Neill K J Adhikari1, R Phillip Dellinger, Stefan Lundin, Didier Payen, Benoit Vallet, Herwig Gerlach, Kwang Joo Park, Sangeeta Mehta, Arthur S Slutsky, Jan O Friedrich. 1. 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.
Abstract
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 (I = 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.
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 (I = 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.
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