Study Design and Oversight

This randomized clinical trial, which was conducted in pediatric intensive care units (ICUs) at 38 children's hospitals in the United States and Canada, involved children who were admitted after out-of-hospital cardiac arrest. The rationale, study design, outcome selection process, protocol summary, and 12-month pilot vanguard phase have been described previously.15-17

The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI). 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.18 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 the fidelity of this report to the study protocol, which is available at NEJM.org.

Patient Population

Children older than 48 hours and younger than 18 years of age were eligible for inclusion in the study if they had a cardiac arrest requiring chest compressions for at least 2 minutes and remained dependent on mechanical ventilation after the return of circulation. Major exclusion criteria were the inability to undergo randomization for any reason within 6 hours after the return of circulation, 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 reduced levels of function), the decision by the clinical team to withhold aggressive treatment, and major trauma associated with the cardiac arrest. A full listing of the 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 either therapeutic hypothermia or therapeutic normothermia. Randomization was performed with the use of permuted blocks stratified according to clinical center and age at entry (<2 years, 2 to <12 years, and ≥12 years).

Targeted temperature management was actively maintained for 120 hours in each group. Children 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 children 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. Children who were randomly assigned to therapeutic normothermia received identical care except that the core temperature was actively maintained with the cooling 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 for all the patients. The probe connected to the cooling unit was designated to be the primary probe; the other probe was connected to the bedside monitor for safety backup. In three patients who received extracorporeal membrane oxygenation (ECMO) at the time of randomization, ECMO was used for temperature control. All other aspects of clinical care were determined by the clinical teams.

Outcomes

The primary outcome was survival with a good neurobehavioral outcome at 12 months of follow-up. A good 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).19 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 trial protocol, enrolled children whose reported VABS-II scores were less than 70 before cardiac arrest (on the basis of data from a standardized caregiver questionnaire completed by a parent or guardian at each site within 24 hours after randomization) were not included in the primary efficacy analysis. Patients for whom no baseline VABS-II score was available were considered to be eligible for the primary analysis if the baseline Pediatric Overall Performance Category (POPC) and Pediatric Cerebral Performance Category (PCPC) scores20 were in the normal or mild disability category.17,21 Both scales range from 1 to 6, with lower scores indicating less disability; patients with scores of either 1 or 2 on both scales were eligible for the primary analysis.

Secondary outcomes were survival 12 months after cardiac arrest and change in neurobehavioral function, measured as the difference between the baseline level before cardiac arrest and the 12-month measurement on the VABS-II. For the latter, patients who had died and patients with the lowest possible VABS-II score were assigned the worst possible outcomes, regardless of baseline function.

A global cognitive score that was based on results of on-site neuropsychological testing was a tertiary outcome (see the Supplementary Appendix). Safety outcomes included the incidences of blood-product use, infection, and serious arrhythmias through 7 days and 28-day mortality. Details of the methods used for the assessment of outcomes are provided in the Supplementary Appendix.

Statistical Analysis

The target sample size was calculated on the basis of an absolute effect size of 15 to 20%, with an estimated primary outcome rate of 15 to 35% in the normothermia group. Assuming that 5% of the patients would be excluded owing to a baseline neurologic deficit and that 5% of patients would be lost to follow-up, we estimated that 276 patients would need to be enrolled to provide the study with 85% power to detect a 20% treatment effect.

The efficacy analysis for the primary outcome was performed with the use of a prespecified modified intention-to-treat approach, excluding children with poor neurobehavioral function before cardiac arrest, as noted above. Secondary efficacy outcomes were analyzed in all the children. Safety analyses were performed according to the treatment received in treated patients only. The primary outcome and 12-month mortality 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,22 with stratification according to age category, treatment of death as the worst outcome, and treatment of the lowest possible VABS-II score at 1 year 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 to 1 year was evaluated by comparing survival curves over time between treatment groups with the use of a log-rank test stratified according to age category. All analyses were performed with the use of SAS software, version 9.3 (SAS Institute).