Steroids in Early ARDS

The long-established anti-inflammatory actions of corticosteroids have made these drugs the most well studied of potential therapies for ARDS. Initial studies examined the use of high dose methylprednisolone in early ARDS. In 1987, Bernard and colleagues published a placebo-controlled trial of four doses of 30 mg/kg of methylprednisolone ( Table 36-1 ). Ninety-nine patients were randomized within 3 days of having ARDS. At 45 days, there were no differences in mortality, pulmonary compliance, or severity of ARDS as determined by arterial blood gas analysis or chest X-ray appearance. Similar results had been observed with high-dose steroids in patients with septic shock who commonly have ARDS.

Further trials of corticosteroids in ARDS followed this initial study. These trials have used lower steroid doses than the original study, but these remain significantly greater than normal physiologic levels, even under stress. In 2006, a retrospective subgroup analysis of patients with ARDS in a study of corticosteroids in sepsis found that in early ARDS patients there was a reduction in mortality in those patients treated with 7 days of low-dose corticosteroids and mineralosteroids. This effect was only seen in the patients who did not show a response to a short Synacthen (ACTH) test.

In 2007, Meduri and colleagues reexamined the use of corticosteroids in early ARDS with patients recruited within 72 hours of onset of ARDS. Ninety-one patients were randomized with a ratio of two patients in the treatment group for each one in the placebo group. The dose of methylprednisolone was 1 mg/kg/day for 2 weeks, which was tapered over a further 2 weeks. Compared with placebo, there was a significant improvement in intensive care unit (ICU) survival and a trend toward an increased hospital survival in the steroid group. At day 7, there were also improvements in length of ICU stay, ventilator-free days, Pa o ₂ /F io ₂ (partial pressure of oxygen in arterial blood/fraction of inspired oxygen) ratio, lung injury score, and multiorgan dysfunction score in the treatment arm of the study compared with placebo.

At longer term follow-up (up to 12 months), there was no significant mortality benefit but a trend to improved survival in the steroid-treated patients. The significantly higher baseline incidence of shock in the placebo group may have contributed to this trend. There were significantly fewer infectious complications in the methylprednisolone group but a nonsignificant trend toward more ventilator-associated pneumonia in this group.

Steroids in Late ARDS

The lack of efficacy of steroid therapy in preventing the development of ARDS prompted researchers to investigate their potential in the later, so-called fibroproliferative stage of lung injury. Steroid therapy has an established, if somewhat controversial, role in the treatment of other causes of pulmonary fibrosis. Meduri and colleagues reported a case series of nine patients with ARDS and fibrotic changes on open lung biopsy. The use of 2 to 3 mg/kg/day of methylprednisolone resulted in improvement in lung injury scores, chest X-ray appearance, and oxygenation in all patients. A reduction in neutrophil levels in BAL specimens was also noted. A larger case series of 25 patients was published by the same author in 1994 using similar doses of methylprednisolone followed by a tapering dose over 6 weeks, resulting in marked improvement in most indices of lung function.

In a further randomized placebo-controlled trial of 24 patients (with 2:1 randomization to the methylprednisolone group), low-dose methylprednisolone, of at least a 7-day duration, improved hospital mortality and indices of lung function. Mortality in the control group was due to unresolved ARDS, with four of five deaths associated with hypercapnic respiratory failure. There was, however, a nonsignificant trend toward increased ventilator-associated pneumonia in the treatment group.

These small studies and case series prompted a larger trial into the use of steroids in late, nonresolving ARDS that was conducted by the ARDS Clinical Trials Network and published in 2006. This was a 25 center trial of methylprednisolone in patients recruited 7 to 28 days after the diagnosis of ARDS. ARDS was due to direct causes of lung injury in 55% of patients. Patients were followed up until death, discharge, or 180 days. Of 4123 patients screened for the trial, only 180 patients were randomized to receive 2 mg/kg/day methylprednisolone or placebo. Major causes of exclusion were due to previous steroids or immunosuppression (22%), chronic lung disease (15%), and physician refusal (8%). The steroids were tapered over a 3 week period unless the patient remained ventilated at 21 days when the steroids were tapered over 4 days.

