A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021)

Abstract

Background: Some patients with hypoplastic left heart syndrome (HLHS) and HLHS-related malformations with ductal-dependent systemic circulation are extremely high-risk for Norwood palliation. We report our comprehensive approach to the management of these patients designed to maximize survival and optimize the utilization of donor hearts. Methods: We reviewed our entire current single center experience with 83 neonates and infants with HLHS and HLHS-related malformations (2015-2021). Standard-risk patients (n = 62) underwent initial Norwood (Stage 1) palliation. High-risk patients with risk factors other than major cardiac risk factors (n = 9) underwent initial Hybrid Stage 1 palliation, consisting of application of bilateral pulmonary bands, stent placement in the patent arterial duct, and atrial septectomy if needed. High-risk patients with major cardiac risk factors (n = 9) were bridged to transplantation with initial combined Hybrid Stage 1 palliation and pulsatile ventricular assist device (VAD) insertion (HYBRID + VAD). Three patients were bridged to transplantation with prostaglandin. Results: Overall survival at 1 year = 90.4% (75/83). Operative Mortality for standard-risk patients undergoing initial Norwood (Stage 1) Operation was 2/62 (3.2%). Of 60 survivors: 57 underwent Glenn, 2 underwent biventricular repair, and 1 underwent cardiac transplantation. Operative Mortality for high-risk patients with risk factors other than major cardiac risk factors undergoing initial Hybrid Stage 1 palliation without VAD was 0/9: 4 underwent transplantation, 1 awaits transplantation, 3 underwent Comprehensive Stage 2 (with 1 death), and 1 underwent biventricular repair. Of 9 HYBRID + VAD patients, 6 (67%) underwent successful cardiac transplantation and are alive today and 3 (33%) died while awaiting transplantation on VAD. Median length of VAD support was 134 days (mean = 134, range = 56-226). Conclusion: A comprehensive approach to the management of patients with HLHS or HLHS-related malformations is associated with Operative Mortality after Norwood of 2/62 = 3.2% and a one-year survival of 75/83 = 90.4%. A subset of 9/83 patients (11%) were stabilized with HYBRID + VAD while awaiting transplantation. VAD facilitates survival on the waiting list during prolonged wait times.

Keywords

hypoplastic left heart syndrome (HLHS)Norwood hybrid ventricular assist device (VAD)

Introduction

The term “functionally univentricular heart” is defined as “a spectrum of congenital cardiac malformations in which the ventricular mass may not readily lend itself to partitioning that commits one ventricular pump to the systemic circulation, and another to the pulmonary circulation”.^1-3 Many patients with functionally univentricular circulation are born with ductal-dependent systemic circulation or ductal-dependent pulmonary circulation, and these patients typically require surgical or transcatheter palliation in the neonatal period. The most common form of functionally univentricular heart with ductal-dependent systemic circulation is hypoplastic left heart syndrome (HLHS), which is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”.^1–4

Since the initial description of the Norwood (Stage 1) Operation,⁵ tremendous advances have been made in the preoperative, intraoperative, and postoperative management of neonates with functionally univentricular hearts and ductal-dependent systemic circulation. Despite these substantial advances in the management of neonates with HLHS and other forms of functionally univentricular hearts with ductal-dependent systemic circulation, a minority of patients with HLHS and these physiologically equivalent HLHS-related malformations are extremely high-risk for conventional Norwood (Stage 1) palliation. Primary cardiac transplantation offers the best option for survival of these challenging neonates; however, waitlist duration is long and waitlist mortality must be minimized.

For neonates with functionally univentricular hearts and ductal-dependent systemic circulation, the roles of conventional Norwood (Stage 1) palliation, hybrid palliation, and cardiac transplantation continue to evolve. We previously reported our initial experience with 9 patients with HLHS bridged to cardiac transplantation with combined pulsatile ventricular assist device (VAD) insertion (Berlin EXCOR, Berlin Heart, Inc, Berlin, Germany) and Stage 1 hybrid palliation, consisting of application of bilateral pulmonary bands, stent placement in the patent arterial duct, and atrial septectomy if needed.^6,7 The purpose of this study is to describe our comprehensive approach to the management of patients with HLHS and HLHS-related malformations, and therefore, to report our entire current single center experience with 83 consecutive neonates and infants managed with this approach between 2015 and 2021, inclusive.

Methods

Overall Approach

At University of Florida, we have developed a comprehensive approach to neonates with HLHS and HLHS-related malformations designed to maximize survival and optimize the utilization of donor hearts; this approach is documented in the flow diagram shown in Figure 1. Our rationale for this approach is that some patients with HLHS or HLHS-related malformations are very high-risk for Norwood (Stage 1) palliation or hybrid palliation, secondary to important cardiac risk factors. Primary cardiac transplantation offers the best option for survival of these challenging neonates; however, waitlist mortality must be minimized. Although risk is a continuous variable, the assignment of a patient to a category of treatment requires categorization of this continuous variable. Consequently, all patients are discussed in detail at a multi-disciplinary Joint Cardiology and Cardiac Surgery Conference in order to select the appropriate individualized plan for treatment.

