Original Article. Survival Trends in Pediatric In-Hospital Cardiac Arrests An Analysis From Get With The Guidelines Resuscitation

Transcription

1 Original Article Survival Trends in Pediatric In-Hospital Cardiac Arrests An Analysis From Get With The Guidelines Resuscitation Saket Girotra, MD, SM; John A. Spertus, MD, MPH; Yan Li, PhD; Robert A. Berg, MD; Vinay M. Nadkarni, MD; Paul S. Chan, MD, MSC; for the American Heart Association Get With the Guidelines Resuscitation Investigators* Downloaded from by guest on April 23, 2018 Background Despite ongoing efforts to improve the quality of pediatric resuscitation, it remains unknown whether survival in children with in-hospital cardiac arrest has improved. Methods and Results Between 2000 and 2009, we identified children (<18 years of age) with an in-hospital cardiac arrest at hospitals with >3 years of participation and >5 cases annually within the national Get With The Guidelines Resuscitation registry. Multivariable logistic regression was used to examine temporal trends in survival to discharge. We also explored whether trends in survival were attributable to improvement in acute resuscitation or postresuscitation care and examined trends in neurological disability among survivors. Among 1031 children at 12 hospitals, the initial cardiac arrest rhythm was asystole and pulseless electrical activity in 874 children (84.8%) and ventricular fibrillation and pulseless ventricular tachycardia in 157 children (15.2%), with an increase in cardiac arrests due to pulseless electrical activity over time (P for trend <0.001). Risk-adjusted rates of survival to discharge increased from 14.3% in 2000 to 43.4% in 2009 (adjusted rate ratio per year, 1.08; 95% confidence interval, ; P for trend=0.02). Improvement in survival was driven largely by an improvement in acute resuscitation survival (risk-adjusted rates: 42.9% in 2000, 81.2% in 2009; adjusted rate ratio per year: 1.04; 95% confidence interval, ; P for trend=0.006). Moreover, survival trends were not accompanied by higher rates of neurological disability among survivors over time (unadjusted P for trend=0.32), suggesting an overall increase in the number of survivors without neurological disability over time. Conclusion Rates of survival to hospital discharge in children with in-hospital cardiac arrests have improved over the past decade without higher rates of neurological disability among survivors. (Circ Cardiovasc Qual Outcomes. 2013;6: ) Key Words: cardiopulmonary resuscitation pediatrics survival In-hospital cardiac arrest in children occurs in 2% to 6% of all pediatric intensive care unit patients 1,2 and is associated with poor survival. 3 Over the past decade, various strategies have been promoted by clinical practice guidelines to improve survival after in-hospital cardiac arrests. These include earlier recognition and management of at-risk patients, greater emphasis on quality of resuscitation (eg, high-quality chest compressions with minimal interruptions, use of extracorporeal membrane oxygenation during resuscitation [ECPR]), and postresuscitation care (eg, multidisciplinary care). 4 7 Despite increased emphasis on these initiatives, no study has yet examined temporal trends in survival for pediatric in-hospital cardiac arrests in part because of the lack of a national pediatric cardiac arrest registry with standardized definitions and uniform data reporting. Although indirect comparisons across single-center studies may suggest that cardiac arrest survival in hospitalized children improved from 9% in the 1980s 8,9 to 27% in 2005, 3 these comparisons do not account for important differences across centers or in patient characteristics over time (eg, age, comorbid conditions, cause of cardiac arrest, or initial rhythm). For example, advances in the management of children with complex congenital heart diseases may have resulted in a temporal decrease in the proportion of cardiac arrests because of ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) rhythms, which are associated with better survival than asystole or pulseless electrical activity (PEA). Furthermore, survivors of cardiac arrest are at significant risk of neurological impairment, and it is unknown whether any improvement in Received July 29, 2012; accepted October 23, From the University of Iowa Hospitals and Clinics, Iowa City (S.G.); Saint Luke s Mid America Heart Institute, Kansas City, MO (J.A.S., Y.L., P.S.C.); University of Missouri-Kansas City (J.A.S., P.S.C.); and Department of Anesthesia and Critical Care, Children s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (R.A.B., V.M.N.). The online-only Data Supplement is available at *The American Heart Association Get With The Guidelines Resuscitation Investigators are listed in the Appendix in the online-only Data Supplement. John A. Spertus, MD, MPH, FACC, Deputy Editor of Circulation: Cardiovascular Quality and Outcomes, is a coauthor on this manuscript. The manuscript was handled independently by Ravi R. Thiagarajan, MBBS as Guest Editor. The Editors had no role in the evaluation of this article or the decision about its acceptance. Correspondence to Saket Girotra, MD, SM, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Ste 4430 RCP, Iowa City, IA saket-girotra@uiowa.edu 2012 American Heart Association, Inc. Circ Cardiovasc Qual Outcomes is available at DOI: /CIRCOUTCOMES