At 60 days, mortality was 28.6% in the placebo group and 29.2% in the treatment group (nonsignificant difference). Patients who had had ARDS for more than 13 days and received steroids had a statistically significant increased 60-day mortality compared with the placebo group. Patients with a raised procollagen type III in BAL specimens (a biologic marker of collagen synthesis and thus pulmonary fibrosis) showed an improvement in mortality in the treatment group.

A number of secondary endpoints were significantly better in the treatment group. These included ventilator-free days during the first 28 days as well as at 180 days. Patients in the treatment group were able to breathe without assistance earlier than patients given placebo. Compared with the placebo group, the methylprednisolone group had significantly fewer days in the ICU during the first 28 days. Indices of oxygenation and respiratory mechanics were improved in the patients receiving steroids. However, more patients in the treatment group required resumption of ventilatory support, and these patients were more likely to be shocked. There was no increase in infectious complications in the steroid group; in fact, there were fewer cases of pneumonia and fewer incidences of septic shock.

The main conclusions drawn from this trial were that administration of methylprednisolone in late ARDS did not result in any survival improvement, and when patients were treated with steroids at later than 13 days into their illness, there was an increase in mortality. It should, however, be noted that there was a high exclusion rate for patients, raising the question of the wider applicability of these data to clinical practice. Second, the rapid tapering of steroids after extubation may have been a factor in causing the higher levels of reintubation in the steroid group.

Timing of Doses

Experimental studies of anti-inflammatory agents in lung injury emphasize that the timing of the intervention is important. Anti-inflammatories are often effective if given before or during the initiation of the injury-inducing agent. Given at a later period, they are commonly ineffective. These studies suggest that earlier intervention is more likely to prevent the progression of ALI. Evidence that lung fibrosis begins at a very early stage of ALI would also support the earliest possible use of anti-inflammatories. Clinical data in ARDS also support this. Inflammatory cytokines are present in the plasma and in the BAL specimens of patients with ARDS from the outset of their illness, and their presence may predate the clinical manifestation of ALI. For example, Park and coworkers found that in patients at risk of ARDS (patients with sepsis or trauma), levels of tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) β were elevated in BAL specimens before the onset of clinical lung injury.

The timing of steroid dose differed significantly in two major studies. The ARDS net study recruited patients at least 7 days into the course of their disease, whereas Meduri’s group recruited patients within 3 days of diagnosis. One interpretation of these trials is that steroids may only be effective if given early in lung injury, before the inflammatory process has caused irreversible damage to the alveoli.

Duration of Treatment

Proinflammatory and anti-inflammatory cytokines are present at raised levels in BAL specimens until at least 21 days into the course of ARDS. If the rationale for treatment is to reduce inflammation in the lungs, then a prolonged course is more likely to be of benefit. However, steroid-related side effects will increase with duration of therapy and could negate any potential benefits.

Steroid Dose

Very little is known about steroid dose/response relationships in the critically ill. Metabolism and tissue distribution of steroids will change in this population. In addition, the principal target of anti-inflammatories remains uncertain with both local (lung) and systemic actions of possible importance. Furthermore, the inflammatory response is extremely complex and multifaceted. Overlapping and redundant pathways are common, and it may be naive to presume that a “one-dose-fits-all strategy” of anti-inflammatory treatment will be successful.

Physiologic Response

In the retrospective analysis of ARDS patients from the sepsis trial conducted by Annane in 2002, there was a difference in outcome from steroid treatment in subgroups depending on their response to a corticotrophin test. Furthermore, the ARDSnet study found different results depending on whether patients had greater than or less than median levels of procollagen type III in BAL specimens. Selection of patients dependent on inflammatory cytokine levels or other biomarkers of inflammation may in the future help predict response to steroids in ARDS.

Direct and Indirect Lung Injury

ARDS is a heterogeneous syndrome with outcome determined by multiple factors including the nature of the initial insult. The mortality of patients with direct lung injury (e.g., pneumonia) may be greater than those with indirect injury (e.g., sepsis). This suggests that different inflammatory pathways may be involved in the pathogenesis of lung injury. The trials differ, to some extent, in recruitment in terms of the cause of lung injury. There is a slightly higher proportion of direct lung injury in one positive study of steroids in ARDS. It may be that the two causes of lung injury behave differently in their response to steroids and other treatments. For example, there are data to suggest that different patterns of lung injury respond differently to lung recruitment strategies.