Outcomes of Pediatric Patients with Defibrillators Following Initial Presentation with Sudden Cardiac Arrest

Abstract

Background –

Implantable cardioverter defibrillators (ICD) are recommended for secondary prevention after sudden cardiac arrest (SCA). The outcomes of pediatric patients receiving an ICD after SCA remain unclear. The objective of this study is to evaluateoutcomes, future risk for appropriate shocks, and identify characteristics associated with appropriate ICD therapy during follow-up.

Methods –

Multi-center retrospective analysis of patients (age≤21 yrs) without prior cardiac disease who received an ICD following SCA. Patient/device characteristics, cardiac function, and underlying diagnoses were collected, along with SCA event characteristics. Patient outcomes including complications and device therapies were analyzed.

Results –

In total, 106 patients were included, median age 14.7 yrs. Twenty (19%) received appropriate shocks and 16 (15%) received inappropriate shocks (median follow up 3 yrs). First-degree relative with SCA was associated with appropriate shocks (p<0.05). In total, 40% patients were considered idiopathic. Channelopathy was the most frequent late diagnosis not made at time of presentation. Neither underlying diagnosis nor idiopathic status was associated with increased incidence of appropriate shock. Monomorphic ventricular tachycardia (HR 4.6 [1.2; 17.3]) and family history of sudden death (HR 6.5 [1.4;29.8]) were associated with freedom from appropriate shock in a multivariable model (AUC=0.8). Time from diagnoses to evaluation demonstrated a non-linear association with freedom from appropriate shock (p=0.015). In patients >2 yrs from implantation, younger age (p=0.02) and positive exercise test (p=0.04) were associated with appropriate shock.

Conclusions –

The risk of future device therapy is high in pediatric patients receiving an ICD after SCA, irrelevant of underlying disease. Lack of a definitive diagnosis after SCA was not associated with lower risk of subsequent events and does not obviate the need for secondary prophylaxis.

Graphical Abstract

Introduction

Pediatric survival of an out-of-hospital sudden cardiac arrest (SCA) remains poor, though the ability to diagnose and treat the underlying mechanisms that lead to cardiac arrest have continued to improve.^1–3 Several underlying disease processes place patients at higher risk for SCA, the majority of which include underlying channelopathy or cardiomyopathy, as well as coronary artery anomalies.⁴ Additionally, there remains an important cohort of pediatric patients presenting with SCA in whom a definitive diagnosis is not found—neither at the time of initial SCA presentation, nor on long-term follow-up. When SCA is not associated with a reversible cause, an implantable cardioverter defibrillator (ICD) may be implanted for secondary prevention of future sudden death, though the outcomes of this approach and therapy remain unclear.^5–8 This gap in the literature is of particular importance. Although ICDs have been proven to be effective in the event of future SCA episodes, they are not without potential complications, including inappropriate discharges and long-term deleterious effects on patient quality of life.^9–15 Because of these effects, it is imperative to understand a patient’s ongoing risk of a future SCA event and weigh those potential risks to the risk-benefit ratio of long-term ICD management. In this study, we analyzed patients without known heart disease at the time of initial presentation to medical care following a resuscitated SCA episode and who had an ICD implant as part of their management. Patients were identified from 10 tertiary care institutions, and outcomes and associated variables potentially correlated with future device shocks were evaluated.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request. This was a multi-center international retrospective cohort study of patients ≤ 21 years of age with a secondary prevention ICD implanted after an initial presentation of out-of-hospital sudden cardiac arrest. This study was conducted under the institutional review board at Cincinnati Children’s Hospital Medical Center and data was included from 10 tertiary pediatric heart centers; additional institutional review board approval was obtained at each of the participating centers. Due to the retrospective chart review, patients were deemed at minimal risk associated with this study and patient consent was waived. Patients were excluded if they had a previous cardiac diagnosis and/or previous evaluation by a cardiologist for any symptom prior to their initial cardiac arrest episode.

