Meta-analysis: Intravenous Immunoglobulin in Critically Ill Adult Patients with Sepsis

6 February 2007 | Volume 146 Issue 3 | Pages 193-203

Background: Intravenous immunoglobulin therapy has been proposed as an adjuvant treatment for sepsis. Yet, its benefit remains unclear, and its use is not currently recommended.

Purpose: To evaluate the effect of polyclonal intravenous immunoglobulin therapy on death in critically ill adult patients with sepsis.

Data Sources: MEDLINE (1966 to May 2006) and the Cochrane Central Register of Controlled Trials (May 2006 edition).

Study Selection: All randomized, controlled trials of critically ill adult patients with sepsis, severe sepsis, or septic shock who received polyclonal intravenous immunoglobulin therapy or placebo or no intervention were selected. No restrictions were made for study language or type of publication.

Data extraction: Data were independently extracted by 2 investigators using a standardized form.

Data Synthesis: The literature search identified 4096 articles, of which 33 were deemed to be potentially eligible. Twenty trials (n = 2621) met eligibility criteria and were included in the analysis. Polyclonal intravenous immunoglobulin therapy was associated with an overall survival benefit (risk ratio, 0.74 [95% CI, 0.62 to 0.89]) compared with placebo or no intervention. In sensitivity analyses, documented survival improved when the analysis was limited to published, peer-reviewed trials (risk ratio, 0.72 [CI, 0.58 to 0.89]) (17 trials [n = 1865]) and blinded trials (risk ratio, 0.61 [CI, 0.40 to 0.93) (7 trials [n = 896]). Severe sepsis or septic shock (risk ratio, 0.64 [CI, 0.52 to 0.79]) (11 trials [n = 689]), receiving a total dose regimen of 1 gram or more per kilogram of body weight (risk ratio, 0.61 [CI, 0.40 to 0.94]) (7 trials [n = 560]), and receiving therapy for longer than 2 days (risk ratio, 0.66 [CI, 0.53 to 0.82]) (17 trials [n = 1847]) were strongly associated with this survival benefit.

Limitations: Most trials were published before new developments modifying the care and outcome of critically ill patients with sepsis including early goal-directed therapy and activated protein C treatment, were introduced.

Conclusions: A survival benefit was observed for patients with sepsis who received polyclonal intravenous immunoglobulin therapy compared with those who received placebo or no intervention. A large, randomized, controlled trial of polyclonal intravenous immunoglobulin therapy should be performed on the basis of the methodological limitations of the current literature, the potential benefit from this therapy in more severely ill patients, and the potential effect of dosage and duration of this therapy.

Editors' Notes Context Effects of polyclonal intravenous immunoglobulin therapy (IVIG) on the mortality rate of critically ill patients with sepsis are unclear. Contribution This meta-analysis of 20 randomized trials that studied 2621 critically ill adult patients with sepsis found that treatment with polyclonal IVIG decreased the risk for death more than placebo or no intervention (risk ratio, 0.74 [95% CI, 0.62 to 0.89]). Survival benefits seemed most prominent with higher doses and prolonged administration of IVIG and in more severely ill patients. Cautions Because most trials had methodological limitations and were performed before modern intensive care management strategies, the authors recommend that a large trial be performed to confirm the findings. —The Editors

 

Author and Article Information

From the Center for Transfusion and Critical Care Research, Ottawa Health Research Institute, the University of Ottawa, and the Canadian Blood Service, Ottawa, Ontario, Cananda.

Note: Presented in part at the fellows' competition of the 10th Toronto Critical Care Medicine Symposium, Toronto, Ontario, Canada, 26-28 October 2005.

Acknowledgments: The authors thank the following study authors for providing additional data or for clarifying the methods of their trial: Drs. Burns, Tugrul, and Masaoka. They also thank Dr. Sandra Froeschl for her translation of German-language studies; Dr. Behrooz M. Yagchi, Jean Burelle, and Üstün B. Reinart for their translation of the Turkish-language study; Dr. Yoko Schreiber and Satoshi Kaj for their translation of the Japanese-language study, as well as Steve Doucette for producing the figures and Leslie Webb, Louise Roy, and Nancy Cleary for their administrative support.

Grant Support: By the Ontario Ministry of Health and Long-Term Care. Dr Turgeon is a recipient of a research fellowship grant from the Fonds de la Recherche en Santé du Québec. Dr. Fergusson holds a Canadian Institutes of Health Research New Investigator Award and an Ontario Ministry of Health and Long-Term Care Career Scientist Award. Dr Tinmouth holds a Canadian Blood Services/Canadian Institutes of Health Research New Investigator Award. Dr. Hébert holds a Chair in Transfusion and Critical Care Research, Ottawa Health Research Institute and the University of Ottawa.

Potential Financial Conflicts of Interest: Honoraria: A.A. Tinmouth (Bayer).

Requests for Single Reprints: Alexis F. Turgeon, MD, MSc, Center for Transfusion and Critical Care Research, Ottawa Health Research Institute, Clinical Epidemiology Unit, 501 Smyth Road, Box 208, Ottawa, Ontario, Canada K1H-8L6; e-mail, alexisturgeon{at}yahoo.ca.

Current Author Addresses: Drs. Turgeon, Fergusson, McIntyre, Tinmouth, Cameron, and Hébert and Mr. Hutton: Clinical Epidemiology Unit, Ottawa Health Research Institute, 501 Smyth Road, Box 201, Ottawa K1H-8L6, Ontario, Canada.

Author Contributions: Conception and design: A.F. Turgeon, B. Hutton, D.A. Fergusson.

Analysis and interpretation of the data: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, P.C. Hébert.

Drafting of the article: A.F. Turgeon, B. Hutton, D.A. Fergusson.

Critical revision of the article for important intellectual content: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, A.A. Tinmouth, D.W. Cameron, P.C. Hébert.

Final approval of the article: A.F. Turgeon, B. Hutton, D.A. Fergusson, L. McIntyre, A.A. Tinmouth, D.W. Cameron, P.C. Hébert.

Statistical expertise: B. Hutton, D.A. Fergusson.

Obtaining of funding: D.A. Fergusson.

Collection and assembly of data: A.F. Turgeon, B. Hutton.

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