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Patients with Traumatic Brain Injury Do Not Benefit from Prophylactic Hypothermia, Large Study Finds

Article In Brief

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Questions remain as to whether the findings will find their way into practice.

The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury–Randomized Clinical Trial did not show benefit from prophylactic hypothermia, and also found that patients who received the therapy were more likely to develop pneumonia or intracranial bleeding than those who did not. Independent commentators suggest the findings should be incorporated into practice guidelines for managing severe brain injury.

Prophylactic hypothermia for patients with severe traumatic brain injury (TBI) does not improve neurologic outcomes at six months, according to a large randomized, controlled trial that may finally help settle the debate over the therapy.

Animal models of TBI had suggested that hypothermia provides neuroprotection in the aftermath of brain injury, but several clinical trials have failed to show any benefits. Researchers were hoping that this latest trial, in which hypothermia was used prophylactically, would turn in favorable results because it was reasoned from animal studies that early cooling might prevent further brain damage from occurring. The so-called Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury–Randomized Clinical Trial (POLAR-RCT) study did not show benefit from prophylactic hypothermia, and also found that patients who received the therapy were more likely to develop pneumonia or intracranial bleeding than those who did not.

An editorial that accompanied the December 4 report in JAMA noted that “the findings of this trial, along with other data, demonstrate that there is no role for 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,” said the lead author of the editorial, Peter J.D. Andrews, MD, MBChB, of Western General Hospital in Edinburgh, and his colleagues. Dr. Andrews co-authored a previous trial called Eurotherm3235 that found hypothermia for elevated intracranial pressure resulted in worse neurologic outcomes and a greater risk of death for patients.

The authors of the new multicenter study had hoped immediate cooling of body temperature, rather than postponement until a specific problem arose, could “attenuate cerebral inflammatory and biochemical cascades, which are activated early after traumatic brain injury, thereby limiting secondary brain injury,” they wrote.

Study Details

The POLAR-RCT enrolled 511 patients at medical centers in Australia, New Zealand, France, Switzerland, Saudi Arabia, and Qatar. Out-of-hospital or paramedic agencies and emergency departments (EDs) screened for patients with TBI who met the study's eligibility criteria: ages 18 to 60, a Glasgow Coma Scale (GCS) score of less than 6, and actual or imminent endotracheal intubation. Exclusion criteria, including significant or possibly uncontrolled bleeding, were also considered.

The 266 patients randomized to the treatment arm were given early induction of hypothermia (at a targeted temperature of 33 degrees C to 35 degrees C) for at least 72 hours and up to seven days if intracranial pressures were elevated, followed by gradual rewarming. Hypothermia was induced, starting in both out-of-hospital and ED settings, using a bolus of up to 2000 mL intravenous ice-cold (4 degrees C) 0.9 percent saline, and surface-cooling wraps once the patients were in the ED. The 245 controls were kept at a target temperature of 37 degrees C using surface-cooling wraps as needed. All other care was at the discretion of the treating physician.

Of the initial group, 466 patients completed the primary outcome evaluation, which was favorable neurologic outcomes or independent living at six months after injury. That status was defined as a Glasgow Outcome Scale-Extended score of 5-8 (scale range is 1-8), based on a blind assessment.

At six months, favorable outcomes were achieved in 48.8 percent of the hypothermia group, compared with 49.1 percent of the controls, which was not a statistically significant difference. In the hypothermia and normal temperature group, the rates of pneumonia were 55 percent and 51.3 percent, respectively, and the rates of increased intracranial bleeding were 18.1 percent versus 15.4 percent.

The researchers, including first author D. James Cooper, MD, of Monash University in Melbourne, also reported that there were no benefits seen in “any of the secondary outcomes, including mortality, or in predefined subgroups, per-protocol analyses, or as-treated analyses.”

The authors noted that this study was the largest trial of prophylactic hypothermia after TBI to date, but acknowledged some possible shortcomings in its methodology. Of the hypothermia patients included in the six-month outcome analysis, 33 percent had fewer than 48 hours of hypothermia and 27 percent never reached the final target temperature of 33 degrees C, they wrote. Also, clinicians and families were not blinded to the intervention. Bedside clinicians also had the option not to enroll a patient if they believed it wasn't in his best interest, which could have introduced bias.

