Et tu, Calcium?

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Picture of David Zimmerman
David Zimmerman
Dave is an associate professor at Duquesne University School of Pharmacy and emergency medicine pharmacist at UPMC Mercy Hospital. He completed residency training at The Johns Hopkins Hospital and Maimonides Medical Center in Brooklyn, NY. His practice interests include medication dosing in patients that are obese and pain management in the ED.

The Pre-brief

We know our core medications for ACLS (epinephrine, amiodarone, lidocaine) but what is the role of other medications, like calcium? We know calcium can be used in the non-ACLS setting for hyperkalemia to prevent or treat arrhythmias or for severe hypocalcemia. Calcium has an unclear role though in our ACLS algorithms for when (or if) it should be routinely utilized.

Thankfully, we had the recent COCA trial to help us answer this question. This study examined the efficacy of calcium administration as a standard ACLS intervention among OHCA patients without known or suspected hyperkalemia.  

What did they do?

  • Randomized clinical trial including 391 adults with out-of-hospital cardiac arrest (OHCA)
  • Double-blind, placebo-controlled study that took place in Denmark from Jan 20, 2020 to April 15, 2021
  • Intervention arm: 5 mmol (735 mg) of calcium chloride with the first dose administered immediately after the first dose of epinephrine. A second dose of calcium or placebo could be given after the second dose of epinephrine
  • Primary outcome: sustained ROSC, defined as spontaneous circulation with no further need for chest compressions for at least 20 minutes
  • Secondary outcomes: Survival and a favorable neurological outcome (modified Rankin scale of 0-3 [mRS]) at 30 and 90 days
  • Inclusion: adult ( 18 years) if they had an OHCA and received at least one dose of epinephrine
  • Exclusion
    • Traumatic cardiac arrest
    • Known or suspected pregnancy
    • Prior enrollment in the trial
    • Receipt of epinephrine outside the trial
    • Clinical indication for calcium administration
  • Statistics
    • Original sample size of 430 patients for 80% power but was updated to 674 after a blinded review of 270 patients
    • Patients randomized in 1:1 manner with calcium or placebo

Results

  • 1,221 patients were initially screened but 824 were excluded
  • Enrolled 193 patients in the calcium chloride group and 198 in the placebo
  • Demographics
    • Mean age: 67 years in the calcium arm vs. 69 in placebo
    • Male: 68% in the calcium arm vs. 74% in placebo
    • Most common co-morbidities: Arterial hypertension, pulmonary disease, coronary artery disease, diabetes, kidney disease, atrial fibrillation, heart failure, and stroke. No major differences between the two groups
    • Location of arrest: Home for ~80% and public area for ~20%
    • Witnessed status
      • Bystander: 52% in calcium vs. 50% in placebo
      • EMS: 8% in calcium vs. 7% in placebo
      • Not witnessed: 39% in calcium vs. 43% in placebo
    • Bystander response: CPR in 82% of patients in the calcium group vs. 89% in placebo
    • AED response: 8% in the calcium group vs. 7% in placebo
    • Initial rhythm
      • Asystole: 53% in calcium vs. 48% in placebo
      • PEA: 24% in calcium vs. 25% in placebo
      • VFib: 20% in calcium vs. 25% in placebo
      • Vtach: 2% in calcium vs. 2% in placebo
    • Route of administration
      • IV: 40% in both groups
      • IO: 60% in both groups
      • Time to administration of epinephrine: ~17 mins for both groups
      • Time to administration of trial drug: ~18 mins for both groups

 

  • Primary outcome 37/193 (19%) in the calcium group who had ROSC vs. 53/198 (27%) in the placebo group. Risk ratio (RR) 0.57 (95% CI 0.27 to 1.18)

 

  • Secondary outcomes: 
    • Survival at 30 days: 10/193 (5.2%) in the calcium group vs 18/198 (9.1%) in the placebo group were alive RR 0.57 (95%CI 0.27 to 1.18)
    • Favorable neurological outcome at 30 days: 7/193 (3.6%) in the calcium group vs. 15/198 (7.6%) in the place group RR 0.48 (95% CI 0.2 to 1.13)
    • For patients with calcium measurements: 26 (74%) in the calcium group vs. 1 (2%) in the placebo group had hypercalcemia

Strengths

  • Study design (randomized, double-blinded, placebo controlled)
  • Similar group characteristics
  • EMS was blinded to the therapy given, and the study followed a rigid protocol

Limitations

  • Trial was stopped early after an interim analysis of 383 patients due to potential harm in the calcium group. Stopping early may overestimate effects; however, would not change that calcium was not found to be superior to placebo
  • Only one dosing regimen of calcium was utilized (~73% of patients got two doses)
  • Majority of patients were in asystole/PEA and may not be as translatable to Vtach or Vfib
  • Bystander response was very high and may limit external validity
  • The doses of calcium given in the trial may not apply to the general practice in the United Stated where Calcium is given at a higher doses (1 gram)

The Debrief

  • In this trial, routine administration of IV/IO Calcium did not improve ROSC compared to placebo in OHCA
  • Trial was stopped early due to potential harm
  • Results may not be as applicable to in-hospital cardiac arrests due to differences in OHCA setting
  • If you suspect hyperkalemia as an “H” for the cause of the cardiac arrest, then still give calcium!

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