ESCORSELL 2016: Terlipressin vs Norepinephrine in Cirrhosis with Septic Shock (2016)

“In patients with cirrhosis and septic shock, terlipressin was not superior to norepinephrine in reversing shock at 6 hours, had more severe adverse effects, and did not improve survival.”

— The Escorsell et al. Study Group

1. Publication Details

  • Trial Title: Terlipressin versus norepinephrine in patients with cirrhosis and septic shock: a randomized controlled trial.
  • Citation: Escorsell À, Pérez-Cerdá F, Bosch J, et al. Terlipressin versus norepinephrine in patients with cirrhosis and septic shock: a randomized controlled trial. Gastroenterology. 2016;150(4):913-924.e2. doi:10.1053/j.gastro.2015.12.016.
  • Published: April 2016, in Gastroenterology.
  • Author: Àngels Escorsell, M.D., Ph.D.
  • Funding: Spanish Ministry of Health and others.

2. Keywords

Septic Shock, Liver Cirrhosis, Terlipressin, Norepinephrine, Vasopressors, Portal Hypertension, Vasodilatory Shock.

3. The Clinical Question

In adult patients with liver cirrhosis and septic shock (Population), does terlipressin (Intervention) compared to norepinephrine (Comparison) as the primary vasopressor improve the rate of shock reversal at 6 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Septic shock in patients with cirrhosis is associated with extremely high mortality. The profound vasodilation in these patients is driven by both sepsis and the underlying portal hypertension. Norepinephrine is the standard first-line vasopressor. Terlipressin, a potent splanchnic vasoconstrictor, is effective in other vasodilatory states in cirrhosis, such as hepatorenal syndrome.
  • Knowledge Gap: It was unknown if terlipressin, by specifically targeting the splanchnic vasodilation that is prominent in cirrhosis, would be a more effective and safer vasopressor than norepinephrine in this specific patient population.
  • Proposed Hypothesis: The authors hypothesized that terlipressin would be more effective than norepinephrine in reversing septic shock in patients with cirrhosis.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, controlled trial.
  • Setting: 19 intensive care units (ICUs) in Spain.
  • Trial Period: Enrollment from March 2010 to December 2013.
  • Population:
    • Inclusion Criteria: Adult patients with cirrhosis and septic shock requiring vasopressors to maintain a MAP >65 mmHg despite fluid resuscitation.
    • Exclusion Criteria: Pregnancy, acute coronary syndrome, or severe peripheral vascular disease.
  • Intervention: Terlipressin infusion, started at 1 mg every 6 hours and titrated up.
  • Control: Norepinephrine infusion, started at 0.5 mg/hour and titrated up.
  • Management Common to Both Groups: Both groups received intravenous albumin. If the study drug was insufficient to reach the target MAP, open-label norepinephrine was added as a rescue therapy.
  • Power and Sample Size: The trial was powered to detect a 25% absolute difference in the rate of shock reversal, requiring 100 patients.
  • Outcomes:
    • Primary Outcome: Reversal of shock at 6 hours, defined as achieving a MAP >75 mmHg without the need for rescue norepinephrine.
    • Secondary Outcomes: Included 28-day survival, resolution of organ failure, and adverse events.

