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

Comment by InpharmD Researcher

The American Heart Association (AHA) does not provide specific recommendations for use of calcium as part of the out-of-hospital cardiac arrest resuscitation systems of care. Based on study results from a recently published randomized controlled trial, treatment with intravenous or intraosseous calcium compared with saline was not associated with significant improvement in sustained return of spontaneous circulation (ROSC). While data from a retrospective study found that higher ionized calcium levels prior to emergency department arrival are associated with ROSC, its clinical application remains uncertain.
  

PubMed: out of hospital ROSC calcium = 10 studies (1 relevant)

Background

According to the American Heart Association (AHA) 2018 statement on out-of-hospital cardiac arrest (OHCA) resuscitation systems of care, the pertinent components of resuscitation management which lead to increased survival include quick recognition of OHCA, immediate activation of 9-1-1, bystander-initiated cardiopulmonary resuscitation (CPR), bystander and/or basic first responder application of an automated external defibrillator (AED) before arrival of other emergency medical services (EMS) providers to the scene, advanced life support, and post-resuscitation care. Administration of calcium is not specifically discussed in any of the steps mentioned above. [1]

While the effects of calcium administration on the return of spontaneous circulation (ROSC) were not directly examined, a 2020 multicenter retrospective cohort study (N= 883; n= 448 ROSC), evaluated the potential role of ionized calcium in predicting resuscitation outcome in patients with OHCA. After analyzing the Korean Cardiac Arrest Research Consortium data (KoCARC) registry, the investigators selected patients aged over 19 years with OHCA and documented laboratory data including calcium, ionized calcium, potassium, phosphorus, creatinine, and albumin at emergency department arrival. [2]

Based on multivariable logistic regression analysis, ionized calcium level was associated with ROSC (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.28 to 2.45; p= 0.001); however, calcium level was not associated with ROSC (OR 0.87; 95% CI 0.70 to 1.08; p= 0.199). Ionized calcium level did not improve survival discharge (OR 0.99; 95% CI 0.72 to 1.36; p= 0.948) or favorable neurologic outcome (OR 0.45; 95% CI 0.03 to 6.55, p= 0.560). Although the results showed that a high ionized calcium level measured during cardiopulmonary resuscitation was associated with an increased likelihood of ROSC, the clinical benefits of administering calcium in this setting remain unclear. [2]

References:

[1] McCarthy JJ, Carr B, Sasson C, et al. Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association. Circulation. 2018;137(21):e645-e660. doi:10.1161/CIR.0000000000000557
[2] Kim SJ, Kim HS, Hwang SO, et al. Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest. PLoS One. 2020;15(10):e0240420. Published 2020 Oct 12. doi:10.1371/journal.pone.0240420
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

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

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest

Design

Double-blind, placebo-controlled, randomized trial

N= 397

Objective

To determine whether administration of calcium during out-of-hospital cardiac arrest improves the return of spontaneous circulation (ROSC) in adults

Study Groups

Calcium (n= 193)

Sodium chloride (n= 198)

Inclusion Criteria

Age ≥ 18 years with an out-of-hospital cardiac arrest who received at least 1 dose of epinephrine during the cardiac arrest

Exclusion Criteria

Traumatic cardiac arrest (including strangulating and foreign body asphyxia), known or strongly suspected pregnancy, prior enrollment in the trial, receipt of epinephrine outside the trial, or clinical indication for calcium administration during the cardiac arrest 

Methods

Patients were randomized (1:1) to receive intravenous or intraosseous calcium (5 mmol of calcium chloride [corresponding to 200 mg of calcium or 735 mg of calcium chloride dihydrate]) or 9 mg/mL of sodium chloride given as a rapid bolus immediately after the first dose of epinephrine. The second dose of the trial drug was administered after the second dose of epinephrine if the patient remained in cardiac arrest.

Duration

Intervention: January 20, 2020, to April 15, 2021

Last 90-day follow-up: July 15, 2021

Outcome Measures

Primary outcome: sustained ROSC (spontaneous circulation with no further need for chest compressions for at least 20 minutes)

Secondary outcomes: survival at 30 days, survival at 30 days with a favorable neurological outcome (score of 0 to 3 on modified Rankin Scale)

Tertiary outcomes: survival at 90 days, survival at 90 days with a favorable neurological outcome, health-related quality of life (assessed using the 5-dimensional, 5-level EuroQol score), Sequential Organ Failure Assessment (SOFA) score

Baseline Characteristics

  

Calcium
(n= 193)

Sodium chloride (n= 198)

      

Age, years

 67 ± 14 69 ± 14      

Female

62 (32%) 52 (26%)      

Bystander response

Cardiopulmonary resuscitation

Automated external defibrillator shock

 

146/177 (82%)

14/177 (8%)

 

164/185 (89%)

13/185 (7%)

      

Initial manual rhythm analysis 

Asystole

Pulseless electrical activity

Ventricular fibrillation

Ventricular tachycardia



103 (53%)

