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 (PC4) registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF.
Methods:
CICU patients ≤ 18 years of age meeting PC4 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), 1,494 (6%) met criteria for analysis. Median age was 0.93 years (IQR 0.1–9.3 years). CHD patients comprised 57% of the cohort. Common therapies included: 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 (IQR 3–18 days) and the CICU readmission rate was 22%. Overall CICU mortality was 15% although higher for patients with CHD vs non-CHD (19% vs 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, ECMO, and cardiac arrest.
Conclusions:
ADHF in children is characterized by co-morbidities, 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.
Introduction
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 (CHD), acquired cardiomyopathies, or acute exacerbations of chronic heart failure from abnormal circulations (e.g., 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 (e.g., 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 amongst 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 pre-existing CHD are at greatest risk of poor outcomes.
Methods
Study Design and Cohort
The Pediatric Cardiac Critical Care Consortium (PC4) is a quality improvement collaborative that collects data on all patients with primary cardiac disease admitted to the CICU service of participating hospitals17. 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 (IPCCC), Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database, and American College of Cardiology Improving Pediatric and Adult Congenital Treatment (IMPACT) Registry, as previously described17. 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 fields18. 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 gonzaleb@med.umich.edu.
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 acute decompensated heart failure (AHDF) 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: (a) continuous infusion of a vasoactive and/or diuretic agent, (b) respiratory support including mechanical ventilation as well as non-invasive high flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP), or (c) 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 non-invasive imaging reports. Additional PC4 definitions of clinical conditions and complications utilized in this analysis can be found in Supplemental Table 1.
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 (i.e. structurally normal heart) and/or those having undergone prior heart transplantation, regardless of history of CHD prior to transplantation. ADHF patients 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, gender), 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 extracorporeal membrane oxygenation (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 amongst the CHD and non-CHD groups of ADHF patients.
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 chi-square 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 non-surgical ADHF admissions were subsequently included in our multivariate analysis of mortality for two reasons: 1) Key differences in variables collected between surgical and non-surgical patients made combining them in one model potentially misleading, 2) The small sample size of the surgical cohort limited additional multivariable analysis in this subgroup. Factors associated with CICU mortality among non-surgical 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% confidence intervals (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 two disease subgroups (CHD and non-CHD + status-post transplant) 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 of less than 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, 1,494 unique ADHF admissions (1,371 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 extra-cardiac congenital anomalies, chromosomal abnormalities and/or known syndromes when compared to non-CHD patients. 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.
