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 are available to reduce or prevent microvascular leakage in clinical practice. We therefore aimed to provide an overview of therapeutic 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: -2.18, CI [-3.21,-1.16], P < 0.0001). Vasoactive agents were found non-effective in reducing microvascular leakage (SMD: -0.86, CI [-3.07,1.36], P = 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.