Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy

Septic shock is a life-threatening syndrome characterized by circulatory failure, immune dysregulation, neuroendocrine activation, and cellular metabolic dysfunction. Norepinephrine (NE) remains the first-line vasopressor for early resuscitation because it restores vascular tone, increases mean arterial pressure, and maintains vital organ perfusion. However, emerging evidence from neuroimmunology and immunometabolism suggests that NE also acts beyond hemodynamic support. This review reexamines the dual role of NE in septic shock from the perspective of high catecholamine burden, which integrates endogenous sympathetic activation, exogenous NE exposure, receptor signaling, and downstream immune-metabolic effects. Prolonged or high-dose NE exposure may regulate NF-κB activation, cytokine release, IL-10 production, phagocytic killing, antigen presentation, and lymphocyte effector function through adrenergic receptor-dependent pathways, particularly β2-adrenergic receptor/cAMP/PKA signaling. These effects may limit excessive inflammation during early disease but may also aggravate immunoparalysis in selected patients. NE may further influence glycolysis, mitochondrial oxidative phosphorylation, reactive oxygen species generation, and metabolic signaling pathways involving HIF-1α, AMPK, and mTOR, thereby reshaping immune-cell activation thresholds and antimicrobial capacity. Catecholamine signaling may also affect host-pathogen interactions by modulating bacterial growth, iron acquisition, and biofilm formation in specific experimental settings. Importantly, associations between NE exposure and adverse outcomes are strongly confounded by shock severity, infection burden, vascular hyporesponsiveness, and organ dysfunction. Future studies should integrate NE dose trajectories, cumulative exposure, immune phenotypes, metabolic states, and infection outcomes to clarify when catecholamine burden shifts from adaptive circulatory support to a potential driver of immune-metabolic dysfunction. This framework may support precision vasopressor strategies that balance hemodynamic load, immune function, and metabolic adaptability while preserving effective tissue perfusion.