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Antitumor Necrosis Factor Therapy Is Associated With Improved Survival in Clinical Sepsis Trials: A Meta-Analysis*

Qiu, Ping MD, PhD1; Cui, Xizhong MD, PhD1; Sun, Junfeng PhD1; Welsh, Judith , BSN, MLS2; Natanson, Charles MD1; Eichacker, Peter Q. MD1

doi: 10.1097/CCM.0b013e3182982add
Review Articles

Objectives: Sepsis is a lethal syndrome annually affecting approximately 900,000 patients in the United States alone. Despite their benefit in rheumatoid disease, selective antitumor necrosis factor agents failed to improve outcome in early sepsis trials in the 1990s. However, data from additional sepsis trials testing these agents are now available. We therefore sought to determine the effect on survival of selective antitumor necrosis factor agents in randomized clinical sepsis trials..

Data Sources: PubMed, Scopus, Embase, and Web of Science.

Study Selection: Randomized human sepsis trials of selective antitumor necrosis factor agents reporting survival rates.

Data Extraction: Two investigators independently collected relevant data on study characteristics, treatment interventions, and patients from each study.

Data Synthesis: Antitumor necrosis factor agents in 15 sepsis trials (n = 8,896 patients) meeting inclusion criteria had similar effects (I 2 = 0, p = 0.84) and compared with controls (placebo in 14 trials or a lower dose in one trial) overall decreased the relative risk of death (95% CI) (0.93 [0.88–0.98], p = 0.01). In subgroup analysis, tumor necrosis factor monoclonal antibodies (10 trials, n = 6,818) alone produced a significant survival benefit (0.93 [0.87, 0.99], p = 0.02) (I 2 = 0, p = 0.83). Tumor necrosis factor polyclonal antibodies (two trials, n = 151) and low-molecular-weight soluble receptor (two trials, n = 1,786) had similar beneficial effects to antitumor necrosis factor agents overall (0.82 [0.49–1.37], p = 0.45; 0.93 [0.81–1.08], p = 0.33, respectively). The effect of tumor necrosis factor high-molecular-weight soluble receptor (one trial, n = 141) was not significantly different from other agents but was on the side of harm (1.50 [0.86–2.61], p = 0.16).

Conclusion: Antitumor necrosis factor agents produced a modest but significant decrease in the risk of dying with sepsis. Prior individual trials failed to demonstrate benefit, likely because they were underpowered. A definitive trial demonstrating the potential benefit of such agents might require 10,000 or more patients with sepsis.

Supplemental Digital Content is available in the text.

1Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD.

2National Institutes of Health Library, Clinical Center, National Institutes of Health, Bethesda, MD.

* See also p. 2458.

Drs. Qiu and Eichacker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Qiu, Cui, Sun, Natanson, and Eichacker conceived and designed the study. Dr. Qiu, Dr. Cui, Ms. Welsh, Dr. Natanson, and Dr. Eichacker acquired the data. Drs. Qiu, Cui, Natanson, and Eichacker analyzed and interpreted the data. Dr. Qiu, Dr. Cui, Dr. Sun, Ms. Welsh, Dr. Natanson, and Dr. Eichacker have done the critical revision of the manuscript for important intellectual content. Drs. Qiu, Cui, Sun, Natanson, and Eichacker performed the statistical analysis. Dr. Qiu, Dr. Cui, Dr. Sun, Ms. Welsh, and Dr. Eichacker provided the administrative or technical support. Dr. Eichacker supervised the study.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH) and the NIH Clinical Center, Bethesda, MD.

The funding source played no role in the design, conduct, or reporting of the study, nor in the decision to submit the manuscript for publication.

Drs. Eichacker, Qiu, Cui, Sun, and Natanson received funding from the National Institutes of Health. Dr. Welsh disclosed that she does not have any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins