Therapeutically Targeting Microvascular Leakage in Experimental Hemorrhagic SHOCK: A Systematic Review and Meta-Analysis

Abstract

Background: Microvascular leakage is proposed as main contributor to disturbed microcirculatory perfusion following hemorrhagic shock and fluid resuscitation, leading to organ dysfunction and unfavorable outcome. Currently, no drugs areavailabletoreduceor preventmicrovascular leakageinclinicalpractice.Wethereforeaimedtoprovideanoverviewoftherapeutic agents targeting microvascular leakage following experimental hemorrhagic shock and fluid resuscitation. Methods: PubMed, EMBASE.com, and Cochrane Library were searched in January 2021 for preclinical studies of hemorrhagic shock using any therapeutic agent on top of standard fluid resuscitation. Primary outcome was vascular leakage, defined as edema, macromolecule extravasation, or glycocalyx degradation. Drugs were classified by targeting pathways and subgroup analyses were performed per organ. Results: Forty-five studies, published between 1973 and 2020, fulfilled eligibility criteria. The included studies tested 54 different therapeutics mainly in pulmonary and intestinal vascular beds. Most studies induced trauma besides hemorrhagic shock. Forty-four therapeutics (81%) were found effective to reduce microvascular leakage, edema formation, or glycocalyx degradation in at least one organ. Targeting oxidative stress and apoptosis was the predominantly effective strategy (SMD: À2.18, CI [À3.21, À1.16], P < 0.0001). Vasoactive agents were found noneffective in reducing microvascular leakage (SMD: À0.86, CI [À3.07, 1.36], P ¼ 0.45). Conclusion: Pharmacological modulation of pathways involved in cell metabolism, inflammation, endothelial barrier regulation, sex hormones and especially oxidative stress and apoptosis were effective in reducing microvascular leakage in experimental hemorrhagic shock with fluid resuscitation. Future studies should investigate whether targeting these pathways can restore microcirculatory perfusion and reduce organ injury following hemorrhagic shock. Systematic review registration number: CRD42018095432.

End organ perfusion and pediatric microcirculation assessment

“…Clinical benefits have been observed in animal shock models where microcirculation and perfusion parameters (red blood cell velocity, functional capillary density) improve with the use of endothelial barrier modulators such as an angiopoietin-1 mimetic vasculotide or platelet-derived growth factor ( 16 ). A follow-up review from this group examined the current investigative therapies, including sex hormones and steroid use, proposed to prevent microvascular leakage related to endothelial glycocalyx damage targeting angiopoietin/Tie2 and sphingosine-1 phosphate signaling ( 90 ). Potential targeted therapies addressed in these models add understanding and novelty to future therapeutic interventions for critically ill patients.…”

Assessment of abnormal skeletal muscle perfusion by contrast-enhanced ultrasound with parametric imaging in rats after severe injury, hemorrhagic shock, and whole blood resuscitation

“…The resulting oxidative stress has complex effects on hemostasis and could result in microthrombi (25,26). Finally, trauma patients with impaired MBF exhibit profound and complex alterations to endothelial cell function, which could impair MBF through several pathways (10,(27)(28)(29)(30)(31). These many known changes have strong implications for microvascular perfusion, but their specific roles and relative importance remain unknown, and further study is needed.…”

Hemorrhagic Shock Assessed by Tissue Microcirculatory Monitoring: A Narrative Review

“…If treatment is not provided in a timely manner, coagulation dysfunction may occur. Local tissue ischemia and hypoxia promote the conversion of aerobic metabolism to anaerobic metabolism in tissue cells, which can lead to cell dysfunction, microvascular dysfunction, and even death in severe cases (6,7).…”