2 2 Circ Cardiovasc Qual Outcomes January 2013 WHAT IS KNOWN Cardiac arrest events in hospitalized children are associated with poor survival. Although efforts over the past decade have been targeted toward improving the quality of resuscitation care in hospitals, it remains unknown whether pediatric in-hospital cardiac arrest survival has improved with these efforts. WHAT THE STUDY ADDS Overall survival in children with an in-hospital cardiac arrest has improved nearly 3-fold over the past decade. This improvement in cardiac arrest survival has occurred in all age categories (neonates, toddlers, and older children). Importantly, the improvement in pediatric in-hospital cardiac arrest survival has not occurred at the expense of worsened neurological disability among surviving children. survival in this population has occurred at the cost of higher rates of neurological disability. To address these existing gaps in knowledge, we examined trends in survival and neurological disability in children with an in-hospital cardiac arrest using data from a large, national, hospital-based clinical registry. A better understanding of trends in survival after pediatric in-hospital cardiac arrest would provide an informed assessment of ongoing quality improvement efforts in pediatric cardiopulmonary resuscitation and lay the foundation for monitoring future improvements in care. Methods Data Source and Study Population Our study patients were derived from Get With The Guidelines Resuscitation (GWTG-Resuscitation), formerly known as the National Registry of Cardiopulmonary Resuscitation. This is a large, hospital-based, clinical registry of in-hospital cardiac arrests that has been enrolling patients since January Its design has been previously described in detail. 10 Briefly, the registry enrolls patients with a pulseless cardiac arrest, defined as the absence of a palpable central pulse, apnea, and unresponsiveness in children without do-not-resuscitate orders in whom a resuscitation effort is attempted. Although data on children who received cardiopulmonary resuscitation for bradycardia and hypotension are also collected, these were not included because they did not meet our study definition of cardiac arrest. To ensure that consecutive cardiac arrest patients are enrolled, multiple case-finding methods are used. These include centralized collection of cardiac arrest flow sheets, review of hospital page system logs, and routine checks of code carts, pharmacy tracer drug records, and hospital billing charges for use of resuscitation medications. The registry uses Utstein-style definitions, which are a standardized template of reporting guidelines developed by international experts, for defining clinical variables and outcomes. 11 Data completeness and accuracy in GWTG-Resuscitation are ensured by rigorous training and certification of study personnel, a periodic reabstraction process, and use of standardized software with internal data checks. The American Heart Association oversees the entire process of data collection, analysis, and reporting through its national center staff, clinical working group, and Executive Database Steering Committee. Study Population Between January 1, 2000, and November 19, 2009, we identified 2555 patients who were 18 years of age with an index in-hospital cardiac arrest (Figure 1). We excluded 13 patients with missing information on survival. We also restricted our sample to cardiac arrests occurring in inpatient locations (eg, intensive care units, including pediatric and neonatal units; inpatient wards; and labor and delivery) and excluded cardiac arrest patients from emergency departments, operating rooms, and procedural suites because of the distinct clinical circumstances and outcomes with cardiac arrest in these locations (n=636). Because we were interested in examining trends in survival over time, we also excluded 875 patients from 183 hospitals with <3 years of data submission or low cardiac arrest volume (<5 cases per year). Our final sample comprises 1031 patients from 12 hospitals. Study Outcome Measures The primary outcome was survival to discharge. To better understand which specific phase of resuscitation care was associated with temporal improvement in survival, we also examined, as secondary outcomes, acute resuscitation survival, defined as return of spontaneous circulation for 20 minutes after the initial pulseless arrest, and postresuscitation survival, defined as survival to hospital discharge among patients who survived the acute resuscitation. Finally, to confirm that any temporal trend in survival was clinically important, we 2555 patients with index arrest due to asystole, PEA, VF and pulseless VT 2542 patients with complete non-missing data 1906 arrests located in a general inpatient ward, or ICU 1031 Arrests from 12 hospitals included in the final study population 13 patients missing data on survival excluded 636 arrests occurring outside of the ICUs and general inpatient wards excluded 875 arrests excluded from 183 hospitals with < 3 years of data or low case volume (< 5/year) Figure 1. Study cohort. PEA indicates pulseless electrical activity; VF, ventricular fibrillation; VT, ventricular tachycardia; and ICU, intensive care unit.

3 Girotra et al Survival Trends in Pediatric In-hospital Cardiac Arrests 3 also examined rates of significant neurological disability among survivors. This was done using previously developed pediatric cerebral performance category (PCPC) scores. 12 A PCPC score of 1 describes children with normal age-appropriate neurodevelopmental functioning; 2, mild cerebral disability; 3, moderate disability; 4, severe disability; 5, coma/vegetative state; and 6, brain death. For our study, we defined significant neurological disability as a PCPC score of 4 or higher among survivors. 