Skip main navigation

Epidemiology and Outcomes of Acute Decompensated Heart Failure in Children

Originally publishedhttps://doi.org/10.1161/CIRCHEARTFAILURE.119.006101Circulation: Heart Failure. 2020;13:e006101

Abstract

Background:

Acute decompensated heart failure (ADHF) is a highly morbid condition among adults. Little is known about outcomes in children with ADHF. We analyzed the Pediatric Cardiac Critical Care Consortium registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF.

Methods:

Cardiac intensive care unit (CICU) patients ≤18 years of age meeting Pediatric Cardiac Critical Care Consortium criteria for ADHF were included. ADHF was defined as systolic or diastolic dysfunction requiring continuous vasoactive or diuretic infusion, respiratory support, or mechanical circulatory support. Demographics, diagnosis, therapies, complications, and mortality are described for the cohort. Predictors of CICU mortality were identified using logistic regression.

Results:

Among 26 294 consecutive admissions (23 centers), 1494 (6%) met criteria for analysis. Median age was 0.93 years (interquartile range, 0.1–9.3 years). Patients with congenital heart disease (CHD) comprised 57% of the cohort. Common therapies included the following: vasoactive infusions (88%), central venous catheters (86%), mechanical ventilation (59%), and high flow nasal cannula (46%). Common complications were arrhythmias (19%), cardiac arrest (10%), sepsis (7%), and acute renal failure requiring dialysis (3%). Median length of CICU stay was 7.9 days (interquartile range, 3–18 days) and the CICU readmission rate was 22%. Overall, CICU mortality was 15% although higher for patients with CHD versus non-CHD (19% versus 11%; P<0.001). Independent risk factors associated with CICU mortality included age <30 days, CHD, vasoactive infusions, ventricular tachycardia, mechanical ventilation, sepsis, pulmonary hypertension, extracorporeal membrane oxygenation, and cardiac arrest.

Conclusions:

ADHF in children is characterized by comorbidities, high mortality rates, and frequent readmission, especially among patients with CHD. Opportunities exist to determine best practices around appropriate use of mechanical support, cardiac arrest prevention, and optimal heart transplantation candidacy to improve outcomes for these patients.

WHAT IS NEW?

  • In this report from Pediatric Cardiac Critical Care Consortium registry, acute decompensated heart failure (ADHF) accounted for 6% of all admission to a pediatric cardiac intensive care unit.

  • Compared with adults, ADHF in children is characterized by higher acuity, including higher rates of ICU mortality (16%), ICU readmission (22%), mechanical ventilation (59%), and CPR (10%).

  • Congenital heart disease is diagnosed in more than half of children hospitalized with ADHF and is strongly associated with mortality.

  • Vasoactive therapies, such as milrinone and epinephrine infusions, are commonly prescribed, though their administration varies widely across centers in the Pediatric Cardiac Critical Care Consortium.

WHAT ARE THE CLINICAL IMPLICATIONS?

  • Data from the Pediatric Cardiac Critical Care Consortium registry provide a contemporary characterization of ADHF along with significant evidence of variability in both management and outcomes for pediatric patients admitted to ICU with ADHF.

  • This analysis identifies opportunities for improved treatment strategies of ADHF across participating centers by shedding light on risk factors for morbidity, readmissions, and mortality.

Introduction

See Editorial by Hsu

Acute decompensated heart failure (ADHF) is a final common pathway for children with congenital and/or acquired heart disease, usually resulting in admission to a cardiovascular intensive care unit (CICU) for specialized care with high risk for cardiac arrest and death.1,2 Multiple reports in adults have described the clinical characteristics and outcomes of ADHF, but our understanding of ADHF in children remains limited due to the heterogeneous nature of pediatric cardiovascular illnesses.2–11 Children may present with failed palliation of congenital/ structural heart disease (congenital heart disease [CHD]), acquired cardiomyopathies, or acute exacerbations of chronic heart failure from abnormal circulations (eg, Fontan circulation for functional single ventricle).12–14 Previous studies in children suggest that the frequency of hospitalization for ADHF may be increasing and that inpatient outcomes for ADHF are poor.2,15,16 Those data have been confounded, however, by reliance on reviews of administrative databases or by a focus on one particular etiology of heart failure (eg, cardiomyopathy) to the exclusion of others.

Consequently, a gap exists in our understanding of the demographics, treatment strategies, complications, and outcomes for children with a broad array of etiologies for ADHF. More specifically, providers seek a basic understanding of risk factors for mortality while searching for best practices among a range of centers and practice variability. Describing the epidemiology of ADHF in children and identifying risk factors for death will add to our current knowledge of this complex cohort while motivating quality improvement strategies to achieve better clinical outcomes.

In this context, we conducted an analysis of pediatric CICU admissions to define the epidemiology of critical ADHF and to determine risk factors for mortality in a multicenter North American clinical registry dedicated to this patient population (Pediatric Cardiac Critical Care Consortium [PC4]). We hypothesized that morbidity and mortality rates are high in children with ADHF admitted to the CICU and that patients with preexisting CHD are at the greatest risk of poor outcomes.

Methods

Study Design and Cohort

The PC4 is a quality improvement collaborative that collects data on all patients with primary cardiac disease admitted to the CICU service of participating hospitals.17 PC4 maintains a clinical registry to support research and quality improvement initiatives. At the time of this analysis, 23 centers were submitting cases to the PC4 Registry.

Each participating center has a trained data manager who has completed a certification exam. The data managers collect and enter data in accordance with the standardized PC4 Data Definitions Manual. The PC4 registry shares common terminology and definitions with applicable data points from the International Pediatric and Congenital Cardiac Code, Society of Thoracic Surgeons Congenital Heart Surgery Database, and American College of Cardiology Improving Pediatric and Adult Congenital Treatment Registry, as previously described.17 Participating centers are audited on a regular schedule and audit results suggest complete, accurate, and timely submission of data across centers, with the most recent published results demonstrating a major discrepancy rate of 0.6% across 29 476 fields.18 Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the PC4 Data Coordinating Center at [email protected].

The University of Michigan Institutional Review Board provides oversight for the PC4 Data Coordinating Center; this study was reviewed and approved with waiver of informed consent.

