The COCA Trial: IV/IO Calcium vs Saline for ROSC in OHCA

Journal Club Presented by: Dr. Anjali Cherukuri

Question:

Does administration of intravenous or intraosseous calcium during out-of-hospital cardiac arrest improve sustained return of spontaneous circulation when compared with administration of saline?

Background:

There is limited data surrounding pharmacological interventions in cardiac arrests. Calcium was thought to have a potential beneficial effect in the setting of cardiac arrest given the inotropic and vasopressor effects. There is contradictory evidence on the benefit of calcium when given during cardiac arrest.

Article Reviewed:

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. 2021;326(22):2268–2276. doi:10.1001/jama.2021.20929

Methodology:

• Population:
  • Adult patients (age >/= 18) with out-of-hospital cardiac arrest that received at least 1 dose of epinephrine during cardiac arrest
• Outcomes
  • Primary:
    • Sustained return of spontaneous circulation (defined as spontaneous circulation without need for chest compressions for at least 20 minutes)
  • Secondary:
    • Survival at 30 days and survival at 30 days with a favorable neurological outcome (defined as a score of 0 – 3 on the modified Rankin Scale). Survival at 90 days and survival at 90 days with a favorable neurological outcome were listed as tertiary outcomes.
• Design
  • Investigator-initiated, placebo-controlled, parallel group, double-blind, superiority, randomized clinical trial
  • Patients randomized to two groups:
    • Calcium (5 mmol calcium chloride given IV or IO with first dose of epinephrine, and a second dose given after the second dose of epinephrine if the patient was still in cardiac arrest)
    • Saline (9 mg/mL of sodium chloride) 397 patients included in the trial from January 20, 2020 to April 15, 2021
  • 6 patients with traumatic arrests were given calcium and were excluded from the analyses.
  • 193 patients were in the calcium group and 198 patients were in the saline group.

Results:

• Primary Results:
  • Sustained ROSC occurred in 37 patients (19%) in the group that received calcium and 53 patients (27%) in the saline group
• Secondary Results:
  • Survival at 30 days occurred in 10 patients (5.2%) in the calcium group and 18 patients (9.1%) in the saline group.
  • Survival at 30 days with a favorable neurologic outcome occurred in 7 patients (3.6%) in the calcium group and 15 patients (7.6%) in the saline group.
• Tertiary Results:
  • Survival at 90 days was identical to 30-day survival.
  • Survival at 90 days with a favorable neurological outcome occurred in 7 patients (3.6%) in the calcium group and 18 patients (9.1%) in the saline group.
  • Quality-of-life scores in survivors were lower in the calcium group.
  • First ionized calcium level after ROSC was higher in the calcium group compared with the saline group.

Strengths:

• Study design (double-blind, placebo-controlled, randomized clinical trial) – lowers bias
• Baseline characteristics of the patients in both groups are similar
• No loss to follow up
• Few protocol deviations, and calcium was not used outside of the protocol
• Study showed that the administration of calcium resulted in a clinically relevant increase in ionized calcium values at hospital arrival (i.e., the dosing of calcium was appropriate)
• Trial also included patient-relevant outcomes, such as quality of life
• Fraction and frequency of chest compressions were comparable between both groups (although the data was only available for 65% of the patients)

Limitations:

• Exclusion criteria (patients that had a clinical indication for calcium administration during the cardiac arrest were not included in this trial)
• Trial was stopped early (trials that are stopped early can overestimate the effects)
• Can only be applicable to out-of-hospital cardiac arrests (cannot be generalized to in-hospital cardiac arrests)
• Trial only tested one dosing regime and timing (cannot be generalized to other doses or timing intervals)
• 75% of the patients had an initial non-shockable rhythm (generally have poorer clinical outcomes)

 Discussion:

• There was no statistical difference in sustained ROSC with administration of calcium when compared with saline.
• There was no statistically significant difference in 30-day survival or 30-day survival with a favorable neurological outcome.
• Patients receiving calcium had worse outcomes, including 30-day survival with a favorable neurological outcome.
• At 90 days, fewer patients in the calcium group had a favorable neurological outcome and quality of life was lower in survivors.
• Potential mechanisms of harmful effect of calcium during cardiac arrest:
  • During ischemia, there is depletion of ATP, leading to increased intracellular Na. This reduces the transmembrane Na gradient, which causes the Na/Ca exchanger to work in reverse. Increased calcium can cause cytosolic and mitochondrial calcium overload, leading to cardiac hypercontraction (stone heart).
  • Calcium is involved in multiple intracellular signaling pathways – can promote oxidative stress; release of proapoptotic factors; and activation of calcium-dependent lipases, proteases, and nucleases