13 Study Variables The main independent variable was calendar year. Patient factors included demographics (age groups [<1 month, 1 month to 5 years, >5 years], sex, race [white, black, other]), initial cardiac arrest rhythm (asystole, PEA, VF, pulseless VT), comorbidities or medical conditions present before the cardiac arrest (congestive heart failure; diabetes mellitus; renal, hepatic, or respiratory insufficiency; pneumonia; hypotension; arrhythmia; sepsis; major trauma; metabolic or electrolyte abnormality; metastatic or hematologic malignancy; pre-arrest PCPC score; baseline motor, cognitive, or functional deficits [central nervous system depression]; acute stroke; acute nonstroke neurological disorder), therapeutic interventions in place before the arrest (mechanical ventilation, antiarrhythmic drugs, vasopressors, dialysis, or extracorporeal filtration), cardiac arrest characteristics (use of ECPR, hospital location [intensive care unit, monitored, nonmonitored], time [work hours: 7 AM to 10:59 PM versus after hours: 11 PM to 6:59 AM], and day [weekday versus weekend] of cardiac arrest), and use of a hospitalwide cardiopulmonary arrest alert. Finally, because hospitals began participation in the registry at different years, we adjusted for the numerical year of hospital participation (eg, first, second) for each arrest to confirm that any observed calendar-year trend was independent of the duration of hospital participation in the registry. Statistical Analyses We evaluated changes in baseline characteristics by calendar year using Mantel-Haenszel test of trend for categorical variables and linear regression for continuous variables. To assess whether survival to discharge has improved over time, we determined risk-adjusted rates of survival for each calendar year. To accomplish this, we constructed multivariable logistic regression models using generalized estimation equations with an exchangeable correlation matrix to account for clustering of patients within hospitals. Because survival rates exceeded 10%, we estimated rate ratios (RRs) with modified Poisson regression with robust variance estimates at all steps. 14,15 Our independent variable, calendar year, was included in the model as a categorical variable, with year 2000 as the reference year. To derive risk-adjusted rates of survival, we then multiplied the adjusted RRs for each subsequent year (2001 through 2009) with the survival rate of the reference year (2000). We also evaluated calendar year as a continuous variable in the model to obtain adjusted RRs for year-over-year survival trends. Variables for model inclusion were selected on the basis of clinical and statistical criteria. All variables with a significant unadjusted association with the outcome (P<0.10) were included in the models, as well as the following variables chosen a priori regardless of statistical significance: age, sex, race, hospital location of arrest, initial cardiac arrest rhythm, and numerical year of hospital participation. Similarly, we constructed multivariable models using the approach above for the secondary end points of acute resuscitation and postresuscitation survival. We also examined whether survival trends were similar within important patient subgroups (age groups, sex, and whether initial rhythm was treatable by defibrillation or not) by including an interaction term with calendar year. Finally, we explored whether the use of ECPR was a mediator of improved survival trends over time by comparing the adjusted RRs for calendar year derived from models that included and excluded ECPR as a variable. These analyses were performed separately for overall survival, acute resuscitation survival, and postresuscitation survival. Overall rates of missing data were low, except for prearrest PCPC scores (missing in 19.8%). These data were assumed to be missing at random and were imputed by the use of multiple imputation with IVEware software. 16 Results with and without imputation were not meaningfully different, so only the former are presented. All statistical analyses were conducted with SAS version (SAS Institute, Cary, NC), IVEware (University of Michigan, Ann Arbor, MI), and R version (Free Software Foundation, Boston, MA). All tests for statistical significance were 2 tailed and were evaluated at a significance level of The Institutional Review Board at the University of Iowa waived the requirement for informed consent. Results Our study included 1031 pediatric in-hospital cardiac arrests from 12 hospitals. Of the participating hospitals, all were urban teaching hospitals with a pediatric residency or fellowship program (Table I in the online-only Data Supplement). The initial cardiac arrest rhythm was asystole or PEA in 874 children (84.8%) and VF or pulseless VT in 157 children (15.2%). Table 1 shows trends in patient characteristics over time. The proportion of cardiac arrests caused by PEA increased from 26.6% during 2000 to 2003 to 70.3% during 2007 to 2009, resulting in an overall increase in the proportion of cardiac arrests resulting from nonshockable rhythms over time (P for trend <0.001; Figure 2). The proportion of the study cohort who were newborns increased over time, whereas the proportion of children >5 years of age decreased (P for trend <0.001; Table 1). There was also a decrease over time in patients with baseline depression in neurological status, an acute nonstroke neurological event, respiratory insufficiency, and preexisting or concurrent heart failure (P for trend <0.001 for all). In contrast, the proportion of patients with an arrest in an intensive care unit, on mechanical ventilation, or receiving intravenous vasoactive agents at the time of cardiac arrest increased over time (P for trend <0.05 for all). Survival to Discharge During the study period, 359 children with in-hospital cardiac arrest (34.8%) survived to hospital discharge, with an increase in the unadjusted survival rate over time in the overall cohort (Table 2) and by initial rhythm (Table 3). After adjusting for differences in patient characteristics, we