Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4)

Abstract

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.

Effect of oxygen affinity and molecular weight of HBOCs on cerebral oxygenation and blood pressure in rats

“…[15][16][17] Clinical and experimental studies suggest that the order of vasoreactivity is highest for the smaller MW HBOCs including diaspirin cross-linked hemoglobin, moderate for polymerized hemoglobins which contain a portion of small MW hemoglobins, and lowest for surface modified hemoglobins that have higher MWs. 26 The current study supports this hypothesis within a single group of chemically modified HBOCs.…”

“…26,35 These positive effects reverse the base deficit, 32,36 reduce lactate production 15 and decrease acute mortality. 15,37,38 Improved outcomes in one experimental study were attributed to an HBOC with lower vasoactive potential and a higher oxygen affinity.…”

Effects of extreme hemodilution with hemoglobin-based O2 carriers on microvascular pressure

“…MP4 was shown in previous studies to be either vasoinactive or to produce lesser levels of vasoactivity (8), whereas ␣␣Hb is known to be vasoactive (32). Thus this study was also made to test the hypothesis that vasoconstriction reduces FCD.…”

Haemoglobin, oxygen carriers and perioperative organ perfusion

“…However, RBCT restored tissue oxygenation better than MP4 and the haemodynamic response and lactate levels were comparable to treatment with hydroxyethyl starch [114][115][116]. However, the haematocrite achieved during these experiments was still relatively high, 15% and 21%, levels which are usually fairly well tolerated even without additional O 2 treatment.…”