COCA

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

MF Vallentin, @LarsWAndersen1. JAMA 2021; Published online November 30, 2021. doi:10.1001/jama.2021.20929

Clinical Question

  • In patients with out-of-hospital cardiac arrest, does the administration of calcium compared with placebo, improve sustained return of spontaneous circulation?

Background

Design

  • Randomised controlled trial
    • Variable block sizes (2,4,6) in a 1:1 ratio
    • Random number generator used
    • Stratified according to mobile emergency care unit stations
  • Double blinded
  • Placebo-controlled
  • Registered on clinicaltrials.gov
  • Sample size calculation:
    • Originally calculated at 430 patients
      • This was updated following blinded review of 1st 270 randomised patients which showed rates of return of spontaneous circulation were lower than anticipated
    • Updated sample size calculation:
      • 674 patients would give 80% power to detect an absolute improvement of 9% in the primary outcome from a baseline of 18%, with a false positive rate of 5%
  • Trial stopped early on recommendation of safety monitoring committee following planned interim analysis
  • Modified intention to treat analysis (only included patients who received at least 1 dose of study drug and met inclusion/exclusion criteria)

Setting

  • Pre-hospital services in central Denmark
  • Patients randomised from Jan 2020 – April 2021

Population

  • Inclusion:
    • ≥18 years
    • Out of hospital cardiac arrest
    • Received at least 1 dose of adrenaline
  • Exclusion:
    • Traumatic cardiac arrest (including drowning and external asphyxia)
    • Known/suspected pregnancy
    • Received adrenaline during cardiac arrest before arrival of prehospital personnel with the study drug
    • Clinical indication for calcium administration
  • 397 patients randomised out of 1221 patients with OOH cardiac arrest
    • A majority of those excluded (578/824) did not meet inclusion criteria
    • 197 randomised to receive calcium chloride, 200 randomised to receive sodium chloride
      • 6 randomised patients excluded from analysis as had exclusion criteria (all traumatic cardiac arrests)
  • Comparing baseline characteristics of intervention (calcium) vs. control (saline) group
    • Age: 67 vs 69
    • Male: 68% vs 74%
    • Co-morbidity
      • Pulmonary disease: 25% vs 28%
      • Coronary artery disease: 24% vs 23%
      • Kidney disease: 18% vs 22%
      • Chronic heart failure: 17% vs 18%
    • Cardiac arrest characteristics
      • Location – home: 83% vs 80%
      • Witnessed: 61% vs 57%
        • Bystander CPR: 82% vs 89%
        • Automated external defibrillator shock: 8% vs 7%
    • Initial cardiac rhythm
      • Asystole: 53% vs 48%
      • PEA: 24% vs 25%
      • VF/VT: 22% vs 27%
    • Administration and drug characteristics
      • IV: 40% vs 40%
      • IO: 60% vs 50%
      • Time to administration
        • Adrenaline: 17 vs 17 min
        • Trial drug: 17 vs 18 min
      • Number of doses of trial drug administered
        • 1: 27% vs 27%
        • 2: 73% vs 73%

Intervention

  • Calcium
    • 5mmol (10ml ampoule) of calcium chloride administered IV or IO immediately after the 1st dose of adrenaline and again following the 2nd dose of adrenaline if needed

Control

  • Normal saline

Management common to both groups

  • An ambulance and a physician manned mobile emergency medical service respond to all cardiac arrests, and almost all patients with sustained return of spontaneous circulation or ongoing CPR are transported to a single tertiary centre that is capable of PCI and ECMO
  • Treatment during and post-arrest generally adheres to standard European guidelines. ~90% of patients who survived at least 24 hours underwent coronary angiography and were treated with targeted temperature management

Outcome

  • Primary outcome: Sustained return of spontaneous circulation (defined as palpable pulses or other signs of circulation without a need for chest compressions for > 20 minutes) – no significant difference
    • 19% in calcium group vs 27% in placebo group
      • Risk ratio: 0.72 [95% CI, 0.49-1.03], P = .09
  • Secondary outcomes:
  • Comparing intervention vs. control group
    • No significant difference in
      • Survival at 30 days
        • 5.2% vs 9.1%
        • Risk ratio: 0.57 [95% CI, 0.27-1.18], P = .17
      • Survival at 30 days with a favourable neurological outcome
        • 3.6% vs 7.6%
        • Risk ratio: 0.48 [95% CI, 0.20-1.12], P = .12
      • Survival at 90 days
        • 5.2% vs 9.1%
        • Risk ratio: 0.57 [95% CI, 0.27-1.18)
    • Significantly less in calcium group
      • Survival at 90 days with a good neurological outcome
        • 3.6% vs 9.1%
        • Risk ratio: 0.40 [95% CI, 0.17-0.91)
  • Tertiary outcomes:
    • 1st ionised calcium after ROSC – significantly higher in calcium group
      • 1.41 vs 1.17 mmol/l
  • Bayesian analysis
    • The probability that calcium has a positive effect (RR > 1) on the primary outcome is 4%

Authors’ Conclusions

  • In patients with out-of-hospital cardiac arrest, treatment with calcium, compared with saline, did not significantly improve sustained return of spontaneous circulation

Strengths

  • Randomised controlled trial
  • Blinded
  • Balanced trial groups (baseline characteristics, intra-arrest and post arrest interventions)
  • Registered on clinicaltrials.gov
  • No loss to follow up

Weaknesses

  • Trial stopped early and did not reach pre-planned sample size
  • Patients received study drug at a median of 17 minutes following cardiac arrest
    • This may not be generalisable to the in-hospital setting
      • In the VAM-IHCA trial drugs were administered in ~8-9 minutes
  • Regional trial in a single country with a pre-hospital set-up that not all areas have, with a physician manned mobile emergency care unit attending all cardiac arrests

The Bottom Line

  • In patients with out-of-hospital cardiac arrest, treatment with calcium compared with saline, at a median of 17 minutes post cardiac arrest, did not significantly improve sustained return of spontaneous circulation.
  • The point estimates suggest clinically significant harm from the use of calcium in this population

External Links

Metadata

Summary author: @davidslessor
Summary date: 1st December 2021
Peer-review editor: George Walker

Image from Pixabay

 

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