Original Article

Therapeutic Hypothermia afterwards In-Hospital Cardiac Arrest in Children

Listing of authors.
  • Frank Due west. Moler, Yard.D.,
  • Faye Southward. Silverstein, M.D.,
  • Richard Holubkov, Ph.D.,
  • Beth South. Slomine, Ph.D.,
  • James R. Christensen, M.D.,
  • Vinay M. Nadkarni, M.D.,
  • Kathleen 50. Meert, One thousand.D.,
  • Brittan Browning, M.S., R.D., C.C.R.C.,
  • Victoria L. Pemberton, R.Northward.C., M.S.,
  • Kent Folio, M.Stat.,
  • Marianne R. Gildea, B.S.North., M.Due south.,
  • Barnaby R. Scholefield, G.B., B.S., Ph.D.,
  • Seetha Shankaran, M.D.,
  • Jamie Southward. Hutchison, M.D.,
  • John T. Berger, 1000.D.,
  • George Ofori-Amanfo, M.B., Ch.B.,
  • Christopher J.L. Newth, G.D.,
  • Alexis Topjian, Yard.D.,
  • Kimberly S. Bennett, Thousand.D., M.P.H.,
  • Joshua D. Koch, M.D.,
  • Nga Pham, Thou.D.,
  • Nikhil G. Chanani, One thousand.D.,
  • Jose A. Pineda, 1000.D.,
  • Rick Harrison, Grand.D.,
  • Heidi J. Dalton, M.D.,
  • Jeffrey Alten, One thousand.D.,
  • Charles L. Schleien, M.D.,
  • Denise M. Goodman, Yard.D.,
  • Jerry J. Zimmerman, Yard.D., Ph.D.,
  • Utpal S. Bhalala, M.D.,
  • Adam J. Schwarz, One thousand.D.,
  • Melissa B. Porter, Thou.D.,
  • Samir Shah, One thousand.D.,
  • Ericka Fifty. Fink, M.D.,
  • Patrick McQuillen, M.D.,
  • Theodore Wu, Thousand.D.,
  • Sophie Skellett, M.B., B.S., M.R.C.P.,
  • Neal J. Thomas, M.D.,
  • Jeffrey Due east. Nowak, 1000.D.,
  • Paul B. Baines, Chiliad.D., Ph.D.,
  • John Pappachan, M.B., B.S.,
  • Mudit Mathur, M.D.,
  • Eric Lloyd, Thou.D.,
  • Elise W. van der Jagt, M.D., Thousand.P.H.,
  • Emily Fifty. Dobyns, G.D.,
  • Michael T. Meyer, K.D.,
  • Ronald C. Sanders, Jr., M.D.,
  • Amy E. Clark, Yard.Due south.,
  • and J. Michael Dean, M.D.
  • for the THAPCA Trial Investigators*

Abstract

Background

Targeted temperature management is recommended for comatose adults and children afterwards out-of-infirmary cardiac arrest; however, data on temperature direction later in-hospital cardiac arrest are limited.

Methods

In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-infirmary cardiac arrest. Inside 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months later on cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with college scores indicating improve role), was evaluated among patients who had had a VABS-Ii score of at to the lowest degree lxx before the cardiac arrest.

Results

The trial was terminated considering of futility later on 329 patients had undergone randomization. Among the 257 patients who had a VABS-2 score of at least lxx earlier cardiac arrest and who could exist evaluated, the rate of the primary efficacy outcome did not differ significantly betwixt the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% conviction interval [CI], 0.67 to one.27; P=0.63). Among 317 patients who could exist evaluated for change in neurobehavioral office, the alter in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did non differ significantly between the hypothermia grouping and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, i.07; 95% CI, 0.85 to i.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well equally 28-twenty-four hours mortality, did not differ significantly between groups.

Conclusions

Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at ane year. (Funded by the National Center, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087.)

