SGEM#353: At the COCA, COCA for OCHA

Background: We have covered adult OHCA multiple times on the SGEM. This has included the following issues:

Calcium has a theoretical benefit on patients with cardiac arrest as it has inotropic and vasopressor effects. Previous small, randomized control trials (RCTs) have shown no superiority to calcium for return of spontaneous circulation (ROSC). However, the point estimated did favor calcium.

Clinical Question: Does administration of calcium during out-of-hospital cardiac arrest improve sustained return of spontaneous circulation?

Reference: Vallentin 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

• Population: Adults 18 years of age and older with OHCA in the central Denmark region from January 2020 to April 2021 who received at least one dose of epinephrine
  • Exclusions: Traumatic cardiac arrest, known or strongly suspected pregnancy, prior enrollment in the trial, receipt of epinephrine outside the trial, or a clinical indication for calcium administration during the cardiac arrest.
• Intervention: Calcium chloride 5 mmol given IV or IO immediately after first dose of ACLS epinephrine up to two doses
• Comparison: Saline placebo given IV or IO immediately after first dose of ACLS epinephrine up to two doses
• Outcome:
  • Primary Outcome: Sustained ROSC defined as no further need for chest compressions for at least 20 minutes
  • Secondary Outcomes: Survival, favorable neurological outcome, and quality of life assessment at 30 and 90 days
• Trial: Double-blind, placebo-controlled, parallel group, superiority, randomized clinical trial

Authors’ Conclusions: “Among adults with out-of-hospital cardiac arrest, treatment with intravenous or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. These results do not support the administration of calcium during out-of-hospital cardiac arrest in adults.”

Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the emergency department. No
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Yes
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes
11. The treatment effect was large enough and precise enough to be clinically significant. No
12. Financial Conflicts of Interest. Yes

Results: There were 1,221 OHCAs during the trial period. They excluded 824 for a variety of reasons with the most common reason (69%) because they did not receive any epinephrine. The mean age was 68 years, 71% male, more than 80% arrested at home, 85% received bystander CPR and half were in asystole.

Key Result: No statistical difference in ROSC

• Primary Outcome: ROSC
  • 19% in the calcium group vs 27% in the saline group
  • Risk ratio (RR) 0.72 (95% CI; 0.49 to 1.03)
  • Risk Difference, −7.6% (95% CI; −16% to 0.8%); P = 0.09)
• Secondary Outcomes: 
  • No statistically significant differences in 30-day survival, 30-day survival with a favorable neurological outcome or 90-day survival
  • Survival at 90-days with favorable neurological outcome was statistical better in the placebo group.
  • Quality of life assessment assessed by the patient was not statistically different at 30-days but was at 90-days favoring calcium

1. Outcomes: It would be great if there was consistency in reporting outcomes. The trial was registered with ClinicalTrials.gov. Primary outcome was the same in the registration, protocol, and published manuscript. However, there was no quality-of-life assessment registered as an outcome, it was called a tertiary outcome in the protocol, categorized as a secondary outcome on the Table 2 of the manuscript and a tertiary outcome in the text of the manuscript. Same thing for the 90-day outcome which was not mentioned in the trial registry, was considered a tertiary outcome in the protocol but elevated to a secondary outcome in Table 2 and tertiary outcome in the body of the text.

2. External Validity: This trial was conducted in Denmark. They have a two-tiered EMS service that has an ambulance and a mobile emergency care unit with a physician. This is different from most places in north America that do not have physicians in the pre-hospital setting.

In addition, the latest statistics from the American Heart Association on cardiac arrests in the USA are different than the cohort included in this trial. The biggest difference was bystander CPR was 39% in the USA vs 85% in this Danish trial. These and other differences could limit the external validity to your own community.

3. Dose of Calcium: It is possible but not likely that a different dose of calcium may have made a difference. Proving a negative is harder than proving a positive. We start with a null hypothesis of no superiority. In this case, the null hypothesis is that calcium is not superior to placebo. The results did not support the alternative hypothesis of superiority, so we accept the null hypothesis. It would be a separate claim to say that calcium does not work for OHCAs. The more accurate statement would be there is no high-quality evidence to support the routine use of calcium in OHCAs.

4. OHCA: This data directly applies to OHCAs and not necessarily IHCA. There are longer times to drug administration in the pre-hospital setting. Time to drug administration was a median of 17 minutes. It could be hypothesized that early time to treatment could provide a patient-oriented outcome of benefit. However, that would need to be demonstrated.

5. Stopping Early: We have discussed the problem of stopping trials early before on the SGEM. It can introduce bias and increase uncertainty of the results. Stopping trials early over-estimates the effect size if there is a regression to the mean. Also, including trials that are stopped early can introduce bias into SRMA making them more difficult to interpret (Bassler et al JAMA 2010).

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.

SGEM Bottom Line: The routine use of calcium in an OHCA is not supported by the available evidence.

Case Resolution: Three rounds of epinephrine are eventually provided without ever achieving ROSC. ECG shows no electrical activity, pupils are fixed and dilated, and POCUS shows no cardiac activity. The patient is pronounced deceased in the ED.

Dr. Spencer Greaves

Clinical Application: We have not and will continue to not routinely give calcium to adult patients with OHCAs.

What Do I Tell the Patient?  You tell the patients family that they had a cardiac arrest. The paramedics did great CPR, put in an airway to help breathing and gave epinephrine to try and restart the heart. Despite everyone’s efforts we were not able to get their heart going again and they have died.

Keener Kontest: Last weeks’ winner was Josh McGough at third year medical student from Stony Brook University. He knew Dr. Pam Bensen was the first EM resident in North America in 1971.

Listen to the SGEM podcast for this weeks’ question. If you know, then send an email to thesgem@gmail.com with keener in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

• First10EM: Calcium for OHCA – The COCA Trial
• The Bottom Line: COCA

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.