VAM-IHCA: Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (2013)

“The combination of vasopressin and methylprednisolone during and after resuscitation and hydrocortisone in the postresuscitation period in patients with in-hospital cardiac arrest was associated with improved survival to hospital discharge with favorable neurologic outcome.”

— The VAM-IHCA Investigators

1. Publication Details

  • Trial Title: Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest: A Randomized Clinical Trial.
  • Citation: Mentzelopoulos SD, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-279. doi:10.1001/jama.2013.7832.
  • Published: July 17, 2013, in The Journal of the American Medical Association (JAMA).
  • Author: Spyros D. Mentzelopoulos, M.D., Ph.D.
  • Funding: Not specified in the publication.

2. Keywords

In-Hospital Cardiac Arrest, Cardiopulmonary Resuscitation (CPR), Vasopressin, Corticosteroids, Methylprednisolone, Epinephrine, Post-cardiac Arrest Syndrome.

3. The Clinical Question

In adult patients with in-hospital cardiac arrest requiring epinephrine (Population), does the addition of vasopressin and methylprednisolone during CPR, plus hydrocortisone for post-resuscitation shock (Intervention), compared to epinephrine and placebo (Comparison), improve survival to hospital discharge with a favorable neurological outcome (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Survival from in-hospital cardiac arrest is poor. Standard care involves epinephrine, but its efficacy is limited. Post-cardiac arrest syndrome involves a systemic inflammatory response and relative adrenal insufficiency, similar to septic shock.
  • Knowledge Gap: It was unknown if treating the vasoplegia and inflammation of post-cardiac arrest syndrome with vasopressin and corticosteroids, in addition to standard epinephrine, could improve outcomes. This combination had shown promise in refractory shock states.
  • Proposed Hypothesis: The authors hypothesized that the combination of vasopressin, steroids, and epinephrine (VSE) would improve the rate of survival to hospital discharge with favorable neurological status compared to epinephrine alone.

5. Study Design and Methods

  • Design: A prospective, single-center, randomized, double-blind, placebo-controlled trial.
  • Setting: A single tertiary care hospital in Athens, Greece.
  • Trial Period: Enrollment from September 2008 to October 2010.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with in-hospital cardiac arrest (asystole or pulseless electrical activity) requiring at least one dose of epinephrine.
    • Exclusion Criteria: Age >75 years, terminal illness, or contraindications to any of the study drugs.
  • Intervention: The VSE protocol. During CPR, patients received vasopressin (20 IU per cycle) plus epinephrine (1 mg per cycle) for the first 5 cycles, followed by epinephrine alone. If ROSC was achieved, they received stress-dose hydrocortisone (300 mg daily) for post-resuscitation shock for up to 7 days.
  • Control: Standard CPR. Patients received saline placebo plus epinephrine (1 mg per cycle) during CPR. If ROSC was achieved, they received saline placebo for post-resuscitation shock.
  • Management Common to Both Groups: All patients received standard advanced cardiac life support (ACLS) according to guidelines.
  • Power and Sample Size: The trial was powered to detect a 12% absolute difference in the primary outcome, requiring 268 patients.
  • Outcomes:
    • Primary Outcome: Survival to hospital discharge with a favorable neurological outcome (defined as a Cerebral Performance Category [CPC] score of 1 or 2).
    • Secondary Outcomes: Included return of spontaneous circulation (ROSC) lasting more than 20 minutes, and survival at 30 days.

6. Key Results

  • Enrollment and Baseline: 268 patients were randomized (130 to VSE, 138 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Significantly more patients in the VSE group survived to hospital discharge with a favorable neurological outcome compared to the control group (13.9% vs 5.1%; P=0.02).
  • Secondary Outcomes: The rate of ROSC for more than 20 minutes was significantly higher in the VSE group (83.9% vs 65.9%; P<0.001).
  • Adverse Events: The rates of adverse events, including hyperglycemia and hypernatremia, were higher in the VSE group but were manageable.