Figure 1.
Patient selection flow-sheet
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 Encounters | 1494 (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 days) | 311 (21) | 219 (26) | 92 (14) | <0.001 |
| Infant (30 days – <1 year) | 443 (30) | 323 (38) | 120 (19) | |
| Child (1 year - <18 years) | 740 (49) | 310 (36) | 430 (67) | |
| Weight at CICU admission, kg | 8 (3.9–26) | 5.3 (3.5–11.7) | 17.7 (6–51.5) | <0.001 |
| Male gender | 814 (55) | 476 (56) | 338 (53) | 0.22 |
| Race | <0.001 | |||
| Caucasian | 900 (60) | 547 (64) | 353 (55) | |
| Black | 337 (23) | 163 (19) | 174 (27) | |
| Asian | 49 (3) | 31 (4) | 18 (3) | |
| Native American | 6 (<1) | 3 (<1) | 3 (<1) | |
| Native Pacific Islander | 2 (<1) | 1 (<1) | 1 (<1) | |
| Other/Multiracial | 148 (10) | 84 (10) | 64 (10) | |
| Unknown | 52 (3) | 23 (3) | 29 (5) | |
| Pre-existing High-Risk Diagnoses ( n=1184) | 376 (32) | 191 (33) | 185 (31) | 0.51 |
| Arrhythmia | 41 (3) | 11 (2) | 30 (5) | <0.001 |
| CPR reason for admit | 50 (4) | 28 (5) | 22 (4) | 0.34 |
| Pulmonary hypertension | 68 (6) | 44 (8) | 24 (4) | 0.009 |
| Heart transplant rejection | 32 (3) | 0 (0) | 32 (5) | <0.001 |
| Cardiomyopathy | 461 (39) | 66(11) | 395(66) | 0.003 |
| Myocarditis | 100 (8) | 6(1) | 94(16) | <0.001 |
| Extra-cardiac Anomalies | 210 (14) | 159 (19) | 51 (8) | <0.001 |
| Chromosomal Abnormality | 122 (8) | 115 (14) | 7 (1) | <0.001 |
| Syndrome(s) | 240 (16) | 209 (24) | 31 (5) | <0.001 |
| Tracheostomy Present | 16 (1) | 13 (2) | 3 (<1) | 0.05 |
| Primary Insurance Type | 0.08 | |||
| Public | 853 (57) | 497 (58) | 356 (55) | |
| Private | 555 (37) | 307 (36) | 248 (39) | |
| Non-U.S. Insurance | 8 (1) | 1 (<1) | 7 (1) | |
| None/Self | 27 (2) | 15 (2) | 12 (2) | |
| Unknown | 51 (3) | 32 (4) | 19 (3) | |
| Source of CICU Admission | 0.99 | |||
| Home | 39 (3) | 22 (3) | 17 (3) | |
| Current Hospital | 919 (62) | 525 (62) | 394 (61) | |
| Outside Hospital | 536 (36) | 305 (36) | 231 (36) | |
Key: ADHF, acute decompensated heart failure; CICU, cardiac intensive care unit; CHD, congenital heart disease; CPR, cardiopulmonary resuscitation
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 to their non-CHD counterparts. Supplemental Table 2 displays the spectrum of vasoactive/inotropic medications used in the care of ADHF patients. Milrinone was the most commonly administered vasoactive agent (80% of admissions). Non-CHD patients were treated with milrinone more frequently than their CHD counterparts while CHD patients were exposed to more calcium and vasopressin infusions than non-CHD patients. 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. (Supplemental Table 3)
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 Encounters | 1494 (100) | 852 (57) | 642 (43) | |
| Respiratory Support | ||||
| Mechanical Ventilation | 876 (59) | 553 (65) | 323 (50) | <0.001 |
| Total Mechanical Ventilation duration, median days (IQR) | 5.2 (2–13) | 5.3 (2–13) | 5.2 (2–13) | 0.68 |
| Reintubation (within 48 hours 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 Cannula | 682 (46) | 454 (53) | 228 (35) | <0.001 |
| Inhaled Nitric Oxide Use | 286 (19) | 176 (21) | 110 (17) | 0.09 |
| Critical Care Resources | ||||
| Central venous line during CICU encounter | 1284 (86) | 719 (84) | 565 (88) | 0.047 |
| Arterial line | 841 (56) | 508 (60) | 333 (52) | 0.003 |
| Foley catheter | 700 (47) | 424 (50) | 276 (43) | 0.009 |
| VIS (peak within 2 hours of admission) | 5 (5–10) | 5 (5–10) | 5 (3.8–10) | 0.24 |
| Complications | ||||
| Arrhythmia | 291 (19) | 153 (18) | 138 (22) | 0.09 |
| Stroke | 69 (5) | 39 (5) | 30 (5) | 0.93 |
