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

Calcium has an important role in myocardial contractility. It has both inotropic and vasopressor effects. In critically ill patients a direct relationship between ionised calcium levels and blood pressure has been shown
Small RCTs in 1985 investigating the use of calcium in patients with out-of-hospital cardiac arrest reported improved point estimates with the use of calcium, although these results were not significant

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

Cardiac Arrest Featured Pharmacology