Why Has Biomarker-Guided Fluid Resuscitation for Sepsis Not Been Implemented in Clinical Practice?

Abstract

Sepsis is a dysregulated, potentially fatal host response to infection, characterized by heterogeneity in clinical presentation and organ failure mechanisms. Early hemodynamic resuscitation and antibiotics are crucial treatments. Current guidelines recommend a one-size-fits-all approach of 30 mL/kg fluids, which may worsen vascular leakage and organ dysfunction in some patients. Personalized strategies using biomarkers and dynamic fluid responsiveness assessments offer a more tailored approach, potentially preventing fluid overload while ensuring perfusion. A recent multiomics analysis identified sepsis subgroups benefiting from either liberal or restrictive fluid resuscitation, highlighting -omics' potential in personalized fluid management and the role of immune regulation and endothelial dysfunction in septic shock. Despite progress, methodological challenges hinder clinical implementation of biomarkers. Addressing issues like rapid point-of-care biomarker assays already at emergency department or ICU admission, standardizing sepsis diagnosis, robust external validation, and clinical trial enrichment is crucial for advancing biomarker-guided fluid management in clinical settings.

Keywords: biomarker; fluid resuscitation; personalized medicine; sepsis.

Figure 1.

Evolution of fluid resuscitation strategies in sepsis: From early goal-directed therapy (EGDT) to personalized approaches by multiomics discovery. Fluid resuscitation in sepsis has evolved significantly over the past 2 decades. In the early 2000s, the EGDT trial by Rivers et al (3) used static hemodynamic targets like central venous pressure to guide fluid administration. However, later subsequent large trials—Protocolized Care for Early Septic Shock (ProCESS), Australasian Resuscitation in Sepsis Evaluation (ARISE), and Protocolised Management in Sepsis (ProMISe)—found no significant advantage of EGDT over usual care, prompting a shift toward dynamic measures and biomarkers. In the 2010s, biomarkers like lactate and procalcitonin were integrated into fluid management strategies, with restrictive fluid approaches—trials such as Conservative vs. Liberal Fluid Therapy in Septic Shock (CLASSIC), Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis (CLOVERS)—gaining attention for preventing fluid overload. Simultaneously, trials such as Assessment of Resuscitation With Capillary Refill Time vs. Lactate in Early Septic Shock (ANDROMEDA-SHOCK) and Fluid Responsiveness Evaluation in Sepsis-associated Hypotension (FRESH) recognized the need for individualized resuscitation targets, using dynamic hemodynamic measures including capillary refill time and fluid responsiveness testing, to guide more personalized resuscitation strategies. The 2020s have seen a move toward personalized, multiomics-driven fluid strategies, utilizing biomarkers, such as Syndecan-1 (Synd-1) and angiopoietin-2 (Ang-2), for fluid restriction in late-phase sepsis. Emerging research, including proteomic studies using machine learning, suggests personalized fluid management may improve outcomes. Created in BioRender.

Figure 2.

Future research directions in sepsis fluid resuscitation: Focus on biomarkers, multiomics, and personalized approaches. The field has progressed from uniform early goal-directed therapy approaches to precision medicine, emphasizing individualized, evidence-based fluid resuscitation. Future research should focus on randomized controlled trials (RCTs) to validate biomarker-driven strategies, integrate multibiomarker panels, and develop real-time point-of-care diagnostics. There is also a need to explore optimal fluid removal timing and biomarkers for deresuscitation, as well as extend personalized fluid strategies to pre-hospital and emergency department settings. Ang-2 = angiopoietin-2, PCT = procalcitonin. Created in BioRender.