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A Systematic Review

Djillali Annane, MD; Eric Bellissant, MD; Pierre-Edouard Bollaert, MD; Josef Briegel, MD; Marco Confalonieri, MD; Raffaele De Gaudio, MD; Didier Keh, MD; Yizhak Kupfer, MD; Michael Oppert, MD; G. Umberto Meduri, MD

JAMA. 2009;301(22):2362-2375.

Context  The benefit of corticosteroids in severe sepsis and septic shock remains controversial.

Objective  We examined the benefits and risks of corticosteroid treatment in severe sepsis and septic shock and the influence of dose and duration.

Data Sources  We searched the CENTRAL, MEDLINE, EMBASE, and LILACS (through March 2009) databases as well as reference lists of articles and proceedings of major meetings, and we contacted trial authors.

Study Selection  Randomized and quasi-randomized trials of corticosteroids vs placebo or supportive treatment in adult patients with severe sepsis/septic shock per the American College of Chest Physicians/Society of Critical Care Medicine consensus definition were included.

Data Extraction  All reviewers agreed on trial eligibility. One reviewer extracted data, which were checked by the other reviewers and by the trials' authors whenever possible. Some unpublished data were obtained from the trials' authors. The primary outcome for this review was 28-day mortality.

Results  We identified 17 randomized trials (n = 2138) and 3 quasi-randomized trials (n = 246) that had acceptable methodological quality to pool in a meta-analysis. Twenty-eight-day mortality for treated vs control patients was 388/1099 (35.3%) vs 400/1039 (38.5%) in randomized trials (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.71-1.00; P=.05; I²=53% by random-effects model) and 28/121 (23.1%) vs 24/125 (19.2%) in quasi-randomized trials (RR, 1.05, 95% CI, 0.69-1.58; P = .83). In 12 trials investigating prolonged low-dose corticosteroid treatment, 28-day mortality for treated vs control patients was 236/629 (37.5%) vs 264/599 (44%) (RR, 0.84; 95% CI, 0.72-0.97; P = .02). This treatment increased 28-day shock reversal (6 trials; 322/481 [66.9%] vs 276/471 [58.6%]; RR, 1.12; 95% CI, 1.02-1.23; P = .02; I² = 4%) and reduced intensive care unit length of stay by 4.49 days (8 trials; 95% CI, –7.04 to –1.94; P < .001; I² = 0%) without increasing the risk of gastroduodenal bleeding (13 trials; 65/800 [8.1%] vs 56/764 [7.3%]; P = .50; I² = 0%), superinfection (14 trials; 184/998 [18.4%] vs 170/950 [17.9%]; P = .92; I² = 8%), or neuromuscular weakness (3 trials; 4/407 [1%] vs 7/404 [1.7%]; P = .58; I² = 30%). Corticosteroids increased the risk of hyperglycemia (9 trials; 363/703 [51.6%] vs 308/670 [46%]; P < .001; I² = 0%) and hypernatremia (3 trials; 127/404 [31.4%] vs 77/401 [19.2%]; P < .001; I² = 0%).

Conclusions  Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefit on mortality. Since 1998, studies have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality.

Author Affiliations: Critical Care Department, Hôpital Raymond Poincaré (Assistance Publique–Hôpitaux de Paris), University of Versailles, Garches, France (Dr Annane); Pharmacology Department–INSERM 0203 Clinical Investigation Center, Hôpital de Pontchaillou, Centre Hospitalier Universitaire, Université de Rennes 1, Rennes, France (Dr Bellissant); Intensive Care Unit, Hôpital Central, Centre Hospitalier Universitaire, Université de Nancy 1, Nancy, France (Dr Bollaert); Klinik für Anaesthesiology, Department of Anesthesiology and Intensive Care Medicine, Munchen, Germany (Dr Briegel); Department of Pneumology, University Hospital of Trieste, Trieste, Italy (Dr Confalonieri); Department of Critical Care, Section of Anaesthesiology and Intensive Care, University of Florence AOUC Careggi, Firenze, Italy (Dr De Gaudio); Intensive Care Unit, Charité-Campus Virchow Clinic, Berlin, Germany (Dr Keh); Division of Pulmonary and Critical Care Medicine, Maimonides Medical Center, New York, New York (Dr Kupfer); Med. Klinik mit Schwerpunkt, Nephrologie und internistische Intensivmedizin, Charité–Campus Virchow Klinikum, Berlin, Germany (Dr Oppert); and Division of Pulmonary, Critical Care, and Sleep Medicine, University of Tennessee Health Science Center, Memphis (Dr Meduri).

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