Key Point

Use of corticosteroids does not prolong survival in patients with persistent ARDS despite their ability to improve cardiopulmonary physiology.

SEATTLE—Results from the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (ARDSNet) do not support the routine use of methylprednisolone for persistent ARDS despite their ability to improve cardiopulmonary physiology.¹ "The results clearly show that steroids do not prolong survival when given to patients with late-stage ARDS," explained Gordon Bernard, MD, Chair of the ARDSNet Steering Committee. "We therefore urge great caution in treating these patients with steroids." Dr. Bernard is also the Director of the Division of Allergy, Pulmonary, and Critical Care Medicine at Vanderbilt University in Nashville.

STUDY DESIGN

Several previous studies have shown that high-dose corticosteroids might increase the risk of secondary infections in patients with sepsis and ARDS; however, a small study of moderate-dose corticosteroids in patients with persistent ARDS demonstrated improvements in physiologic and biochemical outcomes without an increased risk of infection. Therefore, Kenneth P. Steinberg, MD, lead author of the current study, and his colleagues hypothesized that the "administration of moderate-dose methylprednisolone to patients with persistent ARDS would improve clinical outcomes without significantly increasing complications." Dr. Steinberg is an Associate Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at the University of Washington in Seattle.

The researchers randomly assigned 180 patients with ARDS—from 25 hospitals that participated in ARDSNet between August 5, 1997, and November 17, 2003—to receive either methylprednisolone or placebo. Patients had to have at least seven days’ duration of illness and continual mechanical ventilation and persistent bilateral infiltrates to be eligible for enrollment in the study.

Patients receiving methylprednisolone were given a single dose of 2 mg/kg of predicted body weight followed by a dose of 0.5 mg/kg of predicted body weight every six hours for 14 days. They were then given 0.5 mg/kg of predicted body weight every 12 hours for the subsequent seven days, followed by tapering of the drug. The study drug was also tapered if the patient no longer required assisted ventilation or developed septic shock. All patients were assessed daily to determine if they were ready to be weaned off the ventilator, and when acceptable arterial oxygenation could be maintained, they were weaned by pressure support ventilation. Each patient was followed until time of death, time of discharge from the hospital, or day 180—whichever came first.

The primary end point was mortality at 60 days. Secondary end points included the number of ventilator-free days and organ failure–free days, biochemical markers of inflammation and fibroproliferation, and infectious complications.

NO EFFECT ON SURVIVAL

Dr. Steinberg and his colleagues reported that mortality rates between the two treatment groups were not statistically different. At 60 days, the mortality rate was 28.6% in the placebo group and 29.2% in the methylprednisolone group. Corresponding rates at 180 days were 31.9% and 31.5%, respectively. Furthermore, they noted that methylprednisolone appeared to be associated with increased mortality rates among patients enrolled at least 14 days following the onset of ARDS.

In addition, they found that although methylprednisolone did not increase the rate of infectious complications, it was associated with a higher rate of neuromyopathy. Seventy-one percent of patients with neuromyopathy had bilateral weakness of the arms and legs, while 17% experienced sensory deficits.

Dr. Steinberg and his colleagues noted that corticosteroids did, however, result in a number of improved secondary outcomes. During the first 28 days, patients in the methylprednisolone group had increased numbers of ventilator-free and septic shock–free days, as well as improvements in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy. At 180 days, the number of days without assisted ventilation remained higher in the methylprednisolone group compared with the placebo group; however, the duration of hospitalization did not differ significantly between the two groups.

The researchers concluded that their results do not support the routine administration of corticosteroids in patients with persistent ARDS, despite any observed cardiopulmonary improvements.

MORE RESEARCH IS NEEDED

"Whether the positive effects of moderate doses of steroids seen in some ARDS patients outweigh the risks of neuromuscular complications is an issue that physicians, patients, and the patients’ families will need to grapple with," commented Dr. Bernard.

"Clinical research must continue in this area to enhance our understanding of basic mechanisms of lung injury, physiologic defense mechanisms, and tissue repair," wrote Peter M. Suter, MD, in an editorial about the ARDSNet findings.²

According to Dr. Suter, "A potential time frame for corticosteroid therapy in ARDS, as well as the optimal regimen, remains to be defined, but the current study suggests that there is a narrow window of opportunity—between seven and 14 days after the onset of disease—in which cardiopulmonary function and possibly outcome may be improved." He added, "More precise monitoring methods to assess pulmonary and systemic immune-response status are probably necessary to determine optimal time of intervention. It is hoped that progress in this field will add to the survival benefits provided by other essential components of intensive care management in these patients, including nonaggressive ventilatory support and appropriate and timely antimicrobial therapy, in concert with the many other effective treatments provided in today’s intensive care units."

—Karen L. Spittler

References
1. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006; 354:1671-1684.
2. Suter PM. Lung inflammation in ARDS—friend or foe? N Engl J Med. 2006;354:1739-1742.

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