Definitions and Patient Selection

Patients ≤18 years of age admitted to CICUs at participating PC4 centers between August 2014 and April 2017 were included in this analysis if ADHF was identified at the time of admission to the CICU, either as the primary diagnosis or a concurrent comorbidity. The PC4 definition of ADHF, established by a consensus panel of physicians and nurses within the collaborative, was utilized for this analysis: the presence of documented systolic and/or diastolic ventricular dysfunction and receipt of at least one of the following critical care therapies: (1) continuous infusion of a vasoactive and/or diuretic agent, (2) respiratory support including mechanical ventilation as well as noninvasive high flow nasal cannula, continuous positive airway pressure, or bilevel positive airway pressure, or (3) any form of mechanical circulatory support during the CICU admission. Participating PC4 institution data collection teams were made up of clinical data abstractors as well as clinical champions (CICU physicians) who collaborated to ensure accurate interpretation of electronic medical records, including noninvasive imaging reports. Additional PC4 definitions of clinical conditions and complications utilized in this analysis can be found in Table I in the Data Supplement.

Cardiac diagnoses and operative procedures are defined according to the International Pediatric and Congenital Cardiac Code.19 The ADHF population was stratified by presence of underlying CHD versus lack of CHD (ie, structurally normal heart) and/or those having undergone prior heart transplantation, regardless of history of CHD before transplantation. Patients with ADHF with structurally normal hearts were grouped together with those having undergone prior heart transplantation. Patients undergoing any cardiothoracic surgical procedure during the ADHF CICU encounter, including extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD) placement, and/or heart transplantation, were also included. Therefore, patients with CHD were included if they met criteria for ADHF at the time of admission, whether or not they subsequently had cardiothoracic surgery in the same admission. CICU admissions were excluded from analysis if the patient presented with hospice care/do-not-resuscitate orders.

Twenty-three centers participating in the PC4 registry at the time of analysis had submitted qualifying cases. Both hospital-level and CICU admission-level descriptive analyses were performed with all inferential analyses utilizing the CICU admission as the episode of analysis.

Outcomes

Patient demographics (age, sex), presence of extracardiac abnormalities or chromosomal abnormalities/syndromes, weight at CICU admission, CICU resource utilization (mechanical ventilation, pharmacotherapies, arterial/venous access), CICU complications including cardiac arrest, and use of ECMO rescue during active CPR (E-CPR) were chosen a priori as potential factors associated with mortality in the ADHF population. Mortality in the CICU environment is described for the cohort as well as among the CHD and non-CHD groups of patients with ADHF.

Statistical Analysis

Data are presented as frequency (percentage) for categorical variables and median with interquartile range for continuous variables. To identify patient and clinical characteristics associated with CICU mortality, univariate comparisons were performed using the Wilcoxon rank-sum test for continuous variables, and χ2 or Fisher exact test as appropriate for categorical data.

Depictions of variability in mortality across PC4 centers are not annualized as centers contributed data to the registry at different time points during the study era. Raw (observed) mortality rates are presented as percentages. Several variables identified a priori as possible predictors of mortality were subsequently excluded from the final model.

To better understand predictors of mortality, we performed a stratified univariate analysis dividing the cohort into patients who underwent a cardiothoracic surgical procedure during their ADHF admission (N=310) versus those who did not (N=1184). Only nonsurgical ADHF admissions were subsequently included in our multivariate analysis of mortality for 2 reasons: (1) key differences in variables collected between surgical and nonsurgical patients made combining them in one model potentially misleading and (2) the small sample size of the surgical cohort limited additional multivariable analysis in this subgroup. Factors associated with CICU mortality among nonsurgical patients in unadjusted analysis (P<0.1) were included in a multivariable logistic regression model to determine independent associations (P<0.05) with mortality. We also tested models including laboratory values such as B-type natriuretic protein and creatinine, but there was a high percentage of missing values as these studies were not obtained on all patients at the time of admission. We evaluated missingness and found no difference in the distribution of missing data between patients who died and those survived. Addition of laboratory values (actual and predicted) did not improve model performance and resulted in larger standard errors for the coefficients, so we excluded laboratory variables from our final multivariable analysis. These results are not presented further.

Adjusted odds ratios and 95% CI for each predictor are reported. We ran the model accounting for clustering at the hospital-level using a hospital random-effect term. We also evaluated the model adding a random-effect term at the patient-level to account for multiple CICU admissions by the same patient.

We could not perform stratified multivariable analyses in the 2 disease subgroups (CHD and non-CHD + status posttransplant) due to sample size constraints. Therefore, to explore the impact of disease heterogeneity on predictors of mortality, we performed a second multivariable analysis and tested interactions with CHD. Key-independent variables associated with mortality in the initial model (age and exposure to mechanical ventilation, vasoactive infusions, and ECMO) were included with diagnosis as interaction terms to test whether they differentially impacted the effect of diagnosis on mortality. All analyses were performed using SAS Version 9.4 (SAS Institute, Cary, NC) or STATA Version 14 (StataCorp LLC, TX), with statistical significance at a P value <0.05.

Results

Patient Characteristics

Between August 1, 2014 and April 4, 2017, a total of 26 294 CICU admissions were submitted to the PC4 collaborative by 23 participant centers. Of these CICU admissions, 1494 unique ADHF admissions (1371 hospitalizations) were identified (Figure 1). Table 1 displays demographic, clinical, and laboratory characteristics at the time of CICU admission for the entire cohort as well as CHD and non-CHD subgroups. Patients with underlying CHD comprised 57% (N=852) of admissions. The median age at presentation for ADHF was 0.93 years (interquartile range [IQR], 0.1–9.3 years), and patients with CHD were significantly younger than patients without CHD. Patients with ADHF and CHD had significantly lower weight at CICU admission and were more likely to have extracardiac congenital anomalies, chromosomal abnormalities, and/or known syndromes when compared with patients without CHD. Only 4% of patients (58/1494) had undergone a previous cardiothoracic surgical procedure during the same hospitalization and among patients with prior heart transplantation presenting in ADHF, 80% (32/40) were identified as having rejection at the time of admission.

