Inhaled nitric oxide for acute lung injury: no place for NO?

IT IS ESTIMATED THAT UP TO 107000 CASES OF ACUTE LUNG injury (ALI) and acute respiratory distress syndrome (ARDS) occur yearly in the United States. Although the mortality rate from ARDS has been decreasing, between 17000 and 43000 patients die from ALI and ARDS annually. Despite substantial progress in understanding the pathophysiology of this syndrome and numerous randomized controlled trials (RCTs) of both pharmacological agents and mechanical ventilatory strategies, the only interventions shown to reduce mortality have been lung-protective strategies of mechanical ventilation that decreased tidal volume. In the ARDS Network trial, tidal volume limitation was associated with a clinically and statistically significant 22% relative reduction in mortality for patients with ALI and ARDS. Central to the success of these trials is the concept that mechanical ventilation itself perpetuates lung injury. Although this concept has led to positive studies of interventions to decrease iatrogenic lung damage complicating ARDS, no multicenter trial has convincingly demonstrated benefit from interventions such as surfactants, corticosteroids, ketoconazole, or other therapies that treat the underlying pathogenic mechanisms or physiological perturbations that characterize ALI and ARDS. In the context of an empty therapeutic armamentarium for lung injury, considerable research efforts and clinical enthusiasm greeted the discovery of nitric oxide (NO). From a clinical perspective, inhaled nitric oxide has many of the properties of an ideal pulmonary vasodilator. It acts on the endothelial surface of the lung to produce regional vasodilation in ventilated lung units. As a result, nitric oxide was expected to produce relatively selective pulmonary vasodilation that in theory would improve the ventilationperfusion mismatch, hypoxemia, and pulmonary hypertension characteristic of ARDS. The short half-life of nitric oxide suggested that it was free of significant systemic hemodynamic effects. Given the potential role of nitric oxide as a pulmonary vasodilator, its use as a therapeutic agent increased dramatically and rapidly. A survey of members of the European Society of Intensive Care Medicine in 1997 found that 63.2% of respondents (196/310) prescribed inhaled nitric oxide , primarily for treatment of ALI and ARDS. Consistent with the role of nitric oxide as a pulmonary vasodilator, earlier case series and a single-center RCT demonstrated that it induces short-term improvements in oxygenation and pulmonary vascular resistance in patients with lung injury. Unfortunately, these physiologic gains have not translated into improved patient outcomes when nitric oxide was evaluated in larger controlled studies. A recent systematic review of 5 RCTs of inhaled nitric oxide vs placebo or no therapy for acute hypoxemic respiratory failure (including ALI, ARDS, and other diagnoses) in adults and children concluded that inhaled nitric oxide produced modest improvements in oxygenation for up to 72 hours but had no effect on mortality (pooled relative risk using fixed effects model, 0.98; 95% confidence interval, 0.661.44) or on the duration of mechanical ventilation. In addition to direct effects on gas exchange, nitric oxide has potentially beneficial immunological properties; it inhibits platelet aggregation and neutrophil adhesion. The anti-inflammatory properties of nitric oxide have been postulated to explain decreased ischemia-reperfusion lung injury in animal models and in small observational studies of lung transplantation. However, a recent RCT of nitric oxide administered immediately after lung transplantation failed to demonstrate an improvement in either oxygenation variables or clinical outcomes. In this issue of THE JOURNAL, Taylor and colleagues make an important contribution to this literature. Between 1996 and 1999, the investigators enrolled 385 patients with moderately severe ALI and ARDS in a randomized placebocontrolled multicenter trial of inhaled nitric oxide at 5 ppm. The rationale for this dose was based on an earlier placebocontrolled RCT that evaluated several doses of nitric oxide (1.25, 5, 20, 40, or 80 ppm) in 177 patients with ARDS. Although there was no clinical benefit in the nitric oxide group overall in that study, a post-hoc analysis suggested that patients receiving nitric oxide at 5 ppm had significantly improved ventilation-free survival 28 days after randomization.