Is Nitric Oxide Inhalation a "Cosmetic" Therapy in Acute Respiratory Distress Syndrome?

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The trial reported by Michael and colleagues (1) is the first randomized study focused on the time-dependent response to inhaled nitric oxide (INO). They compared the effect of inhaled NO therapy with conventional therapy on the amplitude and time course of the improvement in Pa_O2/FI_O2 as well as the reduction in FI_O2 in 40 patients with acute respiratory distress syndrome (ARDS). After a 72-h observation period, there was no substantial difference between the INO group and the conventionally treated group in terms of improvement in the Pa_O2/FI_O2 ratio and reduction in FI_O2.

Considering the number of patients in their study, generalizations of the results and conclusion are limited. Not only was the study population small (40 patients), but the number of patients who completed the entire 72-h observation period was only 32. It is reasonable to ask what likely effect a larger sample size would have on the observations made in the study. The estimated population size required to demonstrate a statistical significance as calculated by the authors would be 264,000 at 72 h for a 0.2 mm Hg difference in Pa_O2/FI_O2. If such a large sample size is needed for this small improvement, this intuitively implies that the effect of INO is small. To reduce the sample size, the signal (NO effect)-to-noise (multiple interactive factors) ratio has to be greatly improved to detect a putative benefit.

Although negative, in one sense these results confirm the findings in previous nonrandomized acute studies in which the role of INO in ARDS was tested (2). They confirm the rapid increase in Pa_O2/FI_O2 ratio observed after initiating INO therapy with a proportion of "responders" (defined as those showing a > 20% increase in Pa_O2/FI_O2) (3, 4). However, the main contribution of the study by Michael and colleagues concerns the course of such improvement in arterial oxygenation as compared with conventional therapy. Inhaled NO therapy produced only a transient benefit in Pa_O2/FI_O2 as compared with conventional therapy, and the comparative benefit was not sustained. Moreover, INO did not increase the frequency of improved oxygenation (55% [NO] versus 45% [conventional therapy]) or the likelihood of persistent improvement in oxygenation (63% versus 50%).

The present study adds more negative elements to the recently published multicentric clinical trials (4) of the impact of INO in adult ARDS. A Phase II study of different doses of inhaled NO (4) failed to find a difference in mortality or in number of days alive and off mechanical ventilation among patients treated with different levels of inhaled NO versus placebo, despite a similar proportion of "acute" responders (60%). The unpublished prospective, double-blind, randomized French Phase III study of INO in ARDS (5), like the Swedish randomized trial (6), demonstrated also no effect on mortality or duration of mechanical ventilation.

One can then ask if we should continue to test INO therapy in adult ARDS. The present study and the recent multicenter trials suggest that in a large proportion of patients, but not all, INO therapy only temporarily improves Pa_O2/FI_O2. If such improvement is transient as compared with the improvement with conventional therapy, the interest in promoting the use of INO therapy in adult ARDS is questionable.

The "pro" arguments can be listed as follows. First, Michael and colleagues (1) have nicely shown that all patients who had an improvement in Pa_O2/FI_O2 during the first day had a greater tendency for ARDS "reversibility." This was even true for patients who improved with INO. In this way, INO could be considered a test of responsiveness, like other means that have improved arterial oxygenation and predicted outcome as previously shown (7). This could even be considered a prerequisite for selecting patient populations for future clinical trials in ARDS. Patients with "nonreversible" ARDS might then constitute the most challenging group of patients to be investigated and therapeutically tested. Second, none of the previous treatments tested in ARDS has been shown to successfully reduce morbidity or mortality. Although disappointing, these negative results have provided considerable information about the pathophysiology of ARDS. Response to INO therapy shows that in addition to alveolar recruitment, pulmonary vascular manipulations that reduce flow in shunting zones are efficient means for improving arterial oxygenation (1, 8). Third, NO is a physiologic molecule with multiple functions. Among these, NO has been shown to "buffer" the inflammatory process in lung ischemia/reperfusion injury (9), in ARDS (10), and in other well-defined mechanisms of inflammation (11). Moreover, the impact of NO on coagulation may also have some long-term positive effects (12) in ARDS. However, to demonstrate any clinically significant impact of these effects of INO in ARDS, the studied population needs to be rigorously selected to homogenize the sample. The homogeneity might be based on potential reversibility, primary lung injury, and similar evolution time. Fourth, INO therapy might be useful in the extremes of the acute-lung-injury spectrum. As a rescue therapy in the most severely lung-injured patients, INO therapy has reduced the need for extracorporeal lung assistance in children (13) and adults (Falke, personal communication). On the other end of the spectrum, INO combined with other supportive means might be helpful in reducing the number of patients requiring intubation. To confirm this latter hypothesis, objective criteria for the decision to intubate have to be developed and validated.

The "con" arguments have also to be mentioned. First, since the proportion of ARDS patients dying from severe hypoxia is low (< 5%), and the improvement in Pa_O2/FI_O2 appears to be only "cosmetic," the use of a potentially toxic substance may be excessive. In addition, several other simple means have been shown to improve gas exchange, such as the prone position (14, 15). Second, since the benefit obtained with INO appears to be only transient, as shown by Michael and colleagues, and does not lead to a more pronounced reduction in ventilatory patterns and FI_O2, the utility of this therapy becomes limited. Third, considering the causes of death in the ARDS population, it seems clear that most ARDS patients die from multiple organ failure. Although little is known about the uptake of INO (16), its metabolic route, or its extrapulmonary effects in patients with ARDS, one can suspect some organ-deleterious effects. Such a hypothesis is supported by the recognized participation of the excessive production of NO in severe sepsis (17).

Michael and colleagues' study (1) provides an additional argument for questioning the U.S. Food and Drug Administration (FDA) labeling of INO as a therapeutic agent for ARDS patients. This study supports the idea of a transient effect of INO on arterial oxygenation that might constitute part of a strategy to test the potential reversibility of ARDS, and may consequently be useful as a predictor of outcome. Questions that remain to be answered include: (1) what are the determinants of the acute and the delayed response to INO; (2) what is the potential impact of INO on organ failure; and (3) at what step of the acute-lung-injury spectrum might INO therapy be useful?

DIDIER M. PAYEN

Service d'Anesthésie-Réanimation,

Hôpital Universitaire Lariboisière,

Paris, France

	Footnotes

Correspondence and requests for reprints should be addressed to Professor Didier Payen, Service d'Anesthésie-Réanimation, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75 010 Paris, France. E-mail: dpayen.lariboisiere{at}invivo.edu

Acknowledgments: Supported by Direction de la Recherche Clinique (DRC) de l'Assistance Publique-Hôpitaux de Paris, the Institut Féderatif de Recherche INSERM Circulation, and Université Paris VII, Plan Quadrienal 1997-2001.

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