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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature

GU Meduri, PE Marik, GP Chrousos, SM Pastores, W Arlt, A Beishuizen, F Bokhari, G Zaloga, and D Annane.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

This review concluded that prolonged glucocorticoid treatment significantly improved outcomes when administered within 14 days to patients with acute lung injury-acute respiratory distress syndrome. Given several limitations with the included studies (such as small sample size and potential study differences) and poor reporting in the review, the authors' conclusions should be interpreted with caution as they may not be reliable.

Authors' objectives

To examine the evidence on steroid treatment in patients with acute lung injury-acute respiratory distress syndrome (ALI-ARDS).

Searching

Cochrane Central Register of Controlled Trials (CENTRAL) (published in The Cochrane Library, issue 2, 2007) and MEDLINE (1966 to May 2007) were searched to identify relevant publications. Search terms were reported.

Study selection

Randomised controlled trials (RCTs) that assessed effects of prolonged glucocorticoid treatment (seven days or more) in patients with ALI-ARDS were eligible for inclusion.

Included studies were of medical-surgical patients (with or without septic shock) or patients with community acquired pneumonia. Patients had early acute lung injury, early acute respiratory distress syndrome (ARDS) or unresolving ARDS. Initial daily treatment included hydrocortisone (200mg or 240mg, with or without fludrocortisone) or methylprednisolone 1mg/kg or 2mg/kg and were compared to a control group. Most studies administered a loading dose. Some trials administered the treatment as an infusion. Treatment duration ranged from seven days up to 32 days. Primary outcomes reported included mortality at 28 days, 60 days or in intensive care unit. Other outcomes reported included improvement in oxygenation (defined as the ratio of partial pressure of arterial O2 to the fraction of inspired O2 (Pa02/Fi02)) by day eight, improvement in lung injury score by day seven and mechanical ventilation-free days. Some trials included infection surveillance for patients who received more than seven days of treatment.

The authors stated neither how papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

Two reviewers assessed methodological quality of included trials with previously published criteria, including items on: randomisation, blinding, withdrawal, intention-to-treat (ITT) and adherence to protocol. Disagreements were resolved through discussion with the other reviewers. Authors were contacted for clarification where necessary.

Data extraction

Data on the number of patients who experienced an event or outcome were extracted into a 2x2 table by one reviewer to calculate relative risks (RRs) for dichotomous outcomes (mortality) and mean difference for continuous outcomes (such as mechanical ventilation-free days), both with their 95% confidence intervals (CIs). Data extraction was checked by a second reviewer.

Methods of synthesis

A fixed-effect model was used to pool RRs and weighted mean differences (WMDs) with their 95% CIs. A random-effects model was used where there was evidence of statistical heterogeneity. Statistical heterogeneity was investigated with the Χ2 and I2 tests. Subgroup analyses were undertaken based on the size of the study (small versus large), timing of treatment initiation (before day 14 from the onset of ALI-ARDS) and duration of treatment (greater than one week).

Results of the review

Five RCTs (n=518) were included in the review. Sample sizes ranged from 24 to 180 patients. Methodological quality ranged between 11.5 and 14.5. Some trials reported differences in baseline characteristics. Two trials randomised patients after 14 days.

Short-term mortality was significantly reduced in patients who received glucocorticoid treatment (RR=0.76, 95% CI 0.62 to 0.93, p=0.007; five RCTs), but there was evidence of significant statistical heterogeneity (p=0.06). Subgroup analyses by study size showed similar significant reductions in the two small trials, but the reduction in mortality was no longer significant when the three larger trials were combined. Significant reductions in mortality were reported in patients treated before day 14 of ARDS in small trials (p=0.007) and large trials (p=0.02). Significant reductions in mortality were reported in patients who received prolonged prednisolone treatment of greater than one week duration, but randomised before 14 days (p=0.01). There was no evidence of statistical heterogeneity for subgroup analyses.

The number of mechanical ventilation-free days was significantly increased at 28 days in patients who received glucocorticoid treatment (WMD 4.42 days, 95% CI 2.93 to 5.90, p<0.001), but there was evidence of significant statistical heterogeneity (p=0.004). Subgroup analyses indicated a significant increase in the number of mechanical ventilation-free days in trials that investigated treatment (methylprednisolone) of greater than one week duration (WMD 5.59 days, 95% CI 3.49 to 7.68, p<0.001; three trials). There was no evidence of statistical heterogeneity.

Improvements in oxygenation and preventative measures to decrease complications were discussed in the review.

Authors' conclusions

Prolonged glucocorticoid treatment significantly improved meaningful patient-centred outcomes, with particularly significant survival benefit when administered before day 14 of ARDS.

CRD commentary

The review question was broad, but was supported by appropriate inclusion criteria for study design, intervention and participants. The literature search was limited to two electronic databases and was restricted to trials developed by the Cochrane Collaboration, which meant that potentially relevant papers may have been missed. The authors received unpublished data for one of the included trials, but no other apparent attempts were made to identify other unpublished data. Appropriate steps were taken to reduce reviewer error and bias during study selection and data extraction, but not validity assessment, thus the potential for bias could not be ruled out completely. Appropriate methods were used to combine data and investigate statistical heterogeneity. As very little data on patient characteristics were reported, it was unclear whether the patients were comparable at baseline and clinical heterogeneity could not be dismissed. There were differences in study methodology and the primary outcomes of interest for each study. Sample sizes were small and confidence intervals appeared wide for some of the trials, which affected the robustness of the results. Given the above limitations with the included study and reporting in the review, the authors' conclusions should be interpreted with caution as they may not be reliable.

Implications of the review for practice and research

Practice: The authors stated that clinicians should incorporate secondary prevention measures when using prolonged glucocorticoid treatment in patients with ARDS.

Research: The authors stated that a larger trial should be conducted to assess the effects of low-dose methylprednisolone (1mg/kg/day) on mortality in patients with ALI-ARDS. Trials should avoid internal crossover and incorporate secondary prevention measures (infection surveillance and avoidance of paralysis and rebound inflammation) to reduce potential complications associated with glucocorticoid treatment.

Funding

Not stated.

Bibliographic details

Meduri GU, Marik PE, Chrousos GP, Pastores SM, Arlt W, Beishuizen A, Bokhari F, Zaloga G, Annane D. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Medicine 2008; 34(1): 61-69. [PubMed: 18000649]

Indexing Status

Subject indexing assigned by NLM

MeSH

Female; Glucocorticoids /administration & dosage /adverse effects /therapeutic use; Humans; Male; Procollagen /analysis /drug effects; Randomized Controlled Trials as Topic; Registries; Respiratory Distress Syndrome, Adult /drug therapy /mortality; Treatment Outcome

AccessionNumber

12008104671

Database entry date

27/01/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18000649