Use of inhaled nitric oxide in patients with acute respiratory failure with low blood oxygen does not improve survival

Background

When a person has acute respiratory failure, some physicians administer nitric oxide (NO), which is a colourless gas that can dilate the pulmonary vasculature. This gas has been hypothesized to improve acute respiratory failure, as it could improve oxygenation by selectively improving blood flow to healthy lung segments.

Our objective was to evaluate whether this treatment improves outcomes of adults and children with acute respiratory failure.

Study characteristics

We included in this updated review 14 trials with 1275 participants. We found the overall quality of trials to be moderate, with little information provided on how experiments were carried out. Results were limited, and most included trials were small. In most trials, we identified risk of misleading information. Thus, results must be interpreted with caution. The evidence is up-to-date to 18 November 2015.

Key results

No strong evidence is available to support the use of INO to improve survival of adults and children with acute respiratory failure and low blood oxygen levels. In the present systematic review, we set out to assess the benefits and harms of its use in adults and children with acute respiratory failure. We identified 14 randomized trials comparing INO versus placebo or no intervention. We found no beneficial effects: despite signs of oxygenation and initial improvement, INO does not appear to improve survival and might be hazardous, as it may cause kidney function impairment.

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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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 strategy: 

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).

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