Introduction

Therapeutic hypothermia for comatose adults who have had an out-of-hospital cardiac abort was recommended on the basis of results of clinical trials reported in 2002.1-3 More contempo trials accept shown that fever prevention with therapeutic normothermia is equally efficacious as therapeutic hypothermia in adult and pediatric populations.iv,5 Current guidelines recommend either hypothermia or normothermia for temperature management afterward out-of-hospital cardiac arrest in adults and children.6,7

In-hospital cardiac arrest in children normally results in expiry or in a poor long-term functional outcome in survivors; withal, outcomes in the in-hospital setting are significantly better than those in the out-of-hospital setting.8,9 Furthermore, in-hospital outcomes are improving.10,eleven Published results of clinical trials of therapeutic hypothermia versus therapeutic normothermia in adults and children who accept had an in-hospital cardiac arrest are lacking. 2 retrospective studies involving cohorts of children who had in-infirmary or out-of-hospital cardiac arrest showed that therapeutic hypothermia was not associated with improved outcomes.12,thirteen

Cardiac arrests in children and adolescents in the in-hospital setting tin be distinguished from those in the out-of-infirmary setting on the footing of multiple factors, including preexisting weather, the initial cardiac rhythm in the patients, the cause of the cardiac arrest, response times and resuscitation skills of the initial responders, and causes of death in nonsurvivors.eight Thus, patients who accept in-hospital cardiac arrests represent a pathophysiologically singled-out population from those who take out-of-infirmary cardiac arrests, and the potential efficacy of an intervention such as therapeutic hypothermia may differ in the two populations. Therefore, nosotros conducted independent, parallel Therapeutic Hypothermia after Pediatric Cardiac Abort (THAPCA) trials, one in the out-of-hospital setting (THAPCA-OH) and one in the in-infirmary setting (THAPCA-IH).14,xv The results of the THAPCA-OH trial were recently reported in the Journal.5 We now report the results of the THAPCA-IH trial, in which we compared the efficacy of therapeutic hypothermia (target temperature, 33.0°C) with that of therapeutic normothermia (target temperature, 36.8°C) in comatose children and adolescents who were resuscitated subsequently in-hospital cardiac abort.

Methods

Trial Design and Oversight

This randomized trial was conducted in pediatric intensive care units at 37 children'due south hospitals in the U.s., Canada, and the United kingdom of great britain and northern ireland. The rationale, trial pattern, outcome selection process, protocol summary, and 12-month pilot vanguard phase have been described previously.5,14-xvi

The National Heart, Lung, and Blood Institute (NHLBI) funded the trial. The protocol was designed past the showtime, third, and terminal 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) canonical the protocol and informed-consent documents.

The site enquiry coordinators listed in the Supplementary Appendix nerveless all the data, and statisticians at the information coordinating heart performed all the analyses. Details of site grooming, data management, and site monitoring are provided in the Supplementary Appendix. An independent information and safe monitoring board that was appointed by the NHLBI conducted interim safety and efficacy analyses.17 All the authors vouch for the accuracy and abyss 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 eighteen 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 two minutes, and remained dependent on mechanical ventilation after the return of apportionment. Major exclusion criteria were a score of 5 or 6 on the Glasgow Coma Calibration motor-response subscale (on which scores range from i to vi, with lower scores indicating worse function), the inability to undergo randomization within vi hours after the render of apportionment, active and refractory severe bleeding, a preexisting illness associated with a life expectancy of less than 12 months, and a decision past the clinical squad 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 one: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 direction was actively maintained for 120 hours in each grouping. Patients who were assigned to therapeutic hypothermia were pharmacologically paralyzed and sedated, and a Blanketrol 3 temperature-management unit (Cincinnati Sub-Zippo) 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 flow of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.v); this temperature was actively maintained throughout the remainder of the 120-60 minutes intervention period. Patients who were assigned to therapeutic normothermia received identical intendance except that the core temperature was actively maintained with the temperature-management unit of measurement at 36.8°C (range, 36.0 to 37.5) for 120 hours. Dual monitoring of the central temperature (esophageal, rectal, or float temperature) and an automated mode on the temperature-management unit were used. In the patients who received extracorporeal membrane oxygenation (ECMO) at the time of randomization or afterward, ECMO with a single monitor of central temperature was used for temperature command. All other aspects of care were determined by the clinical teams.