Patient Demographics, History and Diagnoses

Patient demographics and patient history were collected and reviewed by a pediatric electrophysiologist at each participating center, including history of seizures or syncope prior to presentation and a history of any first-degree relative with prior SCA. Echocardiographic findings at presentation and last follow-up were reviewed, including evidence of structural heart disease; ventricular function (ejection fraction) was categorized as normal (>55%), mild (45-54%), moderate (35-44%), or severe (<35%) dysfunction and collected both at presentation, as well as follow-up. As enrolled patients had no known cardiac diagnosis prior to initial presentation with resuscitated SCA, we evaluated the presumed diagnosis at the time of initial presentation, which was defined as cardiac diagnosis prior to discharge from the hospital, and the diagnosis at the time of the most recent follow-up. Each diagnosis time period was analyzed separately.

Diagnosis categories included: congenital heart disease (CHD), cardiac channelopathy, cardiomyopathy, myocarditis, coronary artery anomaly, or idiopathic. Patients with a channelopathy diagnosis were further sub-categorized into long QT Syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome. Patients with cardiomyopathy were sub-categorized as hypertrophic, dilated, left ventricular non-compaction (LVNC), and arrhythmogenic right ventricular cardiomyopathy (ARVC). If no diagnosis was made, patients were categorized as idiopathic. Device related data including lead type and device outcomes were collected. Lead type included transvenous, epicardial, and subcutaneous systems.

An ECG was abnormal if the QTc interval was > 470 ms, there was t-wave inversion of the inferior or lateral leads, presence of Brugada pattern or the presence of ventricular pre-excitation. The electrophysiology (EP) study was positive (abnormal) if there was inducible, sustained ventricular arrhythmia. A positive (abnormal) exercise study was defined as the presence of ventricular couplets, ventricular arrhythmia, or ischemic changes that developed during exercise.

Event Characteristics

The characteristics surrounding the presenting SCA episode included resuscitation therapies and event rhythm, if known. Event therapies included: cardiopulmonary resuscitation (CPR) only and CPR with defibrillation. Event rhythms were categorized as ventricular fibrillation, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, and Torsade de Pointes. The presenting rhythm was reviewed and categorized by the managing institution.

Patient Outcomes

The primary outcome was appropriate device therapy during the follow up time period. All device therapy events were captured and categorized as either appropriate or inappropriate, as adjudicated by the managing institution. Device related complications were collected and categorized as infection, lead dislodgement, lead fracture and other. A secondary outcome of patient death in the follow up period was also collected.

Statistical Analysis

Patients were considered to have received appropriate device therapy if at least one appropriate shock was administered over follow-up. Median and interquartile range or frequency and percentage were used to describe continuous and categorical variables. Differences between patients receiving appropriate device therapy or no appropriate device therapy were tested by Wilcoxon rank-sum tests for continuous variables and Fisher exact tests for categorical variables.

Cox proportion hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the time to appropriate device therapy over follow-up according to patient demographic and clinical characteristics at initial presentation. Follow-up time was calculated as the time from device implantation to the first appropriate shock. Patients not experiencing an appropriate shock were censored on their date of death or date of last follow-up. A total of five candidate variables were selected for the multivariable model based on screening the results of the univariate tests. Time from diagnosis to evaluation was modeled using restricted cubic spline terms with knots placed at the 10th, 50th, and 90th percentiles. Knot selection was based on an assessment of model fit as determined by the Akaike information criterion (AIC). Formal testing of the non-linear fit was performed via likelihood ratio tests (LRT) of the full and reduced models. The assumption of proportional hazards was examined by plotting scaled Schoenfeld residuals against time. The ability of the multivariable model to rank-order patients on freedom from appropriate shock was of primary interest and the area under the receiver operating characteristic curve (AUC; concordance statistic) used as the primary measure of model performance. Optimism corrected estimates were obtained using bootstrap resampling (n=1,000 resamples). Kaplan-Meier survival curves were also generated to assess the time to appropriate ICD shock according to idiopathic disease status, family history of sudden death in any first-degree relative, and monomorphic ventricular tachycardia (VT). Differences in event times between groups were tested using the log-rank test. A sub-cohort analysis was performed in patients with 2 or more years of follow-up, comparing variables in patients with and without appropriate device shock.

