Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial

Abstract

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes.

Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury.

Design, setting, and participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018.

Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician.

Main outcomes and measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury.

Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively.

Conclusions and relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

Trial registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.

Figure 1.. Patients Included in the Primary Analysis

Patients were screened by ambulance officers, paramedics, and emergency department staff at many out-of-hospital and intrahospital locations, and the numbers of screened patients were not recorded.

Figure 2.. Hourly Temperature and Intracranial Pressure for the First 4 Days (96 hours) Postrandomization (N = 500)

A and B, Box plots are of the observed data (no imputation). The box shows the interquartile range (IQR), with the bottom and top indicating the 25th and 75th percentiles. The line inside the box indicates the median. The upper whisker extends from the top of the box to the largest value no farther than 1.5 times the IQR, and the bottom whisker extends from the bottom of the box to the smallest value no farther than 1.5 times the IQR. The trajectory line connects the median at each 6-hour block. Box plots have been offset to avoid superimposition. Box plots and numbers of patients in each interval include the hour of the right-hand tick mark. For example, the box plots between tick marks 0 and 6 represent the data for the interval 1 to 6 hours, between 6 and 12 is the interval 7 to 12 hours, etc. For temperature, there are additional box plots at 0 hours. The “number of patients” shown in the figures is the number of unique patients contributing to each interval. Each patient can contribute up to 6 hourly measurements in each interval. The median for the number of observations per patient is temperature, 6 (IQR, 5-6), and intracranial pressure, 6 (IQR, 6-6).

Figure 3.. Distribution of Glasgow Outcome Scale–Extended Scores at 6 Months After Randomization

Each cell corresponds to a score on the scale; the width of each cell represents the proportion of patients with equivalent scores. The vertical hyphenated line indicates the midpoint Glasgow Outcome Scale–Extended score dichotomization.