Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis

Abstract

Objective: To review the literature on the use of inhaled nitric oxide to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and to summarise the effects of nitric oxide, compared with placebo or usual care without nitric oxide, in adults and children with ALI or ARDS.

Design: Systematic review and meta-analysis.

Data sources: Medline, CINAHL, Embase, and CENTRAL (to October 2006), proceedings from four conferences, and additional information from authors of 10 trials.

Review methods: Two reviewers independently selected parallel group randomised controlled trials comparing nitric oxide with control and extracted data related to study methods, clinical and physiological outcomes, and adverse events.

Main outcome measures: Mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, adverse events.

Results: 12 trials randomly assigning 1237 patients met inclusion criteria. Overall methodological quality was good. Using random effects models, we found no significant effect of nitric oxide on hospital mortality (risk ratio 1.10, 95% confidence interval 0.94 to 1.30), duration of ventilation, or ventilator-free days. On day one of treatment, nitric oxide increased the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) (13%, 4% to 23%) and decreased the oxygenation index (14%, 2% to 25%). Some evidence suggested that improvements in oxygenation persisted until day four. There was no effect on mean pulmonary arterial pressure. Patients receiving nitric oxide had an increased risk of developing renal dysfunction (1.50, 1.11 to 2.02).

Conclusions: Nitric oxide is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm. We do not recommend its routine use in these severely ill patients.

Fig 1 Number of trials evaluated at each stage of the systematic review

Fig 2 Effect of nitric oxide on mortality. Weight is the relative contribution of each study to the overall estimate of treatment effect on a log scale assuming a random effects model. Two trials with ≥50% of control patients crossing over to nitric oxide also reported mortality data.^w2w6 Inclusion of these trials did not alter summary mortality estimate (risk ratio 1.09, 0.94 to 1.27)

Fig 3 Funnel plot for outcome of mortality in trials of nitric oxide. Each point represents one trial

Fig 4 Effect of nitric oxide on PaO₂/FiO₂ ratio at 24 hours. Weight is relative contribution of each study to overall estimate of treatment effect (ratio of means, nitric oxide relative to control) on log scale assuming a random effects model. For some trials, number of patients with data is less than number randomised

Fig 5 Effect of nitric oxide on oxygenation index at 24 hours. Weight is relative contribution of each study to overall estimate of treatment effect (ratio of means, nitric oxide relative to control) on log scale assuming a random effects model. For each trial, number of patients with data is less than number randomised

Fig 6 Effect of nitric oxide on renal dysfunction (defined as new renal replacement therapy,^w8 new renal replacement therapy or new raised creatinine concentration (>300 µmol/l^w7), or raised creatinine concentration (>177 µmol/l^w3 or ≥265 µmol/l^w12)). The denominator includes only patients without baseline renal dysfunction,^{w7 w8 w12} except possibly for one trial.^w3 Use of a different definition of renal dysfunction (“adverse event”) in one trial^w3 did not alter the summary estimate (risk ratio 1.49, 1.10 to 2.03). Weight is relative contribution of each study to overall estimate of treatment effect on log scale assuming a random effects model