Resuscitation After Hemorrhagic Shock in the Microcirculation: Targeting Optimal Oxygen Delivery in the Design of Artificial Blood Substitutes

Abstract

Microcirculatory preservation is essential for patient recovery from hemorrhagic shock. In hemorrhagic shock, microcirculatory flow and pressure are greatly reduced, creating an oxygen debt that may eventually become irreversible. During shock, tissues become hypoxic, cellular respiration turns to anaerobic metabolism, and the microcirculation rapidly begins to fail. This condition requires immediate fluid resuscitation to promote tissue reperfusion. The choice of fluid for resuscitation is whole blood; however, this may not be readily available and, on a larger scale, may be globally insufficient. Thus, extensive research on viable alternatives to blood has been undertaken in an effort to develop a clinically deployable blood substitute. This has not, as of yet, achieved fruition, in part due to an incomplete understanding of the complexities of the function of blood in the microcirculation. Hemodynamic resuscitation is acknowledged to be contingent on a number of factors other than volume expansion. The circulation of whole blood is carefully regulated to optimize oxygen delivery to the tissues via shear stress modulation through blood viscosity, inherent oxygen-carrying capacity, cell-free layer variation, and myogenic response, among other variables. Although plasma expanders can address a number of these issues, hemoglobin-based oxygen carriers (HBOCs) introduce a method of replenishing the intrinsic oxygen-carrying capacity of blood. There continue to be a number of issues related to HBOCs, but recent advances in the next-generation HBOCs show promise in the preservation of microcirculatory function and limiting toxicities. The development of HBOCs is now focused on viscosity and the degree of microvascular shear stress achieved in order to optimize vasoactive and oxygen delivery responses by leveraging the restoration and maintenance of physiological responses to blood flow in the microcirculation. Blood substitutes with higher viscous properties tend to improve oxygen delivery compared to those with lower viscosities. This review details current concepts in blood substitutes, particularly as they relate to trauma/hemorrhagic shock, with a specific focus on their complex interactions in the microcirculation.

Keywords: blood substitutes; hemorrhagic shock; microcirculation; oxygen delivery; resuscitation; shear stress; viscosity.

Figure 1

Tissue perfusion in the microcirculation using hyperspectral images from the skin pouch of a Golden Syrian hamster following hemorrhage (50% total blood volume) and a resuscitation using whole blood (25% total blood volume in 5% albumin; Sigma-Aldrich, Saint Louis, MO). The first image (from left to right) is the microcirculation at baseline, the second one is the microcirculation in shock, the third one is the microcirculation immediately after the completion of resuscitation, and the fourth and final image is the microcirculation 60 min post-resuscitation.

Figure 2

Blood flow through the microcirculation. (A) The bulk of red blood cell (RBC) flow, which is related to the shear stress (τ). (B) Cell-free layer in the microcirculation. (C) Endothelial cell lining generating endothelial nitric oxide synthase (eNOS), S-nitrosothiols (RSNO), and nitric oxide (NO) via mechanotransduction. (D) Smooth muscle layer encapsulating the entire vessel.

Figure 3

Arteriolar wall nitric oxide bioavailability as a function of systemic hematocrit percentage for different cell-free layer (CFL) widths.