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“One of the challenges in finding effective treatments for TBI is that the condition is heterogeneous, with many different causes of injury and degrees of severity, and it involves a complex cascade of events. We are targeting just one point in a complex process.”—DR. MICHAEL J. SCHNECK

“Despite these limitations, POLAR-RCT was a well-designed and -executed study that has provided important data for the management of patients with TBI,” the editorial noted.

Expert Commentary

Michael Diringer, MD, professor of neurology, neurosurgery and anesthesiology at Washington University School of Medicine in St. Louis, concurred that the study was well-done. He said it “will fill in some of the gaps that were unaddressed by previous studies.” But he is not certain the unfavorable results will stop interest in pursuing hypothermia for TBI among some scientists and clinicians.

“There have been believers in hypothermia for a long time who have been trying to prove it works,” he said. “I think the track record, in my take on it, has been pretty consistently negative.”

Research studies aside, Dr. Diringer said that as a clinician, “I think shivering is a huge problem with hypothermia. It puts an enormous stress on the body,” and is not always easy to control. Pneumonia is another concern, he said.

The 2016 guidelines from the Brain Trauma Foundation do not support the use of prophylactic hypothermia for TBI, in part because of a lack of Class I evidence. Emily J. Gilmore, MD, associate professor in the division of neurocritical care and emergency neurology at Yale University, said her hospital typically does not use hypothermia for TBI, adding she believes the new study offers more definitive evidence that “at this point there no utility” in doing so.

But it remains to be seen, given the study's limitations, whether the new findings will be viewed by professional committees writing or revising guidelines as clear-cut Class I evidence against using hypothermia prophylactically for TBI, she said.

“Is earlier better? Is faster better? Is longer better? There may be people who will want to continue to ask those questions,” Dr. Gilmore said.

Michael J. Schneck, MD, FAAN, professor of neurology and neurosurgery at Loyola University Medical Center in Maywood, IL, said there has already been a rather indiscriminate adoption of hypothermia for cardiac arrest, an approach he believes needs to be used more selectively. In the case of TBI, “we need to be very careful to engage in healthy skepticism,” he said. Researchers may quibble over details, such as what target temperature or cooling technology is ideal, he said, but the fact remains “that at this time we have not identified any data that support the use of hypothermia for traumatic brain injury.”

“One of the challenges in finding effective treatments for TBI is that the condition is heterogeneous, with many different causes of injury and degrees of severity, and it involves a complex cascade of events, “Dr. Shneck said. “We are targeting just one point in a complex process,” he said of various TBI treatment approaches that target, for instance, inflammation.

The promising results of hypothermia for TBI in animal studies may have not panned out in people, he said, “because human TBI cases are more complicated than animal models.”

There are many different subsets of TBI patients, he added, so treatment needs and responses may differ among those subsets.

Monisha A. Kumar, MD, associate professor of neurology and of anesthesiology and critical care at the University of Pennsylvania, said clinical trials such as the one on prophylactic hypothermia for TBI recently reported in JAMA are hard to conduct, given that patients are in a critically ill state and being enrolled in the study under rapidly changing circumstances.

Despite its disappointing outcome, however, she found the latest study commendable.

“I think it did a better job than prior studies in both controlling temperature in the nontreatment arm and allowing for extended duration of treatment for those who had elevated ICP,” she said. But she found some problematic factors, including the fact that a significant number of patients in the hypothermia group did not reach target temperature, or had the cooling therapy withdrawn early. That could have skewed results, she said.

Experience from using hypothermia for cardiac arrest suggests that the benefit may be due to lowering the risk of fever, Dr. Kumar said, rather than some other biomechanisms resulting from cooling.

“Avoidance of fever in brain-injured patients remains very important, and should not be abandoned,” she said, “whether or not hypothermia is used.”

Disclosures

Drs. Schneck, Diringer, and Kumar reported no disclosures.

Link Up for More Information

• Cooper DJ, Nichol AD, Bailey M, et al; for the POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: The POLAR Randomized Clinical Trial https://jamanetwork.com/journals/jama/fullarticle/2710778. JAMA 2018;320(21)2211–2220.
• Docherty A, Emelifeonwu J, Andrews PJD. Hypothermia after traumatic brain injury https://jamanetwork.com/journals/jama/fullarticle/2710773. JAMA 2018;320(21):2204–2205.