title: Efficacy outcome selection in the therapeutic hypothermia after pediatric cardiac arrest trials.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Consensus assessment of potential outcomes and evaluation timepoints.
  
  
  METHODS
  None.
  
  
  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.
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Holubkov
authors.forename: Amy E
authors.initials: AE
authors.lastname: Clark
authors.forename: Frank W
authors.initials: FW
authors.lastname: Moler
authors.forename: Beth S
authors.initials: BS
authors.lastname: Slomine
authors.forename: James R
authors.initials: JR
authors.lastname: Christensen
authors.forename: Faye S
authors.initials: FS
authors.lastname: Silverstein
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Meert
authors.forename: Murray M
authors.initials: MM
authors.lastname: Pollack
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dean
mesh_terms: D002648:Child; D006323:Heart Arrest / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D007223:Infant; D011446:Prospective Studies; D012107:Research Design; D015996:Survival Rate; D016896:Treatment Outcome