Outcomes

The master outcome was survival with a favorable neurobehavioral outcome at 12 months of follow-upwards. A favorable neurobehavioral result was defined equally an age-corrected standard score of lxx or college (on a scale of twenty to 160) on the Vineland Adaptive Behavior Scales, second edition (VABS-II).eighteen The VABS-II has an age-corrected mean score of 100 and a standard difference of xv; college scores indicate better role. The VABS-II information were collected centrally at the Kennedy Krieger Establish by means of telephone interviews conducted past a trained interviewer who was unaware of the treatment assignments. As prespecified in the protocol, enrolled children with a VABS-2 score of less than seventy before cardiac abort (on the basis of data from a caregiver questionnaire completed at each site inside 24 hours after randomization) were excluded from the primary efficacy analysis. Patients with no baseline VABS-Two score were considered to be eligible for inclusion in the primary assay if their baseline Pediatric Overall Operation 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 ane to 6, with lower scores indicating less disability; patients with a score of i or ii on both scales were eligible for inclusion in the main analysis.

Secondary outcomes were survival at 12 months after cardiac arrest and change in neurobehavioral function, which was measured equally the difference between the baseline measurement (earlier cardiac arrest) and the 12-calendar 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 upshot was a global cognitive score that was based on the results of neuropsychological testing (run across the Supplementary Appendix). Safe outcomes included the incidences of blood-product use, infection, and serious arrhythmias within 7 days afterward randomization, too every bit 28-day mortality. Details of the methods used for effect assessment are provided in the Supplementary Appendix.

Statistical Analysis

We calculated the target sample size assuming an estimated favorable principal outcome rate of 35 to 55% in the normothermia group. Bold that 5% of the patients would be excluded attributable 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 ninety% power to detect a 15-percentage-point absolute treatment outcome.

Nosotros performed the analysis for the primary efficacy consequence using a prespecified modified intention-to-care for approach, excluding children who had poor neurobehavioral office before cardiac arrest. Secondary efficacy outcomes were analyzed amid all children who could be evaluated. Safety analyses were performed in treated patients only, according to the handling received. The main result and 12-month survival were compared between the handling groups with the use of a Cochran–Mantel–Haenszel examination 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 expiry every bit the worst result, and treatment of the everyman possible VABS-II score at 12 months as the second worst outcome. An alpha level of 0.05 was set for the chief assay, and an alpha level of 0.025 was gear up 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 comparing of survival curves between handling groups with the use of a log-rank test stratified according to age category. Analyses were performed with the use of SAS software, version nine.4 (SAS Institute).

When reviewing interim efficacy analyses, the data and safety monitoring lath used an informal threshold for conditional power (i.due east., the chance of detecting a meaning treatment event if the trial were to be connected) of 20%. Provisional ability below this threshold would lead the board to consider stopping farther enrollment because of futility.

Results

Patients

Figure 1. Effigy 1. Enrollment, Randomization, and Treatment.

Scores on the Glasgow Coma Scale (GCS) motor-response subscale range from one to 6, with lower scores indicating worse role. Scores on the Pediatric Overall Performance Category (POPC) and Pediatric Cognitive Performance Category (PCPC) scales range from one to 6, with lower scores indicating less disability. Scores on the Vineland Adaptive Behavior Scales, 2d edition (VABS-II), range from xx to 160, with higher scores indicating better role; the VABS-II has an age-corrected mean score of 100. CNS denotes central nervous organisation, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, ITT intention to care for, and THAPCA Therapeutic Hypothermia afterwards Pediatric Cardiac Abort.

