© 2003 American Thoracic Society
Inhaled Nitric Oxide after Lung TransplantationNo More Cosmesis?The Lung Transplant Unit St. Vincent's Hospital Sydney, Australia Novel therapies often permeate the clinical arena before the development of solid evidence to support their use. Lung transplantation is one such therapy and may never have developed successfully if subjected to a clinical trial in its formative years. Inhaled nitric oxide (NO) is another and remains a therapy seeking a disease. Its marriage to lung transplantation is therefore somewhat appropriate. In this issue of AJRCCM (pp. 1483–1489), the single-center, randomized, placebo-controlled study by Meade and coworkers (1) is a welcome attempt to enhance our scientific use of this expensive therapy. Inhaled NO has been criticized as a cosmetic therapy with only short-term benefit, but a persuasive body of evidence is now accumulating to lend support to a broader benefit in transplant recipients (2, 3). The article by Meade and coworkers (1) challenges that experience. Central to the analysis of their data is the implicit assumption that all lung transplant recipients suffer significant early lung reperfusion injury, and, hence, that universal usage of inhaled NO would lead to a 50% reduction in length of ventilation. Clearly, inhaled NO did not reduce the incidence of reperfusion injury (22% active vs. 19% control), which is similar to that observed by King and coworkers (22%) on whose experience they based their theory that a twofold reduction in total ventilation time would be possible (4). In fact, King and coworkers (4) recorded ventilation times that were sevenfold longer in the reperfusion group (393.5 vs. 56.8 hours), emphasizing the negative impact of this complication and adding further evidence that the two groups should be analyzed separately. Also, no measurable effects on heart rate, mean arterial pressure, mean pulmonary artery pressure, cardiac index, transpulmonary gradient, measured oxygen-to-inspired oxygen ratio, and pulmonary to systemic vascular resistance ratio were found in patients without reperfusion injury in the study of Ardehali and coworkers (2). If we reanalyze the data of Meade and coworkers (1) as two separate populations, the study is seriously underpowered: they compare 9 versus 8 patients, whereas 39 patients are needed in each group to detect an absence of benefit (set at a 50% reduction in ventilation times). A more realistic goal of reducing ventilation times by 20% would have required 350 patients in each arm, representing 3,500 lung transplant recipients in total, equivalent to every lung transplant performed in the last 2 years (5). Nevertheless, useful benefits were apparent in the active group; 25% spent more than 7.5 days in the intensive care unit and more than 37.7 days in hospital as compared with 16.5 days and 46.6 days, respectively, in the placebo group. This may have related to the fact that 25% of the placebo group required assisted ventilation for more than 267 hours as compared with 75.3 hours in the active group. Indeed, median time to successful extubation was 7 hours shorter in the active group. Inhaled NO is a toxic drug with potential risks to recipients (methemoglobinemia), where precision of the delivered dose is critical to avoid rebound pulmonary hypertension (6). Most dose-finding studies in animals favor low-range therapy (10–40 ppm) as used in early case reports (7–11). Prolonged high-range therapy (80–100 ppm) is not only associated with unacceptable toxicity but also appears to lack benefit on permeability although it still reduces intrapulmonary shunt and peripheral airway bronchoconstriction (8, 12–14). When should inhaled NO be commenced, if at all? The current study chooses to use delayed onset NO at 20 ppm based on the work of Eppinger and coworkers (15). In a study of 90-minute warm lung ischemia, these investigators (15) showed that four rats given 80 ppm inhaled NO at the start of reperfusion and killed after 30 minutes reperfusion had more permeable lungs than had four rats that received NO after a delay of 10 minutes (15). The delayed group had received NO for only 20 minutes before being killed. The impact of early NO on permeability was abolished by pretreatment with superoxide dismutase suggesting the increased permeability seen at 30 minutes was secondary to the interaction of NO with endogenous superoxide anions, which have a short half-life in reperfused tissues. Rats studied after 4 hours of reperfusion actually showed a nonsignificant reduction in permeability in the early versus delayed NO groups. Unfortunately, the effect of different NO doses was not studied. Other clinical investigators have used NO at reperfusion without deleterious consequences and also concluded that although reperfusion injury was not eliminated, patients with reperfusion injury treated with NO had superior gas exchange and pulmonary hemodynamics (2). Date and coworkers (3) commenced NO at 20 to 60 ppm on diagnosis of reperfusion injury and observed a reduction in mortality from 4/17 to 1/15. Fujino and coworkers (16) showed a reduction in myeloperoxidase activity in five dog lungs where inhaled NO was given at 60 ppm at time of harvest and postulated a lower risk of neutrophil sequestration syndrome as shown by Bacha and coworkers (7) in pigs given 4 hours of NO during reperfusion. Pulmonary allografts are depleted of glutathione, an endogenous scavenger of reactive oxygen species, and hence are more at risk from high-flow oxygen, another factor that was well controlled in the study of Meade and coworkers. In addition, allografts are subjected to both cold (ex vivo) and warm (in vivo before reperfusion) ischemia unlike many experimental models of lung ischemia. Nevertheless, some clinical progress has been made. The use of a strict weaning protocol, which has allowed the mean ventilation time to be reduced with or without inhaled NO is to be applauded. Within a decade of its first use as a therapy for post-transplant ischemia–reperfusion injury, inhaled NO is now seen as a useful tool in selected patients with clinically significant lung injury (2). Hopes of a panacea have been tempered by the recognition that ischemia–reperfusion injury is not prevented by inhaled NO, but short- to medium-term benefits on gas exchange, pulmonary hypertension, and reduction in neutrophil sequestration are demonstrable in this group. The rationale for all patients receiving inhaled NO after lung transplantation has been further elucidated by the current study with a persuasive argument in the negative. Further adequately powered studies are still required to define the optimum dose and timing of inhaled NO in patients who do have ischemia–reperfusion injury after lung transplantation. REFERENCES
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