Early Vasoplegia and Endothelial Protection in Sepsis: A Physiology-Guided Framework for Timely Albumin and Norepinephrine Therapy

Background/Objective: Early hemodynamic instability in sepsis arises from endothelial dysfunction and vasoplegia before capillary leakage and organ failure occur. Albumin administration guided by serum concentration or shock criteria has not improved outcomes. This review synthesized evidence supporting an early, physiology-guided framework for albumin and norepinephrine use in pre-δ vasoplegic sepsis. Methods: A narrative synthesis of experimental and clinical studies examined endothelial injury, sepsis phenotypes, hemodynamic monitoring, biochemical markers, and intravascular albumin mass. Evidence from phenotype cohorts was integrated to construct a physiology-based therapeutic framework. Results: The δ phenotype consistently emerged as a vasoplegic, hyperinflammatory endotype with hypoalbuminemia, elevated lactate, and the highest mortality. Studies showed 20–25% of patients with community-acquired sepsis exhibit early vasoplegia, with low systemic vascular resistance and high cardiac output. Mass-balance analyses showed intravascular albumin mass declines early in sepsis, correlate inversely with fluid balance, and predict mortality. These findings suggest early low-dose norepinephrine may stabilize perfusion pressure, while albumin use should follow intravascular albumin mass trajectories. A dynamic exclusion concept proposes withholding albumin during capillary leak and reintroducing it when intravascular albumin mass stabilizes. Conclusions: Albumin therapy in sepsis should shift from late concentration-based to early physiology-guided endothelial protection. Monitoring intravascular albumin mass, lactate, and fluid balance may guide targeted norepinephrine and albumin use before δ-type endothelial failure occurs. This framework needs phenotype-stratified validation.