By Betty Tran, MD, MSc
Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago
SYNOPSIS: In this multicenter, randomized clinical trial, the combination of vasopressin and methylprednisolone improved the rate of return of spontaneous circulation in patients with in-hospital cardiac arrest but had no significant effect on longer-term outcomes.
SOURCE: Andersen LW, Isbye D, Kjaergaard J, 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;326:1586-1594.
The Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial was a multicenter, randomized, placebo-controlled, double-blind study designed to evaluate whether the combination of vasopressin and steroids could improve return of spontaneous circulation (ROSC) in patients with in-hospital cardiac arrest. Adult patients with an in-hospital cardiac arrest receiving at least one dose of epinephrine were eligible across 10 hospitals in Denmark. Patients were randomized 1:1 to receive methylprednisolone 40 mg and vasopressin 20 IU vs. placebo as soon possible after the first dose of epinephrine during advanced cardiac life support (ACLS); additional vasopressin doses (20 IU each) could be given after additional epinephrine doses for a maximum of four doses (80 IU).
The primary outcome was ROSC, defined as no further chest compressions needed for at least 20 minutes. Secondary outcomes included survival at 30 days and survival at 30 days with a favorable neurologic status, defined by Cerebral Performance Category (CPC) score of 1 or 2 (with higher scores indicating worse outcomes). Tertiary outcomes included neurologic outcome assessed by modified Rankin Scale and health-related quality of life assessed by the EuroQol 5 Dimension 5 Level at 30, 90, 180, and 365 days (only 30- and 90-day data are available thus far), Sequential Organ Failure Assessment (SOFA) scores at 24, 48, and 72 hours post-arrest, and vasopressor- and ventilator-free days within the first 14 days.
From 2018 to 2021, 512 patients were randomized; after excluding 11 patients based on inclusion/exclusion criteria, 501 patients were analyzed according to their randomization assignment. Mean age was 71 (standard deviation [SD] 13) years, 64% were men, and 90% presented with an initial nonshockable rhythm. Of those receiving vasopressin/placebo, 28% received one dose, 29% received two doses, 16% received three doses, and 26% received four doses.
Overall, 100 patients (42%) in the intervention group achieved ROSC vs. 86 (33%) in the placebo group (risk ratio, 1.30; 95% confidence interval [CI], 1.03-1.63; risk difference, 9.6%; P = 0.03). At 30 days, 23 patients (9.7%) in the intervention group were alive vs. 31 patients (12%) in the placebo group (risk ratio, 0.83; 95% CI, 0.50-1.37; risk difference, –2.0%; P = 0.48). No significant difference was found between groups in terms of favorable neurologic outcomes at 30 days or any of the tertiary outcomes. There were no differences regarding adverse events like hyperglycemia or hypernatremia between the two groups.
COMMENTARY
The VAM-IHCA trial was performed to validate previously published findings from two randomized clinical trials that reported that vasopressin and methylprednisolone, when given with epinephrine as part of advanced life support during cardiopulmonary resuscitation (CPR), resulted in higher probability of ROSC with improved survival to hospital discharge and a favorable neurologic status.1,2 Strengths of the trial included its size, execution (no loss to follow-up yet), and inclusion of multiple centers and longer-term outcomes.
Similar to the prior studies cited, VAM-IHCA did find a similar significant improvement in ROSC with the combination of vasopressin/methylprednisolone as part of ACLS after epinephrine dosing. There is biological plausibility supporting this: Vasopressin is a strong arterial vasoconstrictor, which may increase coronary artery perfusion pressure and chance of ROSC, whereas glucocorticoids upregulate the expression of endothelial α receptors, thereby potentiating the response to adrenergic agents such as epinephrine.3
Notably, however, unlike the trials headed by Mentzelopoulos, VAM-IHCA did not find differences in 30-day survival, neurologic status, or other longer-term outcomes. This could be related primarily to differences in how the trial handled the use of glucocorticoids in the post-cardiac arrest period. Whereas the prior studies stipulated stress dose steroids (300 mg daily for up to seven days) post-resuscitation for persistent shock, this was left to the discretion of the treating team in VAM-IHCA. Among the 124 patients who survived at least 24 hours, 46% from the placebo group vs. 24% from the intervention group received glucocorticoids. It is possible that treatment of post-cardiac arrest vasoplegia and/or adrenal insufficiency with continued steroids may have resulted in improved longer-term outcomes beyond achievement of ROSC. Ultimately, the trial was not powered to assess secondary outcomes, especially given the very low proportion of survivors at 30 days.
Overall, this trial suggests the combination of vasopressin and steroids as a consideration for in-hospital cardiac arrest patients to achieve ROSC. Given the nuances surrounding cardiac arrest and resuscitation (including post-resuscitative efforts) in various locations by different providers, which can limit the generalizability of research findings in this field, further studies will be needed to validate these data with an eye toward outcomes beyond ROSC as well.
REFERENCES
- Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009;169:15-24.
- 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;310:270-279.
- Kadowitz PJ, Yard AC. Influence of hydrocortisone on cardiovascular responses to epinephrine. Eur J Pharmacol 1971;13:281-286.
In this multicenter, randomized clinical trial, the combination of vasopressin and methylprednisolone improved the rate of return of spontaneous circulation in patients with in-hospital cardiac arrest but had no significant effect on longer-term outcomes.
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