ANDROMEDA-SHOCK II Trial Overview
ANDROMEDA-SHOCK II is an ongoing international multicenter randomized controlled trial comparing a personalized, hemodynamic phenotype-based resuscitation strategy using capillary refill time (CRT) targets versus standard care in early septic shock patients. 1, 2
Trial Design and Rationale
The trial builds upon the original ANDROMEDA-SHOCK study, which demonstrated the feasibility of peripheral perfusion-targeted resuscitation. 3 The key innovation is addressing the high heterogeneity in circulatory dysfunction mechanisms among septic shock patients by implementing clinical phenotyping rather than a one-size-fits-all approach. 1
Core Hypothesis
The trial tests whether personalized resuscitation based on hemodynamic phenotyping combined with CRT-targeted therapy reduces morbidity and mortality compared to standard lactate-targeted resuscitation. 1, 2
Intervention Strategy
The experimental arm employs a sequential, phenotype-driven protocol:
- Initial assessment determines fluid responsiveness status before each fluid bolus, preventing unnecessary fluid administration in non-responders 4
- CRT normalization serves as the primary resuscitation target, providing real-time feedback on peripheral perfusion restoration 3
- Sequential escalation includes: fluid loading in responders → vasopressor testing → inodilator testing if needed 3
This contrasts with standard care's lactate-targeted approach, which measures lactate every 2 hours and pursues normalization or >20% reduction. 3
Key Findings from Related ANDROMEDA Studies
Fluid Responsiveness Assessment (Original ANDROMEDA-SHOCK)
Systematic fluid responsiveness assessment allowed safe cessation of fluid boluses in non-responders without negative clinical impact. 4 Specifically:
- 70% of patients were fluid responsive at baseline, but only 13 patients remained fluid responsive throughout the intervention period 4
- Non-responders received significantly less fluid (0 mL vs. 1500 mL median), exhibited less positive fluid balances, but required more vasopressor support 4
- No differences emerged in major outcomes between fluid responders and non-responders, including 28-day mortality (40% vs. 36%), SOFA scores, mechanical ventilation needs, or ICU length of stay 4
Clinical Implications
The systematic assessment approach prevented potentially harmful fluid overload while maintaining equivalent outcomes, suggesting fluid responsiveness-guided therapy is both safe and effective. 4
ANDROMEDA-SHOCK-2 Specific Features
Primary Outcome
The trial uses a hierarchical composite outcome analyzed via stratified win ratio method, prioritizing mortality over morbidity measures. 2 This statistical approach accounts for the clinical reality that death supersedes other adverse outcomes in importance.
Patient Population
- Enrollment occurs within 4 hours of septic shock diagnosis, capturing the critical early resuscitation window 3
- Patients must have evidence of tissue hypoperfusion requiring intervention 3
Sample Size and Power
The original ANDROMEDA-SHOCK calculated 422 patients needed to detect a 15% absolute mortality reduction with 90% power. 3 ANDROMEDA-SHOCK-2 specifications are detailed in the statistical analysis plan published in 2025. 2
Physiological Rationale
The peripheral perfusion approach addresses fundamental limitations of lactate-targeted resuscitation:
- Non-hypoxic lactate sources (stress response, accelerated aerobic glycolysis, decreased clearance) may predominate in unknown proportions of patients, making lactate an imperfect hypoperfusion marker 3
- CRT provides immediate feedback on microcirculatory flow restoration, potentially preventing over-resuscitation and fluid overload 3
- Phenotype-based individualization recognizes that different patients require different interventions based on their specific circulatory dysfunction pattern 1
Current Status
The trial remains ongoing with database lock and final analysis pending. 2 The statistical analysis plan was published in 2025 following best practices to prevent analysis bias. 2
Clinical Context
This trial addresses a critical gap in septic shock management. While the 2016 Surviving Sepsis Campaign guidelines recommend initial 30 mL/kg crystalloid bolus and MAP ≥65 mmHg targets 5, they acknowledge that CVP alone cannot guide fluid resuscitation and recommend dynamic measures of fluid responsiveness. 5 ANDROMEDA-SHOCK-2 operationalizes these principles into a systematic, phenotype-driven protocol that may optimize the balance between adequate resuscitation and avoiding fluid overload complications.