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Fluid support worsens outcome and negates the benefit of protective antigen-directed monoclonal antibody in a lethal toxin-infused rat Bacillus anthracis shock model*

Sherer, Kevin MD; Li, Yan MD; Cui, Xizhong MD, PhD; Li, Xuemei MD, PhD; Subramanian, Mani MD, PhD; Laird, Michael W. PhD; Moayeri, Mahtab PhD; Leppla, Stephen H. PhD; Fitz, Yvonne BS; Su, Junwu MD, PhD; Eichacker, Peter Q. MD

doi: 10.1097/01.CCM.0000266535.95770.A2
Laboratory Investigations

Objective: The aim of this study was to test the effects of normal saline treatment either alone or in combination with protective antigen-directed monoclonal antibody in a lethal toxin-infused rat model of anthrax sepsis.

Design: Prospective controlled animal study.

Setting: Animal research laboratory.

Subjects: Sprague-Dawley rats (n = 539).

Interventions: We initially tested the efficacy of three normal saline doses (5, 10, or 20 mL/kg/hr intravenously for 24 hrs) or none (controls) started when rats were treated with either lethal toxin (24-hr infusion) or, for comparison, lipopolysaccharide (24-hr infusion) or Escherichia coli (intravenous bolus). We then investigated delaying normal saline for 6 hrs or combining it with protective antigen-directed monoclonal antibody following lethal toxin challenge.

Measurements and Main Results: Dose did not alter the effects of normal saline with any challenge (p not significant for all) or when combined with protective antigen-directed monoclonal antibody, so this variable was averaged in analysis. In initial studies, normal saline decreased mortality (mean hazards ratio of survival ± se) significantly with E. coli challenge (−0.66 ± 0.25, p = .009 averaged over normal saline dose) but not lipopolysaccharide (−0.17 ± 0.20). In contrast, normal saline increased mortality significantly with lethal toxin (0.69 ± 0.20, p = .001) in a pattern different from E. coli and lipopolysaccharide (p ≤ .002 for each). In subsequent studies, normal saline alone once again increased mortality (0.8 ± 0.3, p = .006), protective antigen-directed monoclonal antibody alone reduced it (−1.7 ± 0.8, p = .03), and the combination had intermediate effects that were not significant (0.04 ± 0.3).

Conclusions: These findings raise the possibility that normal saline treatment may actually worsen outcome with anthrax lethal toxin. Furthermore, lethal toxin-directed therapies may not be as beneficial when used in combination with this type of fluid support.

From the Critical Care Medicine Department, Clinical Center (KS, YL, XC, XL, YF, JS, PE), and the National Institute of Allergy and Infectious Diseases (MM, SL), National Institutes of Health, Bethesda, MD; Human Genome Sciences, Rockville, MD (MS); and Genentech, South San Francisco, CA (ML).

Supported, in part, by intramural funds, Critical Care Medicine Department, National Institutes of Health, Bethesda, MD.

Presented, in part, at the annual meeting of the American Society for Microbiology, Washington, DC, February 15–18, 2006, and at the annual meeting of the American Thoracic Society, San Diego, CA, May 19–24, 2006.

Dr. Subramanian owns stock options and is an employee of Human Genome Sciences. Dr. Laird has stock ownership and is a former employee of Human Genome Sciences. The remaining authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: peichacker@mail.cc.nih.gov

© 2007 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins