Calcium Administration During Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest inChildren With Heart Disease Is Associated With Worse Survival-A Report From the AmericanHeart Association’s Get With The Guidelines-Resuscitation (GWTG-R) Registry.

Calcium Administration During Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest in Children With Heart Disease Is Associated With Worse Survival-A Report From the American Heart Association’s Get With The Guidelines-Resuscitation (GWTG-R) Registry.

Dhillon GS, Kleinman ME, Staffa SJ, Teele SA, Thiagarajan RR; American Heart Association’s Get With The Guidelines – Resuscitation (GWTG-R) Investigators.Pediatr Crit Care Med. 2022 Nov 1;23(11):860-871. doi: 10.1097/PCC.0000000000003040. Epub 2022 Jul 27.PMID: 35894607

Commentary by:
Bridget K. Pearce, MD 1, Faith J. Ross, MD, MS 2
1 CS Mott Children’s Hospital, University of Michigan, Ann Arbor, MI
2 Seattle Children’s Hospital, University of Washington, Seattle, WA

Take Home Points:

• American Heart Association guidelines recommend against using calcium during cardiopulmonary arrest (CPA) in pediatric patients. Despite these recommendations, calcium is routinely used during CPR for children with heart disease (HD).
• The authors conducted a retrospective, observational database study with propensity matching. They showed that the use of IV calcium during CPR was associated with decreased survival to discharge and worse neurological outcomes for children with HD.
• They found that calcium was administered more frequently to younger children, surgical cardiac patients, and those with longer CPR duration times.
• Decreased survival with calcium administration was seen in patients with surgical HD but not in those with medical HD.
• The authors recommend that calcium administration during CPA in children with HD should be restricted to accepted AHA CPR guideline indications.

In the normal physiologic state, calcium plays an important role in maintaining myocardial contractility and vascular tone which are critically important in children with cardiac disease. However, the role of calcium in the setting of cardiac arrest is less clear. Although calcium administration can be helpful to maintain cellular homeostasis, it can be harmful in the setting of ischemia. In an ischemic state, ATP- dependent ion channels malfunction, leading to a rapid influx of cytosolic calcium and inadequate calcium sequestration by the sarcoplasmic reticulum. This loss of homeostasis results in calcium accumulation in the mitochondria which further compromises ATP production and ultimately leads to cell lysis and death.¹ Retrospective studies have shown an association between calcium administration during cardiac arrest and increased mortality in children. ² As a result, both the AHA and the European Resuscitation Council recommend against the use of calcium during CPA for children. ³⁴

Previous studies on the impact of calcium in CPA included a mixed population of children with and without heart disease. Because of the important role that calcium plays in myocardial contractility and the prevention of arrhythmias from electrolyte imbalances, children with heart disease commonly receive calcium during resuscitation, despite the AHA guidelines. The authors of this study aimed to evaluate the impact of IV calcium administration during CPA specifically in the population of children with medical and surgical HD.

The authors used the AHA Get With The Guidelines-Resuscitation (GWTG-R) multicenter registry that collects information about cardiac arrest and CPR. ⁵ GWTG-R is a quality improvement database that collects data from 300 hospitals about how patients are resuscitated during cardiac arrest, and tracks variability in practice that impacts survival. The authors evaluated patients under 18 years of age with either medical or surgical heart disease who experienced in-hospital cardiac arrest (IHCA) between 2000 and 2019. They defined CA as no palpable pulses or pulse with inadequate perfusion that required CPR with either chest compressions or defibrillation and that terminated with the return of spontaneous circulation (ROSC), e-CPR, or death. They defined ROSC as the return of circulation for greater than 20 minutes without repeat chest compressions. They excluded children with out-of-hospital cardiac arrest and those with missing chest compression or calcium administration data.

Propensity score matching (PSM) was utilized to compare patients who did and did not receive calcium during resuscitation for ICHA.  They utilized nearest neighbor caliper matching for propensity to receive calcium during CPR for the following variables: age, event location, pre-existing conditions, initial pulseless rhythm, CPR duration, and illness category of medical cardiac (MC) or surgical cardiac (SC) disease. Of note, they did not discuss the categorization of MC vs. SC disease.

The following categories were used for propensity matching:

1. Event location: ICU, Procedural areas, or Other, which included clinics, L&D, ED, PACU. 
2. Age: Newborn, Neonate/Infant (1 day to < 1 year), Pediatric (1 – 18 years)
3. Initial rhythm: Pulseless electrical activity/Asystole, Ventricular tachycardia/Ventricular fibrillation
4. CPR duration: Quartiles of variable distribution

After evaluating the quality of matching using standardized mean differences to compare the groups, they analyzed the propensity-matched cohorts with generalized estimating equations modeling. They also assessed the generalizability of their findings by performing a multivariable regression analysis using the entire unmatched cohort, adding an adjustment for propensity score.

Of the 15,921 patients who had IHCA, 4,556 met inclusion criteria including 2,229 MC and 2,327 SC patients. Overall, 44% of patients received calcium during CPR. Calcium use decreased over time overall but remained higher in children with HD. Patients receiving Ca were also more likely to be in the ICU and more likely to have experienced a longer duration of CPR, had higher rates of vasoactive infusion prearrest, a higher number of epinephrine boluses, and were more likely to have received sodium bicarbonate. In the univariate analysis, calcium administration was associated with a lower rate of ROSC (73% vs 88%, p<0.001), lower survival to hospital discharge (38% vs 61%, p<0.001), and a lower rate of survival with favorable neurologic outcomes (26% vs 47%, p<0.001).

The propensity-matched cohort included 678 patients who received calcium and 678 patients who did not. In the matched cohort, children receiving calcium had decreased survival to discharge (39% vs 46%, p=0.02), lower rate of discharge with favorable neurologic outcome (28% vs 34%, p=0.02), and higher rates of E-CPR use (19% vs 15%, p=0.02).

In the subgroup analysis of children with SC and MC disease, there was no difference in outcomes in the MC group. In the SC group, children receiving calcium were less likely to achieve ROSC (76% vs 85%, p=0.004), survive to hospital discharge (45% vs 60%, p<0.001), or survive with a favorable neurologic outcome (32% vs 48%, p,0.001). Analysis of the entire unmatched cohort using adjustment for propensity score also demonstrated lower odds of survival to discharge in the group receiving calcium.

The results demonstrate that although the rate of calcium administration during pediatric CPR has declined overall, it remains high in children with HD. As it is in the general population of children, calcium administration during CPR is associated with worse outcomes in children with cardiac disease. In this study, children with surgical disease but not medical heart disease had an increased risk of adverse effects related to calcium administration. The authors posit that a higher mortality rate in the MC group overall may have blunted the impact of calcium use during CPR.

An accompanying editorial acknowledged the importance of these findings but did point out some limitations of this study. ⁶ The propensity score matching used the duration of CPR as a surrogate for a number of variables that were not examined individually. Also, the categorization of cardiac disease into medical and surgical categories does not reflect other important aspects of the patient’s condition including disease severity and illness acuity. Furthermore, post-cardiac arrest care is an important factor in survival to discharge, but was not included in the propensity matching.

Despite these minor limitations, this study provides strong support for the guidelines restricting calcium administration during pediatric cardiac arrest. Calcium use should be limited to hypocalcemia, hyperkalemia, hypermagnesemia, and calcium channel blocker toxicity. ⁷

References

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