Statistical analysis was conducted using R version 3.5.0 (R Core Team, 2018). The rms package version 5.1.2 was used to perform the proportional hazards regression modeling and to calculate the AUC and optimism corrected AUC values. The survival package version 2.42.3 and survminer package version 0.4.3 were used to generate the Kaplan-Meier curves and conduct the log-rank tests.

Results

Patient Demographics, History and Diagnoses

At total of 106 patients were included in the study. The cohort was predominately male (64%) with a median age at presentation of 14.7 years (IQR 4.5 (0.1 - 18.7). (Table 1) Of the 106 patients, 20 (19%) received one or more appropriate shocks over a median follow up time of 3 years. (Figure 1) The most common final diagnoses were idiopathic (40%) and channelopathy (38%), followed by cardiomyopathy (20%). Two patients died over the follow up time period, one of cardiac causes and one of non-cardiac causes, but neither of SCA. Seven patients were considered to have “other diagnoses” that did not fit in the discrete pre-determined categories. These included: 2 patients with malignant mitral valve prolapse, one patient with HCN4 mutation, one patient with CALM1 mutation, and 3 patients considered to have paroxysmal ventricular tachycardia syndrome. Compared to the patients without shocks, patients who received appropriate shocks were more likely to have a first-degree relative with SCD. Patients with appropriate shocks had a longer follow-up duration, but were not statistically different on univariate analysis (2.8 vs. 4.7 years; p=0.09). A definitive diagnosis could not be elucidated in 40% of patients and idiopathic diagnosis was the most common diagnosis both at initial presentation and at last follow up. (Table 2; Supplemental Table 1) Interestingly, there were frequent changes in diagnosis from the time of presentation to the time of last follow up, particularly within the channelopathy group. There were 12 patients initially considered idiopathic, of whom 8 were later diagnosed with a channelopathy. Of the 8 channelopathy patients, 88% (7/8) were diagnosed with CPVT. Diagnosis was not found to be significant with regards to appropriate device therapy, neither at the time of presentation, nor during follow up. Importantly, the idiopathic group was not associated with a lower device therapy incidence (p=0.6). (Figure 2)

Table 1.

Outcome by Patient Demographics and Diagnosis.

	All Patients (n=106)	No Appropriate Shock (n=86)	Appropriate Shock (n=20)	P-Value
Patient Characteristics
Age at presentation (years), median (IQR)	14.7 (4.5)	15 (4.5)	13 (5.3)	0.21
Age at last follow up (years), median (IQR)	17.5 (6)	17.7 (5.8)	17.1 (6.3)	0.79
Time from diagnosis to evaluation (years), median (IQR)	3 (5.9)	2.8 (6)	4.7 (5.9)	0.09
Male, n (%)	68 (64)	55 (64)	13 (65)	0.99
Race, n (%)
Black	12 (11)	10 (11.6)	2 (10)	0.76
White	82 (77)	65 (75.6)	17 (85)
Other/Mixed	12 (11)	11 (12.8)	1 (5)
Patient History, n (%)
History of sudden death (1st degree relative)	6 (5.7)	2 (2.3)	4 (20)	0.02
History of Seizure Prior to Arrest	13 (12)	9 (11)	4 (20)	0.26
History of Syncope Prior to Arrest	20 (19)	15 (17)	5 (25)	0.53
Patient Outcome of Death at End of Study, n (%)
Cardiac Etiology	1 (0.9%)	0 (0.0)	1 (5.0)	0.19
Non-cardiac etiology	1 (0.9%)	1 (1.2)	0 (0.0)	0.99

Comparison of patient demographics and patient diagnosis by outcome of appropriate device therapy. ARVC – arrhythmogenic right ventricular cardiomyopathy; CPVT – catecholaminergic polymorphic ventricular tachycardia; DCM – dilated cardiomyopathy; HCM – hypertrophic cardiomyopathy; LQTS – long QT syndrome; LVNC – left ventricular non-compaction; SQTS – short QT syndrome. P-value for Wilcoxon rank-sum test or Fisher’s exact test.

