Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4).
Cell-free Hb increases systemic and pulmonary pressure and resistance and reduces cardiac output and heart rate in animals and humans, effects that have limited their clinical development as "blood substitutes." The primary aim of this study was to evaluate the hemodynamic response to infusion of several formulations of a new polyethylene glycol (PEG)-modified human Hb [maleimide PEG Hb (MalPEGHb)] in swine, an animal known to be sensitive to Hb-induced vasoconstriction. Anesthetized animals underwent controlled hemorrhage (50% of blood volume), followed by resuscitation (70% of shed volume) with 10% pentastarch (PS), 4% MalPEG-Hb in lactated Ringer (MP4), 4% MalPEG-Hb in pentastarch (HS4), 2% MalPEG-Hb in pentastarch (HS2), or 4% stroma-free Hb in lactated Ringer solution (SFH). Compared with baseline, restoration of blood volume after resuscitation was similar and not significantly different for the PS (103%), HS2 (99%), HS4 (106%), and MP4 (87%) animals but significantly less for the SFH animals (66%) (P < 0.05). All solutions that contained MalPEG-Hb restored mean arterial and pulmonary pressure and cardiac output. Systemic vascular resistance was unchanged, and pulmonary arterial pressure and resistance were increased slightly. Both systemic and pulmonary vascular resistance increased significantly in animals that received SFH, despite less adequate blood volume restoration. Oxygen consumption was maintained in all animals that received MalPEG-Hb, but not PS. Base excess improved only with MalPEG-Hb and PS, but not SFH. Red blood cell O2 extraction was significantly increased in animals that received Hb, regardless of formulation. These data demonstrate resuscitation with MalPEG-human Hb without increasing systemic vascular resistance and support our previous observations in animals suggesting that the efficacy of low concentrations of PEG-Hb in the plasma results from reduced vasoconstriction.
Drobin
Dan
D
Department of Anesthesiology, Karolinska Institute at Söder Hospital, S-118 83 Stockholm, Sweden.
Kjellstrom
B Thomas
BT
Malm
Elisabeth
E
Malavalli
Ashok
A
Lohman
Jeff
J
Vandegriff
Kim D
KD
Young
Mark A
MA
Winslow
Robert M
RM
D000818:Animals; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005740:Gases / Q000097:blood; D006339:Heart Rate; D006400:Hematocrit; D006439:Hemodynamics; D006454:Hemoglobins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006470:Hemorrhage / Q000503:physiopathology; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood*; D010101:Oxygen Consumption; D010952:Plasma Substitutes / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011652:Pulmonary Circulation; D012151:Resuscitation; D000077325:Ringer's Lactate; D013318:Stroke Volume; D016019:Survival Analysis; D013552:Swine
D004338:Drug Combinations; D005740:Gases; D006454:Hemoglobins; D006895:Hydroxyethyl Starch Derivatives; D007552:Isotonic Solutions; D008301:Maleimides; D010952:Plasma Substitutes; D000077325:Ringer's Lactate; C016484:hemoglobin, stroma free; C493836:maleimide-polyethylene glycol-modified hemoglobin, MP4; D011092:Polyethylene Glycols; D010100:Oxygen