VASST: Vasopressin vs Norepinephrine in Septic Shock (2008)

“Low-dose vasopressin, as compared with norepinephrine, did not reduce mortality rates in patients with septic shock who were being treated with catecholamine vasopressors.”

— The VASST Investigators

1. Publication Details

  • Trial Title: Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock.
  • Citation: Russell JA, Walley KR, Singer J, et al; for the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. doi:10.1056/NEJMoa067373.
  • Published: February 28, 2008, in The New England Journal of Medicine.
  • Author: James A. Russell, M.D.
  • Funding: Canadian Institutes of Health Research.

2. Keywords

Septic Shock, Vasopressin, Norepinephrine, Catecholamines, Vasodilatory Shock, Corticosteroids.

3. The Clinical Question

In adult patients with septic shock requiring norepinephrine (Population), does the addition of low-dose vasopressin (Intervention) compared to continuing norepinephrine titration (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Norepinephrine was the standard first-line vasopressor for septic shock. However, many patients with septic shock develop a relative vasopressin deficiency, which contributes to profound vasodilation.
  • Knowledge Gap: It was unknown if supplementing with low-dose vasopressin, a non-catecholamine vasopressor, could improve survival by restoring vascular tone and reducing the need for high doses of catecholamines, compared to simply escalating norepinephrine doses.
  • Proposed Hypothesis: The authors hypothesized that the addition of low-dose vasopressin to norepinephrine would reduce the mortality rate in patients with septic shock.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, controlled trial.
  • Setting: 27 intensive care units (ICUs) in Canada, Australia, and the United States.
  • Trial Period: Enrollment from August 2001 to April 2006.
  • Population:
    • Inclusion Criteria: Adult patients (≥16 years) with septic shock, defined as refractory hypotension despite fluid resuscitation, who required at least 5 µg/min of norepinephrine for 6 hours.
    • Exclusion Criteria: Acute coronary syndrome, severe bronchospasm, or underlying conditions with a life expectancy of less than 6 months.
  • Intervention: A low-dose infusion of vasopressin (0.01 to 0.03 U/min) was added to the ongoing open-label norepinephrine infusion.
  • Control: A placebo (norepinephrine) infusion was added to the ongoing open-label norepinephrine infusion, which was then titrated as needed.
  • Management Common to Both Groups: All patients were managed with open-label norepinephrine to maintain a target MAP. The use of corticosteroids was stratified at randomization.
  • Power and Sample Size: The trial was powered to detect a 10% absolute reduction in 28-day mortality, requiring 760 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included 90-day mortality, organ dysfunction scores, and rates of adverse events.

6. Key Results

  • Enrollment and Baseline: 778 patients were randomized (396 to vasopressin, 382 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 28-day mortality between the vasopressin and norepinephrine groups (35.4% vs 39.3%; P=0.26).
  • Secondary Outcomes: There was no significant difference in 90-day mortality. In a pre-specified subgroup analysis, patients with less severe septic shock (requiring <15 µg/min of norepinephrine at baseline) had a significantly lower 28-day mortality rate with vasopressin (26.5% vs 35.7%; P=0.05).
  • Adverse Events: The rates of serious adverse events, including digital ischemia, were similar between the two groups.

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 deaths at day 28 was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 28 days with vasopressin: 0.93 (95% CI, 0.79 to 1.10; P=0.26).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.93.
      • Clinical Meaning: An RR of 0.93 means there was a 7% lower relative risk of death in the vasopressin group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.79 to 1.10.
      • Clinical Meaning: Since this confidence interval crosses the line of no effect (1.0), it indicates no statistically significant difference between the two strategies. The true effect is likely somewhere between a 21% benefit and a 10% harm.
    • P-value:
      • Calculation: The reported p-value was 0.26.
      • Clinical Meaning: The p-value of 0.26 is well above the 0.05 threshold, confirming that the observed difference is 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 Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 39.3% – 35.4% = 3.9%.
      • Clinical Meaning: The vasopressin strategy was associated with a non-significant 3.9% absolute reduction in the risk of death at 28 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.039 = 25.6.
      • Clinical Meaning: If the observed effect were true, approximately 26 patients would need to be treated with vasopressin to prevent one additional death at 28 days.
  • Subgroup Analyses: A significant mortality benefit was seen with vasopressin in the pre-specified subgroup of patients with less severe shock (requiring <15 µg/min of norepinephrine).

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized, double-blind trial that provided high-quality evidence on a key question in septic shock management.
  • Generalizability: The inclusion of 27 diverse ICUs increases the external validity of the findings.
  • Important Subgroup Analysis: The pre-specified analysis by shock severity generated a crucial hypothesis for future research.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The results may not apply to patients with septic shock who do not require at least 5 µg/min of norepinephrine.
  • Other: The primary outcome was neutral, with the key positive finding emerging from a subgroup analysis, which is considered hypothesis-generating rather than definitive.

10. Conclusion of the Authors

“The addition of vasopressin to norepinephrine infusion in patients with septic shock did not reduce the overall mortality rate, as compared with norepinephrine alone.”

11. To Summarize

  • Impact on Current Practice: The VASST trial was a foundational study in the management of septic shock. It established that adding low-dose vasopressin was not superior to escalating norepinephrine for the overall population. However, by demonstrating its safety and suggesting a potential benefit in less severe shock, it solidified the role of vasopressin as a reasonable second-line, norepinephrine-sparing agent, a practice that is now common worldwide.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock requiring vasopressors.
    • Actionable Intervention: Norepinephrine should remain the first-line vasopressor. Adding low-dose vasopressin can be considered as a second-line agent to help reach the target MAP and reduce norepinephrine requirements.
    • Expected Benefit: No difference in mortality for the overall population. A potential, but unproven, mortality benefit in patients with less severe shock.
  • What This Trial Does NOT Mean: This trial does not mean that vasopressin is ineffective. It is a safe and effective vasopressor, but not superior to norepinephrine as a first-line agent.
  • Implementation Caveats: Vasopressin is typically added when norepinephrine doses are escalating, with the goal of reducing catecholamine exposure.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was the first large RCT to test the vasopressin-deficiency hypothesis in septic shock.
  • Influence on Subsequent Research: The subgroup finding from VASST was a direct impetus for the VANISH trial (2016), which was designed to specifically test if early vasopressin in less severe shock could prevent kidney failure. VANISH ultimately had a neutral result, questioning the subgroup finding from VASST.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Is there a true benefit for vasopressin in patients with less severe septic shock, or was the subgroup finding in VASST a chance occurrence?
  • Future Directions: Research continues to explore the role of different vasopressor combinations and strategies for personalizing hemodynamic support in septic shock.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a physiologically plausible intervention for a common and lethal condition.
  • Methods: The large, multicenter, randomized, double-blind design was methodologically strong.
  • Results: The trial had a clear neutral result for its primary outcome. The pre-specified subgroup analysis was a key finding but must be interpreted with caution as it is hypothesis-generating.
  • Conclusions and Applicability: The authors’ conclusion is a direct interpretation of the data. The results are highly applicable, confirming norepinephrine’s role as the first-line vasopressor while establishing vasopressin as a safe and reasonable second-line agent.

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.

Scroll to Top