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* : Pediatric Critical Care Medicine

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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, Gurpreet S. MD1,,2; Kleinman, Monica E. MD2; Staffa, Steven J. MS2; Teele, Sarah A. MD3; Thiagarajan, Ravi R. MBBS, MPH3;  for the American Heart Association’s Get With The Guidelines - Resuscitation (GWTG-R) Investigators

Author Information
Pediatric Critical Care Medicine: November 2022 - Volume 23 - Issue 11 - p 860-871
doi: 10.1097/PCC.0000000000003040

Abstract

RESEARCH IN CONTEXT

  • The American Heart Association’s (AHA) cardiopulmonary resuscitation guidelines recommend against the routine administration of IV calcium during pediatric cardiopulmonary arrest (CPA) as it is associated with worse outcomes.
  • However, IV calcium is routinely used in children with heart disease who experience CPA.
  • Using data from the AHA Get With The Guidelines—Resuscitation registry and propensity score matching analysis, we compared survival to hospital discharge for children with heart disease experiencing CPA who received IV calcium during CPA with those who did not.

WHAT THIS STUDY MEANS

  • IV calcium administration in children with heart disease experiencing CPA was more frequent in younger age groups, surgical cardiac patients, longer duration CPA events, and in those receiving other nonadrenergic pharmacologic interventions during arrest.
  • Using a propensity score–matched balanced cohort of children with heart disease receiving and not receiving calcium during CPA, we found that calcium administration was independently associated with worse survival, a finding more prominently seen in the surgical cardiac population.
  • Calcium administration during CPA in children with heart disease should be restricted to accepted AHA CPR guideline indications.

Hospitalized children with congenital and acquired heart disease (HD) are at increased risk for in-hospital cardiac arrest (IHCA) compared with those without underlying HD but have better survival to hospital discharge (1–12). Studies have shown that administration of nonadrenergic pharmacologic interventions (e.g., IV calcium and bicarbonate) during cardiopulmonary resuscitation (CPR) for IHCA in children are associated with worse survival (6,13–19). Because calcium can increase cardiac automaticity and contractility, children with HD frequently receive calcium during CPR (6,11,16). Studies describing effects of calcium on the myocardium exposed to prolonged ischemia show that increased levels of cytosolic calcium led to dissolution of the electrochemical gradient and a loss of osmotic control that results in cell lysis and death (20–26). Similar mechanisms may exist when calcium is administered during CPR in children, resulting in poor survival.

Recent CPR guidelines from the American Heart Association (AHA) do not support the routine use of IV calcium during CPR outside of specific indications, which include the treatment of measured and documented hyperkalemia, hypermagnesemia, ionized hypocalcemia, and the presence of calcium channel blockade intoxication (27,28). We sought to describe the impact of IV calcium administration during CPR on survival to hospital discharge in children with HD using data from the AHA Get With The Guidelines-Resuscitation Registry (GWTG-R) Registry.

MATERIALS AND METHODS

Registry Database Source

The AHA’s GWTG-R is a multicenter registry that prospectively collects cardiac arrest (CA) and CPR information from hospitals across the Unites States for the purposes of quality improvement. Hospitals participating in the registry submit clinical information regarding the medical history, hospital care, and outcomes of consecutive patients experiencing CA using an online, interactive case report form and patient management tool (PMT) (IQVIA, Parsippany, NJ). IQVIA serves as the data collection (through their PMT) and coordination center for the AHA/American Stroke Association GWTG programs. The University of Pennsylvania serves as the data analytic center and has an agreement to prepare deidentified data for research purposes. Full details of data quality management can be found in previously published research and online resources (29–32). This study protocol was reviewed by the Boston Children’s Hospital Institutional Review Board Scientific Review Committee and determined to be exempt from regulatory oversight (SRC no. 10-19-003).

