Tongyoo et al. — Adjunctive Terlipressin in Refractory Septic Shock

1. Publication

• Title: Adjunctive terlipressin versus placebo in the treatment of refractory septic shock: a randomized, placebo-controlled trial
• Acronym: None formally assigned (protocol name: TERESEP)
• Year & Journal: Critical Care, published online October 21, 2025 (2025;29(1):443)
• Citation: Tongyoo S, Chayakul C, Aritajati T, Tanyalakmara T. Adjunctive terlipressin versus placebo in the treatment of refractory septic shock: a randomized, placebo-controlled trial. Crit Care. 2025;29(1):443. doi:10.1186/s13054-025-05669-0

2. Context & Rationale

Background: Norepinephrine is first-line in septic shock; when refractory, guidelines recommend adding vasopressin. Terlipressin, a synthetic vasopressin analog with a longer half-life and greater V1-receptor selectivity than vasopressin, has been proposed as an alternative second-line vasopressor, but its role remained controversial with limited high-quality placebo-controlled data specifically in refractory (high-dose-catecholamine) septic shock.

Research Question/Hypothesis: In adults with refractory septic shock requiring high-dose norepinephrine (>0.2 mcg/kg/min) or epinephrine, does adjunctive terlipressin improve hemodynamic stabilization (achieving MAP ≥65 mmHg with total catecholamine equivalent <0.2 mcg/kg/min at 6 hours) compared with placebo?

Why This Matters: Tests whether terlipressin can meaningfully reduce catecholamine burden in the sickest, most vasopressor-refractory septic shock patients — a population where reducing high-dose catecholamine exposure could plausibly reduce catecholamine-related toxicity.

3. Design & Methods

• Study Type: Single-center, prospective, double-blind, randomized, placebo-controlled trial
• Setting & Centers: Medical ICU, Siriraj Hospital, Thailand
• Population:
• Inclusion: Adults with septic shock requiring norepinephrine >0.2 mcg/kg/min or epinephrine
• Baseline severity: Median norepinephrine equivalent dose 0.39 mcg/kg/min (terlipressin) vs 0.39 mcg/kg/min (placebo) — well-matched at baseline
• Intervention: Terlipressin, up to a maximum of 0.025 mcg/kg/min, added to standard vasopressor therapy
• Comparator: 0.9% sodium chloride solution (placebo), same titration approach
• Randomization: 1:1, 130 patients (66 terlipressin, 64 placebo)
• Blinding: Double-blind
• Statistical Power & Follow-Up: Primary outcome: successful hemodynamic stabilization within 6h, defined as MAP ≥65 mmHg with total catecholamine equivalent dose (norepinephrine + epinephrine + [dopamine]/100 + [dobutamine]/100) <0.2 mcg/kg/min. Secondary: stabilization at 24h and 72h, 28-day mortality, adverse events (new-onset atrial fibrillation, fatal arrhythmias, digital ischemia).

4. Key Results

130 patients randomized (66 terlipressin, 64 placebo).

5. Internal Validity Assessment

• Randomization & Allocation: 1:1 randomization with well-matched baseline norepinephrine-equivalent doses between arms — supports adequate randomization.
• Protocol Adherence & Separation: Standardized titration protocol for both terlipressin and placebo (matched saline) up to a defined maximum dose.
• Blinding & Detection Bias: Full double-blind design — strong protection against both performance and detection bias for this hemodynamic/mortality trial.
• Missing Data & Sensitivity Analyses: Not detailed in available trial text beyond the reported per-protocol-style results.
• Overall Internal Validity Conclusion: Moderate-to-strong — double-blind, well-matched baseline characteristics, and a clear, statistically significant early primary-outcome result with a precisely estimated null for the more important mortality endpoint; single-center design and modest sample size (130 patients) are the main limitations for generalizability and power on secondary/safety outcomes.

6. External Validity Assessment

• Population Representativeness: Very severe, refractory septic shock population specifically selected for high catecholamine requirement (>0.2 mcg/kg/min norepinephrine or epinephrine) — extremely high baseline mortality (60-64% at 28 days) reflects the severity of this specific subgroup.
• Practice Context: Single-center (Thailand) trial; terlipressin availability and regulatory status vary internationally, and the specific dosing protocol (max 0.025 mcg/kg/min) would need local adaptation.
• Overall External Validity Conclusion: Moderate — relevant specifically to the most severe, catecholamine-refractory septic shock subgroup in health systems with terlipressin availability; single-center design limits broader generalizability of exact effect estimates.

7. Strengths & Limitations

Strengths:

• Double-blind, placebo-controlled design — genuine methodological rigor for a vasopressor-comparison trial
• Well-matched baseline catecholamine doses between arms
• Clear, statistically significant early (6h) hemodynamic benefit
• Precisely estimated null mortality result (tight-enough CI to meaningfully inform practice, rather than simply underpowered)
• Comprehensive safety outcome assessment (arrhythmias, digital ischemia)

Limitations:

• Single-center design
• Modest sample size (130 patients), particularly limiting power for secondary/safety outcomes
• Early (6h) benefit did not persist to 24h or 72h — a transient rather than sustained hemodynamic effect
• Extremely high mortality in both arms (60-64%) limits generalizability to less severe septic shock populations

8. Interpretation & Practice Impact

• Clinical Implications: Adjunctive terlipressin can transiently reduce catecholamine burden at 6 hours in refractory septic shock, but this does not translate into a sustained hemodynamic benefit or improved 28-day survival — does not support routine terlipressin use as a mortality-improving strategy in this population.
• Mechanistic Coherence: Consistent with the broader vasopressin-analog-in-septic-shock literature (e.g., VASST-style trials), where catecholamine-sparing effects are often demonstrable but rarely translate into a hard mortality benefit.
• Systems-Level Takeaway: Terlipressin may still have a role as a catecholamine-sparing bridge therapy in the most refractory patients, but should not be expected to improve survival; its value is likely limited to short-term hemodynamic stabilization rather than a disease-modifying effect.

9. Controversies & Subsequent Evidence

• Editorial Commentary/Debates: Independent commentary (Critical Care Blogspot, "Terlipressin as adjunctive therapy in refractory septic shock") situates this trial within the broader norepinephrine-first-line vasopressor literature, noting the catecholamine-sparing effect is real but transient.
• Guideline Integration: Consistent with existing guidance that reserves terlipressin/vasopressin-analog therapy for refractory cases without establishing it as a mortality-improving intervention; does not provide grounds for a guideline shift toward routine adjunctive terlipressin use.

10. Summary & Executive Takeaway

Summary: This single-center, double-blind RCT randomized 130 adults with catecholamine-refractory septic shock to adjunctive terlipressin or placebo. Terlipressin significantly improved hemodynamic stabilization at 6 hours (22.7% vs 9.4%, RR 1.53, P=0.039), but this benefit did not persist at 24h or 72h, and 28-day mortality was not significantly different (60.6% vs 64.1%, RR 0.93, P=0.684) despite very high mortality in both arms.

Overall Takeaway: Adjunctive terlipressin provides a real but transient catecholamine-sparing effect in refractory septic shock without improving survival — useful as a short-term stabilization tool in the most severe, vasopressor-refractory patients, but not a disease-modifying therapy that changes the extremely poor prognosis of this population.

11. Bibliography

• Aritajati T, Chayakul C, Tongyoo S. Terlipressin for refractory septic shock: a study protocol (TERESEP). Clin Crit Care. 2022;30.
• Liu ZM, et al. Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial. Intensive Care Med. 2018;44:1816-1825.