Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Abstract

Importance: It is unclear whether administration of calcium has a beneficial effect in patients with cardiac arrest.

Objective: To determine whether administration of calcium during out-of-hospital cardiac arrest improves return of spontaneous circulation in adults.

Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial included 397 adult patients with out-of-hospital cardiac arrest and was conducted in the Central Denmark Region between January 20, 2020, and April 15, 2021. The last 90-day follow-up was on July 15, 2021.

Interventions: The intervention consisted of up to 2 intravenous or intraosseous doses with 5 mmol of calcium chloride (n = 197) or saline (n = 200). The first dose was administered immediately after the first dose of epinephrine.

Main outcomes and measures: The primary outcome was sustained return of spontaneous circulation. The secondary outcomes included survival and a favorable neurological outcome (modified Rankin Scale score of 0-3) at 30 days and 90 days.

Results: Based on a planned interim analysis of 383 patients, the steering committee stopped the trial early due to concerns about harm in the calcium group. Of 397 adult patients randomized, 391 were included in the analyses (193 in the calcium group and 198 in the saline group; mean age, 68 [SD, 14] years; 114 [29%] were female). There was no loss to follow-up. There were 37 patients (19%) in the calcium group who had sustained return of spontaneous circulation compared with 53 patients (27%) in the saline group (risk ratio, 0.72 [95% CI, 0.49 to 1.03]; risk difference, -7.6% [95% CI, -16% to 0.8%]; P = .09). At 30 days, 10 patients (5.2%) in the calcium group and 18 patients (9.1%) in the saline group were alive (risk ratio, 0.57 [95% CI, 0.27 to 1.18]; risk difference, -3.9% [95% CI, -9.4% to 1.3%]; P = .17). A favorable neurological outcome at 30 days was observed in 7 patients (3.6%) in the calcium group and in 15 patients (7.6%) in the saline group (risk ratio, 0.48 [95% CI, 0.20 to 1.12]; risk difference, -4.0% [95% CI, -8.9% to 0.7%]; P = .12). Among the patients with calcium values measured who had return of spontaneous circulation, 26 (74%) in the calcium group and 1 (2%) in the saline group had hypercalcemia.

Conclusions and relevance: Among adults with out-of-hospital cardiac arrest, treatment with intravenous or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. These results do not support the administration of calcium during out-of-hospital cardiac arrest in adults.

Trial registration: ClinicalTrials.gov Identifier: NCT04153435.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Granfeldt reported being a member of a data and safety monitoring board and receiving personal fees from Noorik Biopharmaceuticals and having a patent pending for Senicapoc. No other disclosures were reported.

Figures

Figure 1.. Screening and Randomization of Patients in the Calcium for Out-of-Hospital Cardiac Arrest Trial

Figure 2.. Subgroup Results for the Primary Outcome of Sustained Return of Spontaneous Circulation

Results are presented for the 5 predefined subgroups. The time from cardiac arrest to trial drug administration was dichotomized at the median. Only cardiac arrests not witnessed by emergency medical services (EMS) were included in the bystander cardiopulmonary resuscitation (CPR) subgroup. The vertical dashed lines represent the estimated effect in the primary outcome analysis. The vertical dotted lines represent no difference between the calcium and saline groups.

Figure 3.. Posterior Probability Distributions Based on Noninformative Priors

The results from the bayesian analyses are presented as posterior probability distributions based on noninformative priors. The x-axis is logarithmic. The vertical dotted lines represent no effect (ie, a risk ratio of 1). The dark blue shaded areas represent values below 1 (ie, a harmful effect of calcium) and the light blue shaded areas represent values above 1 (ie, a beneficial effect of calcium). CrI indicates credible interval. Additional results from the bayesian analysis appear in Supplement 2.