| Intracranial Hemorrhage | 44 (3) | 24 (3) | 20 (3) | 0.74 |
| Seizure | 50 (3) | 31 (4) | 19 (3) | 0.47 |
| Continuous Renal Replacement Therapy for Acute Renal Failure | 50 (3) | 27 (3) | 23 (4) | 0.66 |
| Pneumonia | 52 (3) | 31 (4) | 21 (3) | 0.70 |
| Central Line-associated Bloodstream Infection | 43 (3) | 32 (4) | 11 (2) | 0.019 |
| Sepsis | 98 (7) | 59 (7) | 39 (6) | 0.51 |
| Urinary Tract Infection | 51 (3) | 32 (4) | 19 (3) | 0.40 |
| Hepatic Failure | 52 (3) | 33 (4) | 19 (3) | 0.34 |
| Ventricular Tachycardia | 120 (8) | 42 (5) | 78 (12) | <0.001 |
| Cardiac Arrest During CICU Encounter | 152 (10) | 97 (11) | 55 (9) | 0.08 |
| E-CPR (% of Cardiac Arrest) | 53 (35) | 29 (30) | 24 (44) | 0.09 |
| Cardiac arrest time, minutes (IQR) | 20 (4–44) | 20 (4–40) | 21 (6–52) | 0.36 |
| Mechanical Circulatory Support | ||||
| ECMO | 173 (12) | 84 (10) | 89 (14) | 0.017 |
| ECMO Length of Support, day | 5.6 (3.1–10.1) | 5.3 (3.1–9.8) | 5.6 (3.1–10.1) | 0.89 |
| VAD placement | 65 (4) | 14 (2) | 51 (8) | <0.001 |
| Listed for Heart Transplantation | 159 (11) | 76 (9) | 83 (13) | 0.013 |
| Any Cardiothoracic Surgery During the CICU Encounter | 310 (21) | 267 (31) | 43 (7) | <0.001 |
| Heart transplantation | 66 (22) | 38(14) | 28 (65) | <0.001 |
Key: CICU, cardiac intensive care unit; CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure; PICC, peripherally inserted central catheter; ARDS, acute respiratory distress syndrome; E-CPR, extracorporeal cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; VIS, Vasoactive-Inotropic Score (Gaies M., Jeffries H.E., Niebler R.A., 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 July; 15(6):529–537); VAD, ventricular assist device
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 CHD patients than non-CHD patients (8.4 days [IQR 3.2–18.9] vs 6.8 days [IQR 3.0–17.5]; p=0.027) . No difference in ICU readmission rates was appreciated between the two groups (179/852 [23%] CHD vs 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 ADHF patients 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% CI | p-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) | 1.26† | 1.12 – 1.42 | <0.001 |
| CICU Mortality | 231 (15) | 159 (19) | 72 (11) | 1.82 | 1.35 – 2.45 | <0.001 |
| Withdrawal of life-sustaining therapy | 167 (72) | 111 (70) | 56 (78) | 0.66 | 0.34 – 1.27 | 0.21 |
| Length of ICU stay, days (IQR; non-survivors) | 9.4 (3.4–25.2) | 9.1 (2.9–26.7) | 10.4 (4.3–21.6) | 1.12† | 0.79 – 1.58 | 0.53 |
| VAD or ECMO | 222 (15) | 95 (11) | 127 (20) | 0.51 | 0.38 – 0.68 | <0.001 |
| CICU Mortality | 95 (43) | 56 (59) | 39 (31) | 3.24 | 1.86 – 5.65 | <0.001 |
| Brain Death | 7 (<1) | 1 (<1) | 6 (1) | 0.12 | 0.01 – 1.04 | 0.05 |
| Readmission to CICU During Hospitalization | 301 (22) | 179 (23) | 122 (21) | 1.11 | 0.86 – 1.44 | 0.43 |
| All-cause Readmission within 30 Days of Hospital Discharge | 147 (11) | 96 (12) | 51 (9) | 1.45 | 1.01 – 2.07 | 0.043 |
Key: IRR, incidence rate ratio; CI, confidence interval; OR, odds ratio
Unadjusted
Incidence rate ratio
Complication rates are also displayed in Table 2. The most common complication was arrhythmia treated with pharmacologic therapy and/or cardioversion/defibrillation. Of all complications, only central line-associated blood stream infection was significantly greater amongst CHD patients 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. Non-CHD patients were more likely to be both listed for heart transplantation (83/642 [13%] vs 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 non-CHD patients than their CHD counterparts (ECMO 89/642 [14%] vs 84/852 [10%]; p=0.017 and VAD 51/642 [8%] vs 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 Supplemental Table 4. Hospital mortality reached 19% for the overall ADHF cohort and similar to CICU mortality rates, was much higher for CHD patients.
Figure 2.