Study Population

We extracted data on pediatric patients younger than 18 years old, reported to the registry during January 1, 2000, through January 1, 2019, following an IHCA event and categorized as having medical cardiac (MC) or surgical cardiac (SC) illness. For those with multiple IHCA events, only the “index” IHCA was included. The GWTG-R registry defines CA as no palpable pulse or a pulse with inadequate perfusion, requiring CPR with chest compressions and/or defibrillation terminating with either return of spontaneous circulation (ROSC) or death (17,33). ROSC is defined as return of circulation for greater than 20 minutes without need for repeat chest compressions. Cases using deployment of extracorporeal membrane oxygenation during CPR (extracorporeal CPR, E-CPR) were included. Out-of-hospital cardiac arrests (OHCAs) were excluded. The OHCA location variable was only included in the GWTG-R registry data after 2013. Thus, patients experiencing an index event before 2013 were only included if IHCA occurred in an in-hospital location. Patients with missing data regarding calcium use during CPR were excluded. Trends in calcium use and survival following IHCA in children with HD were compared against noncardiac illness categories. Figure 1 depicts inclusion/exclusion criteria.

F1
Figure 1.:
Inclusion and exclusion criteria. aCardiac arrest event identified by administration of chest compressions ± defibrillation. Including those receiving cardiopulmonary resuscitation for bradycardia. bOut-of-hospital arrest: identified as out-of-hospital arrest by GWTG-R registry questionnaire (after 2013), or arrest location in a rehabilitation/skilled nursing/mental health facility or unknown/not documented locations. cNewborn (< 1 d old), neonate/infant (1 d to < 1 yr old), pediatric (1 yr to < 18 yr old). dAll ICUs (adult ICU, neonatal ICU, PICU, all ICUs, pediatric cardiac ICU), procedural areas (cardiac catheterization laboratory, diagnostic/interventional area, operating room, diagnostic/interventional area including catheterization laboratory/prepatient management tool), and other (ambulatory/outpatient clinic, adult coronary care unit, labor/delivery, emergency department, inpatient ward, newborn nursery, postanesthesia care unit, same-day surgical area, telemetry/step-down unit, other, general inpatient including telemetry/prepatient management tool). GWTG-R = Get With the Guidelines-Resuscitation, PEA = pulseless electrical activity, PSM = propensity score matching, MC = medical cardiac, SC = surgical cardiac, VT = ventricular tachycardia, VF = ventricular fibrillation.

Outcome Measures

The primary outcome for this study was survival to hospital discharge. Secondary outcomes included ROSC, survival to 24 hours post-ROSC, survival to hospital discharge with a favorable neurologic outcome, and hospital length of stay. Hospital length of stay was truncated at 365 days based on GWTG-R registry reporting guidelines.

Neurologic outcome was categorized using the Pediatric Cerebral Performance Category (PCPC) scale assigned at admission and discharge, with scores assigned based on neurodevelopmental function as described in the literature (34). Favorable neurologic outcome was defined as a discharge PCPC score of less than or equal to 3 or no change from admission to discharge PCPC. Unfavorable neurologic outcome was defined as a discharge PCPC greater than 3 if the admission PCPC was less than 3, discharge PCPC worse than the admission PCPC if admission PCPC was greater than 3, and nonsurvivors.

Statistical Analyses

Descriptive statistics were used to summarize the study population and overall outcomes. Continuous data were reported as medians with interquartile ranges (IQRs, 25–75th percentiles) or mean (sd) based on normality of distribution of test variables, and categorical data were reported as number (%). Categorical variables were compared using chi-square test or Fisher exact test when expected cell counts were less than 5. Continuous variables were compared using Student t test or Wilcoxon rank-sum test. Trends over time were assessed using the Cochran-Armitage test.

Propensity Score Matching Analysis

Propensity score matching (PSM) analysis was used to select matched cohorts of patients with IHCA that did and did not receive calcium during CPR for comparison of primary and secondary outcomes. Patients were matched on their propensity to receive IV calcium during IHCA using the following variables selected a priori: age, event location, pertinent pre-existing conditions (metabolic/electrolyte derangements, hypotension), initial pulseless rhythm, CPR duration, and illness category. PSM was performed initially for the entire cohort, followed by MC and SC subgroups. Nearest-neighbor caliper matching on the propensity score was performed using a 1:1 ratio. Absolute standardized mean differences (SMDs) pre and post matching were calculated to evaluate the quality of matching in balancing the groups being studied, with SMD values less than 0.1 indicating good postmatching balance. Matched cohorts were then analyzed using Generalized Estimating Equations modeling to account for clustering by center and within matched sets.

