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Article Reviewed:

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Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.

Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA.

JAMA 1998; 280:159-165. [abstract]

Reviewed by Michael Kelly, MD and Steven Pon, MD, New York Presbyterian Hospital - Weil Medical College of Cornell University

Review posted June 11, 1999

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I. What is being studied?:

The study objective:

Determine the effects of prolonged methylprednisolone therapy on lung function and mortality in unresolving ARDS (acute respiratory distress syndrome).

The study design:

Randomized, double-blind, placebo-controlled with the possibility of cross over.

The patients included:

Patients in four medical intensive care units in Memphis over 18 years of age who met consensus criteria for ARDS; had no evidence of untreated infection, receiving mechanical ventilation for at least 7 days with a lung injury score (LIS) of at least 2.5 with less than a 1 point reduction from day 1 of ARDS.

The patients excluded:

Patients enrolled in another investigational study; patients with ARDS for more than 3 weeks; patients with extensive burns; pregnant patients; patients with life expectancy less than 3 months; history of UGI bleed within the past three months or patients who had a disease process requiring more than the equivalent of 1 mg/kg day of methylprednisolone.

The interventions compared:

Methylprednisolone group (16 patients) received methylprednisolone; eight received placebo. Methylprednisolone was given at dose of 2mg/kg/d for 14 days or until extubation. The dose was then tapered with a set schedule until day 32. Patients whose LIS who did not improve by at least 1 point by study day 10 were crossed over to the other arm.

The outcomes evaluated:

Primary outcomes were changes in LIS and mortality; secondary outcomes were improvement in MODS (multiple organ dysfunction score) and development of nocosomial infection.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomized by a random number generator in blocks of three (2 to methylprednisolone, 1 to placebo), stratified by hospital.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. No patients were lost or excluded in the analysis.

Were patients analyzed in the groups to which they were randomized?

Yes, however 4 patients in the placebo group crossed over to the methylprednisolone arm. In the primary analysis, they were included as part of the placebo group.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. An equal volume of saline was administered to the placebo group, or placebo tablets that were similar to the methylprednisolone tablets.

4. Were the groups similar at the start of the trial?

Groups were similar at onset of ARDS and at study entry with respect to age, APACHE III, LIS and MODS scores, and other variables. The methylprednisolone group, however, had lower LIS and MODS scores at study entry compared with onset of ARDS. The placebo group had higher LIS and MODS score at study entry compared to onset of ARDS (as discussed in the accompanying editorial (1)). (It is actually difficult to ascertain the change in LIS from ARDS onset to study entry, since the first score is reported as a mean with the standard error of the mean, and the second as a median with interquartile ranges) This suggests some pre-randomization improvement in the treated group.

5. Aside from the experimental intervention, were the groups treated equally?

Double blinding probably prevented any differences from being intentional. The only ventilator strategy mentioned is that plateau pressure was kept at 35 cm of water or less. Of note, a subgroup of these patients are reported as part of another study by Meduri where more detail is given on ventilator management (PEEP up to 20 cm H2O to keep FiO2 less than 0.6) (2).

III. What were the results?

1. How large was the treatment effect?

There were no ICU deaths in the methylprednisolone group; 2 patients died after ICU discharge for reasons felt to be unrelated to ARDS. Five patients in the placebo group died, including three of the four who crossed over to the methylprednisolone group. One of these three died after exiting the study due to a large bleeding rectal ulcer. By study day 10, the methylprednisolone group had improved PaO2/FiO2 ratios, LIS and MODS scores, static lung compliance and mean pulmonary artery pressures. No improvements were seen in the placebo group as a whole. Four patients in the placebo group did not cross over; 2 had improvements in LIS and 2 died before 10 days.

Hospital survival was therefore 87% in the treated group compared to 37% in the control group (intention-to-treat analysis), for a relative risk of death of 0.2, and an absolute risk reduction (ARR) of 0.5 in the treated vs. controls.

2. How precise was the estimate of the treatment effect?

The study was stopped after 24 patients were enrolled due to the difference in ICU survival rates; 100% in the methylprednisolone arm vs. 38% in the placebo arm. The small number of patients enrolled limits the strength of conclusions with regard to mortality or clinical indices. For example, the 95% confidence intervals around the ARR of 50% are 11.5% and 88.5%. These are broad intervals, but they do not cross zero.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Pediatric patients were not enrolled and underlying diagnoses were not given. For these reasons, one must be cautious in applying this data to pediatric patients.

2. Were all clinically important outcomes considered?

In addition to mortality, LIS, PaO2/FiO2 ratios and MODS scores, the number of successful extubations and survivors to ICU and hospital discharge were also evaluated. The methylprednisolone group fared significantly better in each of these categories as compared to the placebo group.

