Does the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improve return of spontaneous circulation?
In this randomized trial that included 501 patients with in-hospital cardiac arrest in Denmark, the proportion of patients who achieved return of spontaneous circulation was 42% in the vasopressin and methylprednisolone group and 33% in the placebo group, a difference that was statistically significant.
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone compared with placebo significantly increased the likelihood of return of spontaneous circulation, but it is uncertain whether there is benefit or harm for long-term survival.
Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.
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.
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).
Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71  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.
ClinicalTrials.gov Identifier: NCT03640949
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Lars W. Andersen, MD, MPH, PhD, DMSc, Research Center for Emergency Medicine, Department of Clinical Medicine and Emergency Department, Aarhus University and Aarhus University Hospital, Palle Juul-Jensens Blvd 161, 8200 Aarhus N, Denmark (firstname.lastname@example.org).
Accepted for Publication: September 13, 2021.
Published Online: September 29, 2021. doi:10.1001/jama.2021.16628
Author Contributions: Dr Andersen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Andersen and Granfeldt.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Andersen and Granfeldt.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Andersen and Holmberg.
Obtained funding: Andersen.
Administrative, technical, or material support: All authors.
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.
Funding/Support: Funding for the trial was provided by Aarhus University Research Foundation; the Department of Clinical Medicine, Aarhus University; the Central Denmark Region; and the Independent Research Fund Denmark. Empressin and corresponding placebo ampoules were provided free of charge by Amomed Pharma GmbH.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: Presented via livestream for Critical Care Reviews; September 29, 2021.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the clinical teams that facilitated inclusion of patients at the participating centers as well as the members of the independent data monitoring committee (Christian Fynbo Christiansen, MD, PhD, Aarhus University; Jasmeet Soar, MD, Southmead Hospital; and Hans Friberg, MD, PhD, Skåne University Hospital). We also thank Therese Straarup, MD, PhD, Mette Poulsen, MD, Phillip Caap, MD, all from Viborg Regional Hospital, and Thomas Dissing, MD, PhD, Aarhus University Hospital, for assisting with trial conduct. None of the listed persons were compensated for their work related to this trial.
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