Table 1. Clinical Characteristics of Patients Admitted to CICUs With Acute Decompensated Heart Failure

All ADHF Encounters, n (%)CHD, n (%)Non-CHD, n (%)P Value
CICU encounters1494 (100)852 (57)642 (43)
Age, years (median, IQR)0.93 (0.1–9.3)0.37 (0.1–2.7)5.02 (0.4–13.8)<0.001
Neonate (<30 d)311 (21)219 (26)92 (14)<0.001
Infant (30 d to <1 y)443 (30)323 (38)120 (19)
Child (1 to <18 y)740 (49)310 (36)430 (67)
Weight at CICU admission, kg8 (3.9–26)5.3 (3.5–11.7)17.7 (6–51.5)<0.001
Male sex814 (55)476 (56)338 (53)0.22
Race<0.001
 White900 (60)547 (64)353 (55)
 Black337 (23)163 (19)174 (27)
 Asian49 (3)31 (4)18 (3)
 Native American6 (<1)3 (<1)3 (<1)
 Native Pacific Islander2 (<1)1 (<1)1 (<1)
 Other/multiracial148 (10)84 (10)64 (10)
 Unknown52 (3)23 (3)29 (5)
Preexisting high-risk diagnoses (n=1184)376 (32)191 (33)185 (31)0.51
 Arrhythmia41 (3)11 (2)30 (5)<0.001
 CPR reason for admit50 (4)28 (5)22 (4)0.34
 Pulmonary hypertension68 (6)44 (8)24 (4)0.009
 Heart transplant rejection32 (3)0 (0)32 (5)<0.001
 Cardiomyopathy461 (39)66 (11)395 (66)0.003
 Myocarditis100 (8)6 (1)94 (16)<0.001
Extracardiac anomalies210 (14)159 (19)51 (8)<0.001
Chromosomal abnormality122 (8)115 (14)7 (1)<0.001
Syndrome(s)240 (16)209 (24)31 (5)<0.001
Tracheostomy present16 (1)13 (2)3 (<1)0.05
Primary insurance type0.08
 Public853 (57)497 (58)356 (55)
 Private555 (37)307 (36)248 (39)
 Non-US insurance8 (1)1 (<1)7 (1)
 None/self27 (2)15 (2)12 (2)
 Unknown51 (3)32 (4)19 (3)
Source of CICU admission0.99
 Home39 (3)22 (3)17 (3)
 Current hospital919 (62)525 (62)394 (61)
 Outside hospital536 (36)305 (36)231 (36)

ADHF indicates acute decompensated heart failure; CHD, congenital heart disease; CICU, cardiac intensive care unit; and CPR, cardiopulmonary resuscitation.

Figure 1.

Figure 1. Patient selection flow sheet. ADHF indicates acute decompensated heart failure; and CICU, cardiac intensive care unit.

Critical Care Resource Utilization and Complications

Therapies, procedures, and complications in the CICU are displayed in Table 2. Nearly 60% of ADHF admissions included invasive mechanical ventilation, for a median duration of 5.2 days (IQR, 2–13 days). Patients with CHD were more likely to receive mechanical ventilation and had higher rates of reintubation within 48 hours of planned extubation when compared with their non-CHD counterparts. Table II in the Data Supplement displays the spectrum of vasoactive/inotropic medications used in the care of patients with ADHF. Milrinone was the most commonly administered vasoactive agent (80% of admissions). Patients without CHD were treated with milrinone more frequently than their CHD counterparts while patients with CHD were exposed to more calcium and vasopressin infusions than patients without CHD. The frequency of vasoactive medication prescription varied considerably between individual centers. Milrinone had the highest rate of utilization during ADHF admissions among sites, ranging from 60% to 100% of ADHF admissions across the consortium (Table III in the Data Supplement).

Table 2. Therapies, Procedures, and Complications During CICU Admissions for Acute Decompensated Heart Failure

All ADHF Encounters n=1494 (%)CHD n=852 (%)Non-CHD n=642 (%)P Value
CICU encounters1494 (100)852 (57)642 (43)
Respiratory support
 Mechanical ventilation876 (59)553 (65)323 (50)<0.001
 Total mechanical ventilation duration, d; median (IQR)5.2 (2–13)5.3 (2–13)5.2 (2–13)0.68
 Reintubation (within 48 h after planned extubation)80 (9)60 (11)20 (6)0.021
 Positive airway pressure (CPAP/BiPAP)381 (26)244 (29)137 (21)0.001
 High-flow nasal cannula682 (46)454 (53)228 (35)<0.001
 Inhaled nitric oxide use286 (19)176 (21)110 (17)0.09
Critical care resources
 Central venous line during CICU encounter1284 (86)719 (84)565 (88)0.047
 Arterial line841 (56)508 (60)333 (52)0.003
 Foley catheter700 (47)424 (50)276 (43)0.009
 VIS (peak within 2 h of admission)5 (5–10)5 (5–10)5 (3.8–10)0.24
Complications
 Arrhythmia291 (19)153 (18)138 (22)0.09
 Stroke69 (5)39 (5)30 (5)0.93
 Intracranial hemorrhage44 (3)24 (3)20 (3)0.74
 Seizure50 (3)31 (4)19 (3)0.47
 Continuous renal replacement therapy for acute renal failure50 (3)27 (3)23 (4)0.66
 Pneumonia52 (3)31 (4)21 (3)0.70
 Central line-associated bloodstream infection43 (3)32 (4)11 (2)0.019
 Sepsis98 (7)59 (7)39 (6)0.51
 Urinary tract infection51 (3)32 (4)19 (3)0.40
 Hepatic failure52 (3)33 (4)19 (3)0.34
 Ventricular tachycardia120 (8)42 (5)78 (12)<0.001
 Cardiac arrest during CICU encounter152 (10)97 (11)55 (9)0.08
 E-CPR (% of cardiac arrest)53 (35)29 (30)24 (44)0.09
 Cardiac arrest time, min (IQR)20 (4–44)20 (4–40)21 (6–52)0.36
Mechanical circulatory support
 ECMO173 (12)84 (10)89 (14)0.017
 ECMO length of support, d5.6 (3.1–10.1)5.3 (3.1–9.8)5.6 (3.1–10.1)0.89
 VAD placement65 (4)14 (2)51 (8)<0.001
Listed for heart transplantation159 (11)76 (9)83 (13)0.013
Any cardiothoracic surgery during the CICU encounter310 (21)267 (31)43 (7)<0.001
 Heart transplantation66 (22)38 (14)28 (65)<0.001