The trial was stopped on February 27, 2015, because of futility after a review of acting efficacy analyses by the data and safety monitoring board. Between September 1, 2009, and Feb 27, 2015, a total of 2791 patients were screened for eligibility and met the trial inclusion criteria (Effigy ane). Of these patients, 746 were eligible for enrollment. The families of 334 of these patients provided consent, and 329 patients underwent randomization at 37 sites in the U.s., Canada, and the United kingdom (9 sites did non enroll whatever patients); 166 were assigned to therapeutic hypothermia, and 163 to therapeutic normothermia. A total of 5 patients who were assigned to hypothermia and 3 who were assigned to normothermia did non receive an intervention.

Of the 329 patients who underwent randomization, 31 in the hypothermia group and 29 in the normothermia group were ineligible for inclusion in the primary analysis considering they had a baseline VABS-2 score of less than 70 or a POPC or PCPC score of 3 or college. At 12 months, vital status was unknown in 2 patients in the normothermia group, and VABS-II scores were not obtained for 2 surviving children in the hypothermia group and viii in the normothermia group (Figure 1). Thus, 257 patients could be evaluated for the principal effect, 317 could be evaluated for the secondary outcome of change in neurobehavioral function, and 327 could be evaluated for the secondary outcome of 1-year survival.

Baseline Characteristics and Temperature Intervention

Table 1. Tabular array 1. Baseline Characteristics of the Patients earlier Randomization.

The baseline characteristics of the patients were like in the ii handling groups (Tabular array i, and Tables S1 and S2 in the Supplementary Appendix). There were statistically significant differences between the ii groups at baseline in alanine aminotransferase, aspartate aminotransferase, and hemoglobin levels, but these differences were not clinically significant (Table S3 in the Supplementary Appendix). The median historic period of the patients was 1 year, 196 patients (60%) were male, and 299 patients (91%) had a preexisting medical condition. The initial rhythm was bradycardia in 189 patients (57%) and ventricular fibrillation or ventricular tachycardia in 34 (10%). The median fourth dimension from cardiac arrest to cardiopulmonary resuscitation (CPR) was 0 minutes, and the median elapsing of CPR was 22.0 minutes (interquartile range, 7.0 to 47.0). Cardiac abort occurred at a trial hospital in 307 patients (93%). Baseline functional status based on the VABS-II, PCPC, and POPC scores is shown in Table S4 in the Supplementary Appendix.

The median time from the return of circulation to the initiation of handling was iv.9 hours (interquartile range, 3.nine to five.viii) in the hypothermia group and 4.vii hours (interquartile range, 4.0 to 5.7) in the normothermia group. Fig. S1 in the Supplementary Appendix shows the primary primal (core) temperatures recorded for the two groups. Boosted information regarding temperature command is provided in the Supplementary Appendix.

Outcomes

Table 2. Table 2. Primary and Secondary Outcomes.

The percentage of children with a VABS-II score of 70 or higher at 12 months did not differ significantly between the hypothermia grouping and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63) (Table 2). Sensitivity analyses, including a per-protocol analysis and analyses with imputation of missing data, did non alter the main-upshot result (encounter the Supplementary Appendix). Results of analyses in subgroups divers according to demographic characteristics and characteristics related to the cardiac arrest did not differ significantly betwixt the two treatment groups (Tables S9 and S10 in the Supplementary Appendix).

The secondary outcome of modify in the VABS-Ii score from baseline to 12 months also did not differ significantly between the treatment groups (P=0.70). The overall percent of patients with 12-month VABS-II scores that did not subtract by more than 15 points (one SD) from their baseline measurements did not differ significantly betwixt the hypothermia group and the normothermia grouping (30% [49 of 164 patients] and 29% [44 of 153 patients], respectively) (Tabular array 2).

Figure 2. Figure 2. Kaplan–Meier Estimates of Survival from 0 to 365 Days after Cardiac Arrest.

Shown are Kaplan–Meier estimates of survival from 0 to 365 days after cardiac arrest in the therapeutic hypothermia group and the therapeutic normothermia group (P=0.45 past log-rank test stratified according to age category).

