Therapeutic interventions to restore microcirculatory perfusion following experimental hemorrhagic shock and fluid resuscitation: A systematic review

Abstract

Objective: Microcirculatory perfusion disturbances following hemorrhagic shock and fluid resuscitation contribute to multiple organ dysfunction and mortality. Standard fluid resuscitation is insufficient to restore microcirculatory perfusion; however, additional therapies are lacking. We conducted a systematic search to provide an overview of potential non-fluid-based therapeutic interventions to restore microcirculatory perfusion following hemorrhagic shock.

Methods: A structured search of PubMed, EMBASE, and Cochrane Library was performed in March 2020. Animal studies needed to report at least one parameter of microcirculatory flow (perfusion, red blood cell velocity, functional capillary density).

Results: The search identified 1269 records of which 48 fulfilled all eligibility criteria. In total, 62 drugs were tested of which 29 were able to restore microcirculatory perfusion. Particularly, complement inhibitors (75% of drugs tested successfully restored blood flow), endothelial barrier modulators (100% successful), antioxidants (66% successful), drugs targeting cell metabolism (83% successful), and sex hormones (75% successful) restored microcirculatory perfusion. Other drugs consisted of attenuation of inflammation (100% not successful), vasoactive agents (68% not successful), and steroid hormones (75% not successful).

Conclusion: Improving mitochondrial function, inhibition of complement inhibition, and reducing microvascular leakage via restoration of endothelial barrier function seem beneficial to restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation.

Keywords: animal models; capillary perfusion; fluid resuscitation; hemorrhagic shock.

Figure 1

PRISMA diagram representing the flowchart of study selection. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analyses

Figure 2

The effect of antioxidants and therapeutic agents targeting cell metabolism and coagulation on blood flow or red blood cell velocity following hemorrhagic shock and fluid resuscitation. Forest plots represent standardized mean differences accompanying 95% confidence intervals. Study names are reported as author, year of publication, name of therapeutic agent, and organ of measurement. Studies that did not report group sizes or standard deviations are shown as “not estimable.” No meta‐analysis was performed due to heterogeneity; therefore, no pooled effect is shown

Figure 3

The effect of therapeutics targeting the complement system or systemic inflammation, endothelial barrier modulators, and hormones on blood flow or red blood cell velocity following hemorrhagic shock and fluid resuscitation. Forest plots represent standardized mean differences accompanying 95% confidence intervals. Study names are reported as author, year of publication, name of therapeutic agent, and organ of measurement. Studies that did not report group sizes or standard deviations are shown as “not estimable.” No meta‐analysis was performed due to heterogeneity; therefore, no pooled effect is shown

Figure 4

The effect of vasoactive agents or other therapeutics targeting homeostasis on blood flow or red blood cell velocity following hemorrhagic shock and fluid resuscitation. Forest plots represent standardized mean differences accompanying 95% confidence intervals. Study names are reported as author, year of publication, name of therapeutic agent, and organ of measurement. Studies that did not report group sizes or standard deviations are shown as “not estimable.” No meta‐analysis was performed due to heterogeneity; therefore, no pooled effect is shown. For Olsen et al, ²⁰ only results of the most clinically relevant model are shown, namely the conscious model