ARDS indicates acute respiratory distress syndrome; BiPAP, bilevel positive airway pressure; CICU, cardiac intensive care unit; CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; E-CPR, extracorporeal cardiopulmonary resuscitation; PICC, peripherally inserted central catheter; VAD, ventricular assist device; and VIS, Vasoactive-Inotropic Score.20

The median length of CICU stay for all ADHF admissions was 7.9 days (IQR, 3.0–18.1 days, Table 3). Length of CICU stay was significantly longer for patients with CHD than patients without CHD (8.4 days [IQR, 3.2–18.9] versus 6.8 days [IQR, 3.0–17.5]; P=0.027). No difference in ICU readmission rates was appreciated between the 2 groups (179/852 [23%] CHD versus 122/642 [21%] non-CHD; P=0.43), although 22% of ADHF admissions were classified as an unplanned readmission to the CICU within 48 hours of previous discharge (N=301). Readmission to the hospital within 30 days (all-cause hospital readmission) was noted in 11% (N=147) of patients with ADHF with a higher readmission rate seen in the CHD cohort.

Table 3. Mortality and Disposition Outcomes

All ADHF Encounters n=1494 (%)CHD n=852 (%)Non-CHD n=642 (%)OR/IRR*OR/IRR* 95% CIP Value
Length of CICU stay, days; median (IQR)7.9 (3.0–18.1)8.4 (3.2–18.9)6.8 (3.0–17.5)1.261.12–1.42<0.001
CICU mortality231 (15)159 (19)72 (11)1.821.35–2.45<0.001
 Withdrawal of life-sustaining therapy167 (72)111 (70)56 (78)0.660.34–1.270.21
 Length of ICU stay, days (IQR; nonsurvivors)9.4 (3.4–25.2)9.1 (2.9–26.7)10.4 (4.3–21.6)1.120.79–1.580.53
VAD or ECMO222 (15)95 (11)127 (20)0.510.38–0.68<0.001
 CICU mortality95 (43)56 (59)39 (31)3.241.86–5.65<0.001
Brain death7 (<1)1 (<1)6 (1)0.120.01–1.040.05
Readmission to CICU during hospitalization301 (22)179 (23)122 (21)1.110.86–1.440.43
All-cause readmission within 30 days of hospital discharge147 (11)96 (12)51 (9)1.451.01–2.070.043

ADHF indicates acute decompensated heart failure; CHD, congenital heart disease; CICU, cardiac intensive care unit; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; IRR, incidence rate ratio; OR, odds ratio; and VAD, ventricular assist device.

*Unadjusted.

†Incidence rate ratio.

Complication rates are also displayed in Table 2. The most common complication was arrhythmia treated with pharmacological therapy and/or cardioversion/defibrillation. Of all complications, only central line-associated blood stream infection was significantly greater among patients with CHD in comparison to the non-CHD cohort. Stroke was observed in 69 (5%) ADHF CICU encounters. Of these encounters, 35 (50%) were in patients undergoing mechanical circulatory support via VAD and/or ECMO (VAD only 9/35 [26%], ECMO only 22/35 [63%], VAD, and ECMO 4/35 [11%]).

The most severe morbidity, cardiac arrest, occurred in 10% of ADHF admissions (N=152). No differences were noted between CHD and non-CHD subgroups for cardiac arrest incidence nor for cardiac arrest duration. E-CPR was utilized in over a third of cardiac arrests (35%, N=53/152).

Disparate utilization rates were noted between ECMO and VAD. While ECMO was utilized in 12% of the overall cohort (N=173), only 4% (N=65) underwent VAD implantation during the CICU admission. Of the 65 ADHF admissions in which a VAD was implanted, 24 (36.9%) also underwent heart transplantation during the same hospitalization. Patients without CHD were more likely to be both listed for heart transplantation (83/642 [13%] versus 76/852 [9%]; P=0.013) and undergo heart transplantation during the same hospitalization. ECMO support and VAD implantation were also more commonly used by patients without CHD than their CHD counterparts (ECMO 89/642 [14%] versus 84/852 [10%]; P=0.017 and VAD 51/642 [8%] versus 14/852 [2%]; P<0.001).

Mortality and Associated Risk Factors

The CICU mortality rate for the overall ADHF cohort was 15% (N=231). Variation in mortality across the participating PC4 centers is displayed in Figure 2. Mortality in the CICU ranges from 0% (single center with n=6 total admissions entered into PC4 at the time of data abstraction) to as high as 25% of CICU admissions per center. In contrast to CICU-level outcomes, hospitalization-level morbidity and mortality are described in Table IV in the Data Supplement. Hospital mortality reached 19% for the overall ADHF cohort and similar to CICU mortality rates was much higher for patients with CHD.

Figure 2.

Figure 2. Variation in cardiac intensive care unit (CICU) mortality across participating Pediatric Cardiac Critical Care Consortium centers. ADHF indicates acute decompensated heart failure.

We evaluated the association of patient characteristics, coexisting high-risk diagnoses, therapies received, and complications with CICU mortality solely in patients who did not undergo cardiothoracic surgical procedures during their CICU admission (n=1184; Table 4). Presence of CHD, extracardiac anomalies, neonatal age at presentation, preexisting high-risk diagnoses (CPR as reason for admission; any cardiomyopathy including dilated, hypertrophic, and restrictive; pulmonary hypertension), peak vasoactive inotrope score within 2 hours of admission, mechanical ventilation, ECMO, and key complications were some of the important univariate risk factors for CICU mortality.