The rate of survival at 12 months among all patients who underwent randomization and had a known vital status (99% [327 of 329 patients]) did not differ significantly between the hypothermia grouping and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56) (Table 2). Estimates of survival from 0 to 365 days too did not differ significantly between the groups (P=0.45) (Figure two). The master crusade of expiry was encephalon expiry or withdrawal of life back up owing to a poor neurologic prognosis (in 39% [33 of 85 patients] in the hypothermia group and 33% [29 of 88 patients] in the normothermia group) or cardiovascular failure (in 31% [26 of 85 patients] in the hypothermia group and 38% [33 of 88 patients] in the normothermia group), with no significant differences between the groups (Table S5 in the Supplementary Appendix).

Data on global cognitive operation in survivors are shown in Table S6 in the Supplementary Appendix. The Early Learning Composite scores on the Mullen Scales of Early Learning22 did not differ significantly between the groups; there were also no significant differences between the groups in the IQ score distributions on the Wechsler Abbreviated Scale of Intelligence23 or in the combined categories from both the Mullen and Wechsler tests.

Safety

Table 3. Table 3. Safety Outcomes inside vii Days after Randomization and 28-Mean solar day Mortality.

The incidences of infection, blood-product use, and serious arrhythmias within 7 days after randomization were similar in the 161 patients who received therapeutic hypothermia and the 160 who received therapeutic normothermia (Tabular array three). Mortality at 28 days did not differ significantly between the hypothermia grouping and the normothermia grouping (37% [59 of 161 patients] and 41% [66 of 160 patients], respectively; P=0.40). Information regarding other agin events are provided in Tables S7 and S8 in the Supplementary Appendix; there were no significant differences betwixt the groups in any of the other adverse events.

Discussion

The THAPCA-IH trial evaluated the efficacy of therapeutic hypothermia (target temperature, 33.0°C) and therapeutic normothermia (target temperature, 36.viii°C) in improving outcomes subsequently in-hospital cardiac arrest in children. In that location was no pregnant difference betwixt the groups in the primary issue of survival with a favorable neurobehavioral upshot (VABS-II score of ≥70) at 12 months. The secondary effect of change in the VABS-2 score from baseline to 1 year did not differ significantly betwixt the groups; the proportion of patients with 12-calendar month VABS-II scores that did non subtract by more than than 15 points (i SD) from their baseline scores was like in the ii groups. Survival at 1 year and Kaplan–Meier estimates of survival from 0 to 365 days did not differ significantly between the groups.

An important limitation in the interpretation of our findings is that the trial was stopped at the recommendation of the data and safety monitoring board because of an assessment of futility before attainment of the target trial enrollment. Although slower-than-expected patient recruitment was a factor, termination of enrollment was based primarily on the low conditional power of the trial to show a significant treatment result if continued, since no tendency was observed with respect to the primary or secondary outcomes. Given the number of patients who could be evaluated, the confidence intervals for treatment effect are broad; however, the 15-percentage-signal absolute benefit of hypothermia that was postulated during the trial design tin can exist ruled out. Some other possible limitation was the relatively long time from the return of circulation to the achievement of a temperature within the target temperature range (median time, approximately 6 hours). We did not behave a pretrial site phase-in or use only high-enrolling sites; such strategies have been suggested in other hypothermia trials.24-28 Other limitations are similar to those previously described in the THAPCA-OH trial report.5