For PSM, event location was categorized into three categories: all ICUs (adult ICU, neonatal ICU, PICU, all ICUs, pediatric cardiac ICU), procedural areas (cardiac catheterization laboratory, diagnostic/interventional area, operating room, diagnostic/interventional area including catheterization laboratory/pre-PMT), and other (ambulatory/outpatient clinic, adult coronary care unit, labor/delivery, emergency department, inpatient ward, newborn nursery, post-anesthesia care unit, same-day surgical area, telemetry/step-down unit, other, general inpatient including telemetry/pre-PMT). Age was categorized into three groups: newborn (< 1 d old), neonate/infant (1 d to < 1 yr old), and pediatric (1 yr to < 18 yr old). These age categories were chosen to control for differences in delivery room resuscitation of newborns where calcium is not frequently administered. Initial pulseless rhythms were grouped as pulseless electrical activity/asystole and ventricular tachycardia/ventricular fibrillation. Only subjects with initial pulseless rhythm were included in the PSM analysis. Bradycardic patients with initial pulse were not included because of differences in resuscitation techniques compared with pulseless rhythms (e.g., atrioventricular block requiring pacing). CPR duration was categorized based on quartiles of variable distribution. Initial pulseless rhythm, ICU location of IHCA, and CPR duration were collinear with other variables also known to be associated with IHCA survival and sicker cohorts (i.e., epinephrine doses, mechanical ventilation, use of arterial line, prearrest vasoactive infusions, sodium bicarbonate/amiodarone/lidocaine use, and E-CPR), and thus, those additional variables were not included in PSM due to baseline imbalance of variables and risk of overfitting the PSM model. CPR duration was used as a surrogate/summary variable that accounts for these other variables. Figure 1 shows inclusion criteria and number of patients selected for analysis using PSM. Differences in demographics and CA variables pre and post PSM matching are shown in Supplemental Digital Contents 1, 2, and 3 (https://links.lww.com/PCC/C155). Supplemental Digital Content 1 (https://links.lww.com/PCC/C155) also shows improved balance of three collinear variables not used in PSM (epinephrine doses, sodium bicarbonate, E-CPR).

To assess the generalizability of the outcome assessment without elimination of large portions of our cohort with PSM, a sensitivity analysis of the entire unmatched cohort (including patients with initial rhythm of bradycardia with a pulse) using multivariable logistic regression adjusting for the propensity score to estimate odds of survival in patients receiving calcium during CPR was performed (Supplemental Digital Content 4, https://links.lww.com/PCC/C155). The propensity score was used for multivariable adjustment in the entire unmatched cohort to obtain regression estimates comparing calcium versus no calcium for each outcome while controlling for all variables used in constructing the propensity scores. Overlapping histograms were created to visualize the distribution of the propensity scores for all cohorts studied (Supplemental Digital Content 5, https://links.lww.com/PCC/C156; legend, https://links.lww.com/PCC/C155). A comparison of matched versus unmatched cohorts was also performed to assess generalizability of results in PSM analysis to the full unmatched eligible cohort (Supplemental Digital Content 6, https://links.lww.com/PCC/C155). Differences in baseline characteristics and outcomes between unmatched MC and SC patients are shown in Supplemental Digital Contents 7 and 8 (https://links.lww.com/PCC/C155).

Statistical significance was defined as p value of less than 0.05 level. All p values were two-sided. Statistical analyses were performed using IBM SPSS Version 25 (IBM Corp., Armonk, NY), and PSM was performed using the “calipmatch” procedure in Stata 16.0 (StataCorp LLC, College Station, TX).