Table 4. Associations With CICU Mortality in Acute Decompensated Heart Failure Admissions Who Did Not Undergo Cardiothoracic Surgical Procedures

All ADHF Encounters (n=1184)CICU Encounter MortalityP Value
Yes (n=200)No (n=984)
Congenital heart disease
 Yes585 (49)130 (65)455 (46)<0.001
 No599 (51)70 (35)529 (54)
Male sex657 (55)123 (62)534 (54)0.06
Extracardiac anomalies164 (14)39 (20)125 (13)0.01
Chromosomal abnormality and/or syndrome(s)189 (16)38 (19)151 (15)0.19
Neonate (<30 d)193 (16)63 (32)130 (13)<0.001
Infant (30 d to <1 y)326 (28)51 (26)275 (28)
Child (1 to <18 y)665 (56)86 (43)579 (59)
Race
 White, non-Hispanic516 (44)87 (44)429 (44)0.95
 Hispanic, any race247 (21)39 (20)208 (21)
 Black, non-Hispanic271 (23)48 (24)223 (23)
 All other races, non-Hispanic150 (13)26 (13)124 (13)
Preexisting high-risk diagnoses
 Arrhythmia41 (4)9 (5)32 (3)0.38
 CPR reason for admit50 (4)25 (13)25 (3)<0.001
 Pulmonary hypertension68 (6)22 (11)46 (5)<0.001
 Heart transplant rejection31 (3)6 (3)25 (3)0.71
 Cardiomyopathy461 (39)60 (30)401 (41)0.005
 Myocarditis100 (8)9 (5)91 (9)0.03
Any vasoactive/inotrope infusion1009 (85)193 (97)816 (83)<0.001
Vasoactive/inotrope infusion within 2 h of CICU admission747 (63)131 (65.50)616 (63)0.44
VIS (peak, within 2 h of CICU admission)5 (5–10)7.5 (5–12)5 (5–8)<0.001
VIS categories
 >7.5225 (19)63 (32)162 (16)<0.001
 <7.5, >2.5496 (42)62 (31)434 (44)
 <2.5463 (39)75 (38)388 (39)
Mechanical ventilation573 (48)188 (94)385 (39)<0.001
 Mechanical ventilation, duration, h; median (IQR); n=573113 (40–260)134 (40–393)105 (41–224)0.05
VAD placement42 (4)6 (3)36 (4)0.65
ECMO20 (10)68 (34)52 (5)<0.001
Complications
 Sepsis77 (7)31 (16)46 (5)<0.001
 Hepatic failure36 (3)29 (15)7 (1)<0.001
 CRRT for acute renal failure37 (3)21 (11)16 (2)<0.001
 Stroke50 (4)20 (10)30 (3)<0.001
 Ventricular tachycardia94 (8)41 (21)53 (5)<0.001
 Cardiac arrest during ICU encounter117 (10)81 (41)36 (4)<0.001
  E-CPR (% of cardiac arrest)38 (32)26 (32)12 (33)0.89
  Cardiac arrest time (min; median, IQR)21 (4–48)30 (13–49)5 (1–24)<0.001

CICU indicates cardiac intensive care unit; CPR, cardiopulmonary resuscitation; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; E-CPR, extracorporeal cardiopulmonary resuscitation; VAD, ventricular assist device; and VIS, Vasoactive-Inotropic Score.20

Although a smaller cohort, patients who underwent cardiothoracic surgical procedures (N=310) during ADHF admissions were analyzed for univariate associations with mortality with results presented as Table V in the Data Supplement. Heart transplants were performed for a total of 66 admissions. Overall mortality was 10% and of those who died, 2 (6%) had undergone transplantation during CICU admission. Cardiac arrest occurred in 11% of encounters with ECPR utilized in 43% of arrests.

Several factors persisted as independent risk factors for CICU mortality for the larger cohort of nonsurgical patients after multivariable logistic regression (Table 5). Independent risk factors associated with CICU mortality included age <30 days, presence of CHD, any use of vasoactive infusion, ventricular tachycardia, mechanical ventilation, sepsis, pulmonary hypertension, use of ECMO, and cardiac arrest. When classified by CPR duration categories, admissions experiencing cardiac arrest of >20 minutes duration were found to have higher odds of CICU mortality than cardiac arrest of <20 minutes and all other variables included in the multivariate model.

Table 5. Multivariate Logistic Regression Model of Risk Factors Associated With CICU Mortality in Acute Decompensated Heart Failure Admissions

Risk FactorOdds RatioZ-Score95% CIP Value
Cardiac arrest during ICU admission
 <20-min duration4.364.812.4–7.9<0.001
 >20-min duration20.305.166.5–63.4<0.001
Hepatic failure13.054.784.6–37.4<0.001
Mechanical ventilation7.414.773.3–16.9<0.001
Neonate, <30 d (reference group: >1 to <18 y)3.654.032.0–6.9<0.001
CHD (reference group: non-CHD/transplant)3.474.582.0–5.9<0.001
ECMO2.964.071.8–5.0<0.001
Use of any vasoactive therapy2.933.201.5–5.70.001
Ventricular tachycardia2.602.181.1–6.10.029
Pulmonary hypertension2.082.391.1–3.80.017
Sepsis1.632.041.0–2.60.042
Myocarditis0.22−2.270.1–0.80.023

CHD indicates congenital heart disease; CICU, cardiac intensive care unit; and ECMO, extracorporeal membrane oxygenation.

In our exploratory model to test interactions between CHD, age, vasoactive infusions, mechanical ventilation, and ECMO, only the interaction between age and CHD was statistically significant (P=0.002). Although all age groups interacted with CHD to increase the risk of mortality compared with non-CHD, the strongest effect was the interaction between CHD and neonates; neonates with CHD and ADHF had a 16-fold greater odds of mortality than the reference group (children >1 year old, no CHD; adjusted OR 16.2 [95% CI, 7.2–36.4], P<0.001; Table VI in the Data Supplement).

Discussion

This large, multicenter study represents the first analysis of ADHF in a prospective observational cohort of critically ill children. Our study showed that ADHF occurred in 6% of all CICU admissions and that nearly 1 in 5 ADHF-related hospitalizations resulted in death. Congenital heart disease was present in over half of those hospitalized with ADHF and was associated with greater resource utilization, higher complication rates, longer length of stay, increased likelihood of readmission, and poorer survival when compared with children without CHD. Important additional risk factors associated with death include age <1 year, need for mechanical ventilation, vasoactive infusion exposure, ECMO, cardiac arrest, ventricular tachycardia, co-existing pulmonary hypertension, and hepatic failure.

