Early Vasopressor Initiation versus Standard Fluid Resuscitation in Normotensive Cryptic Shock: A Target Trial Emulation

Background Current sepsis guidelines mandate aggressive fluid resuscitation prior to vasopressor initiation, primarily targeting hypotension (Mean Arterial Pressure [MAP] < 65 mmHg). However, a distinct phenotype of "Cryptic Shock" characterized by severe tissue hypoperfusion (Lactate > 4.0 mmol/L) despite preserved normotension (MAP > 65 mmHg) remains poorly managed. We hypothesized that early initiation of vasopressors, rather than fluid-centric resuscitation, would improve survival in this high-risk phenotype. Methods We performed a Target Trial Emulation using the MIMIC-IV v3.1 database (2008–2019). We identified adult patients meeting criteria for Cryptic Shock within 24 hours of ICU admission. Patients were classified into two treatment strategies based on interventions received within the first 3 hours of phenotype onset: (1) Early Vasopressors (initiation of norepinephrine or vasopressin) versus (2) Standard Care (fluid resuscitation alone). The primary endpoint was 28-day mortality. To adjust for confounding by indication, we employed Inverse Probability of Treatment Weighting (IPTW) based on age, SOFA score, and admission lactate. Survival was analyzed using weighted Kaplan-Meier curves and multivariable Cox proportional hazards models. Results The final cohort comprised 3,558 patients. The Early Vasopressor group (n = 1,245) had significantly higher baseline severity scores (SOFA 9.0 vs. 6.0) compared to the Standard Care group (n = 2,313). After IPTW adjustment, covariate balance was achieved (Standardized Mean Difference < 0.1 for all variables). Early vasopressor initiation was associated with a significant reduction in 28-day mortality compared to standard care (Adjusted Hazard Ratio [HR] 0.48; 95% CI, 0.40–0.58; p < 0.001). This survival benefit persisted across sensitivity analyses. Conclusions In patients with Cryptic Shock, an early vasopressor strategy is associated with superior 28-day survival compared to standard fluid resuscitation. These findings challenge the "fluids-first" paradigm for normotensive hypoperfusion and support a shift toward perfusion-guided resuscitation.