REBEL Cast Ep106: The COCA Trial – Calcium in Cardiac Arrest

Background: The utility of pharmacological interventions for patients with OHCA are rather limited with no robust evidence that they improve outcomes.  Calcium, one of the pharmacological options has both inotropic and vasopressor effects. Additionally, calcium plays an important role in the management of hyperkalemia  which is a significant cause of cardiac arrest. There have been no large randomized clinical trials assessing the effect of calcium during cardiac arrest to date. The prior evidence base of small RCTs and observational trials have found conflicting results . Despite this, calcium is still recommended in many guidelines. [Link is HERE]

REBEL Cast Ep106: The COCA Trial – Calcium in Cardiac Arrest

Paper: Vallentin MF et al. 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. JAMA 2021. PMID: 34847226 (Access on Read by QxMD HERE)

Clinical Question: Does administration of calcium during out-of-hospital cardiac arrest improve sustained ROSC?

What They Did:

  • The Calcium for Out-of-Hospital Cardiac Arrest (COCA) Trial
  • Double-blind, placebo-controlled, parallel group, superiority, randomized clinical trial in Denmark
  • Patients randomized to:
    • Calcium: IV or IO up to 2 doses of 5mmol (corresponding to 200mg of calcium or 735mg of calcium chloride dihydrate) of calcium chloride
    • Saline: 9mg/mL of 0.9% saline solution
    • 1st dose administered immediately after 1st dose of epinephrine
  • Trial terminated early due to concerns about harm in the calcium group


  • Primary: Sustained ROSC (no need for further chest compressions for at least 20 minutes)
  • Key Secondary:
    • Survival at 30d
    • Survival with favorable neurological outcome (mRS of 0 to 3) at 30d


  • Adult (≥18 years of age) patients
  • OHCA
  • Received at least 1 dose of epinephrine during cardiac arrest


  • Traumatic cardiac arrest (including strangulation and foreign body asphyxia)
  • Known or strongly suspected pregnancy
  • Prior enrollment in the trial
  • Receipt of epinephrine outside the trial (from a unit not participating in the trial)
  • Clinical indication (ie. Suspected hypocalcemia or hyperkalemia)


  • 397 patients with OHCA
    • 391 included in the analysis
    • Calcium: 193 patients
    • Saline: 198 patients
    • Mean age: 68 years
    • Female: 29%
    • Cardiac arrest at home: 82%
    • Initial nonshockable rhythm: 75%
    • Median time from cardiac arrest to administration of trial drug: 18min
    • Intraosseous access: 60%
    • Received both doses of trial drug: 73%
  • Sustained ROSC:
    • Calcium: 19%
    • Saline: 27%
    • RR 0.72; 95% CI 0.49 to 1.03
    • Risk Diff: -7.6%; 95% CI -16% to 0.8%; p = 0.09
  • Survival at 30d
    • Calcium: 5.2%
    • Saline: 9.1%
    • RR 0.57; 95% CI 0.27 to 1.18
    • Risk Diff: -3.9%; 95% CI -9.4% to 1.3%; p = 0.17
  • Favorable Neurologic Outcome at 30d:
    • Calcium: 3.6%
    • Saline: 7.6%
    • RR 0.48; 95% CI 0.20 to 1.12
    • Risk Diff: -4.0%; 95% CI -8.9% to 0.7%; p = 0.12
  • Hypercalcemia:
    • Calcium: 74%
    • Saline: 2%


  • Double-blind, placebo-controlled, randomized clinical trial (patients, investigators, and clinical teams unaware of the allocated treatment)
  • Asks a clinically important question
  • No loss to follow up
  • Independent data and safety monitoring committee reviewed all trial data after recruitment of 50, 200, and 400 patients
  • Similar baseline characteristics between groups
  • 65% of patients had data on fraction and frequency of chest compressions and were comparable between groups
  • Few protocol deviations
  • Authors were able to show that administration of calcium did result in increase in ionized calcium values


  • Trial stopped early, which can overestimate effects (or, in this case, harms)
  • Only tested 1 dosing regimen and timing. These results cannot be extrapolated to different doses or timing intervals
  • This was an OHCA setting which may not generalize to an in-hospital setting
  • Excluded group that theoretically would have the most benefit (i.e. clinical evidence of hyperK)
  • Primary outcome is a surrogate thought there was no benefit seen for patient centered outcomes
  • Low rate of shockable rhythms
  • Non-shockable rhythms with low overall survival which could bias results toward the null


  • Administration of calcium compared to saline did not result in a statistically significant difference in sustained ROSC for adult patients with OHCA
  • Additionally, there was no statistically significant difference in 30-day survival or 30-day survival with a favorable neurological outcome
  • Although not statistically significant, patients receiving calcium had numerically worse outcomes
  • At 90 days fewer patients in the calcium group had a favorable neurological outcome and quality of life
  • Signal that Calcium administration caused harm in OHCA:
    • Accumulation of sodium intracellularly, reducing transmembrane sodium gradient, which could cause the sodium-calcium exchanger to operate in reverse mode causing cardiac hypercontraction (i.e. stone heart)
    • Promotion of oxidative stress
    • Release of proapoptotic factors
    • Activation of calcium-dependent lipases, proteases, and nucleases
  • There could still be a role for calcium in special circumstances:
    • Hyperkalemia
    • Hypocalcemia
    • Overdose of calcium channel blockers

Author Conclusion: “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.” 

Clinical Take Home Point: The findings from this trial suggest that treatment with IV or IO calcium in an unselected OHCA did not significantly improve sustained ROSC and the point estimates actually trended toward more harm.  In select patients, however, with hyperkalemia, hypocalcemia, or overdose of calcium channel blockers there is still however a role for calcium treatment. 


  1. Vallentin MF et al. 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. JAMA 2021. PMID: 34847226 (Access on Read by QxMD HERE)

For More Thoughts on This Topic Checkout:

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

Cite this article as: Salim Rezaie, "REBEL Cast Ep106: The COCA Trial – Calcium in Cardiac Arrest", REBEL EM blog, January 3, 2022. Available at:

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