TARTARE-2S — Targeted Tissue Perfusion vs Macrocirculatory-Guided Care

1. Publication

• Title: Targeted Tissue Perfusion Versus Macrocirculatory-Guided Standard Care in Patients With Septic Shock: A Randomized Clinical Trial—The TARTARE-2S Trial
• Acronym: TARTARE-2S
• Year & Journal: Critical Care Medicine, epublished October 17, 2025 (print: 2026;54(1):24-34)
• Citation: Pettilä V, Pfortmüller CA, Perner A, et al. Targeted Tissue Perfusion Versus Macrocirculatory-Guided Standard Care in Patients With Septic Shock: A Randomized Clinical Trial—The TARTARE-2S Trial. Crit Care Med. 2026;54(1):24-34. doi:10.1097/CCM.0000000000006899

2. Context & Rationale

Background: Standard septic shock resuscitation guidelines rely primarily on macrocirculatory targets (MAP, CVP) and surrogate perfusion markers like diuresis. However, both severe hypotension and high vasopressor doses may independently cause harm, and macrocirculatory targets are not based on robust clinical outcome data — raising the question of whether a tissue-perfusion-focused strategy allowing lower MAP could be safer and more effective.

Research Question/Hypothesis: In ICU patients with septic shock and lactate >3 mmol/L, does targeting tissue perfusion (capillary refill time, skin temperature, lactate) while permitting a lower-than-recommended MAP (50-65 mmHg) increase days alive in 30 days with normal lactate and without vasopressor/inotropic support, compared with MAP-guided standard care (per 2012 Surviving Sepsis Campaign targets)?

Why This Matters: Directly tests whether accepting lower blood pressure in favor of tissue-perfusion-based targets is safe and potentially beneficial — a genuinely different hypothesis from ANDROMEDA-SHOCK-2 (which added CRT-guided care on top of, not instead of, adequate MAP).

3. Design & Methods

• Study Type: Randomized, parallel-group, open-label clinical trial with assessor-blinded outcome evaluation
• Setting & Centers: 3 European university hospital ICUs; enrolled 2016–2022
• Population:
• Inclusion: Adults with septic shock and blood lactate >3 mmol/L
• Stratification: By trial site and presence of chronic arterial hypertension
• Intervention: Targeted tissue perfusion (TTP) — capillary refill time, peripheral skin temperature, arterial lactate, and MAP target of only 50-65 mmHg (n=111)
• Comparator: Standard care (SC) per 2012 Surviving Sepsis Campaign hemodynamic targets (n=108)
• Randomization: 1:1, 219 total patients
• Blinding: Open-label treatment delivery, assessor-blinded outcome evaluation
• Statistical Power & Follow-Up: Primary outcome: days alive in 30 days with normal arterial lactate (<2 mmol/L) and without any inotropic/vasopressor agent. Follow-up to 30 days. Sample size recalculation performed after 150 patients by a masked statistician (potentially increasing enrollment up to 300; actual final enrollment was 219).

4. Key Results

219 patients randomized (111 TTP, 108 SC).

5. Internal Validity Assessment

• Randomization & Allocation: Stratified by site and chronic hypertension status; masked mid-trial sample-size re-estimation by an independent statistician is a methodological strength preserving blinding integrity.
• Protocol Adherence & Separation: Explicit MAP target separation (50-65 mmHg in TTP vs standard 2012 SSC targets, typically ≥65 mmHg) provides genuine physiological contrast between arms.
• Blinding & Detection Bias: Open-label treatment delivery but assessor-blinded outcome evaluation — meaningfully reduces detection bias for the primary composite outcome.
• Missing Data & Sensitivity Analyses: Trial did not reach the potential maximum re-estimated sample size (219 vs up to 300), which may have modestly reduced power relative to the upper bound of the adaptive design.
• Overall Internal Validity Conclusion: Moderate-to-good — assessor-blinded outcomes, masked sample-size re-estimation, and clear intervention separation support confidence in the null primary result; the trial's protracted enrollment period (2016-2022, 6 years across only 3 centers) suggests slower-than-expected recruitment, a practical limitation worth noting.

