VANISH: Vasopressin vs Norepinephrine in Septic Shock (2016)

“In this randomized clinical trial of adults with septic shock, the use of vasopressin in addition to norepinephrine did not improve the number of kidney failure-free days. However, vasopressin was not associated with an increased risk of serious adverse events.”

— The VANISH Investigators

1. Publication Details

  • Trial Title: Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.
  • Citation: Gordon AC, Mason AJ, Thirunavukkarasu N, et al; for the VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485.
  • Published: August 2, 2016, in The Journal of the American Medical Association (JAMA).
  • Author: Anthony C. Gordon, M.B., B.S., M.D.
  • Funding: UK National Institute for Health Research.

2. Keywords

Septic Shock, Vasopressin, Norepinephrine, Acute Kidney Injury (AKI), Renal Replacement Therapy (RRT), Corticosteroids.

3. The Clinical Question

In adult patients with septic shock (Population), does early treatment with vasopressin (Intervention) compared to norepinephrine (Comparison) increase the number of kidney failure-free days at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Norepinephrine is the standard first-line vasopressor for septic shock. Vasopressin is often used as a second-line, norepinephrine-sparing agent. The VASST trial had previously shown no overall mortality difference between the two but suggested a potential benefit for vasopressin in patients with less severe shock. There was also a physiological rationale that vasopressin might preferentially constrict the efferent arteriole of the glomerulus, potentially improving renal function.
  • Knowledge Gap: It was unknown if using vasopressin as the initial vasopressor, instead of norepinephrine, could protect the kidneys and improve outcomes in septic shock. The effect of combining vasopressin with hydrocortisone was also uncertain.
  • Proposed Hypothesis: The authors hypothesized that early vasopressin would increase the number of kidney failure-free days compared to norepinephrine in adults with septic shock.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, 2×2 factorial trial.
  • Setting: 18 general adult ICUs in the United Kingdom.
  • Trial Period: Enrollment from February 2013 to May 2015.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock requiring vasopressors despite fluid resuscitation, within a maximum of 6 hours of onset.
    • Exclusion Criteria: Pregnancy, active bleeding, or contraindications to any of the study drugs.
  • Intervention: Patients were randomized to receive either vasopressin (titrated up to 0.06 U/min) or norepinephrine (titrated up to 12 µg/min) as their initial vasopressor. They were also randomized in a factorial design to receive either hydrocortisone or a saline placebo.
  • Control: Norepinephrine as the initial vasopressor.
  • Management Common to Both Groups: If the initial study vasopressor 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 2.5-day difference in kidney failure-free days, requiring 412 patients.
  • Outcomes:
    • Primary Outcome: Kidney failure-free days at 28 days (a composite of mortality and need for RRT).
    • Secondary Outcomes: Included 28-day mortality, rates of renal replacement therapy, and organ failure scores.

6. Key Results

  • Enrollment and Baseline: 409 patients were randomized and included in the final analysis. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the median number of kidney failure-free days at 28 days between the vasopressin and norepinephrine groups (22 days vs 22 days; P=0.85).
  • Secondary Outcomes: There were no significant differences in 28-day mortality (28% with vasopressin vs 31% with norepinephrine) or in the rates of renal replacement therapy (31% vs 36%).
  • Adverse Events: The rates of serious adverse events, including digital ischemia and mesenteric 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 regression model adjusted for baseline covariates.
  • Primary Outcome Analysis: The number of kidney failure-free days was compared between the two groups.
  • Key Statistic(s) Reported: Adjusted mean difference in kidney failure-free days: -0.29 (95% CI, -2.81 to 2.23; P=0.82).
  • Interpretation of Key Statistic(s):
    • Mean Difference:
      • Formula: Conceptually, Mean Difference = (Mean outcome in intervention group) – (Mean outcome in control group).
      • Calculation: The paper reports the adjusted mean difference as -0.29 days.
      • Clinical Meaning: A mean difference of -0.29 means that, on average, patients in the vasopressin group had about 0.3 fewer kidney failure-free days than those in the norepinephrine group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was -2.81 to 2.23 days.
      • Clinical Meaning: This confidence interval is wide and crosses the line of no effect (zero). It indicates that the true effect could be anywhere from a harm of 2.8 days to a benefit of 2.2 days, confirming a high degree of uncertainty and no significant difference.
    • P-value:
      • Calculation: The reported p-value was 0.82.
      • Clinical Meaning: The p-value of 0.82 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: Not applicable, as the intervention showed no benefit for the primary outcome.
  • Subgroup Analyses: There was no significant interaction between the vasopressor and steroid interventions.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, factorial design was methodologically strong and allowed for the efficient testing of two separate hypotheses.
  • Physiologic Rationale: The trial was based on a strong physiologic rationale for a potential renal-protective effect of vasopressin.
  • Important Safety Data: The trial provided important reassurance about the safety of early vasopressin use in septic shock.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial was conducted in a single country (UK), which may limit generalizability.
  • Other: The trial was powered for a renal outcome, not mortality. The primary outcome was a composite endpoint, which can sometimes be difficult to interpret.

10. Conclusion of the Authors

“Among adults with septic shock, the use of vasopressin compared with norepinephrine as the initial vasopressor did not improve the number of kidney failure-free days at 28 days. There was no significant difference in 28-day mortality or rates of serious adverse events.”

11. To Summarize

  • Impact on Current Practice: The VANISH trial was an important study that refuted the hypothesis that early vasopressin is renoprotective in septic shock. It provided strong evidence that there is no benefit to using vasopressin as a first-line agent instead of norepinephrine. This has reinforced international guidelines that recommend norepinephrine as the first-choice vasopressor for septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock requiring vasopressors.
    • Actionable Intervention: Norepinephrine should remain the first-line vasopressor.
    • Expected Benefit: No benefit was demonstrated for early vasopressin on renal outcomes or mortality.
  • What This Trial Does NOT Mean: This trial does not mean that vasopressin has no role in septic shock. It remains a reasonable and effective second-line agent to be added to norepinephrine in patients with refractory shock, as supported by the VASST trial.
  • Implementation Caveats: The findings provide a clear recommendation to continue with the established standard of care (norepinephrine first).

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct follow-up to the VASST trial (2008), designed to specifically test the renal protection hypothesis and the role of vasopressin as a first-line agent in a more targeted way.
  • Influence on Subsequent Research: The VANISH trial has largely settled the question of vasopressin as a first-line agent. Future research on vasopressors in septic shock is focused on other agents and on personalizing hemodynamic management.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there specific phenotypes of septic shock (e.g., hyperdynamic vs. hypodynamic) that might respond differently to vasopressin?
  • Future Directions: Research continues to explore the role of other vasopressors (e.g., angiotensin II) 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 strategy to improve a major patient-centered outcome (kidney failure) in a common critical illness.
  • Methods: The multicenter, randomized, double-blind, factorial design was methodologically superb.
  • Results: The trial had a clear and robustly neutral result for its primary outcome of kidney failure-free days, as well as for mortality and other key secondary outcomes.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the management of septic shock in ICUs worldwide and provide a definitive, evidence-based recommendation to continue using norepinephrine as the first-line vasopressor.

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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