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 surviving to discharge with a CPC of 1 or 2 was compared between the two groups.
  • Key Statistic(s) Reported: Risk Ratio (RR) for survival with favorable neurologic outcome: 2.74 (95% CI, 1.11 to 6.74; P=0.02).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of good outcome in VSE group) / (Risk of good outcome in control group).
      • Calculation: The paper reports the RR as 2.74.
      • Clinical Meaning: An RR of 2.74 means the relative likelihood of surviving to discharge with a good neurological outcome was 174% higher (or nearly 3 times as likely) in the VSE group compared to the control group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 1.11 to 6.74.
      • Clinical Meaning: Since the 95% CI ranges from a 11% benefit to a 574% benefit and does not cross 1.0, the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.02.
      • Clinical Meaning: The p-value of 0.02 is less than the conventional threshold of 0.05, indicating that the observed difference is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Intervention Group) – (Risk in Control Group).
      • Calculation: ARR = 13.9% – 5.1% = 8.8%.
      • Clinical Meaning: For every 100 patients treated with the VSE protocol, about 9 additional patients survived to discharge with a good neurological outcome.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.088 = 11.4.
      • Clinical Meaning: Approximately 11 patients with in-hospital cardiac arrest need to be treated with the VSE protocol to achieve one additional good neurological outcome.
  • Subgroup Analyses: Not reported in detail.

8. Strengths of the Study

  • Study Design and Conduct: This was a randomized, double-blind, placebo-controlled trial that tested a novel, physiologically-based combination therapy.
  • Patient-Centered Outcomes: The primary outcome of survival with favorable neurological status is the most important and patient-centered endpoint for cardiac arrest trials.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The most significant limitation is that this was a single-center study. It is often difficult to replicate the positive findings of single-center trials in larger, multicenter settings.
  • Other: The trial tested a bundled intervention, making it impossible to determine which component (vasopressin, intra-arrest steroids, or post-ROSC steroids) was responsible for the benefit.

10. Conclusion of the Authors

“Among patients with in-hospital cardiac arrest, the combination of vasopressin-epinephrine during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine-placebo during CPR and placebo in postresuscitation shock, resulted in improved survival to hospital discharge with a favorable neurologic outcome.”

11. To Summarize

  • Impact on Current Practice: The VAM-IHCA trial was a highly provocative and promising study. Its strikingly positive results suggested a new paradigm for in-hospital cardiac arrest resuscitation by targeting the underlying pathophysiology of post-cardiac arrest syndrome. However, due to its single-center nature, it did not immediately change international guidelines. Its main impact was to generate a strong hypothesis and provide the justification for a large, multicenter confirmatory trial.
  • Specific Recommendations:
    • Patient Selection: For adult patients with in-hospital cardiac arrest (asystole/PEA).
    • Actionable Intervention: This study provides evidence to consider the use of the VSE protocol.
    • Expected Benefit: A significant improvement in the rate of survival with good neurological outcome, with an NNT of approximately 11.
  • What This Trial Does NOT Mean: This trial does not mean the VSE protocol is the definitive standard of care. Its findings required external validation before widespread adoption.
  • Implementation Caveats: The protocol is complex, involving multiple drug preparations and administrations during and after a chaotic resuscitation event.

12. Context and Related Studies

  • Building on Previous Evidence: This trial built on the known pathophysiology of post-cardiac arrest syndrome and the benefits of vasopressin and steroids in other shock states.
  • Influence on Subsequent Research: This trial was the direct impetus for the large, multicenter VANISH trial (2016), which attempted to replicate these findings but ultimately had a neutral result, and the APROCCHSS trial (2018) which showed benefit of steroids in septic shock. The definitive role of this combination therapy in cardiac arrest remains an area of active investigation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Can the positive findings of this single-center trial be replicated in a large, multicenter setting? Which component of the VSE bundle is most effective?
  • Future Directions: Future research is focused on confirming these findings in larger trials and on understanding the role of each component of the intervention.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant and innovative, testing a novel, multi-faceted approach to a high-mortality condition.
  • Methods: The randomized, double-blind, placebo-controlled design was methodologically strong.
  • Results: The trial showed a surprisingly large and statistically significant benefit for its primary, patient-centered outcome.
  • Conclusions and Applicability: The authors’ conclusion is a direct interpretation of their data. However, the single-center nature of the trial is a major limitation to its immediate applicability. The results are best viewed as compelling, hypothesis-generating findings that require confirmation in a larger, multicenter trial before being adopted as a standard of care.

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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