Figure 1.

Underlying Etiology Diagnosed in Pediatric Patients who Underwent Placement of an Implantable Cardioverter-Defibrillator (ICD) following Sudden Cardiac Arrest. Bar graph demonstrating underlying etiology identified in all cohort patients (n=106) who received an ICD following initial presentation with sudden cardiac arrest, compared to underlying diagnoses in the subgroup of patients (n=20) who received an appropriate device therapy for arrhythmia over the median follow-up time of 3 years. Other patients include a mixed group of patients with additional positive diagnoses not included in the major categories (see text).

Table 2.

Clinical Testing and Event Characteristics

Clinical Diagnoses	All Patients (n=106)
At Presentation, n (%)
Cardiomyopathy	21 (20)
HCM	10 (9.4)
LVNC	1 (0.9)
DCM	1 (0.9)
ARVC	5 (4.7)
Other	5 (4.7)
Channelopathy	40 (38)
LQTS	31 (29)
CPVT	5 (4.7)
Brugada	5 (4.7)
SQTS	1 (0.9)
Other	1 (0.9)
Myocarditis	2 (1.9)
Congenital Heart Disease	1 (0.9)
Coronary Artery Anomaly	3 (2.8)
Idiopathic	41 (39)
Other	8 (7.5)
At End of study, n (%)
Cardiomyopathy	17 (16)
HCM	9 (8.5)
LVNC	1 (0.9)
DCM	0 (0)
ARVC	4 (3.8)
Other	3 (2.8)
Channelopathy	40 (38)
LQTS	19 (18)
CPVT	15 (14)
Brugada	4 (3.8)
SQTS	1 (0.9)
Other	1 (0.9)
Myocarditis	1 (0.9)
Congenital Heart Disease	1 (0.9)
Coronary Artery Anomaly	3 (2.8)
Idiopathic	42 (40)
Other	7 (6.6)

ARVC – arrhythmogenic right ventricular cardiomyopathy; CPVT – catecholaminergic polymorphic ventricular tachycardia; DCM – dilated cardiomyopathy; HCM – hypertrophic cardiomyopathy; LQTS – long QT syndrome; LVNC – left ventricular non-compaction; SQTS – short QT syndrome.

Figure 2.

Percent of Patients with Appropriate Device Therapy According To Disease Type. Patients were grouped by major category of underlying cardiac disease: Comparison and break down of percent of patients that received appropriate shock by disease category: A) Cardiomyopathy, B) Channelopathy, C) Myocarditis, D) Congenital Heart Disease, E) Coronary Artery Anomalies, and F) Idiopathic. Black represents the proportion of patients with appropriate shock, while proportion of patients who did not receive an appropriate shock during the median follow-up time of 3 years is shown in grey.

Clinical Testing, Event Characteristics and Device Characteristics

The majority of patients had normal cardiac function, both at the time of initial presentation (81%) and at the time of last follow up (86%), and overall ventricular function was not associated with eventual appropriate device therapy. (Table 3) EP study and exercise testing were performed in a minority of patients prior to device implant and were not associated with future device therapy. Of the 28 patients (26%) who underwent exercise testing, 2 patients with cardiomyopathy and 4 patients with channelopathy were found to have positive (abnormal) findings on electrocardiogram during exercise. (Supplemental Table 2) Of those with CPVT, only 6 of 15 patients (40%) had an exercise study, with only 3 (50%) found to have a positive finding. Documented arrhythmias and use of defibrillation at the time of the presenting SCA event were not associated with future device therapy. (Table 3)

Table 3.

