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Efficacy Outcome Selection in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials*

Holubkov, Richard PhD1; Clark, Amy E. MS1; Moler, Frank W. MD, MS2; Slomine, Beth S. PhD3,4; Christensen, James R. MD5,6,7; Silverstein, Faye S. MD2; Meert, Kathleen L. MD8; Pollack, Murray M. MD9,10; Dean, J. Michael MD, MBA1

Pediatric Critical Care Medicine: January 2015 - Volume 16 - Issue 1 - p 1–10
doi: 10.1097/PCC.0000000000000272
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Objectives: The Therapeutic Hypothermia After Pediatric Cardiac Arrest trials will determine whether therapeutic hypothermia improves survival with good neurobehavioral outcome, as assessed by the Vineland Adaptive Behavior Scales Second Edition, in children resuscitated after cardiac arrest in the in-hospital and out-of-hospital settings. We describe the innovative efficacy outcome selection process during Therapeutic Hypothermia After Pediatric Cardiac Arrest protocol development.

Design/Setting: Consensus assessment of potential outcomes and evaluation timepoints.

Interventions: None.

Measurements and Main Results: We evaluated practical and technical advantages of several follow-up timepoints and continuous/categorical outcome variants. Simulations estimated power assuming varying hypothermia benefit on mortality and on neurobehavioral function among survivors. Twelve months after arrest was selected as the optimal assessment timepoint for pragmatic and clinical reasons. Change in Vineland Adaptive Behavior Scales Second Edition from prearrest level, measured as quasicontinuous with death and vegetative status being worst-possible levels, yielded optimal statistical power. However, clinicians preferred simpler multicategorical or binary outcomes because of easier interpretability and favored outcomes based solely on postarrest status because of concerns about accurate parental assessment of prearrest status and differing clinical impact of a given Vineland Adaptive Behavior Scales Second Edition change depending on prearrest status. Simulations found only modest power loss from categorizing or dichotomizing quasicontinuous outcomes because of high expected mortality. The primary outcome selected was survival with 12-month Vineland Adaptive Behavior Scales Second Edition no less than two SD below a reference population mean (70 points), necessarily evaluated only among children with prearrest Vineland Adaptive Behavior Scales Second Edition greater than or equal to 70. Two secondary efficacy outcomes, 12-month survival and quasicontinuous Vineland Adaptive Behavior Scales Second Edition change from prearrest level, will be evaluated among all randomized children, including those with compromised function prearrest.

Conclusions: Extensive discussion of optimal efficacy assessment timing, and of the advantages versus drawbacks of incorporating prearrest status and using quasicontinuous versus simpler outcomes, was highly beneficial to the final Therapeutic Hypothermia After Pediatric Cardiac Arrest design. A relatively simple, binary primary outcome evaluated at 12 months was selected, with two secondary outcomes that address the potential disadvantages of primary outcome.

1Department of Pediatrics, University of Utah, Salt Lake City, UT.

2Department of Pediatrics, University of Michigan, Ann Arbor, MI.

3Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, MD.

4Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD.

5Department of Pediatric Rehabilitation Medicine, Kennedy Krieger Institute, Baltimore, MD.

6Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD.

7Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

8Department of Pediatrics, Wayne State University, Detroit, MI.

9Division of Critical Care Medicine, Children’s National Medical Center, Washington, DC.

10Department of Pediatrics, George Washington University School of Health Sciences, Washington, DC.

* See also p. 75.

ClinicalTrials.gov identifiers: THAPCA-OH (NCT00878644), THAPCA-IH (NCT00880087).

Supported, in part, by the Pediatric Emergency Care Applied Research Network (PECARN) under cooperative agreements U03MC00001, U03MC00003, U03MC00006, U03MC00007, and U03MC00008 from the Emergency Medical Services for Children program of the Maternal and Child Health Bureau of the Health Resources and Services Administration, and from the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) under cooperative agreements U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012, and U01HD049934.

Dr. Holubkov served as board member for Pfizer and the American Burn Association (Data and Safety Monitoring Board [DSMB] memberships), consulted for St. Jude Medical and the Physicians Committee for Responsible Medicine (Biostatistical consultancies) and received support for article research from the National Institutes of Health (NIH). Dr. Holubkov and his institution received grant support from the National Heart, Lung, and Blood Institute (NHLBI; chief biostatistician for Therapeutic Hypothermia After Pediatric Cardiac Arrest [THAPCA]). His institution received support for travel from the NHLBI (THAPCA planning meeting). Ms. Clark received support for article research from the NIH. Her institution received grant support from the NIH. Dr. Moler received support for article research from the NIH. His institution received grant support, support for travel, and support for participation in review activities (R21 HD044955 and R34 HD 050531 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD], and by U01 HL094339 [Dr. Dean] and U01 HL094345 [Dr. Moler] from the NHLBI). Dr. Slomine received support for writing/reviewing the article from the NHLBI (U01HL094345/co-investigator), received support from the NHLBI (grant pays for administrative support and overhead), served as board member for the American Board of Clinical Neuropsychology (travel expenses as oral examiner), consulted for the University of Michigan (Executive Committee for Planning Grant) and University of California, Davis (DSMB Member), is employed by Kennedy Krieger Institute, provided expert testimony for private practice, lectured for St. Joseph’s Hospital (presentation at Grand Rounds), and received support for article research from the NIH. Dr. Slomine and her institution received support for travel from the NHLBI (U01HL094345/co-investigator). Her institution received grant support from the NHLBI (U01HL094345/co-investigator). Dr. Christensen is employed by Kennedy Krieger Institute and received support for article research from the NIH. His institution received grant support, support for travel, and support for writing/reviewing the article from the NHLBI (U01HL094345/co-investigator) and received support from the NHLBI (grant pays for administrative support and overhead). Dr. Silverstein received support for travel from the March of Dimes (scientific advisory board) and received support for article research from the NIH. Her institution received grant support from the NHLBI (funding for role as co-investigator on grant UO1 HL094345) and from the NICHD (effort funded on an unrelated project HD073692) and received support for travel from the NHLBI (investigator meeting HL094345). Dr. Meert received support for article research from the NIH. Her institution received grant support from the NIH. Dr. Pollack received support for article research from the NIH. His institution received grant support. Dr. Dean’s institution received grant support from the NHLBI, NICHD, and NIH.

Address requests for reprints to: Richard Holubkov, PhD, Intermountain Injury Control Research Center, 295 Chipeta Way, Suite 2E600, Salt Lake City, UT 84158. E-mail: rich.holubkov@hsc.utah.edu

©2015The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies