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Meta-Analysis
. 2016 Jun 27;2016(6):CD002787.
doi: 10.1002/14651858.CD002787.pub3.

Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults

Fabienne Gebistorf  1 , Oliver Karam, Jørn Wetterslev, Arash Afshari
Affiliations
Meta-Analysis

Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults

Fabienne Gebistorf et al. Cochrane Database Syst Rev. .

Abstract

Background: Acute hypoxaemic respiratory failure (AHRF) and mostly acute respiratory distress syndrome (ARDS) are critical conditions. AHRF results from several systemic conditions and is associated with high mortality and morbidity in individuals of all ages. Inhaled nitric oxide (INO) has been used to improve oxygenation, but its role remains controversial. This Cochrane review was originally published in 2003, and has been updated in 2010 and 2016.

Objectives: The primary objective was to examine the effects of administration of inhaled nitric oxide on mortality in adults and children with ARDS. Secondary objectives were to examine secondary outcomes such as pulmonary bleeding events, duration of mechanical ventilation, length of stay, etc. We conducted subgroup and sensitivity analyses, examined the role of bias and applied trial sequential analyses (TSAs) to examine the level of evidence.

Search methods: In this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015 Issue 11); MEDLINE (Ovid SP, to 18 November 2015), EMBASE (Ovid SP, to 18 November 2015), CAB, BIOSIS and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We handsearched the reference lists of the newest reviews and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception until 18 November 2015.

Selection criteria: We included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data.

Data collection and analysis: Two review authors independently extracted data and resolved disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effects of INO in adults and children and on various clinical and physiological outcomes. We presented pooled estimates of the effects of interventions as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias through assessment of trial methodological components and risk of random error through trial sequential analysis.

Main results: Our primary objective was to assess effects of INO on mortality. We found no statistically significant effects of INO on longest follow-up mortality: 250/654 deaths (38.2%) in the INO group compared with 221/589 deaths (37.5%) in the control group (RR 1.04, 95% CI 0.9 to 1.19; I² statistic = 0%; moderate quality of evidence). We found no statistically significant effects of INO on mortality at 28 days: 202/587 deaths (34.4%) in the INO group compared with 166/518 deaths (32.0%) in the control group (RR 1.08, 95% CI 0.92 to 1.27; I² statistic = 0%; moderate quality of evidence). In children, there was no statistically significant effects of INO on mortality: 25/89 deaths (28.1%) in the INO group compared with 34/96 deaths (35.4%) in the control group (RR 0.78, 95% CI 0.51 to 1.18; I² statistic = 22%; moderate quality of evidence).Our secondary objective was to assess the benefits and harms of INO. For partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), we found significant improvement at 24 hours (mean difference (MD) 15.91, 95% CI 8.25 to 23.56; I² statistic = 25%; 11 trials, 614 participants; moderate quality of evidence). For the oxygenation index, we noted significant improvement at 24 hours (MD -2.31, 95% CI -2.73 to -1.89; I² statistic = 0%; five trials, 368 participants; moderate quality of evidence). For ventilator-free days, the difference was not statistically significant (MD -0.57, 95% CI -1.82 to 0.69; I² statistic = 0%; five trials, 804 participants; high quality of evidence). There was a statistically significant increase in renal failure in the INO groups (RR 1.59, 95% CI 1.17 to 2.16; I² statistic = 0%; high quality of evidence).

Authors' conclusions: Evidence is insufficient to support INO in any category of critically ill patients with AHRF. Inhaled nitric oxide results in a transient improvement in oxygenation but does not reduce mortality and may be harmful, as it seems to increase renal impairment.

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Conflict of interest statement

Fabienne Gebistorf: none.

Oliver Karam: none.

Jørn Wetterslev is a member of the Copenhagen Trial Unit (CTU) task force. The CTU develop the theory and software for Trial Sequential Analysis (TSA) which is available free of charge at: www.ctu/tsa.

Arash Afshari: none.

Figures

1
1
TSA of all trials of the effect of INO on mortality (longest follow‐up). The TSA‐adjusted confidence interval for the meta‐analysis of the primary outcome with continuity correction for zero events trials (0.001 event in each arm) in a fixed‐effect model results in an RR of 1.04 (95% CI 0.90 to 1.19; I² statistic = 0%, diversity D² = 0%). With an accrued information size of 1243 participants and no boundaries crossed so far, only 41.92% of the required information size is actually available at this stage for rejection or acceptance of a 4% RRI for overall mortality. However, solid evidence may be obtained with fewer participants if eventually the cumulative meta‐analysis z‐curve crosses the trial sequential monitoring boundary constructed for a required information size of 3015 randomized participants. However, regarding the TSA analysis for this outcome, it is important to bear in mind that only 4 out of the 14 included studies are classified as low risk of bias trials. Therefore, TSA is not able to directly adjust for the impact of bias.
2
2
TSA of all trials of the effect of INO on PaO2/FiO2 ratio at 24 hours. Application of TSA to analysis of the PaO2/FiO2 ratio at 24 hours indicates statistical significance in favour of improved oxygenation, even with adjustment for repetitive testing on accumulating data in the cumulative meta‐analysis, because the z‐curve crossed the trial sequential monitoring boundary. The a priori information size (335 participants) is determined by a TSA‐adjusted mean difference (MD) of 15.91. The cumulative z‐curve (blue line with filled squares) at the current accrued information size of 614 participants crosses the boundary (red lines with open diamonds) (with 80% power and alpha 0.05, assuming a double‐sided type 1 risk of 5% and type 2 risk of 20%). However, it is important to note that only two trials had low risk of bias and the TSA‐adjusted confidence interval for the meta‐analysis in a random‐effects model results in an MD of 15.91 with substantial heterogeneity and diversity (95% CI 8.25 to 23.56; I² statistic = 25%, diversity D² = 49%).
3
3
INO search result.
4
4
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
5
5
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
6
6
Funnel plot of comparison: 1 Mortality, outcome: 1.1 Longest follow‐up, mortality.
7
7
Funnel plot of comparison: 1 Mortality, outcome: 1.2 28‐ to 30‐day mortality.
1.1
1.1. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 1 Overall mortality: INO vs control.
1.2
1.2. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 2 28‐ to 30‐day mortality: INO vs control.
1.3
1.3. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 3 Mortality: subgroup analysis, paediatric vs adult population.
1.4
1.4. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 4 Mortality: subgroup analysis based on duration of drug administration.
1.5
1.5. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 5 Sensitivity analysis: excluding abstracts, INO vs control.
1.6
1.6. Analysis
Comparison 1 Mortality: INO versus control group, Outcome 6 Sensitivity analysis: excluding trials not fulfilling AECC criteria, INO vs control.
2.1
2.1. Analysis
Comparison 2 Mortality: INO versus control (bias assessment), Outcome 1 Mortality: sensitivity analysis based on overall risk of bias.
3.1
3.1. Analysis
Comparison 3 Bleeding events: INO versus control, Outcome 1 Bleeding events: INO vs control.
4.1
4.1. Analysis
Comparison 4 Complications during the in‐patient stay: INO versus control, Outcome 1 Renal impairment: INO vs control.
4.2
4.2. Analysis
Comparison 4 Complications during the in‐patient stay: INO versus control, Outcome 2 Pneumothorax: INO vs control.
4.3
4.3. Analysis
Comparison 4 Complications during the in‐patient stay: INO versus control, Outcome 3 Severe respiratory failure: INO vs control.
4.4
4.4. Analysis
Comparison 4 Complications during the in‐patient stay: INO versus control, Outcome 4 Circulatory failure and shock: INO vs control.
5.1
5.1. Analysis
Comparison 5 PaO2/FiO2 (mm Hg): INO versus control, Outcome 1 PaO2/FiO2 up to 24 hours.
5.2
5.2. Analysis
Comparison 5 PaO2/FiO2 (mm Hg): INO versus control, Outcome 2 PaO2/FiO2 up to 48 hours.
5.3
5.3. Analysis
Comparison 5 PaO2/FiO2 (mm Hg): INO versus control, Outcome 3 PaO2/FiO2 up to 72 hours.
5.4
5.4. Analysis
Comparison 5 PaO2/FiO2 (mm Hg): INO versus control, Outcome 4 PaO2/FiO2 up to 96 hours.
5.5
5.5. Analysis
Comparison 5 PaO2/FiO2 (mm Hg): INO versus control, Outcome 5 PaO2/FiO2 difference from baseline up to 24 hours.
6.1
6.1. Analysis
Comparison 6 Ventilator‐free days up to day 30: INO versus control, Outcome 1 Ventilator‐free days (28‐30 days), INO vs control.
7.1
7.1. Analysis
Comparison 7 Duration of mechanical ventilation: INO versus control, Outcome 1 Duration of mechanical ventilation.
8.1
8.1. Analysis
Comparison 8 Oxygenation index: INO versus control, Outcome 1 Oxygenation index at 4 hours.
8.2
8.2. Analysis
Comparison 8 Oxygenation index: INO versus control, Outcome 2 Oxygenation index at 12 hours.
8.3
8.3. Analysis
Comparison 8 Oxygenation index: INO versus control, Outcome 3 Oxygenation index at 24 hours.
8.4
8.4. Analysis
Comparison 8 Oxygenation index: INO versus control, Outcome 4 Oxygenation index at 48 hours.
8.5
8.5. Analysis
Comparison 8 Oxygenation index: INO versus control, Outcome 5 Oxygenation index at 72 hours.
9.1
9.1. Analysis
Comparison 9 Mean pulmonary arterial pressure (mm Hg): INO versus control, Outcome 1 MPAP up to 24 hours.
9.2
9.2. Analysis
Comparison 9 Mean pulmonary arterial pressure (mm Hg): INO versus control, Outcome 2 MPAP up to 48 hours.
9.3
9.3. Analysis
Comparison 9 Mean pulmonary arterial pressure (mm Hg): INO versus control, Outcome 3 MPAP up to 72 hours.
9.4
9.4. Analysis
Comparison 9 Mean pulmonary arterial pressure (mm Hg): INO versus control, Outcome 4 MPAP up to 96 hours.
10.1
10.1. Analysis
Comparison 10 Reversal of ALI: INO versus control, Outcome 1 Reversal of ALI.
11.1
11.1. Analysis
Comparison 11 Methaemoglobin concentration > 5%: INO versus control, Outcome 1 Methaemoglobin > 5%.
12.1
12.1. Analysis
Comparison 12 NO2 concentration > 3 ppm: INO versus control, Outcome 1 NO2 concentration > 3 ppm.
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