Effects of maleimide-polyethylene glycol-modified human hemoglobin (MP4) on tissue necrosis in SKH1-hr hairless mice
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EFFECTS OF MALEIMIDE–POLYETHYLENE GLYCOL-MODIFIED HUMAN HEMOGLOBIN (MP4) ON TISSUE NECROSIS IN SKH1-HR HAIRLESS MICE O. Goertz 1, M. H. Kirschner 4, H. Lilienfein 1, P. Babilas 2, H. U. Steinau1, C. Andree 5, A. Daigeler 1, A. Stachon 3, H. Homann 1, S. Langer 1 1 Department
of Plastic and Hand Surgery, Burn Center, University Hospital Bergmannsheil, Ruhr-University Bochum, Germany 2 Department of Dermatology, Regensburg University Medical Center, Germany 3 Institute of Clinical Chemistry, Transfusion, and Laboratory Medicine, Ruhr- University Bochum, Germany 4 BBD Aesculap GmbH, Tuttlingen, Germany 5 Sana Hospital, Düsseldorf, Germany
Abstract Objective: Tissue hypoxia after blood loss, replantation and flap reperfusion remains a challenging task in surgery. Normovolemic hemodilution improves hemorheologic properties without increasing oxygen carrying capacity. Red blood cell transfusion is the current standard of treatment with its attendant risks. The aim of this study was to investigate the potential of the chemically modified hemoglobin, MP4, to reduce skin flap necrosis and its effect on selected blood markers and kidneys. Materials and Methods: Tissue ischemia was induced in the ear of hairless mice (n=26). Hemodilution was performed by replacing one third of blood volume with the similar amount of MP4, dextran, or blood. The extent of non-perfused tissue was assessed by intravital fluorescent microscopy. Results: Of all groups, MP4 showed the smallest area of no perfusion (in percentage of the ear ± SEM: 16.3% ± 2.4), the control group the largest (22.4% ± 3.5). Leukocytes showed a significant increase in the MP4 and dextran group (from 8.7 to 13.6 respectively 15.4*10 9/l). On histology no changes of the kidneys could be observed. Conclusion: MP4 causes an increase of leukocytes, improves the oxygen supply of the tissue and shows no evidence of renal impairment. Key words: MP4, hairless mice, intravital fluorescent microscopy, oxygen carrier, free hemoglobin, intracardiac access, hemodilution
INTRODUCTION The occurrence of tissue hypoxia after blood loss, replantation, transplantation and flap reperfusion remains a challenging task in surgery today. In particular, the occurrence of tissue necrosis in skin flaps is a major problem in microvascular surgery. Impaired microcirculation is known to be a frequent cause of ischemia/reperfusion injury [1-3]. The perfusion depends on an equilibrium of blood pressure and heart rate, vessel diameter and length, blood viscosity, and
interstitial fluid pressure, which is regulated by myogenic autoregulation, metabolic and neural control mechanisms and many other factors [4]. Alteration of one of these parameters can impair the perfusion of the tissue. Vasoconstriction has been a major problem in the clinical development of Hb-based O2 carriers. It narrows the inner vessel diameter, weakening the already impaired microcirculation [5, 6]. With the conjugation of hemoglobin with polyethylene glycol the hemoglobin lost its vasoconstrictiv
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