found a significant improvement in overall survival to discharge (risk-adjusted rates: 14.3% in 2000, 43.4% in 2009; adjusted RR per year, 1.08; 95% confidence interval, ; P for trend=0.02; Table 4). Temporal trends in survival were similar between age groups (<1 month, 1 month to 5 years, >5 years), as well as by sex (male versus female) and initial cardiac arrest rhythm (VF and pulseless VT versus asystole and PEA; P for all interactions >0.40; Figure 3 and Table II in the online-only Data Supplement). Notably, duration of hospital participation in the registry was not significantly associated with overall survival (P=0.36; Table III in the online-only Data Supplement). Secondary Outcomes The increase in overall survival over time was accompanied by a significant improvement in acute resuscitation survival, which increased from 42.9% in 2000 to 81.2% in 2009 (adjusted RR per year, 1.04; 95% confidence interval, ; P for trend=0.006; Table 4). Rates of postresuscitation survival similarly increased over time (Table 2), but this finding was not significant in adjusted analyses (P for trend=0.17; Table 4). Data on neurological disability were

4 4 Circ Cardiovasc Qual Outcomes January 2013 Table 1. Trends in Baseline Characteristics in Children With In-hospital Cardiac Arrest Year Groups, (%) (n=218) (n=372) (n=441) P for Trend Demographics Age groups <0.001 Infant (<1 mo) 39 (17.9) 110 (29.6) 182 (41.3) Toddler (1 mo to <5 y) 100 (45.9) 157 (42.2) 171 (38.8) Children (>5 y) 79 (36.2) 105 (28.2) 88 (20.0) Male sex 119 (54.6) 206 (55.4) 259 (58.7) 0.31 Black race 41 (21.2) 79 (23.2) 88 (23.0) 0.04 Arrest characteristics Initial cardiac arrest rhythm 0.02 Asystole 112 (51.4) 140 (37.6) 88 (20.0) Pulseless electrical activity 58 (26.6) 166 (44.6) 310 (70.3) Ventricular fibrillation 29 (13.3) 36 (9.7) 19 (4.3) Pulseless ventricular tachycardia 19 (8.7) 30 (8.1) 24 (5.4) Arrest at night (11 PM 7 AM) 70 (32.1) 116 (31.3) 131 (29.8) 0.34 Arrest on weekend 67 (30.7) 136 (36.6) 131 (29.7) 0.70 ECPR 17 (8.1) 28 (7.7) 63 (14.3) Hospital location of arrest Intensive care unit 188 (86.2) 344 (92.5) 417 (94.6) Monitored unit 10 (4.6) 10 (2.7) 12 (2.7) Nonmonitored unit 20 (9.2) 18 (4.8) 12 (2.7) PCPC category on admission (53.8) 160 (53.5) 175 (50.6) 2 22 (12.1) 33 (11.0) 36 (10.4) 3 20 (11.0) 35 (11.7) 24 (6.9) 4 42 (23.1) 71 (23.7) 111 (32.1) Hospitalwide response activated 34 (15.6) 44 (11.8) 32 (7.3) Preexisting conditions Heart failure this admission 73 (33.5) 93 (25.0) 36 (8.2) <0.001 Prior heart failure 51 (23.4) 70 (18.8) 22 (5.0) <0.001 Arrhythmia 48 (22.0) 107 (28.8) 122 (27.7) 0.22 Hypotension 90 (41.3) 188 (50.5) 220 (49.9) 0.08 Respiratory insufficiency 150 (68.8) 263 (70.7) 333 (75.5) 0.01 Renal insufficiency 30 (13.8) 50 (13.4) 47 (10.7) 0.12 Hepatic insufficiency 17 (7.8) 22 (5.9) 22 (5.0) 0.13 Metabolic or electrolyte abnormality 46 (21.1) 86 (23.1) 116 (26.3) 0.19 Diabetes mellitus 2 (0.9) 5 (1.3) 2 (0.5) 0.36 Baseline depression in CNS function 48 (22.0) 66 (17.7) 48 (10.9) <0.001 Acute stroke 3 (1.4) 9 (2.4) 5 (1.1) 0.51 Acute nonstroke CNS event 32 (14.7) 33 (8.9) 29 (6.6) Pneumonia 27 (12.4) 31 (8.3) 34 (7.7) 0.07 Septicemia 28 (12.8) 68 (18.3) 64 (14.5) 0.80 Major trauma 14 (6.4) 27 (7.3) 25 (5.7) 0.69 Metastatic or hematologic malignancy 12 (5.5) 21 (5.6) 23 (5.2) 0.35 Interventions in place before the arrest Mechanical ventilation 147 (67.4) 281 (75.5) 360 (81.6) <0.001 Intravenous antiarrhythmic therapy 10 (4.6) 23 (6.2) 29 (6.6) 0.34 Intravenous vasopressor medication 114 (52.3) 180 (48.4) 262 (59.4) 0.02 Dialysis/extracorporeal filtration 10 (4.6) 24 (6.5) 22 (5.0) 0.94 CNS indicates central nervous system; ECPR, extracorporeal membrane oxygenation during cardiopulmonary resuscitation; and PCPC, pediatric cerebral performance category. For illustrative purposes, trends in baseline characteristics are presented as 3 time periods. The P for trend is for temporal changes in patient characteristics by each calendar year.

5 Girotra et al Survival Trends in Pediatric In-hospital Cardiac Arrests 5 Figure 2. Proportion of cardiac arrests attributable to asystole or pulseless electrical activity (PEA) and ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) by calendar year. Over the past decade, the proportion of cardiac arrests treatable by defibrillation (VF and pulseless VT) has decreased (P for trend <0.001). missing in 61 survivors (17%). Although the number of survivors was small, unadjusted rates of neurological disability did not change significantly during the study period (P for trend 0.32; Table 2). Use of ECPR During acute resuscitation, ECPR was used in 108 patients (10.5%); of them, 37 (34.3%) survived to hospital discharge. The use of ECPR during resuscitation increased from 8.1% of cases in 2000 to 2003 to 14.3% in 2007 to 2009 (P for trend=0.004; Table 1). Although the use of ECPR was associated with higher acute resuscitation survival (adjusted RR, 1.22; 95% confidence interval, ; P<0.001), it was associated with lower postresuscitation survival (adjusted RR, 0.80; 95% confidence interval, ; P=0.02). Taken together, the use of ECPR was not associated with overall survival to discharge (adjusted RR, 0.96; 95% confidence interval, ; P=0.73). Moreover, inclusion of ECPR did not result in a meaningful change in the adjusted RRs for calendar year; therefore, higher ECPR use over time was not a mediator of temporal trends in overall survival, acute resuscitation survival, or postresuscitation survival (results not shown) Discussion We found that overall survival in children with an in-hospital cardiac arrest has increased nearly 3-fold during the past decade, despite an increase in cardiac arrests resulting from nonshockable rhythms. This improvement was mediated by