Nitric Oxide Called No Good for Acute Lung Injury

TORONTO, March 23 -- The common practice of giving patients with acute lung injury nitric oxide may do more harm than good, investigators here reported.

In a meta-analysis, patients with acute lung injury or acute respiratory distress syndrome (ARDS) treated with nitric oxide had no significant improvements in in-hospital mortality, duration of ventilation, or ventilator-free days, and were at increased risk for renal dysfunction, the investigators found.

"Nitric oxide improves oxygenation temporarily but does not improve survival and may harm," reported Neill K.J. Adhikari, M.D., of the University of Toronto, and colleagues, online in BMJ. "We do not recommend routine use of nitric oxide in patients with acute lung injury."

They added, "Despite a lack of evidence for benefit, some clinicians may still consider nitric oxide for life threatening hypoxemia, in conjunction with other supportive therapies. Given the challenges of enrolling such severely ill patients into large trials, definitive data supporting or refuting a role for nitric oxide in such desperate situations may not be forthcoming, leaving clinicians to rely on their judgment and the current evidence."

Their meta-analysis added to the evidence garnered in a systematic review of nitric oxide for acute hypoxic respiratory failure in children and adults, published by a separate group of University of Toronto researchers in 2003 in Anesthesia and Analgesia.

In that study, which looked at five randomized trials of nitric oxide, the authors found that there was no effect of the gas on mortality or ventilator-free days, although one study showed an improvement in oxygenation. They concluded that the effect of nitric oxide in this setting was uncertain.

This time, Dr. Adhikari and colleagues cast a wider net, reviewing the literature on use of inhaled nitric oxide to treat acute lung injury and ARDS in adults and children.

Their main outcome measures were mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, and adverse events.

Two independent reviewers identified a total of 12 trials in which 1,237 patients were randomly assigned to either nitric oxide or a comparator (placebo or standard care).

The found that despite its widespread use, the addition of nitric oxide had no significant effect on in-hospital mortality, with a risk ratio of 1.10 (95% confidence interval 0.94 to 1.30); duration of ventilation (17% increase, 95% CI, -20% to 70%, 3.6 additional days, -4.0 to 11.1 days); or ventilator-free days (6% decrease, 95% CI, -16% to 6%, 0.6 fewer days, -1.8 to 0.7 days).

Nitric oxide, however, improved oxygenation on day one of treatment, as measured by an increase in the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) which rose by 13% (range 4% to 23%). In addition, there was a 14% decrease (2% to 25%) in the oxygenation index.

"Some evidence suggested that improvements in oxygenation persisted until day four," the authors wrote. "There was no effect on mean pulmonary arterial pressure."

On the negative side of the ledger, they discovered that patients who received nitric oxide had an increased risk of developing renal dysfunction (risk ratio 1.50, 95% CI, 1.11 to 2.02). The authors cautioned, however, that this finding came from a post-hoc analysis and may have been subject to publication bias, since they did not have data on renal outcomes for eight of 12 smaller trials.

"In addition, the potential physiological mechanisms linking administration of inhaled nitric oxide to acute renal dysfunction -- inhibition of mitochondrial and enzymatic function and damage to deoxyribonucleic acid and membranes -- are controversial because of its simultaneous protective effects on renal blood flow and leukocyte adhesion," they wrote.

The investigators noted that their study was limited by the lack of complete data from some of the studies in the meta-analysis, and uncertainties about the heterogeneity of data on physiological outcomes due to small sample sizes.