Variation in CICU mortality across participating PC4 centers
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, extra-cardiac anomalies, neonatal age at presentation, pre-existing 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 Mortality | p-value | ||
|---|---|---|---|---|
| Yes (n=200) |
No (n=984) |
|||
| Congenital Heart Disease | ||||
| Yes | 585 (49) | 130 (65) | 455 (46) | <0.001 |
| No | 599 (51) | 70 (35) | 529 (54) | |
| Male Gender | 657 (55) | 123 (62) | 534 (54) | 0.06 |
| Extra-cardiac Anomalies | 164 (14) | 39 (20) | 125 (13) | 0.01 |
| Chromosomal Abnormality and/or Syndrome(s) | 189 (16) | 38 (19) | 151 (15) | 0.19 |
| Neonate (< 30 days) | 193 (16) | 63 (32) | 130 (13) | <0.001 |
| Infant (30 days to <1 year) | 326 (28) | 51 (26) | 275 (28) | |
| Child (1 year to <18 years) | 665 (56) | 86 (43) | 579 (59) | |
| Race | ||||
| Caucasian, non-Hispanic | 516 (44) | 87 (44) | 429 (44) | 0.95 |
| Hispanic, any race | 247 (21) | 39 (20) | 208 (21) | |
| Black, non-Hispanic | 271 (23) | 48 (24) | 223 (23) | |
| All other races, non-Hispanic | 150 (13) | 26 (13) | 124 (13) | |
| Pre-existing High-Risk Diagnoses | ||||
| Arrhythmia | 41 (4) | 9 (5) | 32 (3) | 0.38 |
| CPR reason for admit | 50 (4) | 25 (13) | 25 (3) | <0.001 |
| Pulmonary hypertension | 68 (6) | 22 (11) | 46 (5) | <0.001 |
| Heart transplant rejection | 31 (3) | 6 (3) | 25 (3) | 0.71 |
| Cardiomyopathy | 461 (39) | 60 (30) | 401 (41) | 0.005 |
| Myocarditis | 100 (8) | 9 (5) | 91 (9) | 0.03 |
| Any Vasoactive/Inotrope Infusion | 1009 (85) | 193 (97) | 816 (83) | <0.001 |
| Vasoactive/Inotrope Infusion Within 2 hrs. of CICU Admission | 747 (63) | 131 (65.50) | 616 (63) | 0.44 |
| VIS (Peak, within 2 hrs. of CICU Admission) | 5 (5–10) | 7.5 (5–12) | 5 (5–8) | <0.001 |
| VIS Categories | ||||
| > 7.5 | 225 (19) | 63 (32) | 162 (16) | <0.001 |
| < 7.5, > 2.5 | 496 (42) | 62 (31) | 434 (44) | |
| < 2.5 | 463 (39) | 75 (38) | 388 (39) | |
| Mechanical ventilation | 573 (48) | 188 (94) | 385 (39) | <0.001 |
| Mechanical ventilation, duration (hours, median, IQR; n=573) | 113 (40–260) | 134 (40–393) | 105 (41–224) | 0.05 |
| VAD placement | 42 (4) | 6 (3) | 36 (4) | 0.65 |
| ECMO | 20 (10) | 68 (34) | 52 (5) | <0.001 |
| Complications | ||||
| Sepsis | 77 (7) | 31 (16) | 46 (5) | <0.001 |
| Hepatic failure | 36 (3) | 29 (15) | 7 (1) | <0.001 |
| CRRT for acute renal failure | 37 (3) | 21 (11) | 16 (2) | <0.001 |
| Stroke | 50 (4) | 20 (10) | 30 (3) | <0.001 |
| Ventricular tachycardia | 94 (8) | 41 (21) | 53 (5) | <0.001 |
| Cardiac arrest during ICU encounter | 117 (10) | 81 (41) | 36 (4) | <0.001 |
| E-CPR (% of Cardiac Arrest) | 38 (32) | 26 (32) | 12 (33) | 0.89 |
| Cardiac arrest time (minutes, median, IQR) | 21 (4–48) | 30 (13–49) | 5 (1–24) | <0.001 |
Key: CICU, cardiac intensive care unit; CPR, cardiopulmonary resuscitation; CRRT, continuous renal replacement therapy; E-CPR, extracorporeal cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; VIS, Vasoactive-Inotropic Score (Gaies M., Jeffries H.E., Niebler R.A., 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); VAD, ventricular assist device
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 Supplementary Table 5. Heart transplants were performed for a total of 66 admissions. Overall mortality was 10% and of those that 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 non-surgical 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 Factor | Odds Ratio | Z-score | 95% Confidence Interval | p-value |
|---|---|---|---|---|
| Cardiac arrest during ICU admission | ||||
| < 20 minute duration | 4.36 | 4.81 | 2.4 – 7.9 | <0.001 |
| > 20 minute duration | 20.30 | 5.16 | 6.5 – 63.4 | <0.001 |
| Hepatic failure | 13.05 | 4.78 | 4.6 – 37.4 | <0.001 |
| Mechanical ventilation | 7.41 | 4.77 | 3.3 – 16.9 | <0.001 |
| Neonate, <30 days (ref. group: >1 year - <18 year) | 3.65 | 4.03 | 2.0 – 6.9 | <0.001 |
| CHD (reference group: non-CHD/transplant) | 3.47 | 4.58 | 2.0 – 5.9 | <0.001 |
| ECMO | 2.96 | 4.07 | 1.8 – 5.0 | <0.001 |
| Use of any vasoactive therapy | 2.93 | 3.20 | 1.5 – 5.7 | 0.001 |