higher rates of survival during the acute resuscitation period and was not accompanied by increased rates of significant neurological disability among survivors. Our results highlight the substantial progress that has occurred in pediatric resuscitation care in hospitals over the past decade. Table 2. Observed (Unadjusted) Rates of Survival Outcomes and Neurological Disability by Calendar Year 2000 (n=28) 2001 (n=37) 2002 (n=64) 2003 (n=89) 2004 (n=98) 2005 (n=149) 2006 (n=125) 2007 (n=154) 2008 (n=193) Survival to discharge, % (n) 14.3 (4) 24.3 (9) 34.4 (22) 30.3 (27) 29.6 (29) 23.5 (35) 44.0 (55) 41.6 (64) 39.9 (77) 39.4 (37) <0.001 Acute resuscitation survival,* % (n) 42.9 (12) 62.2 (23) 70.3 (45) 55.1 (49) 71.4 (70) 62.4 (93) 77.6 (97) 74.7 (115) 77.7 (150) 77.7 (73) <0.001 Postresuscitation survival, % (n) 33.3 (4) 39.1 (9) 48.9 (22) 55.1 (27) 41.4 (29) 37.6 (35) 56.7 (55) 55.7 (64) 51.3 (77) 50.7 (37) 0.04 Significant neurological disability, % (n/survivors) 0 (0/3) 0 (0/8) 12.5 (2/16) 17.4 (4/23) 4.4 (1/23) 12.0 (3/25) 16.0 (8/50) 13.2 (7/53) 9.2 (6/65) 21.9 (7/32) 0.32 Unadjusted rates for survival to discharge, acute resuscitation survival, postresuscitation survival, and significant neurological disability are reported for the overall cohort by calendar year. *Acute resuscitation survival was determined by the number of patients with return of spontaneous circulation for at least 20 minutes divided by the number of patients with cardiac arrest. Postresuscitation survival was determined by the number of patients with acute resuscitation survival who survived to hospital discharge divided by the number surviving the acute resuscitation. Neurological disability in survivors. Neurological disability was defined as the proportion of patients surviving to hospital discharge with a pediatric cerebral performance category (PCPC) score of >3 (ie, at least severe neurological disability). Discharge PCPC scores were missing in 17% of survivors (n=94) P for Trend

6 6 Circ Cardiovasc Qual Outcomes January 2013 Table 3. Rhythm-Specific Rates of Unadjusted Survival to Discharge by Calendar Year P for Trend Asystole, % (n/n) 20.0 (3/15) 38.1 (8/21) 21.2 (7/33) 23.3 (10/43) 20.5 (8/39) 20.6 (13/63) 47.4 (18/38) 45.0 (18/40) 31.3 (10/32) 31.3 (5/16) 0.05 PEA, % (n/n) 12.5 (1/8) 12.5 (1/8) 46.5 (6/13) 34.5 (10/29) 33.3 (13/39) 26.2 (16/61) 39.4 (26/66) 39.4 (37/94) 40.9 (61/149) 41.8 (28/67) 0.03 VF and pulseless VT, % (n/n) 0 (0/5) 0 (0/8) 50.0 (9/18) 41.2 (7/17) 40.0 (8/20) 24.0 (6/25) 52.4 (11/21) 45.0 (9/20) 50.0 (6/12) 36.4 (4/11) 0.11 Unadjusted rates for survival to discharge are reported separately for patients with asystole, pulseless electrical activity (PEA), and ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) by calendar year. To the best of our knowledge, this is the first study that has documented improved survival over time in children with an in-hospital cardiac arrest. Most of the earlier studies of pediatric in-hospital cardiac arrest were single center and retrospective in nature with only a few years of data collection, thus precluding a trend analysis. 1,2,8,9 Although indirect comparisons with studies done in the 1980s may suggest that cardiac arrest survival in hospitalized patients has improved, differences in inclusion criteria (eg, inclusion of pediatric trauma patients), definitions of cardiac arrest (eg, inclusion of patients with bradycardia), and changing patient and cardiac arrest characteristics over time make these comparisons difficult to interpret. 8,9 The larger size, scope, and high quality of data within GWTG- Resuscitation, along with its use of standardized Utstein-style definitions for variables, allowed us to perform an evaluation of survival trends in children to address an important knowledge gap in pediatric in-hospital resuscitation. We found that the marked improvement in survival was driven largely by a temporal improvement in rates of acute resuscitation survival. A number of factors may have played an important role in achieving these trends. First, clinical practice guidelines over the past decade have emphasized several aspects of the acute resuscitation survival chain. 17 These include greater vigilance and closer monitoring, which may have resulted in shorter response times. In fact, we found that over time, a higher proportion of patients were located in a monitored unit or an intensive care unit at the time of cardiac arrest, which may have allowed earlier recognition of cardiopulmonary compromise and prompt initiation of resuscitation efforts. This might also explain the temporal increase in nonshockable rhythms resulting from PEA that was observed in our study. Second, it is possible that hospital-specific quality improvement efforts may have led to improved survival over time. Initial studies suggest improved patients outcomes with the use of routine mock codes in pediatric hospitals, audiovisual feedback during resuscitation, and postevent debriefing Additional resuscitation factors such as availability of trained personnel, quality of chest compressions (eg, depth, rate) with minimal interruptions, better adherence to resuscitation algorithms, and improved coordination between code team members may have played an important role. Unfortunately, data on these aspects of resuscitation process and quality are difficult to assess accurately and are not collected within GWTG-Resuscitation, limiting our ability to examine their impact on survival. Third, although the success of ECPR in salvaging cardiac arrest patients who otherwise face imminent death because of failure of standard resuscitation efforts has been described, 7,21 we found that benefit was limited to acute resuscitation survival without a significant impact on overall