Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial

Abstract

Importance: Comatose survivors of out-of-hospital cardiac arrest experience high rates of death and severe neurologic injury. Current guidelines recommend targeted temperature management at 32 °C to 36 °C for 24 hours. However, small studies suggest a potential benefit of targeting lower body temperatures.

Objective: To determine whether moderate hypothermia (31 °C), compared with mild hypothermia (34 °C), improves clinical outcomes in comatose survivors of out-of-hospital cardiac arrest.

Design, setting, and participants: Single-center, double-blind, randomized, clinical superiority trial carried out in a tertiary cardiac care center in eastern Ontario, Canada. A total of 389 patients with out-of-hospital cardiac arrest were enrolled between August 4, 2013, and March 20, 2020, with final follow-up on October 15, 2020.

Interventions: Patients were randomly assigned to temperature management with a target body temperature of 31 °C (n = 193) or 34 °C (n = 196) for a period of 24 hours.

Main outcomes and measures: The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. Neurologic outcome was assessed using the Disability Rating Scale, with poor neurologic outcome defined as a score greater than 5 (range, 0-29, with 29 being the worst outcome [vegetative state]). There were 19 secondary outcomes, including mortality at 180 days and length of stay in the intensive care unit.

Results: Among 367 patients included in the primary analysis (mean age, 61 years; 69 women [19%]), 366 (99.7%) completed the trial. The primary outcome occurred in 89 of 184 patients (48.4%) in the 31 °C group and in 83 of 183 patients (45.4%) in the 34 °C group (risk difference, 3.0% [95% CI, 7.2%-13.2%]; relative risk, 1.07 [95% CI, 0.86-1.33]; P = .56). Of the 19 secondary outcomes, 18 were not statistically significant. Mortality at 180 days was 43.5% and 41.0% in patients treated with a target temperature of 31 °C and 34 °C, respectively (P = .63). The median length of stay in the intensive care unit was longer in the 31 °C group (10 vs 7 days; P = .004). Among adverse events in the 31 °C group vs the 34 °C group, deep vein thrombosis occurred in 11.4% vs 10.9% and thrombus in the inferior vena cava occurred in 3.8% and 7.7%, respectively.

Conclusions and relevance: In comatose survivors of out-of-hospital cardiac arrest, a target temperature of 31 °C did not significantly reduce the rate of death or poor neurologic outcome at 180 days compared with a target temperature of 34 °C. However, the study may have been underpowered to detect a clinically important difference.

Trial registration: ClinicalTrials.gov Identifier: NCT02011568.

Figure 1.. Participant Flow

Randomization was stratified by first documented rhythm at the time of the cardiac arrest. Initial rhythms were classified as shockable (ventricular fibrillation or pulseless ventricular tachycardia) or nonshockable (asystole or pulseless electrical activity). All cases of withdrawal of consent were by a legal surrogate.

Figure 2.. Median Body Temperature During the Intervention in Patients Randomized to Moderate Hypothermia (31 °C) or Mild Hypothermia (34 °C)

The early postresuscitative state of patients and the use of ice packs prior to arrival at the cardiac center may have contributed to baseline temperatures being below normal. Randomization was done immediately once the endovascular device was inserted and shown to be functional. Rewarming was commenced 24 hours after reaching the target temperature at a rate of 0.25 °C/h until 37 °C was reached. This temperature was maintained such that the total period from the onset of rewarming was 48 hours. The curves show the medians; error bars indicate IQRs. The median time from randomization to target temperature was 208 (IQR, 163-282) minutes in the 31 °C group and 120 (IQR, 80-174) minutes in the 34 °C group. Nonadherence to the study protocol was noted for 7 patients in each group. In addition, per protocol, temperature was adjusted upward by 3 °C for hemodynamic reasons in 31 patients (16.8%) in the 31 °C group and in 10 patients (5.5%) in the 34 °C group (P = .001).

Figure 3.. Probability of Survival at 180 Days for All Patients, Patients Presenting With a Shockable Rhythm, and Patients Presenting Without a Shockable Rhythm

Kaplan-Meier curves estimating the probability of survival at 180 days for patients randomized to moderate hypothermia (target temperature of 31 °C) or mild hypothermia (target temperature of 34 °C). The follow-up time for all patients was 180 days. Initial rhythms were classified as shockable (ventricular fibrillation or pulseless ventricular tachycardia) or nonshockable (asystole or pulseless electrical activity) on the basis of the first documented rhythm at the time of the cardiac arrest.