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Primary Outcome Measures in Pediatric Septic Shock Trials: A Systematic Review*

Menon, Kusum MD, MSc; McNally, James Dayre MD, PhD; Zimmerman, Jerry J. MD, PhD; Agus, Michael S. D. MD; O’Hearn, Katie BSc, MSc; Watson, R. Scott MD, MPH; Wong, Hector R. MD; Duffett, Mark PhD, RPh; Wypij, David PhD; Choong, Karen MB, MSc

Pediatric Critical Care Medicine: March 2017 - Volume 18 - Issue 3 - p e146–e154
doi: 10.1097/PCC.0000000000001078
Online Review Article

Objective: To evaluate all published pediatric randomized controlled trials of patients with septic shock from any cause to examine the outcome measures used, the strengths and limitations of these measurements and whether the trial outcomes met feasibility criteria.

Data Sources: We used a previously published database of pediatric critical care randomized controlled trials ( derived from searches of MEDLINE, EMBASE, LILACS, and CENTRAL.

Study Selection: We included randomized controlled trials of interventions to children admitted to a PICU with septic or dengue hemorrhagic shock which were published in English.

Data Extraction: Study characteristics and outcomes were retrieved by two independent reviewers with disagreement being resolved by a third reviewer. We defined feasibility as 1) recruitment of at least 90% of the targeted sample size and agreement of the observed outcome rate in the control group with the rate used for the sample size calculation to within 10% or 2) finding of a statistically significant difference in an interim or final analysis.

Data Synthesis: Nineteen of 321 identified articles were selected for review. Fourteen of 19 studies (74%) provided an a priori definition of their primary outcome measure in their “Methods section.” Mortality rate was the most commonly reported primary outcome (8/14; 57%), followed by duration of shock (4/14; 29%) followed by organ failure (1/14; 7%). Only three of 19 included trials met feasibility criteria.

Conclusions: Our review found that use of mortality alone as a primary outcome in pediatric septic shock trials was associated with significant limitations and that long-term patient-centered outcomes were not used in this setting. Composite outcomes incorporating mortality and long-term outcomes should be explored for use in future pediatric septic shock trials.

1Division of Pediatric Critical Care, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON.

2Division of Critical Care, Seattle Children’s Hospital, University of Washington, Seattle, WA.

3Division of Critical Care Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA.

4Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH.

5Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, ON.

*See also p. 296.

Dr. Zimmerman disclosed that he received support from the Society of Critical Care Medicine (SCCM) (travel reimbursement to attend board meetings) and Children's University Medical Group, University of Washington (salary support); he received support for article research from the National Institutes of Health (NIH); and his institution received funding from the NIH/National Institute of Child Health and Human Development (research funding), Immunexpress (research funding), and Elsevier Publishing (royalties). Dr. Watson received funding from UPMC, the NIH, SCCM, the University of Colorado, Seattle Children's Hospital, University of Washington, and University of Pittsburgh; and his institution received funding from the NIH. Dr. Wong received support for article research from the NIH; his institution received funding from the NIH; and he disclosed other support in the form of U.S. Patents for sepsis stratification biomarkers. Dr. Duffett’s institution received funding from the Canadian Institutes of Health Research. Dr. Wypij received funding from the Boston Children's Hospital (employment) and Harvard T.H. Chan School of Public Health (employment), and his institution received funding from NIH/National Heart, Lung, and Blood Institute grants. Dr. Choong received funding from McMaster University (employer), and her institution received funding from the Academic Health Sciences Alternate Funding Plan Innovation Grant. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Dr. Kusum Menon, MD, MSc, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, E-mail:

©2017The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies