Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase ntrial. Inhaled nitric oxide in ards study group

OBJECTIVES: To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. DESIGN: Prospective, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Intensive care units of 30 academic, teaching, and community hospitals in the United States. PATIENTS: Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. INTERVENTIONS: Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25. 5, 20,40. or 80 ppm. MEASUREMENTS & MAIN RESULTS: Acute increases in Pao;, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygénation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygénation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a Pao2 increase > 20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygénation translated into a reduction in the FIOZ over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygénation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at Day 28 (a post hoc analysis) was higher (629I vs 44'7r ) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemogiobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. CONCLUSIONS: From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygénation compared with placebo over the first 4 Iirs of treatment. An improvement in oxygénation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.