survival to discharge. Furthermore, an increase in the use of ECPR did not account for the temporal trends in cardiac arrest survival in this study. It is possible that improvements in postresuscitation care have also contributed to increased survival over time in this population. Although our risk adjustment models did not detect a significant improvement in postresuscitation survival over time, these analyses were likely underpowered because only patients who survived the initial resuscitation are eligible for this analysis. An important finding of our study was the notable reduction in the proportion of cardiac arrests caused by VF and pulseless VT over time. These rhythms are Table 4. Risk-Adjusted Rates* of Survival Outcomes by Calendar Year 2000 (n=28) 2001 (n=37) 2002 (n=64) 2003 (n=89) 2004 (n=98) 2005 (n=149) 2006 (n=125) 2007 (n=154) 2008 (n=193) 2009 (n=94) Adjusted RR per 1 y (95% CI) Survival to discharge, % ( ) 0.02 Acute resuscitation survival, % ( ) Postresuscitation survival, % ( ) 0.17 CI indicates confidence interval; RR, rate ratio. *Risk-adjusted rates and adjusted RRs per year for the study outcomes of survival to discharge, acute resuscitation survival, and postresuscitation survival are reported for the overall cohort by calendar year. *Risk-adjusted rates for each calendar year were obtained by multiplying the observed rate for the reference year (2000) with the corresponding RRs for 2001 through 2009 from a model evaluating calendar year as a categorical variable. Rates are adjusted for age groups, sex, race, initial cardiac arrest rhythm, heart failure this admission, heart failure before admission, hypotension/hypoperfusion, respiratory insufficiency, baseline depression in central nervous system function, acute central nervous system nonstroke event, pneumonia, assisted/mechanical ventilation, use of vasoactive agents, use of extracorporeal membrane oxygenation during resuscitation, hospital location, use of a hospitalwide response, and years of participation in the registry. Acute resuscitation survival was determined by the number of patients with return of spontaneous circulation for at least 20 minutes divided by the number of patients with a cardiac arrest. Postresuscitation survival was determined by the number of patients with acute resuscitation survival who survived to hospital discharge divided by the number surviving the acute resuscitation. P for Trend

7 Girotra et al Survival Trends in Pediatric In-hospital Cardiac Arrests 7 Adj RR (95% CI) P for interaction Age groups 0.70 < 1 month 1.08 (1.00,1.16) 1 month - 5 years 1.08 (1.00,1.16) > 5 years 1.11 (0.97,1.26) Sex 0.44 Male 1.07 (1.00,1.15) Female 1.10 (1.02,1.18) Initial rhythm Asystole & PEA VF & Pulseless VT Overall 1.10 (1.02,1.19) 1.09 (1.00,1.19) 1.08 (1.01,1.16) 0.88 Figure 3. Temporal trends in survival in patient subgroups. Adjusted rate ratios (Adj RR) per year for survival to hospital discharge are presented by age groups (<1 month, 1 month to <5 years, >5 years), sex, and initial cardiac arrest rhythm (asystole and pulseless electri cal activity [PEA] vs ventricular fibrillation [VF] and ventricular tachycardia [VT]). 95% CI indicates 95% confidence interval more common in children with underlying cardiac disease. Although the exact mechanisms behind this changing epidemiology of cardiac arrest rhythms are not clear, it is possible that greater use of minimally invasive approaches in repair of congenital heart disease, advances in intraoperative management of children undergoing cardiac surgery with reduction of ischemia time, and better postoperative management of surgical patients have resulted in a reduction of VF and pulseless VT rhythms in this population. 22,23 At the same time, increasing severity of noncardiac illness in pediatric intensive care unit patients may have led to an increase in the proportion of cardiac arrests resulting from nonshockable rhythms, especially PEA. In our analyses, we explicitly accounted for the above temporal shifts in cardiac arrest rhythms, given that survival resulting from VF and pulseless VT rhythms is better than survival resulting from asystole and PEA arrest rhythms. 3 It may be argued that an improved temporal trend in survival simply represents a decrease in baseline risk over time. However, our data suggest a more complex picture. Although some factors that are associated with in-hospital mortality decreased over time (eg, previous and concurrent heart failure, worse baseline neurological function), other factors associated with a poor prognosis increased over time (eg, cardiac arrest caused by nonshockable rhythms, use of mechanical ventilation, and use of intravenous vasoactive agents before cardiac arrest). Importantly, we adjusted for these variables in our multivariable models to control for potential confounding. Although it is encouraging to note that in-hospital cardiac arrest survival has improved substantially over the past decade, several questions remain unanswered. First, it is unknown to what extent improved survival trends have occurred at the hospital level and whether this trend is consistent across all hospitals. Future studies are needed to examine hospital variation in survival trends. Second, the specific factors that are associated with improvements in hospital survival rates remain unknown. They may include nonstructural hospital characteristics such as timeliness and quality of resuscitation, teamwork, hospital leadership and culture, care coordination, and innovative quality improvement initiatives. Ultimately, a better understanding of practices and interventions at hospitals that achieve superior outcomes with in-hospital resuscitation will likely require a mixed-methods approach using data from detailed site interviews and quantitative surveys. Once identified, these best practices can be disseminated to all hospitals and measured to ensure that they lead to improved resuscitation outcomes. 