PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning

Abstract

<jats:p>We studied the extreme hemodilution to a hematocrit of 11% induced by three plasma expanders: polyethylene glycol (PEG)-conjugated albumin (PEG-Alb), 6% 70-kDa dextran, and 6% 500-kDa dextran. The experimental component of our study relied on microelectrodes and cardiac output to measure both the rheological properties of plasma-expander blood mixtures and nitric oxide (NO) bioavailability in vessel walls. The modeling component consisted of an analysis of the distribution of wall shear stress (WSS) in the microvessels. Our experiments demonstrated that plasma expansion with PEG-Alb caused a state of supraperfusion with cardiac output 40% above baseline, significantly increased NO vessel wall bioavailability, and lowered peripheral vascular resistance. We attributed this behavior to the shear thinning nature of blood and PEG-Alb mixtures. To substantiate this hypothesis, we developed a mathematical model of non-Newtonian blood flow in a vessel. Our model used the Quemada rheological constitutive relationship to express blood viscosity in terms of both hematocrit and shear rate. The model revealed that the net effect of the hemodilution induced by relatively low-viscosity shear thinning PEG-Alb plasma expanders is to reduce overall blood viscosity and to increase the WSS, thus intensifying endothelial NO production. These changes act synergistically, significantly increasing cardiac output and perfusion due to lowered overall peripheral vascular resistance.</jats:p>

Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids

“…This approach has led to the isolation of a product with a molecular radius of 25 nm (Matheson et al 2002), with high viscosity and a high oxygen affinity. It may be noted that high viscogenic materials have emerged as good vasodilators as well as plasma expanders (Cabrales et al 2004;Tsai et al 1998;Sriram et al 2012). Consistent with the high viscosity of the material, the zero length crosslinking results in attenuation of the in vivo hypertensive activity of Hb, and the product is essentially nonhypertensive.…”

“…A protocol for storing this material as lyophilized product has been advanced by (Harrington et al 2011). It is not clear whether this is the reemergence of the concept of avoiding the extravasation by enhancing the molecular dimension to design vasoinactive blood substitute (Cabrales et al 2013) or a chemical approach of enhancing the molecular dimension of Hb to the region of 25 nm for engineering Viscogenicity to the samples of Hb for facilitating NO production to design blood substitute with the benefit of attenuation of in vivo hypertensive activity of the molecule (Cabrales et al 2004;Tsai et al 1998;Sriram et al 2012).…”

“…All the oligomerized molecules are expected to be essentially in a globular shape with very limited flexibility, the packing density of the polymer will not be changed and same as the protein molecule. On the other hand all the high viscogenic materials identified by Intaglietta and colleagues are not materials of high packing density (Cabrales et al 2004;Tsai et al 1998;Sriram et al 2012), and are expected to minimize the damage impacted to the endothelium in inducing shear stress (see Sect.11.3.3 for additional discussions).…”

“…Accordingly, EAF P5K6 albumin and EAF P5K6 Hb have been classed as low viscosity NO producing plasma expanders with low viscosity, as the viscosity of this kind of materials is lower than that of blood. Sriram et al (2012) have recently shown that the common feature of all NO producing plasma expanders is their ability to enhance the shear thinning effect of RBC cells and thus contribute to the supra perfusion. The fundamental question remains what structural aspects of EAF PEG Hb and EAF PEG Albumin, the NO producing low viscosity plasma expanders, endows them with the ability to mimic the NO producing high viscosity plasma expanders .…”

PEGylation of αα-Hb using succinimidyl propionic acid PEG 5K: Conjugation chemistry and PEG shell structure dictate respectively the oxygen affinity and resuscitation fluid like properties of PEG αα-Hbs

“…The extent to which oxygen is delivered by high oxygen affinity PEG Hb in circulation is dictated by the oxygen tension in hypoxic regions in the tissues and the P50 of PEG Hb. Therefore, the current versions of high oxygen affinity PEGylated Hbs are primarily active plasma expanders (Sriram et al 2012, Cabrales et al 2008), and these semisynthetic hybrid biopolymers perform only a secondary function of targeting the oxygen delivery to hypoxic regions.…”