REBEL Cast Ep104: VAM-IHCA – Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest

Background: Two prior trials compared the addition of vasopressin 20 IU (for each dose of epinephrine) and methylprednisolone 40mg to placebo for in hospital cardiac arrest. The 1^st trial was published in 2009 [2] and the second in 2013 [3].  In the 2009 study, the combination of vasopressin-epinephrine and methylprednisolone improved survival.  In the 2013 study, the combination of vasopressin-epinephrine and methylprednisolone improved survival to hospital discharge with favorable neurological status compared to placebo (14% vs 5%). Despite these findings, neither the US or European guidelines recommend the use of vasopressin or glucocorticoids in the treatment of cardiac arrest.  Most resuscitationists await additional data on the treatment approach prior to incorporation into their care.

REBEL Cast Ep104: VAM-IHCA – Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest

Paper: Andersen LW et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients with In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA 2021. PMID: 34587236

Clinical Question: In adult patients with in-hospital cardiac arrest does the use of vasopressin and methylprednisolone compared to placebo increase the rates of ROSC?

What They Did:

• Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA)
• Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark
• After 1^st dose of epinephrine patients randomized to:
  • VAM: Combination of vasopressin 20IU and methylprednisolone 40mg
  • Placebo
  • Additional doses of vasopressin (20 IU) or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses

Outcomes:

• Primary: ROSC
• Key Secondary Outcomes:
  • Survival at 30d
  • Favorable Neurologic Outcome at 30d (CPC of 1 or 2)

Inclusion:

• Adult patients (≥18 years of age)
• In-hospital cardiac arrest
• Received at least 1 dose of epinephrine during cardiac arrest (Patients with cardiac arrest that started outside the hospital were not included)

Exclusion:

• Do-not-resuscitate order
• Prior enrollment in the trial
• Invasive mechanical circulator support (ECMO or LVAD) at the time of cardiac arrest
• Known or suspected pregnancy at the time of cardiac arrest 

Results:

• 512 patients with in-hospital cardiac arrest
  • 501 met all inclusion and no exclusion criteria
  • Mean age = 71 years
  • Men = 64%
  • Cardiac arrest in standard medical or surgical units = 66%
  • Initial non-shockable rhythm = 90%
  • Median time from cardiac arrest to epinephrine = 5min
  • Median time from cardiac arrest to trial drug = 8min
• ROSC:
  • VAM: 100/237 (42%)
  • Placebo: 86/264 (33%)
  • Risk Ratio: 1.30; 95% CI 1.03 to 1.63
  • Risk Diff: 9.6%; 95% CI 1.1% to 18.0%; p = 0.03
  • NNT = ~11
• Survival at 30d:
  • VAM: 9.7%
  • Placebo: 12%
  • Risk Ratio: 0.83; 95% CI 0.50 to 1.37
  • Risk Diff: -2.0%; 95% CI -7.5 to 3.5; p = 0.48
• Favorable Neurological Outcome at 30d:
  • VAM: 7.6%
  • Placebo: 7.6%
  • Risk Ratio: 1.00; 95% CI 0.55 to 1.83
  • Risk Diff: 0.0%; 95% CI -4.7 to 4.9; p >0.99
• In patients with ROSC:
  • Hyperglycemia
    • VAM: 77%
    • Placebo: 73%
  • Hypernatremia:
    • VAM: 28%
    • Placebo: 31%

Strengths:

• Multicenter, randomized, double-blind, placebo-controlled trial
• No loss to follow up
• Hard objective endpoint of ROSC
• Groups fairly well balanced at baseline in terms of medical history and cardiac arrest characteristics
• More patients in this trial (501) compared to the two previous Greek studies combined (368)
• Pre-specified secondary and safety outcomes
• Independent data monitoring committee oversaw the trial

Limitations:

• Large portion of patients who were potentially eligible, were not included (2362 patients screened but 1850 excluded)
• Non-consecutive enrollment which may create a selection bias
• Drug delivery may have been late in some patients which could influence results
• Trial was powered to the primary outcome of ROSC but not more patient oriented outcomes of survival and survival with good neurologic outcomes
• Overall survival was low (8 to 9%) in this trial
• Higher rate of ECMO in the placebo group (14 vs 30%)

Discussion:

• The point estimate for survival at 30 days suggested harm, while the confidence intervals included both clinically relevant harm and benefit (This is different than the two Greek studies [2][3]).
  • Possible explanations:
    • Greek studies gave post-cardiac arrest hydrocortisone in patients with circulatory shock
    • Greek studies had younger patients, cardiac arrest that was witnessed, and occurring in the ICU
  • Why We Can’t Extrapolate this to OHCA:
    • IHCA has a rapid time to compressions and drugs, this may not be the case in the OHCA setting
      • Median time from cardiac arrest to epinephrine = 5min
      • Median time from cardiac arrest to trial drug = 8min
    • Additionally, the cause of arrest is most likely different in the hospital setting compared to the outpatient setting
  • Vasopressin
    • Results in vasoconstriction
    • Increases arterial blood pressure
    • Increases arterial blood pressure increases coronary perfusion pressure
    • End result is increased chance of ROSC
  • Corticosteroids
    • Some evidence shows that levels of cortisol are higher in patients who have been resuscitated compared to those who have not been resuscitated
    • Translation: There may be an impaired endocrine response in non-survivors
    • Data on glucocorticoid administration in human cardiac arrest are limited

Author Conclusion: “Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation.  However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.”

Clinical Take Home Point: The combination of vasopressin and methylprednisolone compared to placebo during in-hospital cardiac arrest resulted in more ROSC but had no statistically significant difference in the more patient oriented outcomes of survival and survival with favorable neurologic status at 30 and 90d. In fact, survival at 30 days appeared to be worse in the VAM group. At this time, we cannot recommend the addition of vasopressin and methylprednisolone in the management of IHCA.

References:

1. Andersen LW et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients with In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA 2021. PMID: 34587236
2. Mentzelopoulos SD et al. Vasopressin, Epinephrine, and Corticosteroids for In-Hospital Cardiac Arrest. Arch Intern Med 2009. PMID: 19139319
3. Mentzelopoulos Sd et al. Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac arrest: A Randomized Clinical Trial. JAMA 2013. PMID: 23860985

For More Thoughts on This Topic Checkout:

• The Bottom Line: VAM-IHCA
• The SGEM: SGEM#350 – How Did I Get Epi Alone? Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrests

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)