Outcome by Event Characteristics and Clinical Testing

	All Patients (n=106)	No Appropriate Shock (n=86)	Appropriate Shock (n=20)	P-Value
SCA Event Characteristics, n (%)
Event Therapy
CPR only	15 (14)	13 (15)	2 (10)
CPR and defibrillation	87 (82)	69 (80)	18 (90)	0.67
Unknown	4 (3.8)	4 (4.7)	0 (0)
Event Rhythm*
Ventricular Fibrillation	77 (73)	65 (76)	12 (60)	0.17
Monomorphic VT	6 (5.7)	3 (3.5)	3 (15)	0.08
Polymorphic VT	9 (8.5)	6 (7)	3 (15)	0.37
Torsades	7 (6.6)	6 (7)	1 (5)	0.99
Unknown	12 (11)	9 (11)	3 (15)	0.69
Clinical Testing Prior to Implant, n (%)
EP study (y/n)	29 (27)	21 (24)	8 (40)	0.17
Positive EP Study	4 (3.8)	4 (4.7)	0 (0.0)	0.61
Exercise Study (y/n)	26 (25)	21 (24)	5 (25)	0.99
Positive Exercise Study	5 (4.7)	2 (2.3)	3 (15)	0.05
Abnormal/Positive ECG	41 (39)	39 (45)	2 (10)	0.004
Cardiac Function (prior to implant), n (%)
Normal (> 55%)	86 (81)	68 (79)	18 (90)	0.17
Mild Dysfunction (45 – 54%)	11 (10)	11 (13)	0 (0.0)
Moderate Dysfunction (35 – 44%)	4 (3.8)	4 (4.7)	0 (0.0)
Severe Dysfunction (< 35%)	2 (1.9)	1 (1.2)	1 (5)
Cardiac Function (Time of study), n (%)
Normal (> 55%)	91 (86)	75 (87)	16 (80)	0.49
Mild Dysfunction (45 – 54%)	5 (4.7)	3 (3.5)	2 (10)
Moderate Dysfunction (35 – 44%)	2 (1.9)	2 (2.3)	0 (0.0)
Severe Dysfunction (< 35%)	0 (0)	0 (0)	0 (0.0)

SCA – sudden cardiac arrest; EP – electrophysiology; CPR – cardiopulmonary resuscitation; P-value for or Fisher’s exact test.

Transvenous device systems were the most common (79%), followed by epicardial and subcutaneous. (Table 4) Device lead type was not associated with appropriate or inappropriate device therapy. Lead fracture was the most common device-related complication over the follow-up time period, although complications were not associated with future appropriate device therapy.

Table 4.

Outcome by Device Characteristics

	All Patients (n=106)	No Appropriate Shock (n=86)	Appropriate Shock (n=20)	P-Value
Device Type, n (%)
Transvenous	84 (79%)	70 (81.4)	14 (70)	0.31
Epicardial	16 (15%)	11 (12.8)	5 (25)
Subcutaneous	6 (5.7%)	5 (5.8)	1 (5)
Device Chamber Type
Transvenous Single Chamber	54 (51%)	47 (54.7)	7 (35)	0.24
Transvenous Dual Chamber	30 (28%)	23 (26.7)	7 (35)
Device Outcomes
Any appropriate Device Therapy (y/n), n (%)	20 (19%)	0 (0%)	20 (100%)	n/a
All inappropriate Device Therapy (y/n), n (%)	16 (15%)	13 (15%)	3 (15%)	0.99
Device Related Complication, n (%)*
None	84 (79%)	70 (81.4)	14 (70%)	0.36
Infection	2 (1.9%)	1 (1.2%)	1 (5%)	0.34
Lead Dislodgement	3 (2.8%)	3 (3.5%)	0 (0%)	0.99
Lead Fracture	9 (8.5%)	6 (7%)	3 (15%)	0.37
Other	14 (13%)	9 (11%)	5 (25%)	0.13

P-value for Fisher’s exact test.

