Elsevier

Resuscitation

Volume 139, June 2019, Pages 329-336
Resuscitation

Clinical paper
Relationships between three and twelve month outcomes in children enrolled in the therapeutic hypothermia after pediatric cardiac arrest trials

https://doi.org/10.1016/j.resuscitation.2019.03.020Get rights and content

Abstract

Aim

To inform design aspects of future trials by comparing 3 and 12-month neurobehavioural outcomes in children enrolled in Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-Of-Hospital and In-Hospital (THAPCA-OH, THAPCA-IH) trials.

Methods

The THAPCA trials evaluated two targeted temperature management interventions (hypothermia, 32.0–34.0 °C; normothermia, 36.0–37.5 °C). Children, aged 2 days to <18 years, were enrolled from 2009–2015. Three and 12-month post-cardiac arrest (CA) outcomes included the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) (population mean = 100, SD = 15) and the pediatric cerebral performance category (PCPC) scale. Children without significant pre-existing neurodevelopmental deficits were included in primary outcome analyses. Among survivors, favorable 12-month outcome was defined as VABS-II ≥ 70.

Results

VABS-II and PCPC were available at 3 and 12 months in 204 of 222 eligible survivors (THAPCA-OH, n = 82; THAPCA-IH, n = 122). Relative to THAPCA-IH, THAPCA-OH had significantly less pre-CA disability and significantly greater 12-month CA impairment, based on both VABS-II and PCPC. Correlations between 3 and 12-month VABS-II scores were strong for THAPCA-OH (r = 0.95) and THAPCA-IH (r = 0.72), and lower (p ≤ 0.001) in THAPCA-IH. Between time-points correlations were lower, but still significant in children <1 year at CA (p < 0.001). In both cohorts, 3-month VABS-II and PCPC categorical outcomes had high sensitivity (≥70%) for predicting favorable 12-month VABS-II outcomes, but specificity was lower for THAPCA-IH (68–89%) relative to THAPCA-OH (≥95%). Overall, 12-month diagnostic accuracy was ≥80% for both VABS-II and PCPC in both cohorts.

Conclusions

In future paediatric cardiac arrest clinical trials that enroll similar cohorts, integration of 3-month neurobehavioral outcome measures should be considered.

Introduction

Children who survive cardiac arrest (CA) are at substantial risk for poor neurobehavioural outcomes. Identification of therapeutic interventions that will improve long-term outcomes is a high priority for resuscitation research. A substantial challenge in the design of clinical trials in this heterogeneous and medically complex population is the selection of appropriate neurobehavioral outcome measures. Assessment measures must be well-standardized, reproducible, and applicable to the full paediatric age-range (i.e. infancy to young adulthood). Selection of the optimal timing for outcome evaluation must balance considerations regarding challenges inherent in cognitive assessments of young children, and pragmatic considerations in time allocation for implementation and completion of major multicenter clinical trials. Recently, the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA−OH) and In-Hospital (THAPCA-IH) Trials evaluated two targeted temperature management strategies, hypothermia or normothermia, in children who were comatose after CA resuscitation.1, 2

The neurobehavioral measure selected for inclusion in the primary outcome was adaptive behavior composite score on the Vineland Adaptive Behavior Scales, Second Edition (VABS-II).3 The detailed rationale for selection of this measure has been reported.4 Briefly, the VABS-II is a caregiver-report of functional skills and provides age-corrected standard scores (mean = 100, SD = 15) in four domains (communication, daily living, socialization, motor skills) and an overall adaptive behavior composite; higher scores denote better functioning. The time-point selected for outcome assessment was 12 months, based on attempting to balance sufficient time for recovery with need to optimize enrollment and follow-up within the study timeframe. In both trials, a dichotomous approach was selected for the primary outcome. Favorable outcome was defined as one-year survival with VABS-II score ≥ 70 (no more than 2SD below the age-corrected standard score); only individuals with pre-CA scores in this range were eligible for the primary outcome. Although the primary outcome was evaluated at 12 months after CA, VABS-II evaluations were also completed at 3 months. The Pediatric Cerebral Performance Scale (PCPC) and the Pediatric Overall Performance Scale (POPC),5, 6 descriptive ordinal function measures of neurological and overall health respectively, were also scored at both time-points, to facilitate comparisons with other paediatric CA outcome studies.