6. External Validity Assessment

• Population Representativeness: European septic shock population with elevated lactate (>3 mmol/L) — a more severely hypoperfused subgroup than unselected septic shock.
• Practice Context: Only 3 European university hospital ICUs — a small center count limiting generalizability beyond similar high-resource academic ICU settings; the tissue-perfusion assessment tools (CRT, skin temperature, lactate) are broadly available without special equipment.
• Overall External Validity Conclusion: Moderate — small number of centers (3) limits generalizability, though the low-cost, broadly available assessment tools support conceptual transportability to other settings if replicated more widely.

7. Strengths & Limitations

Strengths:

• Assessor-blinded outcome evaluation strengthens an open-label treatment trial
• Explicit, biologically meaningful MAP target separation (50-65 vs standard ≥65 mmHg)
• Masked, independent mid-trial sample-size re-estimation
• Demonstrates that lower MAP targets combined with tissue-perfusion guidance can be safely tolerated — a reassuring safety finding even amid a null efficacy result

Limitations:

• Small number of centers (3) and modest final sample size (219, below the potential 300 ceiling)
• Long recruitment period (2016-2022) may introduce temporal practice-pattern heterogeneity
• Open-label treatment delivery
• Clear null result for the primary composite outcome

8. Interpretation & Practice Impact

• Clinical Implications: Does not support routinely lowering MAP targets specifically to improve lactate/vasopressor-free days in septic shock — but importantly demonstrates this can be done safely, without evidence of harm from the lower MAP target itself.
• Mechanistic Coherence: Contrasts informatively with the positive ANDROMEDA-SHOCK-2 result: TARTARE-2S tested lowering MAP alongside tissue-perfusion targets, while ANDROMEDA-SHOCK-2 added CRT-guided titration without necessarily lowering the MAP floor — suggesting the benefit of tissue-perfusion-guided care may come specifically from titration/individualization rather than from tolerating lower blood pressure per se.
• Systems-Level Takeaway: Reinforces that blood pressure targets in septic shock remain an area of active investigation; this trial's safety reassurance (lower MAP tolerated without harm) may still inform individualized care in specific patients (e.g., those with hypertension-related vasopressor intolerance) even without a demonstrated efficacy benefit.

9. Controversies & Subsequent Evidence

• Editorial Commentary/Debates: Featured among "Best Intensive Care Medicine Papers" retrospectives (St Emlyn's) specifically for its informative null result and safety findings regarding lower MAP tolerance.
• Guideline Integration: Read alongside ANDROMEDA-SHOCK-2 (this handbook), the two trials together suggest tissue-perfusion-guided titration and individualization (ANDROMEDA-SHOCK-2's approach) may be more valuable than uniformly lowering MAP targets (TARTARE-2S's approach) — a nuanced, complementary contribution to the ongoing septic shock resuscitation-target debate.

10. Summary & Executive Takeaway

Summary: TARTARE-2S randomized 219 European ICU patients with septic shock and lactate >3 mmol/L to targeted tissue perfusion (allowing MAP as low as 50-65 mmHg) or standard MAP-guided care. The primary outcome (days alive with normal lactate and without vasopressors at 30 days) showed no significant difference, nor did mortality or organ-support-free days — but lower MAP targets were safely tolerated without harm.

Overall Takeaway: Deliberately lowering MAP targets alongside tissue-perfusion guidance did not improve septic shock outcomes compared with standard MAP-guided care, though it was demonstrably safe — a useful complement to the positive ANDROMEDA-SHOCK-2 trial, together suggesting that individualized titration (rather than simply tolerating lower pressure) may be the more valuable lever in septic shock resuscitation.

11. Bibliography

• Pettilä V, Merz T, Wilkman E, et al. TARTARE-2S study protocol and statistical analysis plan. Trials. 2016;17:384.
• ANDROMEDA-SHOCK-2 Investigators. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock. JAMA. 2025. doi:10.1001/jama.2025.20402