Patient Outcomes

In addition to the 20 (19%) patients who received an appropriate shock (Figure 3), 16 (15%) patients received an inappropriate shock including 3 (15%) in the group of patients with appropriate therapies and 13 (15%) in the group without appropriate therapy. The multivariable Cox proportional hazards regression model demonstrated an AUC of 0.79 (optimism corrected AUC = 0.72). Variables associated with time to first appropriate shock included monomorphic VT (4.6 [1.2; 17.3]), family history of sudden death in any first-degree relative (6.5 [1.4; 29.8]) (Table 5) and time from diagnosis to evaluation (Figure 4). Time from diagnosis to evaluation exhibited a non-linear association with freedom from appropriate shock increasing from one to five years, and then decreasing thereafter. (LRT for departure from additive linear model: χ2 = 4.81, d.f. = 1, p-value = 0.028; LRT of null model excluding time from diagnosis to evaluation: χ2 = 8.44, d.f. = 2, p-value = 0.015).

Figure 3.

Kaplan Meyer Curves Demonstrating Freedom from Appropriate Shock.Freedom from appropriate shock over time for A) patients with non-idiopathic diagnosis (dark grey) vs. patients with an idiopathic diagnosis (light grey); B) patients with a family history of sudden death in any first-degree relative (dark grey) vs. those without a significant family history (light grey); and C) patients without documented monomorphic ventricular tachycardia (VT) (dark grey) vs. those with documented monomorphic VT (light grey).

Table 5.

Categorical Predictors of Appropriate Shock

	Hazard Ratio
Estimate
Monomorphic VT	4.56 (1.2; 17.28)
History of sudden death	6.45 (1.40; 29.83)
Channelopathy	0.58 (0.13; 2.53)
Cardiac Function	0.49 (0.06; 3.95)
Performance
AUC	0.79
AUCOC*	0.72

Hazard ratios obtained from Cox proportional hazards regression. Time from diagnosis to evaluation modeled using restricted cubic spline terms with knots placed at the 10th, 50th, and 90th percentiles.

^*AUC_OC obtained using 1,000 bootstrap resamples.

AUC – Area under the curve; AUC_OC – optimism correct area under the curve; VT – ventricular tachycardia; SCD – sudden cardiac death

Figure 4.

Log relative hazard for freedom from appropriate shock according to time from diagnosis to evaluation. Values obtained from Cox proportional hazards regression with time from evaluation to diagnosis modeled using restricted cubic spline terms with knots placed at the 10^th, 50^th, and 90^th percentiles. Grey band reflects 95% confidence interval.

Two sensitivity analyses were also performed. In the first analysis, patients with potentially medically treatable forms of disease, including patients with LQTS and CPVT, were compared to other diagnoses. Patients with LQTS and CPVT had no difference in future appropriate device therapy compared to the rest of the cohort, either based on initial diagnosis at the time of diagnosis (p=0.6) or most recent diagnosis at the time of most recent follow up (p=0.8). In the second analysis, patients with fewer than two years of follow-up were excluded in order to mitigate bias of shorter follow-up duration and underestimation of appropriate shock rates. Younger patient age at time of device implant (14.7 vs. 12.0 years; p=0.02), a non-diagnostic ECG at initial evaluation (17.3% vs. 53.3%; p=0.01) and a positive exercise stress test (3.8% vs. 20.0%; p=0.04) were associated with future appropriate device shock in median 5.8 years of follow up.

Discussion

Pediatric patients presenting with SCD often receive ICD therapy as secondary prevention, although the outcomes of these patients remain largely unknown. In this study, only 60% of patients who presented with SCD were found to have a causative diagnosis. Neither the specific underlying disease, nor an idiopathic diagnosis, was associated with future device therapy. Over a short follow-up time period, a relatively high percentage of patients received appropriate device therapies. Documented monomorphic VT and family history of sudden death in any first-degree relative were found to be statistically associated with future appropriate shock delivery. Additionally, in patients at least two years from device implant, younger age at presentation and positive exercise stress testing were associated with future appropriate device shock.

