The RAMER Reviews: Effect of Intravenous or Intraosseous Calcium vs Saline on ROSC in adults with out of hospital cardiac arrest. The COCA Trial

Written By: John Paul Kwak, DO; Edited by: Timothy Khowong, MD, MSEd

Background

Calcium has an important role in stabilizing myocardial electrical membranes. It is a temporizing treatment to help reverse the cardiac toxicity of hyperkalemia, which is one of the reversible causes of PEA arrest.  The objective of the study was to determine if for patients with out of hospital cardiac arrest, the administration of calcium compared to a placebo improved sustained return of spontaneous circulation. 

The study

The study was a randomized controlled trial that was double blinded, and placebo controlled, performed in Denmark, looking at whether administration of 5 millimoles of calcium chloride administered either through IV or IOR after the first dose of epinephrine and again following the second dose improved sustained ROSC. Sustained ROSC defined as operable pulses or other signs of circulation without a need for chest compressions for greater than 20 minutes. Secondary outcomes evaluated  included survival at 30 days and at 90 days as well as survival with good neurological outcomes at 30 days and 90 days. 

The trial was stopped early at the recommendation of the safety monitoring committee after an interim analysis raised concerns for potential harm. The studies results show no significant difference in rates of sustained ROSC, survival at 30 or 90 days, nor survival at 30 days with  favorable neurological outcomes. It did show a significant decrease in survival at 90 days with good neurological outcome in the calcium group 3.6% 9.1% with a risk ratio of 0.40 (95% confidence interval, 0.17–0.91.)

Discussion

While generalizability of the study may be limited as it was performed in the out-of-hospital setting, the average time to administration of calcium was reported to be 17 minutes, which could be comparable to some situations within the emergency department. It was also a regional trial in a single country, where each of these cardiac arrests are handled by physician equipped mobile emergency care units.

Additional Studies

A subsequent study was performed using the same subjects, following up on long-term outcomes, which showed that at one year the same deficit to survival with favorable neurological outcome was observed in the study group that received calcium. 3.6% in calcium group versus 8.6% and placebo group with a risk ratio of 0.42 (95% confidence interval of 0.18, 0.97.).

The neurophysiological basis of worse neurological outcomes as a result of calcium administration could be explained by calcium’s role as a mediator of neuronal cell apoptosis. In any state of hypoxia, such as cardiac arrest, neurons starved of oxygen start their apoptotic process and calcium is a known accelerant of this cell death. It thus raises the question for us as clinicians when considering administration of calcium in the setting of cardiac arrest, whether we are balancing the likelihood of their cardiac arrest being directly as a cause of hyperkalemia and weighing whether pursuing treatment for presumed hyperkalemia, is worth risking what these studies seem to show evidence of as poor neurological outcomes down the line.

This raises the question of whether or not there are any easily obtainable additional pieces of information that can help to raise our suspicion of hyperkalemia and when to reach for calcium.

Another interesting follow up study was performed as a substudy of the COCA trial, looking at electrocardiograph characteristics, potentially associated with hyperkalemia and ischemia for the same patients. The results were different ECGs which were studied and separated into calcium versus placebo groups and are shown in the following figure. No clear signal for ECG findings were found that favor calcium administration, though one may argue T-wave positive amplitude of 2 mm may be a suboptimal measure when looking for signs of hyperkalemia on EKGs. 

No clear signal for ECG findings were found that favor calcium administration, though one may argue T-wave positive amplitude of 2 mm may be a suboptimal measure when looking for signs of hyperkalemia on EKGs. 

As emergency medicine physicians, we never want to walk away from cardiac arrest with the feeling that we held anything back, or that we didn't do everything we possibly could. The COCA trial and its subsequent studies and isolation does not provide adequate evidence on its own to dictate whether or not to administer calcium in the efforts to achieve ROSC. However, with the potential for long-term non-favorable neurological outcomes based on physiology it does raise the concern with the common practice of treating calcium administration as a completely safe move that does not have any consequences associated with it. 

In practice, calcium should be used for the specific treatment of hyperkalemia, as one of the reversible causes of cardiac arrest. A clinical story such as having missed dialysis, EKG findings like “eiffel tower” T-wave morphology suggestive of hyperkalemia, or actual point of care testing findings of hyperkalemia as things to consider obtaining before administering calcium, considering the long-term potential harm that calcium in the setting of developing hypoxic brain injury may cause to the patients and their families.

References:

Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, Iversen BN, Mærkedahl R, Mortensen LR, Nyboe R, Vandborg MP, Tarpgaard M, Runge C, Christiansen CF, Dissing TH, Terkelsen CJ, Christensen S, Kirkegaard H, Andersen LW. 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 Dec 14;326(22):2268-2276. doi: 10.1001/jama.2021.20929. PMID: 34847226; PMCID: PMC8634154.

Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, Iversen BN, Mærkedahl R, Mortensen LR, Nyboe R, Vandborg MP, Tarpgaard M, Runge C, Christiansen CF, Dissing TH, Terkelsen CJ, Christensen S, Kirkegaard H, Andersen LW. Effect of calcium vs. placebo on long-term outcomes in patients with out-of-hospital cardiac arrest. Resuscitation. 2022 Oct;179:21-24. doi: 10.1016/j.resuscitation.2022.07.034. Epub 2022 Jul 30. PMID: 35917866.

Vallentin MF, Povlsen AL, Granfeldt A, Terkelsen CJ, Andersen LW. Effect of calcium in patients with pulseless electrical activity and electrocardiographic characteristics potentially associated with hyperkalemia and ischemia-sub-study of the Calcium for Out-of-hospital Cardiac Arrest (COCA) trial. Resuscitation. 2022 Dec;181:150-157. doi: 10.1016/j.resuscitation.2022.11.006. Epub 2022 Nov 18. PMID: 36403820.