RESULTS

Study Population and Trends in Calcium Administration During CPR

Among 15,921 unmatched patients who had index pediatric IHCA events during the study period, 4,556 events met inclusion criteria, including 2,229 MC and 2,327 SC patients. Overall, 1,986 patients (44%; 810 MC and 1,176 SC) received calcium during CPR (Fig. 1). Figure 2 shows trends in IV calcium use during CPR for IHCA among cardiac and noncardiac medical and surgical groups. Although calcium use decreased over time in all patient groups (non-SC categories p < 0.001; SC p = 0.002), calcium use remained higher in children with HD. The proportion of patients receiving calcium increased linearly with longer CPR duration across the four groups (p < 0.001) (Fig. 3). Overall survival trends for IHCA improved during the study period in all cardiac patients and those not receiving calcium during CPR but not for patients receiving calcium (Supplemental Digital Content 9, https://links.lww.com/PCC/C157; legend, https://links.lww.com/PCC/C155).

F2
Figure 2.:
Calcium use during cardiopulmonary resuscitation from January 2000 to January 2019 by illness category. p value calculated using Cochran-Armitage test for trend.
F3
Figure 3.:
Proportion of calcium use in illness categories by cardiopulmonary resuscitation (CPR) duration. p value calculated using Cochran-Armitage test for trend.

Comparison of Patients Receiving and Not Receiving Calcium During CPR

Differences in demographics, arrest characteristics, and CPR management in the unmatched study cohort based on calcium use are shown in Supplemental Digital Content 10 (https://links.lww.com/PCC/C155). The study cohort contained a larger proportion of children 29 days to < 12 months old (n = 1,687; 37%) and those with IHCA in ICU settings (n = 3,582; 79%). Calcium administration was more common in ICU locations (n = 1,644; 83%). Among 631 cases with metabolic/electrolyte derangements preceding CA, calcium was administered during CPR in 325 cases (16%; p < 0.001). Patients receiving calcium during CPR had higher rates of vasoactive infusion use prearrest, received a higher number of epinephrine doses, and more frequently received sodium bicarbonate (Supplemental Digital Content 10, https://links.lww.com/PCC/C155). Median CPR duration was significantly longer for events where calcium was administered, and E-CPR was deployed more frequently for events with calcium administration during CPR (Supplemental Digital Content 10, https://links.lww.com/PCC/C155).

Univariate analysis showed that those receiving calcium during CPR had lower rates of ROSC (73% vs 88%; p < 0.001), lower survival to hospital discharge (38% vs 61%; p < 0.001), and lower rates of survival with favorable neurologic outcome (26% vs 47%; p < 0.001) compared with those not receiving calcium (Supplemental Digital Content 10, https://links.lww.com/PCC/C155).

Propensity Score Matched Analysis

Postmatching differences in demographics, prearrest, and arrest variables in the propensity-matched cohort of patients receiving and not-receiving calcium during CPR are shown in Table 1. Overlapping histograms of the propensity scores demonstrated an adequate degree of overlap between groups indicating good quality of matching (Supplemental Digital Content 5, https://links.lww.com/PCC/C156; legend, https://links.lww.com/PCC/C155).

TABLE 1. - Postmatching Comparison of Baseline Variables for Propensity Score Matching Analysis, All Cardiac Patients
Postmatching Comparison of Baseline Variables Based on 1:1 Propensity Score Matching
Variable Calcium (N = 678) No Calcium (N = 678) Absolute Standardized Mean Difference
Age group a
 Newborn 264 (38.9) 289 (42.6) 0.08
 Neonate/infant 328 (48.4) 297 (43.8) 0.09
 Pediatric 86 (12.7) 92 (13.6) 0.03
Event location b
 ICUs 540 (79.7) 538 (79.4) 0.01
 Procedural areas 58 (8.6) 55 (8.1) 0.02
 Other 80 (11.8) 85 (12.5) 0.02
Pre-existing conditions
 Metabolic/electrolyte  derangement 109 (16.1) 110 (16.2) < 0.01
 Hypotension 253 (37.3) 244 (36) 0.03
Initial rhythm
 Pulseless electrical activity/asystole 543 (80.1) 538 (79.4) 0.02
 Ventricular Tachycardia/ventricular Fibrillation 135 (19.9) 140 (20.7) 0.02
Cardiopulmonary resuscitation duration c
 First quartile 215 (31.7) 232 (34.2) 0.05
 Second quartile 138 (20.4) 137 (20.2) < 0.01
 Third quartile 119 (17.6) 114 (16.8) 0.02
 Fourth quartile 206 (30.4) 195 (28.8) 0.04
Illness category
 Medical cardiac 303 (44.7) 329 (48.5) 0.08
 Surgical cardiac 375 (55.3) 349 (51.5) 0.08
aNewborn < 1 d old; neonate/infant 1 d to < 1 yr old; pediatric 1 yr to < 18 yr old.
bEvent locations categorized into three categories: ICUs (adult ICU, neonatal ICU, PICU, all ICUs, pediatric cardiac ICU), procedural areas (cardiac catheterization laboratory, diagnostic/interventional area, operating room, diagnostic/interventional area including cath laboratory/pre-patient management tool [PMT]), and other (ambulatory/outpatient clinic, adult coronary care unit, labor/delivery, emergency department, inpatient ward, newborn nursery, postanesthesia care unit, same-day surgical area, telemetry/step-down unit, other, general inpatient including telemetry/pre-PMT).
cCardiopulmonary resuscitation duration categorized based on quartiles of variable distribution.
Data presented as n (%).
Standardized mean difference values < 0.1 indicating good postmatching balance.