Our overall findings in the THAPCA-IH trial are consistent with those of contempo trials investigating the efficacy of hypothermia versus normothermia after out-of-hospital cardiac arrest.4,v In contrast to earlier trials in the out-of-hospital setting involving only adults,two,3 in more recent trials involving adults and children,4,5 fever was prevented in the normothermia group through an agile intervention similar to that used in our normothermia group. The elapsing of temperature command was identical in the THAPCA-OH trial and the THAPCA-IH trial (120 hours) but was longer than the duration used in both the earlier and the more than recent trials involving only adults. The characteristics of the in-infirmary population included in the THAPCA-IH trial differed markedly from those of the out-of-hospital population included in the THAPCA-OH trial, equally expected on the basis of the results of our pretrial cohort study.8 The leading crusade of cardiac arrest in the THAPCA-IH trial was a cardiac cause or a cause related to congenital heart affliction (in 50% and 16% of patients, respectively, or in 65% of patients combined); in contrast, in the THAPCA-OH trial, 72% of patients had a respiratory cause of cardiac arrest. A lower percentage of patients in the THAPCA-IH trial than in the THAPCA-OH trial had asystole (7% vs. 58%), and a much higher percentage had bradycardia (57% vs. half dozen%). Shockable rhythms were infrequent in both trials (occurring in 8 to 10% of patients). Encephalon death or withdrawal of life back up owing to a poor neurologic prognosis was the cause of expiry in approximately 79% of patients in the THAPCA-OH trial merely in just 36% of patients in the THAPCA-IH trial, whereas a cardiac cause of death was more than common in the THAPCA-IH trial than in the THAPCA-OH trial (in 34% vs. 13% of patients). A favorable main event occurred in a essentially higher pct of patients in the THAPCA-IH trial than in the THAPCA-OH trial (37% [96 of 257 patients] vs. 16% [42 of 260 patients]).

Trials comparing therapeutic hypothermia with therapeutic normothermia have shown no significant differences between the ii interventions in outcomes.4,5 A possible mechanism underlying the initial reportsii,3 of a benefit of hypothermia over conventional treatment (i.due east., care that does not include targeted temperature management to prevent fever) is that therapeutic normothermia is too beneficial. Fever unremarkably occurs afterwards hypoxic–ischemic brain injury.29-32 In initial trials of hypothermia for neonatal asphyxial encephalopathy and adult out-of-hospital cardiac arrest, the control groups did not receive therapeutic normothermia.2,33-35 A modest trial of cooling versus normal temperature control in neonates who were receiving ECMO and were at high run a risk for neurologic injury showed no difference in result between the two interventions.36 Studies of hypothermia in children with traumatic brain injury showed that hypothermia had no efficacy and may take resulted in higher mortality.24,37 A recent registry report of outcomes in adults who had in-hospital cardiac arrest showed college bloodshed and lower survival with a favorable neurologic outcome among patients who received therapeutic hypothermia than amid those who received usual care.38 In dissimilarity, we plant no trends toward higher mortality or higher incidences of infection, arrhythmias, claret-product use, or other serious adverse events in the therapeutic hypothermia group than in the therapeutic normothermia group in the THAPCA-IH trial.

Unanswered questions remain regarding the role of targeted temperature management in children after in-hospital cardiac arrest. A different therapeutic window for attaining the target temperature (shorter), a different elapsing of temperature control (longer or shorter), and different depths of temperature control (higher or lower) are modifications that take been suggested previously and might be considered for future trials.5 In neonates with hypoxic–ischemic encephalopathy, use of a lower target temperature (32.0°C vs. 33.five°C) and a longer duration of temperature control (120 hours vs. 72 hours) did not subtract mortality.39 Modification of inclusion and exclusion criteria and the combination of targeted temperature management with neuroprotective agents might also be considered in future trials of therapies after cardiac arrest in children.xl

In conclusion, in asleep children who survived in-hospital cardiac abort, therapeutic hypothermia (target temperature, 33.0°C), as compared with therapeutic normothermia (target temperature, 36.eight°C), did non confer a pregnant benefit with respect to survival with a practiced functional outcome at 1 twelvemonth.

Funding and Disclosures

Supported past grants from the National Center, Lung, and Claret Institute (HL094345, to Dr. Moler; and HL094339, to Dr. Dean), federal planning grants for the planning of the THAPCA trials (HD044955 and HD050531, both to Dr. Moler), cooperative agreements from the Pediatric Emergency Care Applied Research Network (U03MC00001, U03MC00003, U03MC00006, U03MC00007, and U03MC00008) and the Collaborative Pediatric Disquisitional Care Inquiry Network (U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012 and U01HD049934), and a National Emergency Medical Services for Children Information Analysis Resource Center Demonstration grant (U07MC09174). Several centers were supported by supplemental grants or cooperative agreements (UL1RR024986, UL1TR000433, U54HD087011, UL1TR000003, and P30HD040677).