In our initial analyses of THAPCA trial neurobehavioral outcomes in long-term survivors, we noted unexpectedly strong correlations between 3 and 12 month outcomes7, 8; however, direct comparison of correlations between the THAPCA cohorts and within the youngest age subgroups were not explored. Understanding the relationship between 3 and 12 month outcomes is important for future trial design in these populations. Incorporation of 3 month outcomes could optimize subject retention and follow-up, reduce costs and allow for adaptive trial design strategies (i.e. incorporating initial outcome data to modify treatment and patient allocation options, and to potentially inform early stopping rules for interim efficacy monitoring). The goals of this study are to understand the relationships between 3 and 12-month neurobehavioral outcome measures in both THAPCA cohorts, to evaluate the influence of age on these relationships, to explore agreement between 3 and 12 month classifications of favorable outcomes, and to compare outcome classifications based on VABS-II and PCPC.

Section snippets

Study population

Children, ages 2 days to 18 years, were enrolled (THAPCA-OH, n = 295; THAPCA-IH, n = 329). Full inclusion and exclusion criteria, randomization, and enrollment details are published.9 Two hundred and four of 222 eligible survivors (those without pre-existing neurodevelopmental deficits) had both 3 and 12 month neurobehavioural outcomes.

Global functioning

PCPC provides a measure of neurological functioning and POPC measures overall health (including neurological functioning).5, 6 These clinician-rated scales,

Sample characteristics

Table 1 shows the characteristics of the 204 survivors with 3 and 12 month neurobehavioral outcomes. The THAPCA-OH (n = 82) and THAPCA-IH (n = 122) participants differed significantly in several respects. The THAPCA-OH group was older, more likely to be male, had less pre-CA disability, and were more likely to have CA due to respiratory etiology. The THAPCA-OH group received fewer doses of epinephrine, included more cases with estimated duration of chest compressions in the 15–30 min range, and

Discussion

This is the first detailed, prospective study examining correlations between relatively early and longer-term neurobehavioural outcomes in two groups of paediatric CA survivors who were comatose following resuscitation. Based on a preceding retrospective study17 that delineated significant differences between paediatric OH-CA and IH-CA populations with respect to CA etiology, medical co-morbidities, and outcomes, the THAPCA targeted temperature treatment trials were conducted independently in

Conclusion

In this population of children who incurred OH-CA or IH-CA and were comatose after resuscitation, we found significant correlations between 3 and 12-month assessments, even in the youngest children. Favorable neurobehavioral outcome based on 3-month VABS-II and PCPC were accurate classifiers for 12 month outcomes in both cohorts. Results illustrate the potential utility of incorporating 3 month neurobehavioral outcome assessment into the design of paediatric cardiac arrest clinical trials

Contributors’ statements

Beth Slomine: Dr. Slomine contributed substantially to study design and data interpretation, oversaw neurobehavioural data collection, drafted the manuscript, and approved the final manuscript as submitted.

Faye Silverstein: Dr. Silverstein contributed to study design and data interpretation, reviewed and revised the manuscript, and approved the final manuscript as submitted.

James Christensen: Dr. Christensen contributed to the study design, acquisition of data, and interpretation, reviewed and

Funding/support

The Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital (THAPCA-IH and OH) trials were primarily supported by funding from the National Institutes of Health National Heart, Lung, and Blood Institute grants HL094345 (Dr Moler) and HL094339 (Dr Dean).

Additional support from the Eunice Kennedy Shriver National Institute of Child Health and Development federal planning grants HD044955 and HD050531 (both, Dr Moler) contributed to the planning of the THAPCA Trials.

Clinical trial registration

THAPCA-OH ClinicalTrials.gov number, NCT00878644; THAPCA-IH ClinicalTrials.gov number, NCT00880087.

Role of the funding source

This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health.

Conflict of interest

All the authors reports grants from NIH.

References (19)

There are more references available in the full text version of this article.

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    Slomine et al. incorporated two definitions of favorable outcome with the first being PCPC 1 (normal) or 2 (mild disability) and the second being PCPC 1 to 3 and compared each with Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 12-month outcomes. The accuracy of both classification groups was similar.24 Including moderate disability after pediatric cardiac arrest in a dichotomized favorable outcome category is debatable.

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