Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were rescued from the discussion as they declared a conflict of interest: None
The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Lars W Andersen, Asger Granfeldt, and Mathias J Holmberg were all investigators on the primary clinical trial that informed this CoSTR. These task force members participated in discussion, but did not comment on risk of bias of their paper and were not part of the systematic review team.
CoSTR Citation
Hsu CH, Couper K, Nix T, Drennan I, Reynolds J, Kleinman M, Berg KM on behalf of the Advanced Life Support and Paediatric Life Support Task Forces at the International Liaison Committee on Resuscitation (ILCOR). Calcium During Cardiac Arrest in Adults and Children Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2022 December 1. Available from: http://ilcor.org
Methodological Preamble and Link to Published Systematic Review
The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review (PROSPERO CRD42022349641) conducted by the ALS task force. Evidence for adult and paediatric literature was sought and considered by the Advanced Life Support Task Force and the Pediatric Task Force groups respectively. The adult literature was considered for this CoSTR, and these data were taken into account by the ALS task force when formulating the Treatment Recommendations.
Systematic Review
Hsu CH, Couper K, Nix T, Drennan I, Reynolds J, Kleinman M, Berg KM on behalf of the Advanced Life Support and Paediatric Life Support Task Forces at the International Liaison Committee on Resuscitation (ILCOR). Calcium During Cardiac Arrest: A Systematic Review. In preparation.
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
Population: Adults and children in any setting (in-hospital or out-of-hospital) with cardiac arrest
Intervention: Administration of calcium (intravenous or intraosseous) during cardiac arrest
Comparators: No administration of calcium during cardiac arrest
Outcomes: Any clinical outcome, including return of spontaneous circulation (ROSC), short-term survival and neurological outcomes (e.g., hospital discharge, 28-days, 30-days, and 1-month) and long-term survival and neurological outcomes (e.g., 3-months, 6-months, 1-year)
Study Designs: Randomised controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) with a control group were eligible for inclusion. Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, and unpublished studies were excluded.
Timeframe: All years and all languages were included as long as there was an English abstract. Literature search was conducted on July 8, 2022 and updated on September 31, 2022.
PROSPERO Registration CRD42022349641
Consensus on Science
The systematic review identified 12 studies on adult patients, including 4 studies from 3 randomised trials for adult OHCA patients and 8 observational studies for adult OHCA and/or IHCA patients. The review also identified 3 observational studies on paediatric IHCA patients, which are discussed in the Pediatric Life Support CoSTR. Given that the individual observational studies were limited by critical risk of bias due to confounding, only the 3 randomised trials (Stueven 1985 626; Stueven 1985 630; Vallentin 2021 2268) were considered for the consensus on science for adult patients in cardiac arrest.
For the important outcome of ROSC, we have identified 3 randomised trials (Stueven 1985 626; Stueven 1985 630; Vallentin 2021 2268). We identified very low certainty evidence (downgraded for serious risk of bias and very serious risk of imprecision) from one randomised trial enrolling 90 OHCA patients in refractory electromechanical dissociation (Stueven 1985 626) that found no significant difference with calcium chloride compared to placebo for successful resuscitation (16.7% [8/48] vs 4.8% [2/42]; RR 3.50 [95% CI, 0.79-15.58]; ARD 119 more per 1,000 [from 10 fewer to 694 more]). We identified another randomised trial enrolling 73 patients in refractory asystole (Stueven 1985 630) which provided very low certainty evidence (downgraded for serious risk of bias and very serious risk of imprecision) of no significant difference with calcium chloride for successful resuscitation (7.7% [3/39] vs 2.9% [1/34]; RR 2.43 [95% CI, 0.26-22.31]; ARD 42 more per 1,000 [from 22 fewer to 627 more]). We identified moderate certainty evidence (downgraded for imprecision) from one randomised trial (Vallentin 2021 2268) enrolling 397 patients with OHCA that found no significant difference in ROSC with calcium chloride compared to placebo (19% [37/391] vs 27% [53/198]; RR 0.72 [95% CI, 0.49-1.03]; ARD 75 fewer per 1,000 [from 137 fewer to 8 more]; p = 0.09). This trial was stopped early due to concern for possible harm.
For the critical outcome of mid-term survival, we identified moderate certainty evidence (downgraded for imprecision) from one randomised trial enrolling 391 patients (Vallentin 2021 2268, Vallentin 2022 21) that showed no difference in 30-day, 90-day, or 6-month survival with calcium chloride compared to placebo (5.2% [10/193] vs 9.1% [18/198]; RR 0.57 [95% CI, 0.27-1.18]; ARD 39 fewer per 1,000 [from 66 fewer to 16 more]).
For the critical outcome of survival with favourable neurologic outcome at 30 days, we identified moderate certainty evidence (downgraded for imprecision) from one randomised trial enrolling 391 patients (Vallentin 2021 2268) showing no difference with calcium chloride compared to placebo (3.6% [7/193] vs 7.6% [15/198]; RR 0.48 [95% CI, 0.20 to 1.12]; ARD 39 fewer per 1,000 [from 61 fewer to 9 more]).
For the critical outcome of survival with a favourable neurological outcome at 90 days, we have identified moderate certainty evidence (downgraded for imprecision) from one randomised trial enrolling 391 patients showing harm from calcium chloride compared to placebo (3.6% [7/193] vs 9.1% [8/198], RR 0.40 [95% CI, 0.17-0.91]; ARD 55 fewer per 1,000 [from 75 fewer to 8 fewer])(Vallentin 2021 2268).
