What were the design, interventions, and primary outcomes of the ANDROMEDA‑SHOCK‑2 trial comparing capillary refill time‑guided resuscitation versus lactate‑guided standard care in adult patients with early septic shock?

ANDROMEDA-SHOCK-2 Trial Overview

ANDROMEDA-SHOCK-2 is an ongoing international, multicenter randomized controlled trial comparing hemodynamic phenotype-based, capillary refill time (CRT)-targeted resuscitation versus standard lactate-guided care in early septic shock, with a primary outcome assessed by hierarchical analysis of mortality, time to organ support cessation, and hospital length of stay. 1, 2

Trial Design & Population

• Study Type: Multicenter, multinational randomized controlled trial enrolling 1,500 patients with early septic shock (diagnosed < 4 hours prior to enrollment) 2
• Randomization: Patients are allocated 1:1 to either CRT-targeted resuscitation based on hemodynamic phenotyping or standard care resuscitation 1, 2
• Intervention Duration: 6-hour active resuscitation protocol in the experimental arm 2

Intervention Arm: CRT-Targeted, Phenotype-Based Resuscitation

The experimental strategy uses an hourly CRT assessment with a stepwise algorithm based on hemodynamic phenotyping 2:

Step 1: Pulse Pressure Assessment

• If CRT is abnormal (> 3 seconds), measure pulse pressure 2
• Pulse pressure < 40 mmHg: Proceed to fluid responsiveness testing and administer fluids if responsive 2
• Pulse pressure > 40 mmHg: Titrate norepinephrine to maintain diastolic arterial pressure > 50 mmHg 2

Step 2: Echocardiographic Evaluation

• If CRT remains abnormal after Step 1, perform critical care echocardiography to assess for cardiac dysfunction and guide subsequent management 2

Step 3: Vasopressor & Inodilator Optimization

• If CRT persists abnormally, conduct vasopressor and inodilator tests to further optimize peripheral perfusion 2

Control Arm: Standard Care

• Standard lactate-guided resuscitation following current Surviving Sepsis Campaign guidelines 2
• Targets include MAP ≥ 65 mmHg, urine output ≥ 0.5 mL/kg/h, and lactate normalization or clearance > 20% every 2 hours 3, 4

Primary Outcome

Hierarchical composite outcome analyzed using the stratified win ratio method, assessing in order 1, 2:

1. 28-day all-cause mortality
2. Time to organ support cessation (mechanical ventilation, vasopressors, renal replacement therapy)
3. Hospital length of stay

Secondary Outcomes

• Organ dysfunction at 72 hours measured by SOFA score 1, 2
• 90-day mortality 2
• Ventilator-free, vasopressor-free, and renal replacement therapy-free days at 28 days 2
• ICU and hospital length of stay 2

Rationale & Pathophysiological Basis

Limitations of Lactate-Guided Resuscitation

• Lactate elevation in sepsis may arise from non-hypoxic sources including beta-adrenergic stimulation, liver dysfunction, and accelerated aerobic glycolysis—not solely tissue hypoperfusion 5, 6
• Up to 23% of septic patients demonstrate "cryptic shock" with lactate ≥ 2 mmol/L despite ScvO₂ > 70%, reflecting impaired cellular oxygen utilization rather than inadequate oxygen delivery 6
• Lactate normalization may lag behind actual tissue reperfusion, potentially leading to over-resuscitation and fluid overload 7

Advantages of CRT-Targeted Resuscitation

• Real-time perfusion assessment: CRT provides immediate bedside feedback on peripheral perfusion status, allowing more timely decisions to stop fluid administration 8, 7
• Phenotype-based approach: Tailoring interventions to hemodynamic phenotypes (low vs. high pulse pressure, cardiac dysfunction) addresses the heterogeneity of circulatory failure in septic shock 7, 2
• Preliminary evidence: The original ANDROMEDA-SHOCK trial (n=424) showed a trend toward reduced 28-day mortality (34.9% vs. 43.4%, HR 0.75,95% CI 0.55-1.02, p=0.06) and significantly lower SOFA scores at 72 hours (mean difference -1.00, p=0.045) with CRT-targeted resuscitation 9

Statistical Considerations

• Sample size: 1,500 patients calculated to provide 88% power to detect superiority of the CRT-targeted strategy 2
• Analysis: Intention-to-treat principle with stratified win ratio method for the hierarchical primary outcome 1
• Subgroup analyses: Planned to explore treatment effects across different patient populations 1

Clinical Implications

If ANDROMEDA-SHOCK-2 demonstrates superiority of phenotype-based, CRT-targeted resuscitation, this would support a paradigm shift toward personalized septic shock management using bedside clinical assessment rather than relying solely on laboratory markers. 7, 2 This approach could reduce over-resuscitation, minimize fluid overload complications, and optimize resource utilization in intensive care settings 8, 7.