Primary and secondary outcomes for PSM cohorts are shown in Table 2. In the matched cohort of 678 children, those receiving calcium had decreased survival to hospital discharge (39% vs 46%; p = 0.02), lower rates of discharge with a favorable neurologic outcome (28% vs 34%; p = 0.02), and higher rates of E-CPR deployment (19% vs 15%; p = 0.02) compared with those not receiving calcium during CPR (Table 2).

TABLE 2. - Comparison of Outcomes in Propensity-Matched Cohorts, Full Cohort, and Subgroup Analysis
Primary and Secondary Outcomes Calcium No Calcium p
All cardiac patients N = 678 N = 678
Survival to hospital discharge 267 (39.4) 309 (45.6) 0.02
 ROSC 478 (70.5) 498 (73.5) 0.19
Survival to 24 hr 418 (61.7) 447 (65.9) 0.08
 Discharge with favorable neurologic outcome (PCPC score) a 161 (27.8) 194 (34.2) 0.02
 E-CPR b 128 (19.1) 99 (14.7) 0.02
Survival to discharge after E-CPR 57 (44.5) 52 (52.5) 0.24
 Hospital length of stay, d c 20 (5,49) 19 (6,47) 0.60
Medical cardiac N = 322 N = 322
Survival to hospital discharge 105 (32.6) 113 (35.1) 0.48
 ROSC 206 (64) 202 (62.7) 0.72
Survival to 24 hr 169 (52.5) 168 (52.2) 0.93
 Discharge with favorable neurologic outcome (PCPC score) a 72 (24.7) 67 (24.1) 0.86
 E-CPR b 31 (9.7) 27 (8.4) 0.53
Survival to discharge after E-CPR 16 (51.6) 12 (44.4) 0.54
 Hospital length of stay, d c 10 (2,30) 12 (2,36) 0.33
Surgical cardiac N = 339 N = 339
Survival to hospital discharge 154 (45.4) 203 (59.9) < 0.001
 ROSC 259 (76.4) 287 (84.7) 0.004
Survival to 24 hr 238 (70.2) 275 (81.1) < 0.001
 Discharge with favorable neurologic outcome (PCPC score) a 90 (32.1) 124 (47.5) < 0.001
 E-CPR b 80 (24.0) 68(20.3) 0.21
Survival to discharge after E-CPR 41 (51.3) 35 (51.5) 0.86
 Hospital length of stay, d c 28 (13,63) 26 (11,53) 0.50
E-CPR =extracorporeal cardiopulmonary resuscitation, PCPC = Pediatric Cerebral Performance Category, ROSC = return of spontaneous circulation.
aFor all cardiac patients, PCPC scores available for n = 580 in “Calcium” group and n = 567 in “No Calcium” group. For medical cardiac patients, PCPC scores available for n = 291 in “Calcium” group and n = 278 in “No Calcium” group. For surgical cardiac patients, PCPC scores available for n = 280 in “Calcium” group and n = 261 in “No Calcium” group.
bFor all cardiac patients, E-CPR data available for n = 670 in “Calcium” group and n = 675 in “No Calcium” group. For medical cardiac patients, E-CPR data available for n = 320 in “Calcium” group and n = 321 in “No Calcium” group. For surgical cardiac patients, E-CPR data available for n = 333 in “Calcium” group and n = 335 in “No Calcium” group.
cHospital length of stay data truncated at 365 d.
Data presented as n (%) for categorical variables and median (interquartile range) for continuous variables. p values calculated using Generalized Estimating Equations modeling in order to account for the matched set ID from propensity matching.