For the critical outcome of survival with favourable neurological outcome at 6 months, we have similarly identified moderate certainty evidence (downgraded for imprecision) from this trial that showed no significant difference with calcium chloride compared to placebo (5.2% [10/193] vs 9.1% [18/198]; RR 0.57 [95% CI, 0.27-1.18]; ARD 39 fewer per 1000 [66 fewer to 16 more])(Vallentin 2022 21).
For the critical outcome of survival and survival with favourable neurological outcome at one year, we have identified moderate certainty evidence (downgraded for imprecision) from one randomised trial enrolling 391 patients that showed possible decrease in survival in the calcium chloride group compared to placebo (4.7% [9/193] vs 9.1% [18/198]; RR 0.51 [95% CI, 0.24-1.09]; ARD 45 fewer per 1,000 [from 69 fewer to 8 more])(Vallentin 2022 21). The same trial found 3.6% (7/193) survival with favourable neurological outcome at one year in the calcium chloride group and 8.6% (17/198) in the placebo group (RR 0.42 [95% Cl, 0.18-0.97]; ARD 55 fewer per 1,000 [from 70 fewer to 3 fewer]).
For the critical outcome of quality of life, we identified moderate certainty evidence (downgraded for imprecision) from one randomised trials enrolling 391 patients, finding quality-of-life scores in survivors (5-dimensional, 5-level EuroQol score) were lower in the calcium group at 30 days, 90 days, and 6 months (mean score 72 [SD 29] in calcium group compared with 82 [SD 22] in the placebo group at 6 months, mean difference -15 [95% CI -38, 8]), although this was not statistically significant (Vallentin 2021 2268, Vallentin 2022 21). At one year, quality-of-life scores in survivors were also lower in the calcium group (71 [SD 31] compared with 83 [SD 11], mean difference -8% [95% CI -25%, 9%]), although this was not statistically significant.
Calcium has not been studied in the in-hospital cardiac arrest setting. Therefore, the certainty of evidence for adult in-hospital cardiac arrest was additionally downgraded for indirectness and thus judged as overall low certainty.
Treatment Recommendations
We recommend against routine administration of calcium for the treatment of out-of-hospital cardiac arrest in adults (strong recommendation, moderate certainty of evidence).
We suggest against routine administration of calcium for the treatment of in-hospital cardiac arrest in adults (weak recommendation, low certainty of evidence).
Justification and Evidence to Decision Framework Highlights
This topic was prioritised by the ALS and PLS Task Force based on a recent large RCT comparing calcium administration to no calcium administration during adult OHCA. We note that the last ILCOR CoSTR on this topic was in 2010, at which time the treatment recommendation was: “Routine administration of calcium for treatment of in-hospital and out-of-hospital cardiac arrest is not recommended” (Morrison 2010 S345). In considering the importance of this topic, we note that calcium administration remains common during cardiac arrest despite the 2010 ILCOR CoSTR on this topic.
In making these updated recommendations, the Task Force considered the following:
- This CoSTR and its systematic review focus on the routine administration of calcium during cardiac arrest in adults.
- We did not identify any RCTs comparing calcium administration to no calcium administration during IHCA or for specific patient groups such as hyperkalemic cardiac arrest.
- The trial by Vallentin et al was stopped early based on suggestions of harm in a pre-planned interim analysis (Vallentin 2021 2268), which could have increased the risk of effect size over-estimation.
- The risk of harm with calcium administration may depend on the scenario in which the intervention is performed.
- The number of patients in Vallentin et al with mid- and long-term survival was low with wide confidence intervals (Vallentin 2021 2268; Vallentin 2022 21).
- We considered that, as no evidence has been identified, the effect of calcium administration remains unknown for adults in cardiac arrest from special circumstances such as hyperkalemia, wide QRS interval on electrocardiogram, hypocalcemia, hypermagnesemia, calcium channel blocker overdose, or haemorrhage.
- Only small trials or observational studies have attempted to stratify based on initial rhythm or potassium levels, which have been limited by critical risk of bias due to confounding.
- We did not include animal or mechanistic studies in our systematic review.
Knowledge Gaps
- No RCTs evaluated this question in adult IHCA
- No RCTs evaluated this question for adults in cardiac arrest from special circumstances such as hyperkalemia, wide QRS interval on electrocardiogram, hypocalcemia, hypermagnesemia, calcium channel blocker overdose, or haemorrhage.
- How does calcium cause harm when routinely administered during cardiac arrest?
Attachment: Calcium Et D
References
References listed alphabetically by first author last name in this citation format (Circulation)
Morrison LJ, Deakin CD, Morley PT, Callaway CW, Kerber RE, Kronick SL, et al. Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S345–421.
1. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. The effectiveness of calcium chloride in refractory electromechanical dissociation. Ann Emerg Med 1985;14:626–9.
2. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. Lack of effectiveness of calcium chloride in refractory asystole. Ann Emerg Med 1985;14:630–2.
3. Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, 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;326:2268–76.
4. Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, et al. Effect of calcium vs. placebo on long-term outcomes in patients with out-of-hospital cardiac arrest. Resuscitation 2022;179:21–4.