Acute Respiratory Distress Syndrome: Steroids Revisited
Acute Respiratory Distress Syndrome: Steroids Revisited
ABSTRACT & COMMENTARY
Synopsis: In a controlled, randomized, double-blind trial in patients whose ARDS failed to resolve, methylprednisolone was associated with improved measures of lung injury and reduced mortality.
Source: Meduri GU, et al. JAMA 1998;280:159-183.
Ards has challenged critical care physicians and pulmonologists for the past quarter century. It remains a common cause of respiratory failure and death in the intensive care unit and still continues to affect young patients. It remains an important complication of surgery, cancer chemotherapy, and systemic and respiratory infection. Mortality, though declining, still remains in the 35-65% range. While clinical trials have continued to explore numerous avenues to confront this problem, most innovative strategies have proven disappointing. Recent attempts to improve outcome by manipulating ventilatory settings to reduce transpulmonary pressure-the so-called permissive hypercapnia approach-have not convincingly demonstrated improved outcomes. In initial descriptions of this syndrome, corticosteroids were the standard therapeutic approach. However, randomized trials, in early ARDS (< 48 hours), failed to demonstrate that steroids were of benefit.1,2 Meduri et al now build on their experience using corticosteroids to suppress inflammation in the latter stages of ARDS. After 4-7 days, fibrotic and proliferative changes occur, presumably because of uncontrolled inflammation. These investigators examine a small group of patients with severe ARDS diagnosed by conventional criteria that had been on mechanical ventilation at least seven days and had significant lung injury. If they had no evidence of active infection as assessed by bronchoalveolar lavage, corticosteroids were administered--initially a dose of 2 mg/kg for an average of approximately one month.
Randomization schedule was 2:1 (treatment to placebo) and provided for crossover in treatment failures. Physiologic and severity scores for both sets of patients were similar at the start of the study. Improvement in the methylprednisolone group was observed by day 5, with improvement of PAO2/FIO2 ratio from 161 to 217, in static lung compliance by day 7 from 25 to 32, in lung injures scores by day 5 from 3 to 2.2, and in pulmonary artery pressures from 30 to 22. Circulating bands did not change. All patients initially randomized to methylprednisolone demonstrated an improvement in lung injury score, but only two of four who were crossed over had similar responses. Duration of mechanical ventilation decreased by 50% (23 to 12 days) in the treatment group. Intensive care survival improved from 37% in the placebo group to 100% in those treated. Hospital mortality was 12% in the treatment group vs. 62% of the placebo group. Infections were significant in both groups but remained higher in the methylprednisolone group (1.8).
COMMENT BY ALAN M. FEIN, MD
The management of acute respiratory distress syndrome has remained challenging despite evidence that the overall mortality rate has declined over the past 25 years. Outcomes in general remain poor, especially when severe gas exchange abnormalities persist or sepsis supervenes. Neither the use of lung intervention strategies, surfactant replacement, nor anti-inflammatory strategies with anti-cytokines has proved to be useful. Trials of methylprednisolone for ARDS conducted in the 1980s offered little evidence of benefit during the acute phases of the syndrome. Meduri et al previously demonstrated that ongoing inflammation, as indicated by circulating and pulmonary cytokine levels, is associated with increased mortality. Descriptive studies of steroid use suggested that, after the first week, patients treated with corticosteroids tended to improve physiologically, coincidentally, with a decline in markers of inflammation.
Now the same investigators report, in a very small randomized, control trial, that methylprednisolone, when given to patients requiring mechanical ventilation, after approximately one week, improved not only their physiology but also their chance of discharge from the hospital. The authors were meticulous in guaranteeing that no active infection was present in the treatment group, as steroids could certainly exacerbate this problem. Steroids inhibit host defenses at multiple points and could just as well promote overwhelming infection as inhibit the development of pulmonary fibrosis. The mechanisms for improved outcomes were unclear but likely relate to inhibition of the progressive pulmonary fibrosis and cystic lung disease known to complicate prolonged ARDS. Should this therapy be adopted by clinicians, the randomized, double-placebo nature of the control does provide a high level of confidence. However, the very small numbers of patients and the early termination of the trial suggest that further confirmatory trials should be undertaken. In my own practice, I use corticosteroids in patients with ARDS who fail to respond after five days and who do not have an active infection. Pneumonia remains an increasing cause of ARDS, and care should be undertaken in initiating steroid therapy when the problem remains present. The dosage and timing also remain to be further clarified. The data from Meduri et al provide further back-up for what, up until this time, had been highly empirical anti-inflammatory therapy for a devastating critical illness.
References
1. Lefering R, Neugebauer EAM. Crit Care Med 1995; 23:1294-1303.
2. Cronin L, et al. Crit Care Med 1995;23:1430-1439.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.