This study demonstrated that future appropriate device therapies were relatively frequent, occurring in 19% of the total cohort over a median follow-up time of 3 years. While appropriate therapies during follow-up were common, only two patients (2%) died, neither from SCA underscoring the important role of secondary ICD placement in this population. Unfortunately, inappropriate device therapies were also relatively common with 16 patients (15%) receiving at least one inappropriate shock over the same mean follow-up of 3 years.

Expectedly, not all patients were found to have a clear cardiac diagnosis at presentation, and in some patients the initial clinical impression changed during follow-up. Furthermore, many patients had an idiopathic or unknown underlying etiology at presentation, and there continued to be 40% of patients with an idiopathic or unknown underlying etiology at the mean follow-up time of 3 years. As has been previously documented in adult studies, idiopathic ventricular arrhythmia was associated with a relatively high incidence of future events and does not obviate the need for ICD therapy in and of itself.(15) In our patients, 20% were initially diagnosed as a cardiomyopathy, but only 16% had this diagnosis at last follow-up. Ongoing and potentially repeated testing in patients initially considered idiopathic is important as 24% of patients initially diagnosed as idiopathic had an eventual diagnosis. CPVT was the most common late diagnosis, likely underscoring the importance of exercise testing at the time of initial presentation, and potential repeated testing of idiopathic patients. Several factors may contribute to a late diagnosis in pediatric patients: inability to perform exercise testing during the initial hospitalization immediately following SCA, delays to obtaining comprehensive genetic testing, and cryptogenic manifestations of some diseases with a delayed clinical phenotype (for example, hypertrophic cardiomyopathy).

Importantly, family history of sudden death in any first-degree relative was the strongest predictor of future appropriate shock following ICD placement after SCA (20% v. 2.3%), emphasizing the importance of familial cascade screening as part of the acute work up of SCA events.^16–19 Although this correlation has been shown in some diseases such as hypertrophic cardiomyopathy, it appears family history also plays an important role in patients with idiopathic etiologies, advocating the need for family history identification and work up in young individuals.¹⁹ Given the diverse group of underlying disease processes represented in this cohort, further sub-group analysis regarding family history and risk of future appropriate shock was not possible. In contrast to prior pediatric studies, that have demonstrated a decreasing incidence of appropriate therapy over time,²⁰ this study demonstrated a non-linear relationship, with risk for appropriate therapy increasing over the first 5 years, followed by a progressive decrease. Other studies involving ICD placement in pediatric patients have only examined factors at implantation and short-term outcomes.^20–22 The relationship between the increased risk of appropriate therapy and monomorphic VT deserves ongoing study. Whether this relationship is related to differing underlying diagnosis or proclivity of recurrence of the underlying mechanism is unclear, but raises additional questions as to whether attempts at early ablation in this subset of patients would reduce future therapies or potentially obviate the need for secondary device therapy.

In patients with longer follow-up durations (minimum 2 years), younger patient age at presentation was associated with appropriate device shock over a median of 5.8 years follow up. While avoiding ICD implantation at earlier ages would be logistically advantageous, this data does not support avoidance despite the known increase in device complications at younger age. Lastly, this sub cohort demonstrated the importance of exercise stress testing and its association with future device therapy and improved diagnosis. Studies have recently demonstrated the importance of exercise testing of CPVT and its impact on delayed diagnosis. Although not specifically studied, lack of early exercise testing appears to have played a role in late or erroneous initial diagnoses in a subset of this population.²³ Potentially of more importance, was its association with long term device therapies, further underlying the importance of exercise stress testing in patients following cardiac arrest.