PSM was similarly performed in MC and SC subgroups (Table 2). There were no differences in outcomes among patients receiving and not receiving calcium during CPR in the MC group. However, in the SC group, ROSC (76% vs 85%; p = 0.004), survival to hospital discharge (45% vs 60%; p < 0.001), and survival with a favorable neurologic outcome (32% vs 48%; p < 0.001) were significantly lower in those receiving calcium during CPR.

Multivariable regression analysis performed using the entire unmatched study cohort, to eliminate risk of bias for excluding unmatched patients, adjusting for baseline covariates and propensity score, also demonstrated lower odds of survival to hospital discharge with calcium use during CPR (odds ratio [OR], 0.78 [CI, 0.64–0.95]; p = 0.01) and in the SC subgroup (OR, 0.60 [CI, 0.46–0.79]; p < 0.001) (Supplemental Digital Content 4, https://links.lww.com/PCC/C155).

Subgroup Comparisons

Because calcium is commonly administered in children younger than 1 year old, a secondary analysis of the association of calcium administration during CPR with baseline characteristics and unadjusted outcomes was performed, which also showed decreased odds of survival with calcium administration (Supplemental Digital Content 11, https://links.lww.com/PCC/C155).

DISCUSSION

In a propensity-matched cohort of children with HD experiencing IHCA, we found that administration of IV calcium during CPR was frequent and independently associated with decreased survival to hospital discharge. Calcium use was more frequent in younger children, surgical cardiac patients, longer CPR duration events, and in those receiving other nonadrenergic pharmacologic interventions during arrest. Sensitivity analyses on the full unmatched cohort also showed worse outcomes when calcium was used during arrest, indicating that the PSM results are generalizable to children with HD. Although a lower likelihood of survival with a favorable neurologic outcome was noted in children with HD when calcium was used during arrest in our analysis, a high degree of missingness of PCPC scores limited the reliability of this secondary outcome.

A previous study by Srinivasan et al (16) used an earlier cohort of children of all disease categories with IHCA from the same registry (then the National Registry of CPR, currently the AHA GWTG-R registry) and found that calcium administration during CPR for pediatric IHCA was associated with decreased event survival and poor neurologic outcome. Our study focused only on children with HD, given the frequent use of calcium during arrest in this population, and found that calcium administration during CPR remained associated with decreased event survival and survival to hospital discharge. Additionally, our study used PSM to balance important confounders when comparing outcomes. In prior studies by Nayler et al (21) and Oliveira et al (22), it is demonstrated that exposure of the myocardium to extracellular calcium in the postischemic reperfusion phase activates specific pathways that lead to a loss of cell structure/function (24). It is possible that the exposure of myocardial and neurologic tissues to IV boluses of calcium during arrest leads to an in vivo milieu of elevated extracellular calcium stores during the ischemic and reperfusion periods of CA, which may be detrimental to cellular function and recovery. These mechanisms may be operational in decreased survival in children receiving calcium during CPR.

