Microvascular Po₂during extreme hemodilution with hemoglobin site specifically PEGylated at Cys-93(β) in hamster window chamber

Abstract

Intaglietta. Microvascular PO 2 during extreme hemodilution with hemoglobin site specifically PEGylated at Cys-93(␤) in hamster window chamber. Am J Physiol Heart Circ Physiol 287: H1609 -H1617, 2004. First published June 10, 2004 10.1152/ajpheart.00146.2004.-The oxygen transport capacity of nonhypertensive polyethylene glycol (PEG)-conjugated hemoglobin solutions were investigated in the hamster chamber window model. Microvascular measurements were made to determine oxygen delivery in conditions of extreme hemodilution [hematocrit (Hct) 11%]. Two isovolemic hemodilution steps were performed with a 6% Dextran 70 (70-kDa molecular mass) plasma expander until Hct was 35% of control. Isovolemic blood volume exchange was continued using two surface-modified PEGylated hemoglobins (P5K2, P 50 ϭ 8.6, and P10K2, P50 ϭ 8.3; P50 is the hemoglobin PO2 corresponding to its 50% oxygen saturation) until Hct was 11%. P5K2 and P10K2 are PEG-conjugated hemoglobins that maintain most of the hemoglobin allosteric properties and have a cooperativity index of n ϭ 2.2. The effects of these molecular solutions were compared with those obtained in a previous study using MP4, a PEG-modified hemoglobin whose P 50 was 5.4 and cooperativity was 1.2 (Tsai et al., Am J Physiol Heart Circ Physiol 285: H1411-H1419, 2003). Tissue oxygen levels were higher after P5K2 (7.0 Ϯ 2.5 mmHg) and P10K2 (6.3 Ϯ 2.3 mmHg) versus MP4 (1.7 Ϯ 0.5 mmHg) or the nonoxygen carrier Dextran 70 (1.3 Ϯ 1.2 mmHg). Microvascular oxygen delivery was higher after P5K2 and P10K2 (2.22 and 2.34 ml O 2/dl blood) compared with MP4 (1.41 ml O2/dl blood) or Dextran 70 (0.90 ml O2/dl blood); however, all these values were lower than control (7.42 ml O2/dl blood). The total hemoglobin in blood was similar in all cases; therefore, the improvement in tissue PO 2 and oxygen delivery appears to be due to the increased cooperativity of the new molecules.surface-modified hemoglobin; functional capillary density; oxygencarrying capacity; blood substitutes; tissue oxygen delivery; hemoglobin cooperativity THE DEVELOPMENT of blood substitutes [oxygen-carrying plasma expanders (OCPEs)] has traditionally focused on devising fluids whose transport properties are equivalent to those of blood. This requires using an oxygen carrier that provides an oxygen transport capacity and release properties similar to those of erythrocytes, a task for which hemoglobin (Hb) placed inside the red blood cell (RBC) is ideally suited.

A quantitative framework for the design of acellular hemoglobins as blood substitutes: Implications of dynamic flow conditions

“…Animal studies have shown that isolated decreases in p50 [24], increases in n [38], or increases in molecular size [39] all correlate with increased tissue perfusion. In vivo experiments have also shown that Hbs with a combination of high p50 and small molecular size cause vasoconstriction and hypertension [3,4].…”

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

“…After the level 2 exchange, level 3 exchange was performed with animals randomly divided into two experimental groups by sorting a set of random numbers produced in a random ordering scheme (2). Experimental group 1, labeled ␣␣Hb, was hemodiluted with ␣␣Hb to a Hct of 11%.…”

“…Group 2, labeled MP4, was similarly hemodiluted with MP4. This procedure was used to compare with previous studies of extreme hemodilution using OCPEs and oxygen noncarrying plasma expanders (2)(3)(4)26). Results were compared with control (no hemodilution) and to a previous study carried out under identical circumstances using PBH solution (13.1 g hemoglobin/dl) in a modified lactated Ringer solution (Oxyglobin, Biopure; Boston, MA) (3,23).…”

Blood viscosity maintains microvascular conditions during normovolemic anemia independent of blood oxygen-carrying capacity

“…Progressive hemodilution to a final systemic Hct level of 11% was accomplished with three isovolemic exchange steps. This protocol is described in detail in our previous reports (2,6,39). Briefly, the volume of each exchange-transfusion step was calculated as a percentage of the blood volume, estimated as 7% of body weight.…”

“…Because mixed blood and dilution material was withdrawn during the exchanges, a 110% blood volume exchange was needed to reduce the functional Hct to 11% (2,6,34,39,42). Dilution material was infused and filtered (in-line, 0.22-m filter) into the jugular vein catheter at a rate of 100 l/min.…”