47 (24%)

39 (20%)

4 (2%)



96 (48%)

49 (25%)

49 (25%)

4 (2%)

      

Administration

Intravenous

Intraosseous

Tibial

Humeral

 

78 (40%)

115 (60%)

103 (90%)

12 (10%)

 

79 (40%)

119 (60%)

103 (87%)

16 (13%)

      

Median time to administration, minutes (IQR)

Epinephrine

Trial drug



17 (12 to 22)

17 (13 to 23)



17 (14 to 22)

18 (15 to 23)

      

Number of trial drug doses

1

2


53 (27%)

140 (73%)


53 (27%)

145 (73%)

      

IQR: interquartile range

Six patients with a traumatic cardiac arrest (an exclusion criterion) inadvertently received the trial drug and were excluded from the analyses, leaving 193 patients in the calcium group and 198 patients in the saline group.

Results

Endpoint

Calcium
(n= 193)

Sodium chloride (n= 198)

Risk ratio (95% confidence interval [CI]

Between-group difference (95% CI)

p-value

Sustained ROSC

 37 (19%) 53 (27%) 0.72 (0.49 to 1.03) -7.6 (-16 to 0.8) 0.09

Survival at 30 days

 10 (5.2%) 18 (9.1%) 0.57 (0.27 to 1.18) -3.9 (-9.4 to 1.3) 0.17

Survival at 30 days with a favorable neurological outcome

 7 (3.6%) 15 (7.6%) 0.48 (0.2 to 1.12) -4 (-8.9 to 0.7) 0.12

5-dimensional, 5-level EuroQol score at 30 days

Assessed by the patient

Index value



58 ± 25

52 ± 23



66 ± 12

62 ± 30



-

-



-8 (-24 to 7)

-10 (-29 to 9)



-

-

Survival at 90 days

10 (5.2%)

18 (9.1%)

0.57 (0.27 to 1.18)

-3.9 (-9.4 to 1.3)

-

Survival at 90 days with a favorable neurological outcome

 7 (3.6%) 18 (9.1%) 0.4 (0.17 to 0.91) -5.5 (-11 to -0.7) -

5-dimensional, 5-level EuroQol score at 90 days

Assessed by the patient

Index value



62 ± 33

59 ± 35



79 ± 14

85 ± 11



-

-



-17 (-37 to 4)

-26 (-47 to -5)



-

-

Laboratory values after ROSC

Ionized calcium, mmol/L

Potassium, mmol/L

pH

Lactate, mmol/L

 

1.41 ± 0.15

4.2 ± 0.8

7.13 ± 0.12

7.8 ± 4

 

1.17 ± 0.07

4.5 ± 1.1

7.1 ± 0.16

8.3 ± 4.6

 

-

-

-

-

 

0.23 (0.18 to 0.28)

-0.3 (-0.7 to 0.1)

0.03 (-0.03 to 0.09)

-0.5 (-2.3 to 1.3)

 

-

-

-

-

SOFA score

2 hours (n= 36; n= 45)

24 hours (n= 32; n= 41)

48 hours (n= 32; n= 39)

72 hours (n= 27; n= 36)

 

10.1 ± 2.6

11.1 ± 2.5

10.8 ± 3.8

10.3 ± 4.1

 

10.3 ± 2.1

11 ± 2.2

10.4 ± 3.4

8.6 ± 4.3

 

-

-

-

-

 

-0.2 (-1.2 to 0.8)

0.1 (-1 to 1.2)

0.4 (-1.2 to 2.1)

1.7 (-0.4 to 3.8)

 

-

-

-

-

Adverse Events

In patients with ROSC (calcium [n= 37] vs. sodium chloride [n= 53]): mild hypercalcemia (1.33 to 1.46 mmol/L, 34% vs. 2%), moderate hypercalcemia (1.47 to 2 mmol/L, 40% vs. 0), tachyarrhythmia (22% vs 26%), acute kidney failure requiring dialysis (19% vs. 6%), gastrointestinal ulcer (3% vs. 0), acute pancreatitis (8% vs. 2%)

In patients surviving at least 24 hours (calcium [n= 32] vs. sodium chloride [n= 41]): mild hypercalcemia (38% vs. 2%), moderate hypercalcemia (38% vs. 0), tachyarrhythmia (22% vs. 29%), acute kidney failure requiring dialysis (22% vs. 7%), gastrointestinal ulcer (3% vs. 0), acute pancreatitis (9% vs. 2%)

Study Author Conclusions

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

InpharmD Researcher Critique

The trial was stopped early due to interim analysis results and did not reach its preplanned sample size to reach 80% power, which increases the risk of a type II error. A statistical difference between treatment groups might have been observed if the preplanned sample size had been met. Additionally, only one dosing regimen was evaluated, which may limit generalizability to other doses or a different timing interval of administration.

 

References:

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