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Meta-Analysis
. 2004 Oct 18;2004(4):CD004477.
doi: 10.1002/14651858.CD004477.pub2.

Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome

N Adhikari  1 , K E A Burns, M O Meade
Affiliations
Meta-Analysis

Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome

N Adhikari et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Multiple pharmacologic treatments have been studied for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Objectives: Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS.

Search strategy: We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to week 2, January 2004), EMBASE (1980 to week 4, 2004), CINAHL (1982 to week 2, January 2004), and HEALTHSTAR (1995 to December 2003); proceedings from four conferences (1994 to 2003); and bibliographies of review articles and included studies.

Selection criteria: Randomized controlled trials of pharmacologic treatments compared to no therapy or placebo for established ALI or ARDS in adults admitted to an intensive care unit, with measurement of early mortality (primary outcome), late mortality, duration of mechanical ventilation, ventilator-free days to day 28, or adverse events. We excluded trials of nitric oxide, partial liquid ventilation, fluid and nutritional interventions, oxygen, and trials in other populations reporting outcomes in subgroups of patients with ALI or ARDS.

Data collection and analysis: Two reviewers independently screened titles and abstracts, rated studies for inclusion, extracted data and assessed methodologic quality of included studies. Disagreements were resolved by consensus in consultation with a third reviewer. For each pharmacologic therapy, we quantitatively pooled the results of studies using random effects models where permitted by the available data. We contacted study authors when clarification of the primary outcome was required.

Main results: Thirty three trials randomizing 3272 patients met our inclusion criteria. Pooling of results showed no effect on early mortality of prostaglandin E1 (seven trials randomizing 697 patients; relative risk [RR] 0.95, 95% confidence interval [CI] 0.77 to 1.17), N-acetylcysteine (five trials randomizing 239 patients; RR 0.89, 95% CI 0.65 to 1.21), early high-dose corticosteroids (two trials randomizing 187 patients; RR 1.12, 95% CI 0.72 to 1.74), or surfactant (nine trials randomizing 1441 patients; RR 0.93, 95% CI 0.77 to 1.12). Two interventions were beneficial in single small trials; corticosteroids given for late phase ARDS reduced hospital mortality (24 patients; RR 0.20, 95% CI 0.05 to 0.81), and pentoxifylline reduced one-month mortality (RR 0.67, 95% CI 0.47 to 0.95) in 30 patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show a beneficial effect on prespecified outcomes.

Reviewers' conclusions: Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.

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Conflict of interest statement

None known

Figures

Figure 1
Figure 1
Summary of reported methodologic characteristics of included trials Legend (1) Baseline similarity: Yes = pre‐randomization factors (age, severity of illness, non‐pulmonary organ failures, presence of sepsis, and duration of hospitalization, ICU stay, or mechanical ventilation) were clinically similar between treatment and control groups; Yes (A) = at least one baseline factor differed but was included in an adjusted analysis. (2) Blinding: Yes = caregivers were blinded or the term "double‐blind" was used. (3) Cointerventions: Yes = at least one cointervention (including positive end‐expiratory pressure, lung protective ventilation, weaning protocols, corticosteroids, other) was standardized, or its use was documented in both groups. (4) Zero withdrawals of patients after randomization and complete follow‐up refer to the outcome of early mortality.
Figure 2
Figure 2
Funnel plot of standard error (SE) of treatment effect (log relative risk [RR]) versus treatment effect (RR) for outcome of early mortality in trials of prostaglandin E1
Figure 3
Figure 3
Funnel plot of standard error (SE) of treatment effect (log relative risk [RR]) versus treatment effect (RR) for outcome of early mortality in trials of N‐acetylcysteine
Figure 4
Figure 4
Funnel plot of standard error (SE) of treatment effect (log relative risk [RR]) versus treatment effect (RR) for outcome of early mortality in trials of surfactant
Analysis 1.1
Analysis 1.1
Comparison 1 Prostaglandin E1, Outcome 1 Early mortality.
Analysis 2.1
Analysis 2.1
Comparison 2 N‐acetylcysteine, Outcome 1 Early mortality.
Analysis 3.1
Analysis 3.1
Comparison 3 Early high‐dose corticosteroids, Outcome 1 Early mortality.
Analysis 4.1
Analysis 4.1
Comparison 4 Surfactant, Outcome 1 Early mortality.
See this image and copyright information in PMC

