Calcium for Out-of-Hospital Arrest (COCA)

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Clinical Question

In adults with out-of-hospital arrest, does calcium improve return of spontaneous circulation(ROSC)?

Bottom Line

Intravenous or intraosseus calcium was not associated with improved ROSC and may instead be associated with harm.

Major Points

Calcium is known to act as a vasopressor and inotrope. Two early small randomized trials from 1985 found that calcium did not improve ROSC in out-of-hospital cardiac arrests or pulseless electrical activity. Though these trials did not find a statistically significant effect, their point estimates favored calcium [1,2].

This is the first randomized trial to build upon this limited data, which demonstrated signals of harm in the calcium arm during a pre-specified interim analysis, prompting early termination of the trial.

Guidelines

Design

  • Double-blind, parallel-group, randomized, controlled trial
  • N=391
    • Calcium (n=193)
    • Saline (n=195)
  • Setting: Central Denmark Region with 2-tired Emergency Medical Services System (ambulance + physician-led mobile emergency care unit) with transportation of patients with ongoing CPR to a single university hospital with catheterization and revascularization capabilities.
  • Enrollment: January 20, 2020 to April 15, 2021 [of 1221 patients with out-of-hospital arrest, 397 received the trial drug and 6 were excluded due to traumatic arrest (4 in calcium, 2 in saline group)
  • Last date of follow-up: July 15, 2021
  • Analysis: Intention-to-treat
  • Primary outcome: sustained ROSC (ROSC without further need for chest compressions for at least 20 minutes)

Population

Inclusion Criteria

  • Age 18+ years old
  • out-of-hospital cardiac arrest with administration of at least 1 dose of epinephrine

Exclusion Criteria

  • traumatic arrest (including strangulation or foreign body asphyxiation)
  • pregnancy
  • prior enrollment in this trial
  • administration of epinephrine outside of the trial (from team not participating in the trial)
  • other clinical indications for administration of calcium (such as hypocalcemia or hyperkalemia)

Baseline Characteristics

  • Mean age: 68 years
  • Female: 29%
  • Initial non-shockable rhythm: 75%
  • Unwitnessed: 41%
  • Median time to study drug administration: 18 minutes

Interventions

  • Randomized 1:1 in blocks of 2, 4, or 6 to receive either calcium [5 mmol of CaCl corresponding to 200mg of calcium or 735mg of calcium chloride dihydrate] or saline [9mg/mL sodium chloride] administered as rapid bolus immediately after first dose of epinephrine and a second dose after second dose of epinephrine if still in arrest.

Outcomes

Comparisons are intravenous or intraosseus calcium vs saline.

Primary Outcomes

Sustained ROSC
19% vs 27% (RR 0.72; 95% CI 0.49-1.03; P=0.09)

Secondary Outcomes

Survival at 30 days
5.2% vs 9.2% (RR 0.57; 95% CI 0.27-1.18; P=0.17)
Survival at 30 days with favorable neurologic outcome (defined by Rankin Scale score of 0 to 3)
3.6% vs. 7.6% (HR 0.48; 95% CI 0.20-1.12; P=0.12)

Subgroup Analysis

Outcome = maintained ROSC

Initial Rhythm
  • shockable
40% vs 45% (RR 0.87; 95% CI 0.54-1.39)
  • non-shockable
13% vs 20% (RR 0.67; 95% CI 0.40-1.12)
Timing of calcium or saline administration
  • 18+ minutes
16% vs 25% (RR 0.67; 95% CI 0.38-1.17)
  • <18 minutes
22% vs 29% (RR 0.73; 95% CI 0.45-1.19)
intravenous vs intraosseus calcium
  • intravenous
18% vs 28% (RR 0.64; 95% CI 0.36-1.15)
  • intraosseus
20% vs 26% (RR 0.77; 95% CI 0.48-1.23)
witnessed vs unwitnessed cardiac arrest
  • bystander
24% vs 33% (RR 0.71; 95% CI 0.45-1.11)
  • EMS
19% vs 38% (RR 0.49; 95% CI 0.15-1.58)
  • unwitnessed
13% vs 17% (RR 0.75; 9% CI 0.36-1.55)
whether bystander cardiopulmonary resuscitation was initiated
  • CPR initiated
21% vs 27% (RR 0.77; 95% CI 0.51-1.14)
  • CPR not initiated
13% vs 19% (RR 0.68; 95% CI 0.20-2.30)

Adverse Events

Among those achieving ROSC (calcium: n = 37 vs saline: n=53):

Hypercalcemia
  • mild (1.33-1.46 mmol/L)
34% vs 2%
  • moderate (1.47 - 2.00 mmol/L):
40% vs 0%
  • severe (2.00 mmol/L):
0% vs 0%
tachyarrhythmia
22% vs 26%
AKI requiring dialysis
19% vs 6%
GI ulcer
3% vs 0%
acute pancreatitis
8% vs 2%

Among those who survive at least 24 hours (calcium: n = 34 vs saline: n=41):

Hypercalcemia
  • mild (1.33-1.46 mmol/L)
38% vs 2%
  • moderate (1.47 - 2.00 mmol/L):
38% vs 0%
  • severe (2.00 mmol/L):
0% vs 0%
tachyarrhythmia
22% vs 29%
AKI requiring dialysis
22% vs 7%
GI ulcer
3% vs 0%
acute pancreatitis
9% vs 2%

Criticisms

  • Interpretation of trial results should be approached with caution given the early termination of the trial. The original intended sample size was 430 (interim analysis conducted at n = 383).
  • The median time to drug administration was 18 minutes. This may limit generalizability to other settings (such as within hospital) where administration could be quicker.

Funding

Novo Nordic Foundation, Aarhus University, Heath Research Foundation of Central Denmark Region, and Fonden til Laegevidenskabens Fremme

Further Reading

Study paper: Vallentin MF, Granfeldt A, Meilandt C, 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. Published online November 30, 2021. doi:10.1001/jama.2021.20929

References:

1. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. The effectiveness of calcium chloride in refractory electromechanical dissociation.  Ann Emerg Med. 1985;14(7):626-629.
2. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. Lack of effectiveness of calcium chloride in refractory asystole.  Ann Emerg Med. 1985;14(7):630-632. doi:10.1016/S0196-0644(85)80875-1


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