Disclosure forms provided by the authors are available with the full text of this commodity at NEJM.org.

The views expressed in this article are solely those of the authors and do not necessarily stand for the official views of the National Center, Lung, and Blood Institute or the National Institutes of Health.

This commodity was published on January 24, 2017, at NEJM.org.

Author Affiliations

From the University of Michigan, Ann Arbor (F.Due west.1000., F.S.South.), and Wayne Country Academy, Detroit (K.L.1000., S. Shankaran) — both in Michigan; University of Utah, Salt Lake City (R. Holubkov, B.B., Grand.P., Yard.R.Yard., K.Due south.B., A.E.C., J.M.D.); Kennedy Krieger Constitute and Johns Hopkins University (B.S.Southward., J.R.C.) and Johns Hopkins Children'due south Center (UsB.), Baltimore, and the National Heart, Lung, and Blood Institute, Bethesda (V.L.P.) — both in Maryland; Children's Hospital of Philadelphia, Philadelphia (V.Thou.Due north., A.T.), Academy of Pittsburgh Medical Center, Pittsburgh (East.L.F.), and Penn State Children's Hospital, Hershey (Northward.J.T.) — all in Pennsylvania; Birmingham Children's Hospital, Birmingham (B.R.S.), Great Ormond Street Hospital, London (S. Skellett), Alder Hey Children'due south Hospital, Liverpool (P.B.B.), and University Hospital Southampton, Southampton (J.P.) — all in the United Kingdom; Hospital for Ill Children, Toronto (J.S.H.); Children's National Medical Eye, Washington, DC (J.T.B.); Duke Children's Hospital, Durham, NC (Yard.O.-A.); Children'due south Infirmary Los Angeles (C.J.Fifty.North.) and Mattel Children's Infirmary UCLA (R. Harrison), Los Angeles, Children's Infirmary of Orangish County, Orange (A.J.South.), University of California, San Francisco Benioff Children's Hospital, San Francisco (P.M.), and Hill Linda Academy Children's Infirmary, Colina Linda (M.M.) — all in California; Children's Medical Center Dallas, University of Texas Southwestern Medical School, Dallas (J.D.One thousand.); University of Texas Wellness Sciences Heart at San Antonio, San Antonio (T.W.); Children's Healthcare of Atlanta, Atlanta (N.P., N.Grand.C.); Washington University, St. Louis (J.A.P.); Phoenix Children's Infirmary, Phoenix, AZ (H.J.D.); the Children's Infirmary of Alabama, Birmingham (J.A.); Children's Infirmary of New York, Columbia University Medical Center, New York (C.L.S.), and Golisano Children'southward Infirmary, Academy of Rochester Medical Center, Rochester (E.Westward.J.) — both in New York; Ann and Robert Lurie Children's Hospital of Chicago, Chicago (D.M.1000.); Seattle Children's Hospital, Seattle (J.J.Z.); Kosair Children'due south Hospital, University of Louisville, Louisville, KY (K.B.P.); University of Tennessee Health Science Center, Memphis (Due south. Shah); Children's Infirmary and Clinics of Minnesota, Minneapolis (J.Due east.N.); Nationwide Children's Infirmary, Columbus, OH (E.L.); Children'south Infirmary Colorado, Aurora (Due east.50.D.); Medical Higher of Wisconsin, Milwaukee (Thou.T.Grand.); and Arkansas Children's Hospital, Picayune Stone (R.C.S.).

Accost reprint requests to Dr. Moler at the Academy of Michigan Health System, F-6900 UH S., SPF 5243, 1500 E. Medical Eye Dr., Ann Arbor, MI 48109-5243, or at [electronic mail protected].

A complete list of the Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) trial investigators is provided in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

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