In addition to impact on patient outcome, we bring attention to the frequent use of calcium during CPR for IHCA among children with HD (Fig. 2). Since the institution of the 2000 AHA guidelines on pediatric CPR and the publication of the results by Srinivasan et al in 2008 (16,35), calcium use during IHCA has decreased in noncardiac illness categories from nearly 45% to 20% during the 19-year study period. In contrast, contemporary rates of calcium use during CPR among children with HD have remained disproportionately higher. The higher rate of calcium use in children with HD may be in part due to use of calcium to correct metabolic derangements (e.g., hyperkalemia, hypocalcemia) that can be secondary to blood product exposure and other intraoperative/postoperative management techniques (36,37). Additionally, maintaining extracellular calcium stores to increase cytosolic calcium availability in neonates/infant with immature sarcoplasmic reticulum may promote myocardial contractility (36–40). Extrapolation of these mechanisms to periods of CA may explain the higher frequency of calcium administration during CPR in children with HD, younger children, and SC populations (16). Nonetheless, our data demonstrate that even when adjusting for age, metabolic/electrolyte derangements, CPR duration, and illness category, children with HD experienced worse survival when calcium was used during CPR. Our finding that decreased survival with calcium administration during CPR in subgroup analysis was only present in the SC population is interesting. Our study, and others, have shown that survival following CPR for IHCA is generally lower in MC compared with SC patients (10). The MC population may have irreversible causes for CA or have comorbid conditions that preclude successful CPR. It is possible that increased mortality in MC patients may have dulled the adverse effects of calcium administration during CPR.

Our study confirms the results of previous reports which show that calcium is administered at higher frequencies in longer CPR duration events (14,16). This may reflect the challenges of following the Pediatric Advanced Life Support algorithm when historical practices, availability of new clinical information, or “last ditch efforts” result in administration of calcium during CPR. Our data show that even with matching for CPR duration, a variable known to be associated with worse outcomes (11), calcium, remained an independent risk factor for poor survival. The findings of our study would support the practice of calcium avoidance during CPR when not indicated, as per the AHA guidelines, as a specific targeted measure to promote survival and neuroprotection.

This is a retrospective, observational study of a large registry database. Calcium use is reported as a binary variable in the registry; therefore, reasons for use, timing of calcium administration during the CPR event, and number of doses are not captured in the registry; thus, a time- or dose-dependent analysis could not be performed. Despite PSM, some covariates (e.g., epinephrine doses, sodium bicarbonate) remained unbalanced. We chose to not match on all unbalanced variables to prevent loss of patients for comparison resulting from matching on many variables, thus balancing bias with generalizability. Additionally, due to limitations of the GWTG-R registry, evaluating the number of epinephrine doses and bicarbonate doses administered prior to calcium administration during CPR cannot be ascertained. Confounding from unmeasured covariates may exist despite balancing measured covariates with PSM. Although we show a higher frequency of unfavorable neurologic outcomes for survivors in children receiving calcium during CPR, missing PCPC data (among 4,556 eligible patients meeting inclusion criteria, only 2,487 had admission PCPC scores and 609 had discharge PCPC scores) greatly limited the interpretation of this outcome. Finally, it is important to note that several differences in demographic and arrest characteristics were noted in the matched and unmatched cohorts (Supplemental Digital Content 6, https://links.lww.com/PCC/C155). Specifically, the matched cohort included fewer newborns/neonates/infants. Since most complex cardiac surgeries are performed in neonates/infants, fewer patients in these age ranges could overestimate differences in IHCA survival and possibly indicate a greater effect in SC and younger age groups.

CONCLUSIONS

IV calcium administration during CPR for IHCA occurs at higher rates in children with HD. Calcium use is independently associated with decreased survival to hospital discharge. Our findings support current AHA CPR guidelines restricting administration of calcium during pediatric CA to specific clinical indications. Future studies should focus on designing interventions to reduce calcium administration during CPR when not indicated.

ACKNOWLEDGMENTS

American Heart Association’s Get With The Guidelines - Resuscitation Pediatric Research Task Force members are as follows: Anne-Marie Guerguerian, MD, PhD, FRCPC; Dianne Atkins, MD; Elizabeth E. Foglia, MD, MSCE; Ericka Fink, MD; Javier J. Lasa, MD, FAAP; Joan Roberts, MD; Jordan Duval-Arnould, MPH, DrPH; Lillian Su, MD; Linda L. Brown, MD, MSCE; Maya Dewan, MD, MPH; Melania M. Bembea, MD, MPH, PhD; Monica Kleinman, MD; Punkaj Gupta, MBBS; Robert M. Sutton, MD, MSCE, FAAP, FCCM; Ron Reeder, MS, PhD; Taylor Sawyer, DO Med; Todd Swenberg, MD, MBA.

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Keywords:

calcium; cardiac arrest; cardiopulmonary resuscitation; congenital heart disease; pediatric; survival

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