humans, however, did not prove successful, perhaps because human cannot be cooled as rapidly after injury as animals. Concurrent injuries can require time-consuming treatment or diagnostic tests.
“Although POLAR commenced cooling very rapidly, it took patients 10 hours to reach the coolest (33°C) of the two temperature targets,” he wrote. “It could also be that maintaining normal temperature in the POLAR control patients was sufficient alone.” He noted that the EUROTHERM trial from the United Kingdom and Europe found that inducing hypothermia in the intensive care unit in patients with brain swelling from injury was ineffective and even harmful in some cases.
Approximately 50 percent of POLAR patients were started on cooling in the out-of-hospital setting by paramedics using cold intravenous saline and patient exposure. “Early commencement of cooling was one of the trial aspects, aiming to maximize benefit from hypothermia therapy,” Dr. Cooper wrote. “Patients overall in POLAR were successfully cooled to the first hypothermia target of 35 degrees C in just 2.5 hours. However, even this speed of induction is much slower than the old laboratory studies, which cooled rapidly, straight after the brain injury.”
Half of patients in the hypothermia arm of the study began cooling in the field and the other half in the emergency department, but the study was not powered to determine if there were differences between the two groups, wrote Dr. Cameron, who is also faculty in the School of Public Health and Preventive Medicine at Monash University.
To date, most neuroprotective agents tried in this group of patients have proven ineffective. “There is nothing on the horizon that appears promising for patients with neurological injury,” Dr. Cameron wrote. “It is likely that most of the damage is done at the time of injury. Our job is to limit further damage—hemodynamics, oxygenation, temperature control, intracranial pressure control. All are good ICU care.”
In an accompanying editorial, Drs. Annemarie Docherty, John Emelifeonwu, and Peter J.D. Andrews, all of the University of Edinburgh in the United Kingdom, wrote, “Why has hypothermia failed in translation from bench to bedside? Is it lack of benefit from cooling on neurology recovery related to the larger (human) size or due to differences in gyrencephalic (human) compared with lissencephalic (rodent) brains or perhaps due to an imbalance in co-interventions between the two groups?”
No study to date has been able to answer those questions, the authors wrote. They concluded that POLAR was a well-designed study and that “the findings of this trial along with other data demonstrate that there is no role for the initiation of hypothermia during the acute phases of TBI management. This important finding should now be incorporated into relevant guidelines and adopted in emergency departments and intensive care units.”
Ms. SoRellehas been a medical and science writer for more than 40 years, previously at the University of Texas MD Anderson Cancer Center, the Houston Chronicle, and Baylor College of Medicine. She has received more than 60 awards, including the Texas Human Rights Foundation Award. She has been a contributor to EMN for more than 20 years.