24 Our study should be interpreted in the context of the following limitations. First, although the rich data in GWTG- Resuscitation allowed us to adjust for a number of variables in our models, the potential for residual confounding remains. Second, data on specific resuscitation variables (eg, quality of chest compressions), treatments (eg, use of hypothermia), and hospital facility characteristics (eg, number of pediatricians, quality improvement efforts) were not available, precluding an assessment of their potential impact on improved survival over time. Third, given the smaller sample size and high rates of missing data (17%), we were able to examine only unadjusted trends in rates of neurological disability. Therefore, our findings on this secondary outcome should be interpreted with caution. Fourth, the size of our study sample did not allow us to compute risk-adjusted survival by calendar year within important patient subgroups (eg, initial cardiac arrest rhythm, monitored versus nonmonitored unit). Fifth, our study was limited to in-hospital survival, and information on long-term survival and neurological function was not collected within GWTG-Resuscitation. Sixth, we were unable to calculate cardiac arrest incidence rates because of a lack of information on the pediatric admission volumes of the hospitals. As a result, we are unable to examine how cardiac arrest incidence over time relates to survival trends. Finally, although this is the largest study to examine survival trends in pediatric in-hospital cardiac arrests, our study included 12 hospitals and 1031 patients. It is possible that hospitals participating in a quality improvement registry differ from nonparticipating hospitals in important ways, limiting the generalizability of our results. Conclusion In conclusion, we found that overall survival in children with an in-hospital cardiac arrest has improved substantially over the past decade without higher rates of significant neurological disability. Future studies are needed to identify which factors are responsible for the improvements in cardiac arrest survival in children. Sources of Funding Dr Chan is supported by a Career Development Grant Award (K23HL102224) from the National Heart, Lung and Blood Institute. Dr Spertus is supported by a Clinical and Translational Science Award (1UL1RR033179). GWTG-Resuscitation is sponsored by the

8 8 Circ Cardiovasc Qual Outcomes January 2013 American Heart Association, which had no role in the study design, data analysis, or manuscript preparation and revision. None. Disclosures References 1. Suominen P, Olkkola KT, Voipio V, Korpela R, Palo R, Räsänen J. Utstein style reporting of in-hospital paediatric cardiopulmonary resuscitation. Resuscitation. 2000;45: Reis AG, Nadkarni V, Perondi MB, Grisi S, Berg RA. A prospective investigation into the epidemiology of in-hospital pediatric cardiopulmonary resuscitation using the international Utstein reporting style. Pediatrics. 2002;109: Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, Nichol G, Lane-Truitt T, Potts J, Ornato JP, Berg RA; National Registry of Cardiopulmonary Resuscitation Investigators. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295: Berg MD, Schexnayder SM, Chameides L, Terry M, Donoghue A, Hickey RW, Berg RA, Sutton RM, Hazinski MF. Part 13: pediatric basic life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(suppl 3):S862 S de Mos N, van Litsenburg RR, McCrindle B, Bohn DJ, Parshuram CS. Pediatric in-intensive-care-unit cardiac arrest: incidence, survival, and predictive factors. Crit Care Med. 2006;34: Raymond TT, Cunnyngham CB, Thompson MT, Thomas JA, Dalton HJ, Nadkarni VM; American Heart Association National Registry of CPR Investigators. Outcomes among neonates, infants, and children after extracorporeal cardiopulmonary resuscitation for refractory inhospital pediatric cardiac arrest: a report from the National Registry of Cardiopulmonary Resuscitation. Pediatr Crit Care Med. 2010;11: Thiagarajan RR, Laussen PC, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation to aid cardiopulmonary resuscitation in infants and children. Circulation. 2007;116: Gillis J, Dickson D, Rieder M, Steward D, Edmonds J. Results of inpatient pediatric resuscitation. Crit Care Med. 1986;14: Zaritsky A, Nadkarni V, Getson P, Kuehl K. CPR in children. Ann Emerg Med. 1987;16: Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, Berg RA, Nichol G, Lane-Trultt T. Cardiopulmonary resuscitation of adults in the hospital: a report of cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003;58: Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zideman D; International Liaison Committee on Resuscitation; American Heart Association; European Resuscitation Council; Australian Resuscitation Council; New Zealand Resuscitation Council; Heart and Stroke Foundation of Canada; InterAmerican Heart Foundation; Resuscitation Councils of Southern Africa; ILCOR Task Force on Cardiac Arrest and Cardiopulmonary Resuscitation Outcomes. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004;110: Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M. Relationship of pediatric overall performance category and pediatric cerebral performance category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med. 2000;28: Samson RA, Nadkarni VM, Meaney PA, Carey SM, Berg MD, Berg RA; American Heart Association National Registry of CPR Investigators. Outcomes of in-hospital ventricular fibrillation in children. N Engl J Med. 2006;354: Greenland S. Model-based estimation of relative risks and other epidemiologic measures in studies of common outcomes and in case-control studies. Am J Epidemiol. 2004;160: Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159: Raghunathan TE, Solenberger PW, Van Hoeyk J. IVEware: Imputation and Variance Estimation Software User Guide. Ann Arbor, MI: Survey Research Center, Institute for Social Research University of Michigan; Kleinman ME, Chameides L, Schexnayder SM, Samson RA, Hazinski MF, Atkins DL, Berg MD, de Caen AR, Fink EL, Freid EB, Hickey RW, Marino BS, Nadkarni VM, Proctor LT, Qureshi FA, Sartorelli K, Topjian A, van der Jagt EW, Zaritsky AL. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(suppl 3):S876 S Abella BS, Edelson DP, Kim S, Retzer E, Myklebust H, Barry AM, O Hearn N, Hoek TL, Becker LB. CPR quality improvement during in-hospital cardiac arrest using a real-time audiovisual feedback system. Resuscitation. 2007;73: Edelson DP, Litzinger B, Arora V, Walsh D, Kim S, Lauderdale DS, Vanden Hoek TL, Becker LB, Abella BS. Improving in-hospital cardiac arrest process and outcomes with performance debriefing. Arch Intern Med. 2008;168: Hunt EA, Walker AR, Shaffner DH, Miller MR, Pronovost PJ. Simulation of in-hospital pediatric medical emergencies and cardiopulmonary arrests: highlighting the importance of the first 5 minutes. Pediatrics. 2008;121:e34 e Kane DA, Thiagarajan RR, Wypij D, Scheurer MA, Fynn-Thompson F, Emani S, del Nido PJ, Betit P, Laussen PC. Rapid-response extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in children with cardiac disease. Circulation. 2010;122(suppl 11):S241 S Vida VL, Padalino MA, Motta R, Stellin G. Minimally invasive surgical options in pediatric heart surgery. Expert Rev Cardiovasc Ther. 2011;9: Bronicki RA, Chang AC. Management of the postoperative pediatric cardiac surgical patient. Crit Care Med. 2011;39: Chan PS, Nallamothu BK. Improving outcomes following in-hospital cardiac arrest: life after death. JAMA. 2012;307:

9 Survival Trends in Pediatric In-Hospital Cardiac Arrests: An Analysis From Get With The Guidelines Resuscitation Saket Girotra, John A. Spertus, Yan Li, Robert A. Berg, Vinay M. Nadkarni, Paul S. Chan and for the American Heart Association Get With the Guidelines-Resuscitation Investigators Circ Cardiovasc Qual Outcomes. published online December 18, 2012; Circulation: Cardiovascular Quality and Outcomes is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2012 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Quality and Outcomes can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation: Cardiovascular Quality and Outcomes is online at:

10 Supplemental Material Survival Trends in Pediatric In-Hospital Cardiac Arrests: An Analysis from Get With The Guidelines-Resuscitation Saket Girotra MD, SM; John A. Spertus MD, MPH; Yan Li, PhD; Robert A. Berg MD; Vinay Nadkarni MD; Paul S. Chan MD, MSc for the American Heart Association Get With the Guidelines-Resuscitation Investigators* * Besides the authors Robert A. Berg, MD, Vinay M. Nadkarni, MD, and Paul S. Chan, MD, MSc, members of the Get With The Guidelines-Resuscitation Science Advisory Board/Clinical Working Group and Pediatric Task Force include: Mary E. Mancini, RN, PhD, University of Texas at Arlington; Emilie Allen, MSN, RN, Parkland Health & Hospital System; Scott Braithwaite, MD, MSc, New York University School of Medicine; Robert Clark, MD, University of Pittsburgh Medical Center; Heidi J. Dalton, MD, Children's National Medical Center; Michael W. Donnino, MD, Beth Israel Deaconess Medical Center; Kathy Duncan, Institute for Healthcare Improvement; Brian Eigel, PhD and Lana Gent, PhD, American Heart Association; Robert T. Faillace, MD, St. Joseph's Regional Medical Center; Elizabeth A. Hunt, MD, MPH, PhD, Johns Hopkins Medicine Simulation Center; Lynda Knight, RN, Lucile Packard Children's Hospital at Stanford; Kenneth LaBresh, MD, RTI International; Peter C. Laussen, MB BS, Children's Hospital Boston; Frank W. Moler, MD, University of Michigan; Marilyn Morris, MD, The Children's Hospital of New York; Graham Nichol, MD, MPH, University of Washington-Harborview Medical Center; Joseph P. Ornato, MD and Mary Ann Peberdy, MD, Virginia Commonwealth University Health System; Chris Parshuram, MD, The Hospital for Sick Children; Comilla Sasson, MD, MS, University of Colorado; Mindy Smyth, MSN, RN; and Arno L. Zaritsky, MD, Children's Hospital of the King's Daughters.

11 Supplemental Table 1 Characteristics of Study Hospitals Characteristic N=12 Geographic Region Northeast 2 (16.7%) Southeast 4 (33.3%) Midwest 1 (8.3%) Southwest 2 (16.7%) West 3 (25.0%) Location Urban 12 (100%) Ownership Government 3 (25.0%) Non-profit 9 (75.0%) Hospital Bed Size (58.3%) > (41.7%) Academic Status Hospital with pediatric fellowship program 9 (75%) l Hospital with pediatric residency program 3 (25%) Non-teaching hospital 0

12 Supplemental Table 2. Age-Group Specific Rates of Adjusted Survival to Discharge by Calendar Year. Adjusted rates for survival to discharge are reported separately for patients aged less than 1 month, 1 month to less than 5 years, and 5 years or more by calendar year P for Trend < 1 month month to < 5 years > 5 years

13 Supplemental Table 3. Independent Predictors of Survival to Hospital Discharge. Adjusted risk ratio, 95% confidence intervals and P values are provided for all model covariates included in the multivariable model for survival to discharge in the overall cohort. Variable Risk Ratio 95% CI P value Calendar Year 2000 Referent , , 4.41 < , , , , 5.81 < , , , Age (per 1-year) Infant (< 1 month) Referent Toddler (1 month to <5 years) , Children (> 5 years) , Sex (Male vs. Female) , Race White Referent Black , Other , Initial Cardiac Arrest Rhythm Asystole Referent PEA , VF , Pulseless VT , 2.15 < 0.001