Targeting capillary leak in experimental sepsis and endotoxemia: a systematic review of therapeutic agents, methods and models in animal studies

Abstract

Sepsis-induced capillary leak is a major contributor to circulatory dysfunction and tissue edema, yet remains therapeutically unaddressed: numerous interventions showing promise in preclinical models have failed to demonstrate clinical efficacy. This systematic review aimed to characterise preclinical studies evaluating therapeutic interventions specifically targeting capillary leak and to identify candidates with the highest potential for clinical translation. A systematic search of PubMed, Embase, and Web of Science identified in vivo studies in experimental sepsis and endotoxemia evaluating interventions targeting capillary leak. Data on animal models, sepsis induction methods, capillary leak assessment, therapeutic targets, and intervention timing were extracted. Risk of bias was assessed using the SYRCLE tool. As a complementary step, all retained interventions were cross-referenced against randomized or prospective clinical studies in sepsis published since January 2015 and appraised using a four-criterion translational quality score (reproducibility, quality of the model, clinically relevant timing, and multimodal read-out). Three hundred and three preclinical studies were included, exhibiting substantial heterogeneity in both models and outcomes. Rodent models predominated (81.2%), and lipopolysaccharide-induced endotoxemia was the most common induction method (59.7%). Dye-based assays constituted the most frequent capillary leak read-out in rodents (81.7%), whereas fluid balance and lymph-to-plasma ratios predominated in large-animal studies. The lung was the most frequently evaluated organ. Endothelial activation (12.2%), intercellular junctions (11.2%), and the nitric oxide pathway (8.9%) were the most targeted pathways. A beneficial effect of the intervention on at least one capillary leak outcome results was reported in 93.1% of studies, raising substantial concerns regarding publication bias. Of 232 distinct interventions, only a minority had been evaluated in randomized clinical trials since 2015, and no capillary leak-specific therapy has yet reached high translational priority. Preclinical research on sepsis-induced capillary leak is characterized by methodological heterogeneity, a disproportionately high rate of studies reporting capillary leak reduction, and an overreliance on endotoxemia models. Bridging the translational gap will require standardized assessment of capillary leak, broader use of live-pathogen large-animal models, post-treatment dosing paradigms, and clinical trials enriched for endothelial dysfunction. International Prospective Register of Systematic Reviews (PROSPERO) number CRD42024522372.