3. Are the likely treatment benefits worth the potential harms and costs?

The infection rate per day of mechanical ventilation was 1.8 times higher in the methylprednisolone group compared to the placebo group, although there was no statistically significant difference in the absolute number of infections. The difference in infection rate per day of mechanical ventilation might be due to the fact that the methylprednisolone group had fewer total days of mechanical ventilation. These data are not provided in the study. This however would be a small price to pay for a treatment that might improve ICU survival (given the caveat that these results are borne out in larger trials).

Reviewers' Comments

This study of the use of prolonged methylprednisolone study in unresolving ARDS has provoked numerous comments (1,3) which have mainly revolved around the study design, and in particular, the opportunity to cross over. Three out of the four patients who crossed over to the methylprednisolone arm died while two of the four who did not cross over survived. The small number of patients enrolled in the study is also a limitation. Meduri and colleagues (4) in reply to Wheeler et al. (3) address these concerns.

Despite these limitations, as well as previous large trials that did not show any benefit from steroids in ARDS, the possibility that the results of Meduri et al. are valid is attractive and intriguing. It is attractive because despite reports in the adult literature of improved survival in ARDS (5), therapy remains supportive while new strategies such as inhaled nitric oxide, prone positioning and the "open lung" approach are designed to limit ventilator induced lung injury. If the data in this study were validated in larger studies, it would represent a first step in the ability to modulate the pathophysiology of ARDS. The results are intriguing furthermore because in this study steroids were used more for their antifibrotic effects rather than their anti-inflammatory effects. As Meduri outlines in this study and a parallel study (2) published in the American Journal of Respiratory and Critical Care Medicine, patients treated with methylprednisolone have a significant decline in serum levels of Procollagen Types I and III Aminoterminal Propeptide (PINP and PIIINP), metabolites of the predominant collagens in lung fibrosis. In addition, serum levels of these antigens are elevated in all patients with ARDS but survivors had significantly lower levels than non-survivors by day 5 of ARDS. Also, patients who improved within the first ten days of ARDS (by more than one point in LIS) had no change in the serum levels of PIIINP or PINP over time whereas those who died or did not improve had increasing levels. Interestingly, the patients who did not improve but survived to day 10 had higher levels of PIIINP and PINP than the patients who died in the first ten days of ARDS. These results suggest that the timing and potency of any antifibrotic strategy is critical as some fibrotic response is necessary for lung repair.

Fibrosis was once thought to occur in mid to late stage ARDS but recent studies suggest that collagen metabolism is increased within 24 hours after lung injury (6,7). The role of the host defense response in ARDS has been extensively reviewed (8,9) but we still need to learn more about the nature of the fibrotic response to acute lung injury in order to optimize antifibrotic strategies. It is difficult to quantify the contribution of lung fibrosis to mortality but intuitively it is crucial. In the adult population, levels of collagen metabolites have been correlated to mortality10 but data is lacking in the pediatric population.

In summary, the conclusions from this study must be viewed cautiously but they give hope that true treatments for ARDS are attainable.

References

1. Brun-Buisson C, Brochard L. Corticosteroid therapy in acute respiratory distress syndrome: better late than never? JAMA 1998 Jul 8;280(2):182-183. [PubMed link]
2. Meduri GU, Tolley EA, Chinn A, Stentz F, Postlethwaite A. Procollagen Types I and III Aminoterminal Propeptide Levels during Acute Respiratory Distress Syndrome and in Response to Methylprednsiolone Treatment. Am J Respir Crit Care Med 1998; 158:1432-1441. [abstract]
3. Wheeler A, Bernard G, Schoenfeld D, Steinberg K. Methylprednisolone for Unresolving ARDS (letter). JAMA 1998; 280: 2074.
4. Tolley EA, Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA. In Reply. JAMA 1998; 280: 2074.
5. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995; 273:306-309. [abstract]
6. Chesnutt AN, Matthay MA, Tibayan FA, Clark JG. Early Detection of Type III Procollagen Peptide in Acute Lung Injury. . Am J Respir Crit Care Med 1997; 156: 840-845. [abstract]
7. Deheinzelin D, Jatene FB, Saldiva PHN, Brentani RB. Upregulation of Collagen Messenger RNA Expression Occurs Immediately After Lung Damage. Chest 1997; 112: 1184-1188. [abstract]
8. Meduri GU. The role of the host defense response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996;9: 2650-2670. [abstract]
9. Meduri GU. Host Defense Response and Outcome in ARDS. Chest 1997; 112: 1154-1158. [PubMed link]
10. Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III Procollagen Peptide in the Adult Respiratory Distress Syndrome - Association of Increased Peptide Levels in Bronchoalveolar Lavage Fluid with Increased Risk for Death. Ann Intern Med 1995; 122: 17-23. [abstract]

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