6. Key Results

  • Enrollment and Baseline: 104 patients were randomized (52 to terlipressin, 52 to norepinephrine). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the rate of shock reversal at 6 hours between the terlipressin and norepinephrine groups (73% vs 71%; P=0.81).
  • Secondary Outcomes: There was no significant difference in 28-day survival between the groups (54% in the terlipressin group vs 52% in the norepinephrine group).
  • Adverse Events: Serious adverse events were significantly more common in the terlipressin group than in the norepinephrine group (44% vs 21%; P=0.01), particularly respiratory failure requiring intubation and ischemic events.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of patients with shock reversal at 6 hours was compared between the two groups.
  • Key Statistic(s) Reported: Shock reversal at 6 hours: 38/52 (73.1%) in the terlipressin group vs 37/52 (71.2%) in the norepinephrine group; P=0.81.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of reversal in Intervention Group) / (Risk of reversal in Control Group).
      • Calculation: RR = 73.1% / 71.2% = 1.03.
      • Clinical Meaning: An RR of 1.03 means that shock reversal was 3% more likely in the terlipressin group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The calculated 95% CI for the RR is approximately 0.81 to 1.31.
      • Clinical Meaning: Since this confidence interval widely crosses the line of no effect (1.0), it indicates no statistically significant difference between the two vasopressors.
    • P-value:
      • Calculation: The reported p-value was 0.81.
      • Clinical Meaning: The p-value of 0.81 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Intervention Group) – (Risk in Control Group). Note: Here we calculate Absolute Risk Increase as it’s a positive outcome.
      • Calculation: Absolute Risk Increase = 73.1% – 71.2% = 1.9%.
      • Clinical Meaning: The terlipressin strategy was associated with a non-significant 1.9% absolute increase in the rate of shock reversal.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
  • Subgroup Analyses: Not reported in detail.

8. Strengths of the Study

  • Study Design and Conduct: This was a multicenter, randomized, double-blind trial that provided high-quality evidence on a specific and important clinical question.
  • Focused Population: The trial appropriately focused on the unique pathophysiology of septic shock in patients with cirrhosis.
  • Important Safety Data: The trial provided a clear and definitive safety signal, demonstrating increased harm with terlipressin in this context.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The results are specific to the use of these drugs as first-line agents in cirrhotic septic shock and do not address their use in other conditions.
  • Other: The study was powered for a surrogate outcome (shock reversal at 6 hours) rather than mortality.

10. Conclusion of the Authors

“In patients with cirrhosis and septic shock, terlipressin is not superior to norepinephrine in reversing shock and is associated with a higher incidence of severe adverse effects. Therefore, norepinephrine should be considered the vasopressor of choice in these patients.”

11. To Summarize

  • Impact on Current Practice: This was a definitive “negative” trial that was practice-affirming for norepinephrine. It provided strong evidence that terlipressin should not be used as a first-line vasopressor for septic shock in patients with cirrhosis due to a lack of benefit and a clear signal of harm. It reinforced norepinephrine as the standard of care for this high-risk population.
  • Specific Recommendations:
    • Patient Selection: For adult patients with liver cirrhosis and septic shock.
    • Actionable Intervention: Use norepinephrine as the first-line vasopressor agent. Avoid the use of terlipressin for this indication.
    • Expected Benefit: No benefit from terlipressin. Using norepinephrine avoids the increased risk of severe adverse events associated with terlipressin.
  • What This Trial Does NOT Mean: This trial does not negate the established role of terlipressin in the treatment of hepatorenal syndrome or acute variceal bleeding.
  • Implementation Caveats: The findings provide a clear recommendation against a specific intervention and in favor of the existing standard of care.

12. Context and Related Studies

  • Building on Previous Evidence: This trial tested whether the known benefits of terlipressin in other vasodilatory states of cirrhosis (e.g., Sort et al. 1999 for HRS) would extend to septic shock.
  • Influence on Subsequent Research: This trial has largely settled the question of the first-line vasopressor in cirrhotic septic shock. Its findings are consistent with general sepsis trials like SOAP II (2010) that established norepinephrine as the vasopressor of choice.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Is there a role for terlipressin as a second-line, norepinephrine-sparing agent in this population?
  • Future Directions: Research continues to focus on other aspects of managing septic shock in cirrhosis, including immunomodulation and therapies targeting the underlying portal hypertension.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a physiologically plausible alternative vasopressor in a specific, high-mortality population.
  • Methods: The multicenter, randomized, double-blind design was methodologically strong.
  • Results: The trial had a clear neutral result for its primary efficacy outcome and, crucially, a clear signal of harm from the intervention in terms of serious adverse events.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the management of septic shock in patients with cirrhosis and provide a definitive, evidence-based recommendation to use norepinephrine as the first-line agent and to avoid terlipressin for this indication.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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