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Cellular-Type Hemoglobin-Based Oxygen Carrier as a Resuscitative Fluid for Hemorrhagic Shock: Acute and Long-Term Safety Evaluation Using Beagle Dogs

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Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics

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Abstract

Hemoglobin-vesicles (HbV, d = 251 nm) are an artificial oxygen carrier encapsulating a concentrated Hb solution in polyethylene glycol-modified phospholipid vesicles (liposomes). Their safety and efficacy as artificial red blood cells and a fluid for oxygen therapeutics have been extensively studied in various rodent models. We have previously reported the efficacy of HbV as a resuscitation fluid in canine hemorrhagic shock model. However, long term safety was not yet studied. In this chapter, we report the results of efficacy and safety study in Beagle dog using hemorrhagic shock model. We observed the animals for one year. Twenty-six male beagle dogs were used. For acute study, a dog was anesthetized by 2.0–2.5 % sevoflurane and spontaneous respiration was maintained. A thermodilution catheter was introduced into pulmonary artery for measurement of cardiovascular parameters. Fifty percent of estimated blood volume was withdrawn from right femoral artery, and the shock state was stabilized for 1 h. The dogs were resuscitated either with isovolemic 5 % recombinant human serum albumin alone (rHSA) HbV suspended in rHSA (HbV/rHSA), or shed autologous blood (SAB). HbV/rHSA group showed immediate recovery of hemodynamic and blood gas parameters as did SAB, and no abnormal hypertension was observed. HbV contributed to about 34-38 % of the total delivery of oxygen and 26–29 % of total consumption of oxygen for 4 h. For chronic phase study, the beagle dogs resuscitated with HbV/rHSA or SAB were caged for up to 1 year. All dogs survived and gained weight. Results of hematological and plasma biochemical analyses and pathological examination showed no notable abnormalities except the transient accumulation of HbV in reticuloendothelial system and a release of cholesterol derived from HbV. The present results using beagle dogs reassure that HbV suspended in rHSA shows a similar resuscitative ability and safety to that of SAB.

Supported by Health and Labour Sciences Research Grants, Ministry of Health, Labour and Welfare, Japan

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Acknowledgments

The authors acknowledge Mr. Toshio Ohtake (Keio University) for assistance with animal model preparations. The rHSA used for this study was obtained from Nipro Corp. This work was supported in part by Health and Labour Sciences Research Grants (Research on Regulatory Science of Pharmaceuticals and Medical Devices 2006–2008 to Kobayashi K), Ministry of Health, Labour and Welfare, Japan and in part by Research Fund from Nipro Corp to Kobayashi K. This study was conducted under the auspices of late Prof. Eishun Tsuchida (Dept. Polymer Chemistry, Waseda University).

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Authors and Affiliations

  1. Department of General Thoracic Surgery, Saitama-city Hospital, Mimuro 2460, Midori-ku, Saitama-city, Saitama, 336-8522, Japan

    Hirohisa Horinouchi

  2. Department of General Thoracic Surgery, School of Medicine, Keio University, Tokyo, 160-8582, Japan

    Tatsuhiko Ikeda, Hirohisa Horinouchi, Yoraro Izumi & Koichi Kobayashi

  3. Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Hiromi Sakai

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  1. Tatsuhiko Ikeda
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  2. Hirohisa Horinouchi
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  3. Yoraro Izumi
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  4. Hiromi Sakai
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  5. Koichi Kobayashi
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Correspondence to Hirohisa Horinouchi .

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  1. Brown University, Barrington, Rhode Island, USA

    Hae Won Kim

  2. Brown University, Barrington, Rhode Island, USA

    A. Gerson Greenburg

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Ikeda, T., Horinouchi, H., Izumi, Y., Sakai, H., Kobayashi, K. (2013). Cellular-Type Hemoglobin-Based Oxygen Carrier as a Resuscitative Fluid for Hemorrhagic Shock: Acute and Long-Term Safety Evaluation Using Beagle Dogs. In: Kim, H., Greenburg, A. (eds) Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40717-8_28

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