Early Norepinephrine Attenuates Fluid-Associated Albumin Decline in Sepsis: A Prospective Longitudinal Study

Background/Objectives: Hypoalbuminaemia is a consistent predictor of mortality in sepsis; however, the temporal dynamics of albumin decline and its relationship with fluid exposure and early norepinephrine therapy remain incompletely characterised. Determining whether early norepinephrine use is associated with attenuation of albumin loss could inform fluid management strategies and identify therapeutic windows for combined vasopressor-albumin interventions. The study aimed to assess whether serum albumin trajectories in sepsis are associated with fluid exposure, modulated by early norepinephrine therapy, and related to 30-day mortality. Methods: We conducted a prospective longitudinal study of patients admitted to an intermediate care unit (IMCU) with community-acquired sepsis. Serum albumin concentrations, cumulative fluid balance (CFB), and vasopressor use were recorded during the first 5 days of hospitalisation. Longitudinal mixed-effects and segmented linear models assessed the association of CFB and vasopressor therapy with albumin trajectories. Lagged mediation modelling explored the potential mediating role of albumin in the association between fluid exposure and 30-day mortality. Results: A total of 389 patients with community-acquired sepsis were included. Thirty-day mortality was 18%. Mean serum albumin at baseline was 2.58 g/dL and declined early to 2.24 g/dL at 72 h. Serum albumin was inversely correlated with cumulative fluid balance over time (r ranging from -0.235 to -0.348; p < 0.001). In longitudinal models, each 1% increase in ΔCFB was associated with a -0.029 g/dL decrease in serum albumin (p < 0.001), supporting an independent effect of fluid exposure. Before norepinephrine initiation, the albumin slope was -0.043 g/dL per interval and was -0.008 g/dL after vasopressor initiation (interaction p = 0.012). Lower albumin concentrations at 72 h predicted 30-day mortality (OR 1.49 per 0.5 g/dL decrease), and serum albumin mediated 18.6% of the association between fluid exposure and mortality. Conclusions: Cumulative fluid exposure was associated with a progressive decline in serum albumin in patients with community-acquired sepsis. Early norepinephrine initiation was associated with attenuation of this trajectory, consistent with the hypothesis that vasopressor-guided haemodynamic stabilisation may limit fluid-associated albumin loss.