CALCIUM USE DURING IN-HOSPITAL PEDIATRIC CARDIO PULMONARY RESUSCITATION:

A Report From the National Registry of Cardiopulmonary Resuscitation

Srinivasan V, Morris M C, Helfaer M. A, Berg R.A , Nadkarni V.M

Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania;

Department of Pediatrics, Morgan Stanley Children’s Hospital of New York-Presbyterian and Columbia University Medical Center, New York, New York;

Department of Pediatrics, Steele Children’s Research Center, University of Arizona, Tucson, Arizona

Pediatrics 2008;121;1144-1151

• The role of calcium administration during cardiopulmonary resuscitation (CPR) remains controversial.

• Although calcium ions play a critical role in myocardial contractile performance and impulse formation, limited retrospective and prospective studies of calcium administration during CPR have not shown any benefit.

• Furthermore, high serum calcium levels induced by calcium administration may be detrimental. Several studies have implicated cytoplasmic calcium accumulation in the final common pathway of cell death.

• Calcium accumulation results from calcium’s entering cells after ischemia and during reperfusion of ischemic organs; increased cytoplasmic calcium concentration activates intracellular enzyme systems, resulting in cellular necrosis.

• In 2000, the American Heart Association (AHA) published guidelines limiting the recommended use of calcium to selected resuscitation circumstances: documented hypocalcemia, hyperkalemia, hypermagnesemia, and calcium channel blocker overdose.

• These guidelines also explicitly stated that calcium should not be used routinely to support circulation in the setting of cardiac arrest (class III recommendation: not useful and may cause harm).

• The National Registry of Cardiopulmonary Resuscitation (NRCPR) is a large, multicenter database that prospectively and rigorously documents adult and pediatric in-hospital cardiac arrests.

• The authors conducted this study using the NRCPR database to characterize patterns of calcium use during in-hospital pediatric CPR.

• They hypothesized that calcium continues to be used frequently during in-hospital pediatric CPR and that its use varies by hospital-specific, patient-specific, and event-specific characteristics.

• They also hypothesized that calcium use during in-hospital pediatric CPR is associated with worse survival to hospital discharge, and worse event survival and unfavorable neurologic outcome.

Methods• Data were analyzed from 167 participating NRCPR hospitals that recorded

cardiopulmonary arrests of patients who were younger than 18 years and provided 6 months of data.

• All patients who were younger than 18 years and experienced cardiopulmonary arrest that required CPR at participating institutions were eligible for this study.

• An event was defined as an arrest that required chest compressions and/or defibrillation. An index event was defined as the patient’s first cardiopulmonary arrest that required CPR during hospitalization. Only index events were eligible for inclusion in the study.

• Out-of-hospital arrests, arrests that occurred in the delivery room or NICU, arrests in patients with “do not attempt resuscitation” orders, and arrests that were resolved by implantable defibrillator shocks were excluded.

• The prospectively selected primary outcome measure was survival to hospital discharge.

• The secondary outcome measures included survival of event (defined as return of spontaneous circulation for 20 minutes) and neurologic outcome.

• The neurologic outcome was determined according to the pediatric cerebral performance category (PCPC) scale as follows: – (1) a normal neurologic state,– (2) mild disability, – (3) moderate disability,– (4) severe disability, – (5) coma or vegetative state, and– (6) death.

• A favorable neurologic outcome was defined by a PCPC score of 1, 2, or 3 or no change from baseline PCPC scores

Statistics• All statistical analyses were performed with a commercially

available statistical package (Stata 8, College Station, TX).

• Results are presented as means ± SD for variables that are distributed normally.

• Variables that were not distributed normally are presented as medians and interquartile ranges.

• Differences between groups were analyzed by the Wilcoxon rank-sum test for continuous variables and the 2 test for dichotomous variables

• Hospital, patient, and event variables associated with calcium use by univariate analysis were included in stepwise multivariable logistic regression analysis.

• All factors associated with primary and secondary outcomes on univariate

analysis were included in stepwise multivariable logistic regression to describe the association of calcium use with outcome measures adjusted for confounding factors.

• Odds ratios (ORs) with 95% confidence intervals (Cis) were reported. The sample size was not planned.

RESULTS

• Calcium was provided during CPR significantly more often in events that occurred in pediatric facilities (62% vs 35% in mixed facilities vs 3% in adult facilities; and ICUs (77% vs 7% in emergency departments).

• Cardiac illness (both surgical and medical) was significantly associated with calcium use during CPR.

• A greater proportion of patients who subsequently received calcium during CPR were on a vasoactive infusion at the time of the arrest, compared with those who did not receive calcium (50% vs 28%).

• In both groups, acute respiratory insufficiency and hypotension were the most common immediate precipitating causes of the arrest. Notably, preexisting major trauma and acute airway obstruction were less likely to be associated with calcium use during CPR.

• Of the 1477 events, 874 (59%) were pulseless throughout the entire event, 274 (19%) became pulseless during the event, and 329 (22%) had pulses throughout the event.

• Overall, more survivors than nonsurvivors underwent CPR for 15 minutes (54% vs 29%).

• The median duration of CPR was 30 minutes in the group that received calcium, compared with 15 minutes in the group that did not receive calcium.

• Similarly, the median number of epinephrine doses administered was 4 in the group that received calcium compared with 2 in the group that did not receive calcium.

• Loss of pulses during the event was more often associated with calcium use, whereas presence of pulses throughout the event was less likely to be associated with calcium use.

