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Just Say No To NO
Abstract and Commentary
Synopsis: In a randomized, clinical trial involving patients with ALI/ARDS from non-sepsis etiologies, inhaled nitric oxide at 5 ppm failed to improve any of the clinically meaningful outcomes.
Source: Taylor RW, et al. JAMA. 2004;291:1603-1609.
In this randomized, controlled clinical trial performed between 1996 and 1999, Taylor et al studied effects of inhaled nitric oxide (NO) at 5 ppm in intubated patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) within 72 hours of illness onset. Their hypothesis was that inhaled NO would improve the outcomes of patients with ALI/ARDS who have only pulmonary dysfunction. To test their hypothesis, they used a modified definition of ARDS/ALI and included a group of patients that had PaO2/FIO2 ratios of < 250 mm Hg. Patients were excluded from the study if they had evidence of sepsis or septic shock or if they had significant non-pulmonary organ failure. The patients were followed until 28 days, or until taken off assisted breathing, or death. End points for the study included alive and ventilator free at day 28, overall mortality rate as well as number of days patients were alive following a successful unassisted ventilation test. The investigators, the care providers and the patients were blinded to treatment assignments.
A total of 385 patients were enrolled in the study. An intent-to-treat analysis found no difference in the number of days patients were alive and off assisted breathing. The mean (SD) for the NO group was 10.7 (9.7) days compared to 10.6 (9.8) days in the placebo group. There was a statistically significant improvement in the NO group in oxygenation after starting NO that was observed for up to 48 hours only. Overall mortality was similar between the 2 groups (23% for the NO group, 20% for the placebo group). Similarly, number of days the patients were alive following successful 2-hour unassisted ventilation trial were similar between the NO group (11.4) and the placebo (11.9) group. Similar numbers of patients were treated in prone position to help with oxygenation and similar number of infections and ventilator alarms were noted.
Overall, the study did not detect any benefit of using inhaled NO at 5 ppm in this group of patients with ALI/ARDS.
Comment by Uday B. Nanavaty, MD
With this trial, hopefully, inhaled NO will be added to the long list of pharmacotherapies that have failed to show any measurable improvement in outcome in patients with ALI/ARDS. The only intervention thus far to have significant impact in mortality of patients with ARDS has been the ventilator strategy using low tidal volume. It is important to remember that in this particular trial, ARDS Network strategy of low tidal volume was not used. Time and again it is noted that there seems to be little correlation between correction of hypoxemia and improvement in outcome.
Nitric oxide has vasodilator properties in pulmonary, as well as systemic, circulation. It has been shown to have immunomodulatory properties such as reducing neutrophil adhesion and preventing platelet aggregation. Why then does it fail to have an impact in ARDS patients? There are multiple explanations of this question. One thing is clear that NO does act as a vasodilator, in pulmonary circulation, in ARDS patients. The improvement in oxygenation seen early on is thought to represent vasodilation in ventilated areas of lung that get the inhaled NO and improvement in the V/Q mismatch. It is possible that the capillary beds that are affected by the underlying pathogenic mechanism somehow do not respond to the inhaled NO; thus only healthy areas of lung somehow participate in the improvement in oxygenation. In the healthy areas of lungs, there would be no apparent benefit of its "immunomodulatory" effects. It is also possible that some of the benefit of improved oxygenation is offset by an as yet unidentified toxicity of NO. Inhaled NO is expensive and somewhat cumbersome to use. In spite of its inability to improve outcome in the wider population of ALI/ARDS population, unfortunately use of NO will continue without sound evidence in the very sick patient population with refractory hypoxia and ARDS as a "salvage" therapy until a trial in such patients proves or disproves the notion of such "salvage" therapies.
Uday B. Nanavaty, MD, Pulmonary and Critical Care Medicine, Rockville, Maryland, and Associate Editor of Critical Care Alert.