Plasma-derived human antithrombin attenuates ventilator-induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats

Authors

  • H. ASLAMI,

    1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
    2. Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center
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  • J. J. HAITSMA,

    1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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  • J. J. HOFSTRA,

    1. Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center
    2. Department of Intensive Care, Academic Medical Center
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  • S. FLORQUIN,

    1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • C. DOS SANTOS,

    1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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  • C. STREUTKER,

    1. Department of Pathology, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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  • H. ZHANG,

    1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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  • M. LEVI,

    1. Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • A. S. SLUTSKY,

    1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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  • M. J. SCHULTZ

    1. Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center
    2. Department of Intensive Care, Academic Medical Center
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Hamid Aslami, Laboratory of Experimental Intensive Care and Anesthesiology, H0–127 Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Tel.: +31 20 5668224; fax: +31 20 6979441.
E-mail: h.aslami@amc.uva.nl

Abstract

Summary.  Background: Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma-derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats. Methods: Forty-eight hours after induction of S. pneumoniae pneumonia rats were subjected to mechanical ventilation (tidal volume 12 mL kg−1, positive end-expiratory pressure 0 cmH2O and inspired oxygen fraction 40%). Rats were randomized to systemic treatment with AT (250 IU administered intravenously (i.v.) before the start of mechanical ventilation) or placebo (saline). Non-ventilated, non-infected rats and non-ventilated rats with pneumonia served as controls. The primary endpoints were pulmonary coagulation and inflammation in bronchoalveolar lavage fluid (BALF). Results: Pneumonia was characterized by local activation of coagulation and inhibition of fibrinolysis, resulting in increased levels of fibrin degradation products and fibrin deposition in the lung. Mechanical ventilation exaggerated pulmonary coagulopathy and inflammation. Systemic administration of AT led to supra-normal BALF levels of AT and decreased ventilator-associated activation of coagulation. AT neither affected pulmonary inflammation nor bacterial outgrowth from the lungs or blood.Conclusions: Plasma-derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats.

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