• Calcium use during CPR was significantly more likely when the first documented pulseless rhythm was asystole; one third of children who received calcium during CPR had asystole as the first documented rhythm.

RESULT - ANALYSIS• After controlling for confounding factors (ethnicity, facility type, event

location, illness category, preexisting conditions, interventions in place at the time of the event, immediate precipitating causes, arrest rhythm, concurrent advanced cardiac life support medications, and duration of CPR for 15 minutes), calcium administration during CPR was independently associated with poor survival to discharge and unfavorable neurologic outcome after in-hospital pediatric CPR, as hypothesized.

• Twenty-one percent of patients survived to discharge when calcium was used, compared with 44% who survived when calcium was not used (aOR: 0.6; 95% CI: 0.5– 0.9).

• In addition, only 15% of patients had favorable neurologic outcome when calcium was administered during CPR, compared with 35% with favorable neurologic outcome when calcium was not administered

• The authors also examined calcium use during CPR in specific circumstances of interest in which administration of calcium might be indicated.

• First, in the settings of metabolic electrolyte abnormalities and toxicologic abnormalities, calcium use during CPR was not associated with worse event survival or survival to discharge after adjustment for confounding factors.

• Second, in the population of postcardiac surgical infants, after adjustment for confounding factors, the use of calcium during CPR was associated with worse event survival; however, in this setting, calcium use during CPR was not significantly associated with reduced survival to hospital discharge or unfavorable neurologic outcome.

• After we excluded patients in the settings of metabolic/electrolyte abnormalities, toxicologic abnormalities, and postcardiac surgical infants, calcium use during CPR (n = 898) continued to be associated with worse survival to discharge and was not associated with favorable neurologic outcome after adjustment for potentially confounding variables.

DISCUSSION• This report of in-hospital pediatric cardiopulmonary arrests in 1477

consecutive children documents calcium administration during resuscitation of 659 (45%) children.

• This study shows that calcium use during CPR is strongly influenced by hospital-specific, patient-specific, and arrest-specific characteristics.

• Previous studies of adults had speculated that calcium administration during CPR might benefit a subset of patients with asystole and pulseless electrical activity; however, subsequent limited prospective and retrospective adult studies of calcium administration during resuscitation in these settings failed to demonstrate any benefit.

• Later studies that consisted of large prospective cohorts of adults who sustained both in-hospital and out-of-hospital cardiac arrests did not show any association between the use of standard advanced cardiac life support medications (including calcium) and survival.

• On the basis of these data, the AHA 2000 guidelines recommended limiting the use of calcium to select resuscitation circumstances.

• Specific indications for calcium use during CPR (hyperkalemia, documented hypocalcemia, hypermagnesemia, and calcium channel blocker overdose) are captured in the NRCPR under the categories of metabolic/ electrolyte abnormalities and toxicologic abnormalities.

• This study revealed that calcium was administered to 45% of children who were treated with CPR.

• The combined incidence of metabolic/electrolyte and toxicologic abnormalities (as both preexisting conditions and immediate precipitating causes) in the NRCPR database is only 25%.

• Also, calcium was administered in asystole (49%) and pulseless electrical activity (42%). This suggests that calcium is often used in circumstances other than those recommended by the pediatric advanced life support guidelines.

• There are several reasons that calcium might be used so frequently during CPR in children. In neonates and infants, the immature myocardium depends more on extracellular calcium levels because intracellular calcium stores are limited. This age group has significant risk factors such as cardiac bypass surgery, sepsis, and prematurity that have a significant impact on myocardial function and extracellular ionized calcium concentrations. Perhaps in part because of these factors, practitioners chose to provide calcium in 44% of events involving neonates and infants in this study. Nevertheless, in this age category, those who received calcium during CPR had worse survival to discharge (26%) compared with those who did not (55%).

• Specifically, in the population of postcardiac surgical infants, after adjustment for confounding factors, the use of calcium during CPR was associated with worse event survival; however, calcium use during CPR was not significantly associated with reduced survival to hospital discharge or unfavorable neurologic outcome.

• The frequent use of calcium during CPR in other age and diagnostic categories may reflect medical futility and a “last-ditch” attempt to try all possible therapies during resuscitation.

• Irrespective of event duration, calcium use during CPR was associated with worse survival to discharge and unfavorable neurologic outcome. This finding has important implications because of the widely known role of calcium in mediating reperfusion injury in the setting of ischemia resulting in cell death.

• An important limitation of the study results from the lack of explicit documentation of specific indications for calcium use and details of calcium dosing during CPR as captured in the NRCPR. A dose-response effect, if observed, could have provided stronger evidence for the effect of calcium administration on outcome.

• Another important limitation is the inability to adjust for variation in facility characteristics and physician and nurse staffing in different settings, resulting in our inability to use hierarchical cluster modeling.

LIMITATIONS

CONCLUSION• This study has important implications. First, the results emphasize that

calcium continues to be used frequently during in-hospital pediatric CPR, despite guidelines that recommend limiting the use of calcium to specific circumstances. Pediatric advanced life support guidelines published by the AHA in 2005 continue to restrict the use of calcium to specific circumstances, including hyperkalemia, documented hypocalcemia, hypermagnesemia, and calcium channel blocker overdose.

• Second, the use of calcium during CPR without such indications is associated with worse survival to discharge and unfavorable neurologic outcome, perhaps because of reperfusion injury to the ischemic brain, heart, and other organs mediated by calcium.

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