References

References to studies included in this review

    1. Abraham E, Park YC, Covington P, Conrad SA, Schwartz M. Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo‐controlled, randomized, double‐blind, multicenter clinical trial. Critical Care Medicine 1996;24(1):10‐5. [MEDLINE: ] - PubMed
    1. Abraham E, Baughman R, Fletcher E, Heard S, Lamberti J, Levy H, et al. Liposomal prostaglandin E1 (TLC C‐53) in acute respiratory distress syndrome: a controlled, randomized, double‐blind, multicenter clinical trial. TLC C‐53 ARDS Study Group. Critical Care Medicine 1999;27(8):1478‐85. [MEDLINE: ] - PubMed
    1. Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventos AA, et al. Aerosolized surfactant in adults with sepsis‐induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. New England Journal of Medicine 1996;334(22):1417‐21. [MEDLINE: ] - PubMed
    1. Ardizzoia A, Lissoni P, Tancini G, Paolorossi F, Crispino S, Villa S, et al. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study. Supportive Care in Cancer 1993;1(6):331‐3. [MEDLINE: ] - PubMed
    1. The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000;283(15):1995‐2002. [MEDLINE: ] - PubMed

References to studies excluded from this review

    1. Bernard GR, Swundell BB, Meredith MJ, et al. Glutathione (GSH) repletion by N‐acetylcysteine (NAC) in patients with the adult respiratory distress syndrome. American Review of Respiratory Disease 1989;139(4):A221.
    1. Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, et al. Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. American Review of Respiratory Disease 1991;144(5):1095‐01. [MEDLINE: ] - PubMed
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    1. Bigatello LM, Greene RE, Sprung CL, Panacek EA, Straube RC, Zimmerman JL, et al. HA‐1A in septic patients with ARDS: results from the pivotal trial. Intensive Care Medicine 1994;20(5):328‐34. [MEDLINE: ] - PubMed
    1. Bone RC, Fisher CJ, Jr, Clemmer TP, Slotman GJ, Metz CA. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome [published erratum appears in Chest 1988;94(2):448]. Chest 1987;92(6):1032‐6. [MEDLINE: ] - PubMed

References to ongoing studies

    1. Acute respiratory distress syndrome. http://www.leo‐pharma.com/w‐site/leo/docs.nsf/2addbdd119e92fb08025690a00...2004.
    1. ARDS Clinical Network. Late steroid rescue study (LaSRS): the efficacy of corticosteroids as rescue therapy for the late phase of acute respiratory distress syndrome. http://www.ardsnet.org/documents/lasrs6200web.pdf [Accessed 20 April 2004]2000.

Additional references

    1. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi‐Filho G, et al. Effect of a protective‐ventilation strategy on mortality in the acute respiratory distress syndrome. New England Journal of Medicine 1998;338(6):347‐54. [MEDLINE: ] - PubMed
    1. Anzueto A. Surfactant supplementation in the lung. Respiratory Care Clinics of North America 2002;8(2):211‐36. [MEDLINE: ] - PubMed
    1. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine 2000;342(18):1301‐8. [MEDLINE: ] - PubMed
    1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967;2(7511):319‐23. [MEDLINE: ] - PubMed
    1. Bernard GR. Potential of N‐acetylcysteine as treatment for the adult respiratory distress syndrome. European Respiratory Journal Supplement 1990;11:496s‐8s. [MEDLINE: ] - PubMed

References to other published versions of this review

    1. Adhikari N, Burns KEA, Meade MO. Pharmacologic treatments for the acute respiratory distress syndrome and acute lung injury: systematic review and meta‐analysis. Treatments in Respiratory Medicine, in press. - PubMed

MeSH terms

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