One of the important observations from this analysis is the negative impact of CHD on outcomes in children with ADHF. This highly comorbid patient population (younger age at presentation, frequent extracardiac anomalies, and genetic syndromes) not only suffered greater morbidity and mortality compared with their counterparts without CHD, but they were also less likely to receive potentially life-saving therapies such as ECMO, VAD, and cardiac transplantation. This may be due in part to their younger age and smaller size at the time of hospitalization but also due to the heterogenous anatomic and pathophysiological features of CHD, which may complicate or preclude mechanical circulatory support in this group. Possibly recognizing a disparity, the Organ Procurement and Transplantation Network recently revised its listing criteria for children awaiting cardiac transplantation, giving waitlist priority to children with CHD. Advances in technology may soon bring new treatment options for this population, especially if further miniaturization of mechanical circulatory support devices proves feasible.21–24 In the interim, this study provides further evidence for risk stratification and anticipatory management of patients with CHD with ADHF.

Another important observation from this study is the difference between adult and pediatric hospitalizations for ADHF. Our data showed that children with ADHF are more acutely ill than has been described in adults, with greater use of vasoactive infusions and mechanical ventilation, longer lengths of stay, and higher mortality rates.9,11,15,25,26 Although the definitive clinical features of HF are present in both adults and children (ie, ventricular dysfunction, fluid retention, neurohormonal activation), the manifestations of ADHF and presentation seem to be different. Although adults with ADHF may present in cardiogenic shock, they are more likely to present with features of congestion and fluid overload, requiring treatment with diuretics, rather than with features of a low cardiac output state or respiratory failure necessitating the addition of vasoactive medications or mechanical ventilation.27 Children in the PC4 cohort were at high risk of respiratory failure requiring mechanical ventilation and utilized vasoactive medications at high rates.

Indeed, inotropic medications are utilized in 14% to 53% of adults hospitalized in an ICU for ADHF,6,9,27 while the children in our study were treated with inotropes much more frequently (up to 88%). In fact, at least one of the PC4 sites administered milrinone in 100% of patients with ADHF. Such routine use of inotropes was not completely unexpected. Although the definition of ADHF includes the potential treatment with vasoactive agents, prior studies in children hospitalized with advanced heart failure have reported similarly high rates of inotrope use.2,3,28 Notwithstanding the acuity of illness, such extensive use of inotropes is curious given the known adverse effects and mortality risks associated with their use in adults. This common management may represent a dearth of evidence-based treatment options in pediatric ADHF.

The higher mortality rate in children with ADHF reinforces the differences with adults.8,26,29 In our study, hospital-wide and CICU-specific mortality rates were 19% and 15%, respectively, compared with reports of 4% to 9% all-cause 30-day mortality in adults with acute HF syndromes admitted to higher acuity units.5,6,10,15,25,27,30 Separate studies in children with advanced HF have reported lower mortality rates but always in cohorts that encompassed ICU and non-ICU locations and excluded patients with CHD.2,12,15,16 Few adults who are hospitalized for ADHF have CHD as its etiology and, unlike children, about half of adults with ADHF have preserved ventricular systolic function, which is less likely to require an ICU admission. Hence, these patients have low mortality rates and shorter ICU and hospital stays.25

Wide variability in CICU mortality across the collaborative was also noted, ranging from 0% to 25% across centers, although not risk-adjusted for patient complexity or referral center for transplant-center status. Several factors may contribute to this mortality including case-mix variability and institutional volume. We speculate that institutional volume may contribute to variability in mortality, particularly for centers that perform cardiac transplantation. Cardiac arrest occurred in a minority of patients with ADHF admitted to the CICU (10%), but the event was strongly associated with death, regardless of whether or not the patients had CHD. This incidence of cardiac arrest in CICU patients with ADHF is higher than reported for all CICU patients in the PC4 registry.31 Previously identified risk factors for cardiac arrest in the pediatric population such as underlying cardiovascular disease and younger age were highly prevalent in our cohort of patients with ADHF.32,33

Readmission to the CICU during hospitalization was common in this cohort (22%). Several patient factors may necessitate a readmission for ADHF and include arrhythmias, worsening symptoms, and need for initiation or escalation of vasoactive therapies. Critical care bed space capacity remains a finite hospital resource that requires active management, especially in the current era of increased pediatric ADHF admissions. Organizational factors including average daily census and nurse-bed ratio limitations may play a role in encouraging premature transfer from critical care to acute care wards. In addition, quality of care provided in the CICU may also impact their need for readmission during the same hospitalization. Premature discontinuation of vasoactive therapies and failure to initiate standard-of-care oral heart failure medications may determine a patient’s need for continued higher level of care. Such a high rate of CICU readmissions, or bounce backs, represents an opportunity for further investigation of clinical predictors that may determine candidacy for transfer to lower acuity settings from the CICU environment. Of note in our study, the overall 30-day hospital readmission rate for our cohort (11%) was lower than previously published reports in children (13%–34%)2 and may be an under-representation since patients may have been readmitted to other non-PC4 centers after discharge from a PC4 center.

This study has several important limitations. Although PC4 diagnostic criteria for ADHF are consistent with adult studies, a consensus definition of ADHF in children does not exist. Second, certain quantitative surrogate markers of heart failure (eg, ejection fraction, left ventricular end-diastolic dimension) were not collected due to the myriad of ventricular anatomies in the cohort, but qualitative assessments were required in conjunction with receipt of certain therapies (vasoactives, diuretic infusions, mechanical ventilation, mechanical circulatory support). Last, we are also aware of the potential impact of unmeasured confounders not captured by this data set.

In summary, although children with ADHF comprise a minority of admissions to pediatric CICU’s, these patients carry high burdens of morbidity and mortality during their CICU admissions, especially in patients with underlying CHD. Complex critical care resources are frequently employed in this population yet significant variability in therapeutic utilization exists across sites. Mechanical circulatory support seems to be utilized less frequently in the CHD population and, last, readmission rates to the ICU are exceedingly high. We hope the results of this study will provide a foundation for the development of risk adjustment models that explore true variation in CICU resource utilization and mortality across pediatric CICUs while also identifying high-performing centers with respect to management of the ADHF population. Ultimately, we expect these results will inform the heart failure, transplant, and critical care communities while also fueling targeted research and quality improvement initiatives that reduce CICU-related morbidity and mortality in the ADHF population, especially among those patients with underlying CHD.

