Trial Design and Oversight

This randomized trial was conducted in pediatric intensive care units at 37 children’s hospitals in the United States, Canada, and the United Kingdom. The rationale, trial design, outcome selection process, protocol summary, and 12-month pilot vanguard phase have been described previously.5,14-16

The National Heart, Lung, and Blood Institute (NHLBI) funded the trial. The protocol was designed by the first, third, and last authors. The institutional review board at each participating site and the data coordinating center at the University of Utah (see the Supplementary Appendix, available with the full text of this article at NEJM.org) approved the protocol and informed-consent documents.

The site research coordinators listed in the Supplementary Appendix collected all the data, and statisticians at the data coordinating center performed all the analyses. Details of site training, data management, and site monitoring are provided in the Supplementary Appendix. An independent data and safety monitoring board that was appointed by the NHLBI conducted interim safety and efficacy analyses.17 All the authors vouch for the accuracy and completeness of the submitted data, the third and last authors vouch for the data management and statistical analyses, and all the authors vouch for fidelity of the study to the trial protocol (available at NEJM.org).

Patient Population

Children older than 48 hours and younger than 18 years of age were eligible for inclusion if they had a cardiac arrest that began within the walls of a hospital, received chest compressions for at least 2 minutes, and remained dependent on mechanical ventilation after the return of circulation. Major exclusion criteria were a score of 5 or 6 on the Glasgow Coma Scale motor-response subscale (on which scores range from 1 to 6, with lower scores indicating worse function), the inability to undergo randomization within 6 hours after the return of circulation, active and refractory severe bleeding, a preexisting illness associated with a life expectancy of less than 12 months, and a decision by the clinical team to withhold aggressive treatment. A full list of exclusion criteria is provided in the Supplementary Appendix. Written informed consent from a parent or legal guardian was obtained for each participant.

Randomization and Intervention

Eligible patients were randomly assigned, in a 1:1 ratio, to therapeutic hypothermia or therapeutic normothermia. Randomization was performed with the use of permuted blocks stratified according to clinical center and age category (<2 years, 2 to <12 years, or ≥12 years).

Targeted temperature management was actively maintained for 120 hours in each group. Patients who were assigned to therapeutic hypothermia were pharmacologically paralyzed and sedated, and a Blanketrol III temperature-management unit (Cincinnati Sub-Zero) was used, with blankets applied anteriorly and posteriorly, to achieve and maintain a core temperature of 33.0°C (range, 32.0 to 34.0) for 48 hours. The patients were then rewarmed over a period of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.5); this temperature was actively maintained throughout the remainder of the 120-hour intervention period. Patients who were assigned to therapeutic normothermia received identical care except that the core temperature was actively maintained with the temperature-management unit at 36.8°C (range, 36.0 to 37.5) for 120 hours. Dual monitoring of the central temperature (esophageal, rectal, or bladder temperature) and an automatic mode on the temperature-management unit were used. In the patients who received extracorporeal membrane oxygenation (ECMO) at the time of randomization or later, ECMO with a single monitor of central temperature was used for temperature control. All other aspects of care were determined by the clinical teams.

Outcomes

The primary outcome was survival with a favorable neurobehavioral outcome at 12 months of follow-up. A favorable neurobehavioral outcome was defined as an age-corrected standard score of 70 or higher (on a scale of 20 to 160) on the Vineland Adaptive Behavior Scales, second edition (VABS-II).18 The VABS-II has an age-corrected mean score of 100 and a standard deviation of 15; higher scores indicate better function. The VABS-II data were collected centrally at the Kennedy Krieger Institute by means of telephone interviews conducted by a trained interviewer who was unaware of the treatment assignments. As prespecified in the protocol, enrolled children with a VABS-II score of less than 70 before cardiac arrest (on the basis of data from a caregiver questionnaire completed at each site within 24 hours after randomization) were excluded from the primary efficacy analysis. Patients with no baseline VABS-II score were considered to be eligible for inclusion in the primary analysis if their baseline Pediatric Overall Performance Category (POPC) and Pediatric Cerebral Performance Category (PCPC) scores were in the normal or mild disability category.19,20 On both these scales, scores range from 1 to 6, with lower scores indicating less disability; patients with a score of 1 or 2 on both scales were eligible for inclusion in the primary analysis.

Secondary outcomes were survival at 12 months after cardiac arrest and change in neurobehavioral function, which was measured as the difference between the baseline measurement (before cardiac arrest) and the 12-month measurement on the VABS-II. Patients who had died and patients with the lowest possible VABS-II score were assigned the worst possible outcomes, regardless of baseline function. A tertiary outcome was a global cognitive score that was based on the results of neuropsychological testing (see the Supplementary Appendix). Safety outcomes included the incidences of blood-product use, infection, and serious arrhythmias within 7 days after randomization, as well as 28-day mortality. Details of the methods used for outcome assessment are provided in the Supplementary Appendix.

Statistical Analysis

We calculated the target sample size assuming an estimated favorable primary outcome rate of 35 to 55% in the normothermia group. Assuming that 5% of the patients would be excluded owing to baseline neurologic deficit and that 5% of the patients would be lost to follow-up, we estimated that 558 patients would need to be enrolled to provide the trial with 90% power to detect a 15-percentage-point absolute treatment effect.

We performed the analysis for the primary efficacy outcome using a prespecified modified intention-to-treat approach, excluding children who had poor neurobehavioral function before cardiac arrest. Secondary efficacy outcomes were analyzed among all children who could be evaluated. Safety analyses were performed in treated patients only, according to the treatment received. The primary outcome and 12-month survival were compared between the treatment groups with the use of a Cochran–Mantel–Haenszel test stratified according to age category. The change in the VABS-II score was analyzed with the use of van Elteren’s modification of the Mann–Whitney test,21 with stratification according to age category, treatment of death as the worst outcome, and treatment of the lowest possible VABS-II score at 12 months as the second worst outcome. An alpha level of 0.05 was set for the primary analysis, and an alpha level of 0.025 was set for each of the two formal secondary analyses, with two-sided tests used in all instances. The probability of survival from 0 to 365 days was evaluated by comparison of survival curves between treatment groups with the use of a log-rank test stratified according to age category. Analyses were performed with the use of SAS software, version 9.4 (SAS Institute).

When reviewing interim efficacy analyses, the data and safety monitoring board used an informal threshold for conditional power (i.e., the chance of detecting a significant treatment effect if the trial were to be continued) of 20%. Conditional power below this threshold would lead the board to consider stopping further enrollment because of futility.