| Ventricular tachycardia | 2.60 | 2.18 | 1.1 – 6.1 | 0.029 |
| Pulmonary hypertension | 2.08 | 2.39 | 1.1 – 3.8 | 0.017 |
| Sepsis | 1.63 | 2.04 | 1.0 – 2.6 | 0.042 |
| Myocarditis | 0.22 | −2.27 | 0.1 – 0.8 | 0.023 |
Key: CICU, cardiac intensive care unit; CHD, congenital heart disease, 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 to 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, no CHD; adjusted OR 16.2 [95% CI 7.2 – 36.4], p<0.001; Supplemental Table 6).
Discussion
This large, multi-center 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 to 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 co-morbid patient population (younger age at presentation, frequent extra-cardiac anomalies and genetic syndromes) not only suffered greater morbidity and mortality compared to 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 anatomical 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. 20–23 In the interim, this study provides further evidence for risk stratification and anticipatory management of CHD patients 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. 9,11,15,24,25 Although the definitive clinical features of HF are present in both adults and children (i.e., ventricular dysfunction, fluid retention, neurohormonal activation), the manifestations of ADHF and presentation appear 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. 26 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 14–53% of adults hospitalized in an ICU for ADHF 6,9,26, 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. 2,3,27 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. 8,25,28 In our study, hospital-wide and CICU-specific mortality rates were 19% and 15%, respectively, compared to reports of 4–9% all-cause 30-day mortality in adults with acute HF syndromes admitted to higher acuity units.5,6,10,15,24,26,29 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. 24
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 ADHF patients 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.30 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 ADHF patients. 31,32
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. Secondly, certain quantitative surrogate markers of heart failure (e.g., 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). Lastly, 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 appears to be utilized less frequently in the CHD population and, lastly, 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.
Supplementary Material
What is new?
In this report from Pediatric Cardiac Critical Care Consortium (PC4) registry, acute decompensated heart failure (ADHF) accounted for 6% of all admission to a pediatric cardiac intensive care unit.
Compared to 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 PC4.
What are the clinical implications?
Data from the PC4 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.
Acknowledgements
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.
Funding Sources
This study was supported in part by funding from the University of Michigan Congenital Heart Center, Champs for Mott, and the Michigan Institute for Clinical & Health Research (NIH/NCATS UL1TR002240). Dr. Gaies is supported in part by funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (K08HL116639).
Non-standard Abbreviations and Acronyms:
- ADHF
acute decompensated heart failure
- BiPAP
bilevel positive airway pressure
- CHD
congenital heart disease
- CI
confidence interval
- CICU
cardiac intensive care unit
- CPAP
continuous positive airway pressure
- ECMO
extracorporeal membrane oxygenation
- HFNC
high flow nasal cannula
- IMPACT
American College of Cardiology Improving Pediatric and Adult Congenital Treatment Registry
- IPCCC
International Pediatric and Congenital Cardiac Code
- IQR
interquartile range
- PC4
Pediatric Cardiac Critical Care Consortium
- STS
Society of Thoracic Surgeons Congenital Heart Surgery Database
- VAD
ventricular assist device
Footnotes
Disclosures: none
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