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Ethyl pyruvate improves survival in awake hemorrhage

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Abstract

Classical experimental models of hemorrhage are characterized by the use of anesthetics that may interfere with the typical immune responses and pathology of hemorrhage/resuscitation. Thus, therapeutic strategies successful in anesthetized animals might not be beneficial in clinical trials. In this study, we analyzed whether ethyl pyruvate could provide therapeutic benefits during resuscitation in awake (unanesthetized) hemorrhage. Our results indicate that hemorrhage in unanesthetized animals required approximately 25% higher blood withdrawal than anesthetized animals to achieve the same targeted mean arterial blood pressure. Resuscitation with Hextend reestablished circulatory volume and improved survival during resuscitation of awake rodents. Yet, over 75% of the animals resuscitated with Hextend died within the first hours after hemorrhage. Resuscitation with Hextend containing 50 mM ethyl pyruvate protected over 87% of the animals. This survival benefit did not correlate with significant changes in the metabolic markers but with an anti-inflammatory potential during resuscitation. Unlike classical hemorrhage in anesthetized animals, ethyl pyruvate reestablished mean arterial blood pressure significantly earlier than Hextend in unanesthetized rodents. Unanesthetized animals showed twofold higher serum tumor necrosis factor (TNF)-α than anesthetized animals subjected to the same blood pressure. This process was not due to the response of a single organ, but affected all the analyzed organs including the lung, heart, spleen, and liver. Although resuscitation with Hextend failed to attenuate systemic TNF-α levels, it inhibited TNF-α levels in the lung, heart, and liver but not in the spleen. Unlike Hextend, resuscitation with ethyl pyruvate prevented high serum TNF-α levels and blunted TNF-α responses in all the organs including the spleen. These studies indicate that the inflammatory responses in anesthetized animals differ from that in unanesthetized animals and that awake hemorrhage can provide advantages in the study of anti-inflammatory strategies during resuscitation. Ethyl pyruvate may attenuate systemic inflammatory responses during resuscitation and improve survival in experimental models of awake hemorrhage.

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Acknowledgments

LU is supported by the faculty program of the Department of Surgery of the New Jersey Medical School, and grants from the US Army Medical Research Command (USAMRMC#05308004), the American Heart Association (AHA06352230N), and the NIH (RO1-GM084125).

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Authors and Affiliations

  1. Laboratory of Anti-inflammatory Signaling and Surgical Immunology, Center of immunity and Infection, UMDNJ–New Jersey Medical School, Medical Science Building F-673, 185 South Orange Avenue, PO Box 1709, Newark, NJ, 07103, USA

    Bolin Cai, Michael Brunner & Luis Ulloa

  2. Department of Surgery, UMDNJ–New Jersey Medical School, Medical Science Building F-673, 185 South Orange Avenue, PO Box 1709, Newark, NJ, 07103, USA

    Edwin A. Deitch & Luis Ulloa

  3. Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY, 11030, USA

    Haichao Wang

  4. Department of Surgery, North Shore University Hospital, Manhasset, NY, 11030, USA

    Ping Wang

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  1. Bolin Cai
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  2. Michael Brunner
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  4. Ping Wang
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  6. Luis Ulloa
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Correspondence to Luis Ulloa.

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Cai, B., Brunner, M., Wang, H. et al. Ethyl pyruvate improves survival in awake hemorrhage. J Mol Med 87, 423–433 (2009). https://doi.org/10.1007/s00109-009-0441-8

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