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The Association Between Inhaled Nitric Oxide Treatment and ICU Mortality and 28-Day Ventilator-Free Days in Pediatric Acute Respiratory Distress Syndrome*

Bhalla, Anoopindar K., MD1,2; Yehya, Nadir, MD3; Mack, Wendy J., PhD4,5; Wilson, Melissa L., MPH, PhD4,5; Khemani, Robinder G., MD, MSCI1,2; Newth, Christopher J. L., MD, FRCPC1,2

doi: 10.1097/CCM.0000000000003312
Pediatric Critical Care

Objectives: To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome.

Design: Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the analysis.

Setting: Two quaternary care PICUs.

Patients: Children with pediatric acute respiratory distress syndrome.

Interventions: None.

Measurements and Main Results: There were 499 children enrolled in this study with 143 (28.7%) receiving inhaled nitric oxide treatment. Children treated with inhaled nitric oxide were more likely to have a primary diagnosis of pneumonia (72% vs 54.8%; p < 0.001), had a higher initial oxygenation index (median 16.9 [interquartile range, 10.1–27.3] vs 8.5 [interquartile range, 5.8–12.2]; p < 0.001), and had a higher 72-hour maximal Vasoactive-Inotrope Score (median 15 [interquartile range, 6–25] vs 8 [interquartile range, 0–17.8]; p < 0.001) than those not receiving inhaled nitric oxide. Mortality was higher in the inhaled nitric oxide treatment group (25.2% vs 16.3%; p = 0.02), and children in this group had fewer 28-day ventilator-free days (10 d [interquartile range, 0–18 d] vs 17 d (interquartile range 5.5–22 d]; p < 0.0001). We matched 176 children based on propensity score for inhaled nitric oxide treatment. In the matched cohort, inhaled nitric oxide treatment was not associated with mortality (odds ratio, 1.3 [95% CI, 0.56–3.0]) or 28-day ventilator-free days (incidence rate ratio, 0.91 [95% CI, 0.80–1.04]). These results remained consistent in the entire study cohort when the propensity score for inhaled nitric oxide treatment was used for either inverse probability weighting or stratification in regression modeling with the exception that subjects treated with inhaled nitric oxide were more likely to have 0 ventilator-free days (p ≤ 0.02). In secondary analysis stratified by oxygenation response, inhaled nitric oxide treatment was not associated with mortality or 28-day ventilator-free days in children with a positive oxygenation response (all p > 0.2)

Conclusions: Treatment with inhaled nitric oxide in pediatric acute respiratory distress syndrome is not associated with improvement in either mortality or ventilator-free days and may be associated with harm. Further prospective trials are required to define the role of inhaled nitric oxide treatment in pediatric acute respiratory distress syndrome.

1Department of Anesthesiology and Critical Care Medicine, Children’s Hospital Los Angeles, Los Angeles, CA.

2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA.

3Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA.

4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

5Southern California Clinical and Translational Science Institute Biostatistics Core, University of Southern California, Los Angeles, CA.

*See also p. 1879.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by Institutional funds from the Children’s Hospital Los Angeles Department of Critical Care and Anesthesiology.

Dr. Bhalla disclosed that the work described in this application has been submitted as a master’s thesis at the University of Southern California; she disclosed off-label product use of inhaled nitric oxide treatment in acute respiratory distress syndrome; and she is supported through a grant from National Center for Advancing Translational Sciences (NCATS) (UL1TR001855). Dr. Yehya’s institution received funding from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Wilson received funding from the Global Collaboration (collaborative group that provides funding to attend annual executive meeting). Drs. Mack and Wilson are supported through grants from NCATS (UL1TR001855 and UL1TR000130). Dr. Khemani received funding from Orange Med (consulting work unrelated to this project). Dr. Newth received funding from Philips Research North America and Covidien.

For information regarding this article, E-mail: abhalla@chla.usc.edu

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