Objective: Treatment with inhaled nitric oxide improves oxygenation but not survival in mechanically ventilated patients with acute respiratory distress syndrome, but the effect may depend on the severity of hypoxemia. Our objective was to determine whether nitric oxide reduces hospital mortality in patients with severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 100 mm Hg) but not in patients with mild-moderate acute respiratory distress syndrome (100 < PaO2/FIO2 ≤ 300 mm Hg) at the time of randomization.
Data Sources: Data were collected from Medline, Embase, and Cochrane CENTRAL electronic databases (inception to May 2013); proceedings from five conferences (to May 2013); and trial registries (http://www.clinicaltrials.gov and http://www.controlled-trials.com). No language restrictions were applied.
Study Selection: Two authors independently selected parallel-group randomized controlled trials comparing nitric oxide with control (placebo or no gas) in mechanically ventilated adults or postneonatal children with acute respiratory distress syndrome.
Data Extraction: Two authors independently extracted data from included trials. Trial investigators provided subgroup data. Meta-analyses used within-trial subgroups and random-effects models.
Data Synthesis: Nine trials (n = 1,142 patients) met inclusion criteria. Overall methodological quality was good. Nitric oxide did not reduce mortality in patients with severe acute respiratory distress syndrome (risk ratio, 1.01 [95% CI, 0.78–1.32]; p = 0.93; n = 329, six trials) or mild-moderate acute respiratory distress syndrome (risk ratio, 1.12 [95% CI, 0.89–1.42]; p = 0.33; n = 740, seven trials). Risk ratios were similar between subgroups (interaction p = 0.53). There was no between-trial heterogeneity in any analysis (I2 = 0%). Varying the PaO2/FIO2 threshold between 70 and 200 mm Hg, in increments of 10 mm Hg, did not identify any threshold at which the nitric oxide–treated patients had lower mortality relative to controls.
Conclusions: Nitric oxide does not reduce mortality in adults or children with acute respiratory distress syndrome, regardless of the degree of hypoxemia. Given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of nitric oxide in patients with acute respiratory distress syndrome and severe hypoxemia will not be available for the foreseeable future.
1Department of Critical Care Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada.
2Division of Critical Care Medicine, Department of Medicine, Cooper University Hospital, Camden, NJ.
3Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden.
4Department of Critical Care and Anesthesiology and SAMU, Hôpital Lariboisière, Université Paris 7 Denis Diderot, Paris, France.
5Department of Anesthesiology and Intensive Care Medicine, University Hospital of Lille, Lille, France.
6Departments for Anesthesia, Intensive Care Medicine, and Pain Management, Vivantes–Klinikum Neukoelln, Berlin, Germany.
7Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea.
8Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto ON, Canada.
9The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto ON, Canada.
10Departments of Critical Care and Medicine, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital and University of Toronto, Toronto, ON, Canada.
* See also p. 472.
Ikaria provided subgroup data for three trials (references , , ) and reviewed and commented on a draft manuscript approved by all authors before journal submission; Ikaria did not have the right to force changes to the manuscript. Ikaria did not provide financial or other in-kind support. Ikaria had no role in the design or conduct of the study; management, analysis, or interpretation of data; or preparation or approval of the manuscript.
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Dr. Dellinger’s institution has received payment from Ikaria (coinvestigator for National Institute of Health sponsored study of inhaled nitric oxide in septic shock, Ikaria supplying device and gas) for a grant and for his membership on a board for new drug development. His institution consulted for Ikaria (New Drug Development advisory board). Dr. Payen is a board member for Vytech Comp (advisory board for Pulse Contour analysis) and has received payment from Vytech, BioMerieux (consultant for immunodepression), Ferrer (expert opinion for mediator removal), and BBraun (lectures). Dr. Vallet’s institution received grant support from Le programme hospitalier de recherche clinique. Dr. Gerlach has received payment for lectures from Merck Sharpe & Dohme and Thermo Fisher. Dr. Slutsky chaired an advisory board for Ikaria, Canada. He consulted for Maquet Medical, Novalung, and Gambro and has received payment from Ikaria (advisory board chair). The remaining authors have disclosed that they do not have any potential conflicts of interest.
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