The initial evaluation of this patient population continues to evolve. Exercise testing at initial evaluation remains important, though the physical ability for patients to appropriately exert and sustain exercise may be limited immediately following cardiac arrest. Given the number of patients with a clinical diagnosis of idiopathic sudden cardiac arrest, repeated exercise testing may be warranted over time. Longitudinal exercise testing may also contribute higher diagnostic yield, given that 50% of the exercise tests were positive in patients diagnosed in this cohort with CPVT. Furthermore, while QTc prolongation may be present at the time of initial evaluation, confirmatory studies are necessary to avoid misinterpretation of QTc following arrest.

Limitations

This study had several limitations, in addition to those inherent to retrospective study design. In order to obtain an appropriate number of patients for this study, a multicenter approach was necessary. As such, data entry was performed at each participating site and local differences in patient population and practice may vary. Likewise, adjudication of patient/family history, discriminating details of presentation (including cardiac rhythm), and authentication of diagnoses were made by each participating site. Despite the multicenter approach, the limited number of patients at risk and number of appropriate shocks occurring over follow-up contributed to imprecision when estimating hazard ratios in multivariable models and limited statistical power to detect small to medium effect sizes. Further, the variable screening prior to fitting the multivariable model would be expected to contribute to optimistic p-values and confidence intervals that may not retain their claimed nominal level. Additionally, detailed genetic evaluation was not included and further study will be necessary to quantify the genetic and functional follow up of this patient cohort, including any genetic variants of unknown significance that may be identified. Given the limited duration of clinical follow-up for the patients in this study, longitudinal data was not available to assess characteristics of diagnostic studies over time, including exercise stress testing. Though lead fractures were responsible for the majority of inappropriate device therapy, other device parameters, including programming and detection information, were not collected in this study. Appropriate device therapy may be the result of specific ICD programming; however, details of ICD platforms and programming were not included in this study. While it is noteworthy that only a minority of patients across multiple centers had an EP study or exercise test at the time of initial evaluation, the generalizability of these findings may be therefore limited. Lastly, it should be noted that this study was a convenience sample and not powered to specifically evaluate specific diagnoses such as LQTS or CPVT in isolation and subgroup analysis was not robust. Moreover, we did not include patients with SCA in whom a device was not placed. As such, this study does not speak to whether patients with channelopathies such as CPVT or LQTS who were previously untreated need secondary device protection following an initial presentation with SCA.

Conclusions

There are heterogeneous disease processes that cause sudden cardiac arrest in pediatric patients without a prior cardiac history. The risk of future therapy is high in pediatric patients receiving an implantable cardioverter defibrillator after initial cardiac arrest, despite the underlying etiology. A significant number of these patients continue to have no clear underlying cardiac disease at initial presentation and during clinical follow up. The presence of a definitive diagnosis after sudden cardiac arrest is not associated with a higher risk for an appropriate shock in the future. This study supports that implantable cardioverter defibrillator therapy should be strongly considered for all pediatric patients following sudden cardiac arrest in whom reversible or treatable causes are not identified.

What Is Known?

• Current guidelines recommend an implantable cardioverter defibrillator (ICD) for secondary prevention in pediatric patients presenting with sudden cardiac arrest.

• Various cardiac diseases may result in sudden cardiac arrest in young people, including idiopathic causes, whether diagnosed at initial presentation or later in clinical follow up.

What the Study Adds?

• After initial ICD placement for secondary prevention, subsequent appropriate shock was common, irrespective of underlying diagnosis.

• In patients at least two years from device implant, younger age at presentation and positive exercise stress testing were associated with future appropriate device shock.

Nonstandard Abbreviations and Acronyms

ARVC

arrhythmogenic right ventricular cardiomyopathy

CHD

congenital heart disease

CPR

cardiopulmonary resuscitation

CPVT

catecholaminergic polymorphic ventricular tachycardia

EP

electrophysiology

ICD

implantable cardioverter defibrillator

LQTS

long QT syndrome

LVNC

left ventricular non-compaction

SCA

sudden cardiac arrest

VT

ventricular tachycardia