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Score-based immunoglobulin G therapy of patients with sepsis: The SBITS study *

Werdan, Karl MD; Pilz, Günter MD; Bujdoso, Oskar MS; Fraunberger, Peter MD; Neeser, Gertraud MD; Schmieder, Roland Erich MD; Viell, Burkhard PhD; Marget, Walter MD; Seewald, Margret MD; Walger, Peter MD; Stuttmann, Ralph MD; Speichermann, Norbert MD; Peckelsen, Claus MD; Kurowski, Volkhard MD; Osterhues, Hans-Heinrich MD; Verner, Ljiljana MD; Neumann, Roswita PhD; Müller-Werdan, Ursula MD for the Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group

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Objective: Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta-analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28-day mortality and improved morbidity in patients with score-defined severe sepsis.

Design: Randomized, double-blind, placebo-controlled, multicenter trial.

Setting: Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals.

Patients: Patients (n = 653) with score-defined sepsis (sepsis score 12–27) and score-defined sepsis-induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20–35).

Interventions: Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight).

Measurements and Main Results: The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7-day all-cause mortality, short-term change in morbidity, and pulmonary function at day 4. Six hundred fifty-three patients from 23 active centers formed the intention-to-treat group, 624 patients the per-protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28-day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p= .6695). Seven-day mortality was not reduced, and 4-day pulmonary function was not improved. Drug-related adverse events were rare in both groups. Exploratory findings revealed a 3-day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin-6 and tumor necrosis factor receptors I and II.

Conclusions: In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality.

From the Department of Medicine III, University Hospital, Martin-Luther-University Halle-Wittenberg, Germany (KW, UM-W); the Department of Medicine, Hospital Agatharied, Academic Teaching Hospital University of Munich, Germany (GP); Bayer HealthCare, Leverkusen, Germany and Berkeley, CA (OB, RN); the Medizinisches Zentrallaboratorium GesmbH, Feldkirch, Austria (PF); Central Hospital Augsburg, Department of Anaesthesiology and Intensive Care Medicine, Germany (GN); Department of Medicine, South-Hospital Nuremberg, University of Erlangen-Nürnberg, Germany (RES); Medical Policlinics, University of Bonn, Germany (PW); Department of Anaesthesiology and Intensive Care Medicine, Klinikum Bergmannstrost, Halle/Saale, Germany (RS); Department of Anaesthesiology, Hospital Ludwigsburg, Germany (NS); Center of Acute Internal Medicine and Prevention, Städtisches Klinikum München GmbH–Klinikum Harlaching, Munich Municipal Clinic, Academic Teaching Clinic University of Munich, Germany (CP); Department of Medicine, University Hospital Lübeck, Germany (VK); Department of Medicine, University Hospital Ulm, Germany (H-HO); Department of Anaesthesiology, University Hospital Hannover, Germany (LV); Federal Institute for Risk Assessment (BfR), Berlin, Germany (BV); MedQM Berlin (MS); Department of Pediatrics, University of Munich, Germany (WM, emeritus). Additional institutions and investigators participating in the study are listed in the appendix.

Supported, in part, by Bayer Vital GmbH Biological Products, Leverkusen, Germany.

Dr. Werdan and Dr. Müller-Werdan engaged in clinical and experimental work on immunoglobulins in inflammation and sepsis. With this respect, the following categories of financial interest existed or do exist with Bayer Company (Polyglobin) and Biotest Company (Pentaglobin, Intraglobin): consultancies, honoraria/speaking fees, grants. Mr. Bujdoso is an employee of the sponsor of this paper. Dr. Viell is a study consultant to Bayer Company. Dr. Seewald has been financially remunerated for travel costs (study meetings) and honoraria for the analysis of microbiology data according to the prospectively defined criteria. Dr. Neumann is employed by the former manufacturer of the study drug. Last year the production unit and marketing rights were sold to another company. The remaining authors have not disclosed any potential conflicts of interest.

Address requests for reprints to: Karl Werdan, MD, Universitätsklinik und Poliklinik für Innere Medizin III, Klinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Strasse 40, D-06097 Halle/Saale, Germany. E-mail:

*See also p. 2852.

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