Nonstandard Abbreviations and Acronyms

ADHF

acute decompensated heart failure

CHD

congenital heart disease

CICU

cardiac intensive care unit

ECMO

extracorporeal membrane oxygenation

PC4

Pediatric Cardiac Critical Care Consortium

VAD

ventricular assist device

Acknowledgments

The investigative team acknowledges the data collection teams and clinical champions from each of the PC4 hospitals for their efforts in obtaining the high-quality data used in this analysis.

Footnotes

For Sources of Funding and Disclosures, see page 10.

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.119.006101.

Correspondence to: Javier J. Lasa, MD, Department of Pediatrics, Divisions of Critical Care Medicine and Cardiology, Texas Children’s Hospital/Baylor College of Medicine, W Tower, B06041, 6621 Fannin St, Houston, TX 77030. Email

References

  • 1. Kirk R, Dipchand AI, Rosenthal DN, Addonizio L, Burch M, Chrisant M, Dubin A, Everitt M, Gajarski R, Mertens L, et al. The international society for heart and lung transplantation guidelines for the management of pediatric heart failure: executive summary.J Heart Lung Transplant. 2014; 33:888–909. doi: 10.1016/j.healun.2014.06.002CrossrefMedlineGoogle Scholar
  • 2. Shamszad P, Hall M, Rossano JW, Denfield SW, Knudson JD, Penny DJ, Towbin JA, Cabrera AG. Characteristics and outcomes of heart failure-related intensive care unit admissions in children with cardiomyopathy.J Card Fail. 2013; 19:672–677. doi: 10.1016/j.cardfail.2013.08.006CrossrefMedlineGoogle Scholar
  • 3. Moffett BS, Humlicek TJ, Rossano JW, Price JF, Cabrera AG. Readmissions for Heart Failure in Children.J Pediatr. 2016; 177:153–158.e3. doi: 10.1016/j.jpeds.2016.06.003CrossrefMedlineGoogle Scholar
  • 4. Wong CM, Hawkins NM, Jhund PS, MacDonald MR, Solomon SD, Granger CB, Yusuf S, Pfeffer MA, Swedberg K, Petrie MC, et al. Clinical characteristics and outcomes of young and very young adults with heart failure: The CHARM programme (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity).J Am Coll Cardiol. 2013; 62:1845–1854. doi: 10.1016/j.jacc.2013.05.072CrossrefMedlineGoogle Scholar
  • 5. Tromp J, Meyer S, Mentz RJ, O’Connor CM, Metra M, Dittrich HC, Ponikowski P, Teerlink JR, Cotter G, Davison B, et al. Acute heart failure in the young: Clinical characteristics and biomarker profiles.Int J Cardiol. 2016; 221:1067–1072. doi: 10.1016/j.ijcard.2016.06.339CrossrefMedlineGoogle Scholar
  • 6. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E, Burrows N, McLean A, Vilas-Boas F, Mebazaa A. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF).Intensive Care Med. 2011; 37:619–626. doi: 10.1007/s00134-010-2113-0CrossrefMedlineGoogle Scholar
  • 7. Adams KFFonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP; ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE).Am Heart J. 2005; 149:209–216. doi: 10.1016/j.ahj.2004.08.005CrossrefMedlineGoogle Scholar
  • 8. Harjola VP, Follath F, Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Hochadel M, Komajda M, Lopez-Sendon JL, Ponikowski P, et al. Characteristics, outcomes, and predictors of mortality at 3 months and 1 year in patients hospitalized for acute heart failure.Eur J Heart Fail. 2010; 12:239–248. doi: 10.1093/eurjhf/hfq002CrossrefMedlineGoogle Scholar
  • 9. Zannad F, Mebazaa A, Juillière Y, Cohen-Solal A, Guize L, Alla F, Rougé P, Blin P, Barlet MH, Paolozzi Let al; EFICA Investigators. Clinical profile, contemporary management and one-year mortality in patients with severe acute heart failure syndromes: The EFICA study.Eur J Heart Fail. 2006; 8:697–705. doi: 10.1016/j.ejheart.2006.01.001CrossrefMedlineGoogle Scholar
  • 10. Webster G, Zhang J, Rosenthal D. Comparison of the epidemiology and co-morbidities of heart failure in the pediatric and adult populations: a retrospective, cross-sectional study.BMC Cardiovasc Disord. 2006; 6:23. doi: 10.1186/1471-2261-6-23CrossrefMedlineGoogle Scholar
  • 11. Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB; OPTIMIZE-HF Investigators and Coordinators. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF).J Am Coll Cardiol. 2008; 52:347–356. doi: 10.1016/j.jacc.2008.04.028CrossrefMedlineGoogle Scholar
  • 12. Rossano JW, Goldberg DJ, Mott AR, Lin KY, Shaddy RE, Kaufman BD, Rychik J. Heart Failure related hospitalizations in children with single ventricle heart disease in the united states: costly and getting more expensive.J Card Fail. 2012; 18:S73.CrossrefGoogle Scholar
  • 13. Nandi D, Rossano JW, Wang Y, Jerrell JM. Risk factors for heart failure and its costs among children with complex congenital heart disease in a medicaid cohort.Pediatr Cardiol. 2017; 38:1672–1679. doi: 10.1007/s00246-017-1712-8CrossrefMedlineGoogle Scholar
  • 14. Mahle WT, Hu C, Trachtenberg F, Menteer J, Kindel SJ, Dipchand AI, Richmond ME, Daly KP, Henderson HT, Lin KYet al; Pediatric Heart Network Investigators. Heart failure after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial.J Heart Lung Transplant. 2018; 37:879–885. doi: 10.1016/j.healun.2018.02.009CrossrefMedlineGoogle Scholar
