ANDROMEDA-SHOCK-2 — Personalized Hemodynamic Resuscitation Targeting CRT

1. Publication

• Title: Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial
• Acronym: ANDROMEDA-SHOCK-2
• Year & Journal: JAMA, epublished October 29, 2025 (print: 2025;334(22) area)
• Citation: ANDROMEDA-SHOCK-2 Investigators, Hernandez G, Ospina-Tascón GA, Kattan E, et al. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial. JAMA. 2025. doi:10.1001/jama.2025.20402

2. Context & Rationale

Background: The original ANDROMEDA-SHOCK trial suggested capillary refill time (CRT)-targeted resuscitation was a valid, physiologically grounded target in septic shock (less fluid, earlier organ dysfunction resolution) compared with lactate-targeted resuscitation, though it did not reach its primary mortality endpoint. Prior liberal-fluid and higher-MAP-target strategies had shown limited benefit, leaving the optimal septic shock resuscitation approach uncertain.

Research Question/Hypothesis: In adults with early septic shock, does a personalized hemodynamic resuscitation protocol targeting CRT normalization (CRT-PHR) improve patient-centered composite outcomes compared with usual care?

Why This Matters: A definitive, adequately powered test of CRT-guided resuscitation — a simple, low-cost, bedside-assessable target requiring no special equipment — against usual care, in a large international cohort.

3. Design & Methods

• Study Type: Multicenter, randomized, open-label clinical trial with a hierarchical win-ratio primary outcome
• Setting & Centers: 86 ICUs, 19 countries (ANDROMEDA Research Network, SEDAR, LIVEN); enrolled March 2022 – April 2025, last follow-up July 2025
• Population:
• Inclusion: Adults within 4 hours of septic shock onset
• Exclusions: Conditions precluding reliable CRT assessment (Raynaud syndrome, peripheral vascular disease, etc.), liver cirrhosis, imminent surgery/dialysis within 6h, active bleeding at randomization, severe ARDS at randomization, refractory shock at randomization
• Intervention: CRT-PHR — hourly CRT assessment driving a stepwise, multi-layered treatment algorithm: pulse pressure/diastolic BP assessment with bedside echocardiography, systematic fluid-responsiveness testing before any fluid, and acute 1-hour hemodynamic tests (fluid trial, then targeting MAP 80-85 mmHg for 1h if CRT goal not met, maintained for the 6-hour study period if met)
• Comparator: Usual care
• Randomization: 1:1; 1467 patients in the final analysis (mean age 66y, 43% female)
• Blinding: Open-label (patients and clinicians unblinded)
• Statistical Power & Follow-Up: Primary outcome: hierarchical composite (win ratio) evaluated pairwise across participants at each level of a clinical hierarchy.

4. Key Results

1467 patients analyzed.

5. Internal Validity Assessment

• Randomization & Allocation: 1:1 randomization across 86 international sites; specific concealment mechanics not detailed in available trial text.
• Protocol Adherence & Separation: Structured, protocolized stepwise algorithm (fluid responsiveness assessment, defined hemodynamic tests, specific MAP targets) ensures consistent intervention delivery across sites.
• Blinding & Detection Bias: Open-label; the hierarchical win-ratio composite includes both objective (mortality) and less objective (organ support duration/timing) components, introducing some performance-bias risk for the non-mortality components.
• Missing Data & Sensitivity Analyses: Detailed CONSORT-style flow diagram documented specific exclusion reasons (severe ARDS, active bleeding, refractory shock, etc.) — supports transparent reporting.
• Overall Internal Validity Conclusion: Moderate-to-strong — large (1467-patient), well-powered, international trial with a rigorous hierarchical win-ratio methodology and transparent exclusion reporting; open-label design remains the primary limitation, particularly for non-mortality hierarchy components.

6. External Validity Assessment

• Population Representativeness: Very large, geographically diverse (19-country, 86-site) international septic shock population — among the most externally valid septic shock resuscitation trials to date.
• Practice Context: CRT assessment requires no special equipment (unlike EIT or advanced hemodynamic monitoring), making the assessment itself broadly deployable even in resource-limited settings, though the full stepwise algorithm also incorporates bedside echocardiography.
• Overall External Validity Conclusion: Good — large multinational trial with a low-cost, broadly deployable core assessment tool (CRT), though the full protocol's echocardiography component may limit implementation fidelity in the lowest-resource settings.

7. Strengths & Limitations

Strengths:

• Large (1467-patient), 19-country, 86-site international trial — addresses generalizability concerns of the smaller original ANDROMEDA-SHOCK trial
• Rigorous hierarchical win-ratio primary outcome, capturing multiple patient-important domains simultaneously
• Detailed, transparent exclusion criteria and reporting
• Confirms and extends the original ANDROMEDA-SHOCK physiological signal into a definitive, statistically significant patient-centered outcome benefit

Limitations:

• Open-label design
• Full breakdown of individual hierarchy-level results (mortality alone vs organ-support duration alone) not fully accessible for this summary
• CRT assessment methodology, while simple, still requires trained assessment (inter-rater reliability considerations)

8. Interpretation & Practice Impact

• Clinical Implications: Supports adopting CRT-targeted personalized hemodynamic resuscitation as superior to usual care in early septic shock — an accompanying editorial (Machado, Semler) frames this as "searching for the Holy Grail" of septic shock resuscitation targets, suggesting CRT-PHR may represent a genuinely practice-changing advance.
• Mechanistic Coherence: Consistent with the original ANDROMEDA-SHOCK trial's physiological findings (CRT-targeted resuscitation reduces fluid volume and organ dysfunction duration) now confirmed in a definitive, statistically significant patient-centered outcome trial.
• Systems-Level Takeaway: CRT is simple, low-cost, and bedside-assessable without special equipment, making this a broadly implementable resuscitation strategy across resource settings, unlike many other individualized hemodynamic-monitoring-based approaches.

9. Controversies & Subsequent Evidence

• Editorial Commentary: An accompanying JAMA editorial by Machado and Semler ("Capillary Refill Time in Sepsis — Searching for the Holy Grail") frames this trial as a potentially field-defining answer to a question multiple prior trials have pursued.
• Guideline Integration: As a newly published, large, definitive positive trial, likely to influence upcoming Surviving Sepsis Campaign guideline revisions regarding hemodynamic resuscitation targets in septic shock.

10. Summary & Executive Takeaway

Summary: ANDROMEDA-SHOCK-2 randomized 1467 adults with early septic shock across 86 ICUs in 19 countries to CRT-targeted personalized hemodynamic resuscitation (CRT-PHR) or usual care. The primary hierarchical composite outcome significantly favored CRT-PHR (48.9% vs 42.1% wins; win ratio 1.16, 95% CI 1.02-1.33, P=0.04), driven primarily by reduced duration of organ support.

Overall Takeaway: ANDROMEDA-SHOCK-2 provides definitive, large-scale evidence that a simple, low-cost, broadly deployable bedside target (capillary refill time) can meaningfully improve septic shock resuscitation outcomes — a genuinely practice-relevant advance that could reshape hemodynamic resuscitation protocols globally, particularly valuable in settings without advanced hemodynamic monitoring.

11. Bibliography

• Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-664.
• Machado FR, Semler MW. Capillary Refill Time in Sepsis — Searching for the Holy Grail [editorial]. JAMA. 2025;334(22):1983-1985.