EFFECTS OF INHALED NITRIC-OXIDE IN PATIENTS WITH ACUTE RESPIRATORY-DISTRESS SYNDROME - RESULTS OF A RANDOMIZED PHASE-II TRIAL

Objectives: To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrom e (ARDS). In addition, the effect of various doses of inhaled NO on cl inical outcome parameters was assessed. Design: Prospective, multicent er, randomized, double-blind, placebo-controlled study. Setting: Inten sive care units of 30 academic, teaching, and community hospitals in t he United States. Patients: patients with ARDS, as defined by the Amer ican-European Consensus Conference, were enrolled into the study if th e 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 and M ain Results: Acute increases in Pao(2) decreases in mean pulmonary art erial pressure, intensity of mechanical ventilation, and oxygenation i ndex were examined. Clinical outcomes examined were the dose effects o f inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation c riteria for extubation. A total of 177 patients were enrolled over a 1 4-month period. An acute response to treatment gas, defined as a Pao(2 ) increase greater than or equal to 20%, was seen in 60% of the patien ts receiving inhaled NO with no significant differences between dose g roups. Twenty-four percent of placebo patients also had an acute respo nse to treatment gas during the first 4 hrs. The initial increase in o xygenation translated into a reduction in the Fio(2) over the first da y and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no dif ferences among the pooled inhaled NO groups and placebo with respect t o mortality rate, the number of days alive and off mechanical ventilat ion, or the number of days alive after meeting oxygenation criteria fo r extubation. However, patients receiving 5 ppm inhaled NO showed an i mprovement in these parameters. In this dose group, the percentage of patients alive and off mechanical Ventilation at day 28 (a post hoc an alysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported a mong those patients receiving inhaled NO compared with placebo. Four p atients had methemoglobin concentrations >5%. The mean inspired nitrog en dioxide concentration in inhaled NO patients was 1.5 ppm. Conclusio ns: 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 oxygenation compared with placebo over the first 4 hrs of treatment. An improve ment in oxygenation 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 outc ome.