  • 15. Wittlieb-Weber CA, Lin KY, Zaoutis TE, O’Connor MJ, Gerald K, Paridon SM, Shaddy RE, Rossano JW. Pediatric versus adult cardiomyopathy and heart failure-related hospitalizations: a value-based analysis.J Card Fail. 2015; 21:76–82. doi: 10.1016/j.cardfail.2014.10.011CrossrefMedlineGoogle Scholar
  • 16. Hollander SA, Bernstein D, Yeh J, Dao D, Sun HY, Rosenthal D. Outcomes of children following a first hospitalization for dilated cardiomyopathy.Circ Heart Fail. 2012; 5:437–443. doi: 10.1161/CIRCHEARTFAILURE.111.964510LinkGoogle Scholar
  • 17. Gaies M, Cooper DS, Tabbutt S, Schwartz SM, Ghanayem N, Chanani NK, Costello JM, Thiagarajan RR, Laussen PC, Shekerdemian LS, et al. Collaborative quality improvement in the cardiac intensive care unit: development of the Paediatric Cardiac Critical Care Consortium (PC4).Cardiol Young. 2015; 25:951–957. doi: 10.1017/S1047951114001450CrossrefMedlineGoogle Scholar
  • 18. Gaies M, Donohue JE, Willis GM, Kennedy AT, Butcher J, Scheurer MA, Alten JA, William Gaynor J, Schuette JJ, Cooper DS, et al. Data integrity of the Pediatric Cardiac Critical Care Consortium (PC4) clinical registry.Cardiol Young. 2016; 26:1090–1096. doi: 10.1017/S1047951115001833CrossrefMedlineGoogle Scholar
  • 19. Bergersen L, Everett AD, Giroud JM, Martin GR, Franklin RC, Béland MJ, Krogmann ON, Aiello VD, Colan SD, Elliott MJ, et al. Report from the international society for nomenclature of paediatric and congenital heart disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 1 - Procedural nomenclature).Cardiol Young. 2011; 21:252–259. doi: 10.1017/S104795111000185XCrossrefMedlineGoogle Scholar
  • 20. Gaies M, Jeffries HE, Niebler RA, et al. Vasoactive-inotropic score (VIS) is associated with outcome after infant cardiac surgery: an analysis from the Pediatric Cardiac Critical Care Consortium (PC4) and Virtual PICU System Registries.Pediatric Critical Care Medicine. 2014; 15:529–537. doi: 10.1097/PCC.0000000000000153CrossrefMedlineGoogle Scholar
  • 21. Conway J, St Louis J, Morales DL, Law S, Tjossem C, Humpl T. Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device.JACC Heart Fail. 2015; 3:70–77. doi: 10.1016/j.jchf.2014.07.011CrossrefMedlineGoogle Scholar
  • 22. Blume ED, Rosenthal DN, Rossano JW, Baldwin JT, Eghtesady P, Morales DL, Cantor RS, Conway J, Lorts A, Almond CSet al; PediMACS Investigators. Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS).J Heart Lung Transplant. 2016; 35:578–584. doi: 10.1016/j.healun.2016.01.1227CrossrefMedlineGoogle Scholar
  • 23. Burki S, Adachi I. Pediatric ventricular assist devices: current challenges and future prospects.Vasc Health Risk Manag. 2017; 13:177–185. doi: 10.2147/VHRM.S82379CrossrefMedlineGoogle Scholar
  • 24. Poh CL, Chiletti R, Zannino D, Brizard C, Konstantinov IE, Horton S, Millar J, d’Udekem Y. Ventricular assist device support in patients with single ventricles: the Melbourne experience.Interact Cardiovasc Thorac Surg. 2017; 25:310–316. doi: 10.1093/icvts/ivx066CrossrefMedlineGoogle Scholar
  • 25. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC; ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database.J Am Coll Cardiol. 2006; 47:76–84. doi: 10.1016/j.jacc.2005.09.022CrossrefMedlineGoogle Scholar
  • 26. Gheorghiade M, Pang PS. Acute heart failure syndromes.J Am Coll Cardiol. 2009; 53:557–573. doi: 10.1016/j.jacc.2008.10.041CrossrefMedlineGoogle Scholar
  • 27. van Diepen S, Podder M, Hernandez AF, Westerhout CM, Armstong PW, McMurray JJ, Eapen ZJ, Califf RM, Starling RC, O’Connor CM, et al. Acute decompensated heart failure patients admitted to critical care units: insights from ASCEND-HF.Int J Cardiol. 2014; 177:840–846. doi: 10.1016/j.ijcard.2014.11.007CrossrefMedlineGoogle Scholar
  • 28. Chen S, Dykes JC, McElhinney DB, Gajarski RJ, Shin AY, Hollander SA, Everitt ME, Price JF, Thiagarajan RR, Kindel SJ, et al. Haemodynamic profiles of children with end-stage heart failure.Eur Heart J. 2017; 38:2900–2909. doi: 10.1093/eurheartj/ehx456CrossrefMedlineGoogle Scholar
  • 29. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW; ADHERE Scientific Advisory Committee and Investigators. Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart Failure National Registry (ADHERE).Am Heart J. 2007; 153:1021–1028. doi: 10.1016/j.ahj.2007.03.012CrossrefMedlineGoogle Scholar
  • 30. Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors Aet al; PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.N Engl J Med. 2010; 363:1419–1428. doi: 10.1056/NEJMoa0912613CrossrefMedlineGoogle Scholar
  • 31. Alten JA, Klugman D, Raymond TT, Cooper DS, Donohue JE, Zhang W, Pasquali SK, Gaies MG. Epidemiology and outcomes of cardiac arrest in pediatric cardiac ICUs.Pediatr Crit Care Med. 2017; 18:935–943. doi: 10.1097/PCC.0000000000001273CrossrefMedlineGoogle Scholar
  • 32. 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; 34:1209–1215. doi: 10.1097/01.CCM.0000208440.66756.C2CrossrefMedlineGoogle Scholar
  • 33. Tibballs J, Kinney S. A prospective study of outcome of in-patient paediatric cardiopulmonary arrest.Resuscitation. 2006; 71:310–318. doi: 10.1016/j.resuscitation.2006.05.009CrossrefMedlineGoogle Scholar