Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial

Abstract

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.

Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.

Design, setting, and participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.

Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.

Main outcomes and measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).

Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03640949.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Andersen reported receiving grants from Aarhus University Research Foundation, the Department of Clinical Medicine at Aarhus University, and Independent Research Fund Denmark, and nonfinancial support from Amomed Pharma GmbH, which provided trial drug during the conduct of the study. Dr J. Kjærgaard reported receiving grants from the Novo Nordisk Foundation (NNF17OC0028706) outside the submitted work. Dr Lauridsen reported receiving grants from Independent Research Fund Denmark during the conduct of the study. Dr Kurth reported receiving personal fees from Teva, TotalEnergies, Eli Lilly & Company, and The BMJ outside the submitted work. Dr Granfeldt reported receiving personal fees from Noorik Biopharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Screening and Randomization in the VAM-IHCA Trial of Methylprednisolone and Vasopressin for In-Hospital Cardiac Arrest

aLogistic reasons included not enough personnel (n = 61), no study drug available (n = 45), inability to obtain surrogate consent (n = 1), and other (n = 32), which included patients isolated with COVID-19. bPatients who were excluded after receiving the trial drugs had inclusion/exclusion criteria not known at the time of the cardiac arrest.

Figure 2.. Subgroups Results for Return of Spontaneous Circulation

Subgroup results are presented for 5 predefined subgroups. Continuous variables were dichotomized at the median. The time of the cardiac arrest corresponds to the recognition of the cardiac arrest. The blue dashed lines indicate overall effect.