Study Population

In this study, we report our consecutive series of all neonates with HLHS and HLHS-related malformations with ductal-dependent systemic circulation who presented to University of Florida for their initial surgical intervention during the seven-year time interval of January 1, 2015 through December 31, 2021, inclusive, with their initial episode of care complete by December 31, 2021, and follow-up information provided through April 26, 2022; this consecutive series of 83 neonates includes the following four subgroups:

62 standard-risk patients underwent initial Norwood (Stage 1) palliation.

9 high-risk patients with risk factors other than major cardiac risk factors underwent initial Hybrid Stage 1 palliation, consisting of application of bilateral pulmonary bands, stent placement in the patent arterial duct, and atrial septectomy if needed.

9 high-risk patients with major cardiac risk factors were bridged to transplantation with initial combined Hybrid Stage 1 palliation and pulsatile VAD insertion (HYBRID + VAD).

3 patients early in this series were bridged to transplantation with prostaglandin.

Patients

Standard-risk patients: Standard-risk patients (n = 62) underwent initial Norwood (Stage 1) Operation. Median weight of these 62 patients at Norwood (Stage 1) was 3.22 kg (mean weight = 3.25 kg, weight range = 1.64-6.12 kg). Median age at Norwood (Stage 1) was 11.3 days (mean age = 12.2 days, age range = 3-47 days). The fundamental cardiac diagnosis for these patients was:

31 Hypoplastic left heart syndrome (HLHS), Aortic atresia + Mitral atresia

9 Hypoplastic left heart syndrome (HLHS), Aortic atresia + Mitral stenosis

1 Hypoplastic left heart syndrome (HLHS), Aortic stenosis + Mitral atresia

11 Hypoplastic left heart syndrome (HLHS), Aortic stenosis + Mitral stenosis

1 Hypoplastic left heart syndrome (HLHS), Aortic stenosis + Mitral stenosis + Total anomalous pulmonary venous connection (TAPVC)

3 Aortic atresia + Ventricular septal defect (VSD)

2 Single ventricle, Unbalanced AV canal defect (Unbalanced atrioventricular septal defect), Right dominant

2 Single ventricle, Tricuspid atresia + Transposition of the great arteries (TGA)

1 Single ventricle, Double inlet left ventricle (DILV) + Double outlet right ventricle (DORV)

1 Interrupted aortic arch (IAA), Type B2 (Interruption between the carotid and subclavian arteries with both subclavian arteries arising from the aorta distal to the interruption)

Of the 9 patients with aortic atresia and mitral stenosis, 3 had coronary sinusoids and/or fistulas between the left ventricle and the coronary circulation but did not have evidence of ventricular-dependent coronary circulation. Of note, all patients with aortic atresia and mitral stenosis undergo cardiac catheterization and evaluation of their coronary arteries prior to any intervention, as do any other patients with echocardiographic evidence of coronary arterial abnormalities.

High-risk patients with risk factors other than major cardiac risk factors: High-risk patients with risk factors other than major cardiac risk factors (n = 9) underwent initial Hybrid Stage 1 palliation. An initial hybrid approach was utilized for these patients secondary to the elevated risks of Norwood (Stage 1) Operation in the setting of associated concomitant diagnoses including:

clinically significant necrotizing enterocolitis (NEC, n = 2),

Turner syndrome⁸ (i.e., chromosomal karyotype 45,X0, n = 2),

stroke prior to initial surgical palliation (n = 1),

Kabuki syndrome (n = 1),

congenital third-degree atrioventricular block (n = 1),

heterotaxy syndrome with asplenia (n = 1), and

portal vein thrombosis suggestive of liver infarction (n = 1).

Median weight of these 9 patients at Hybrid Stage 1 was 3.4 kg (mean weight = 3.21 kg, weight range = 2.42-3.8 kg). Median age at Hybrid Stage 1 was 27 days (mean age = 31 days, age range = 8-77 days). The median age at Hybrid Stage 1 palliation was older than the median age at Norwood (Stage 1) palliation because many of these patients undergoing Hybrid Stage 1 palliation were quite ill secondary to associated problems such as NEC or stroke, and they needed to be optimized prior to initial surgical palliation.

This group of patients with risk factors other than major cardiac risk factors ultimately includes 2 subgroups. Patients with recoverable noncardiac illness like necrotizing enterocolitis or portal vein thrombosis are bridged with Hybrid Stage 1 palliation prior to Comprehensive Stage 2. Meanwhile, patients with syndromes felt to be high risk for staged palliation (eg, Turner syndrome)⁸ are bridged with Hybrid Stage 1 palliation prior to cardiac transplantation.

High-risk patients with major cardiac risk factors: High-risk patients with major cardiac risk factors (n = 9) underwent initial HYBRID + VAD. Median weight of these 9 patients at HYBRID + VAD was 3.19 kg (mean weight = 3.28 kg, weight range = 2.43-4 kg). Median age at HYBRID + VAD was 20 days (mean age = 35.1 days, age range = 13-143 days). All 9 patients who underwent initial palliation with HYBRID + VAD presented with anatomical and/or physiological features associated with substantially increased risk for conventional univentricular palliation with the Norwood (Stage 1) Operation:

4 patients presented with large coronary sinusoids and/or fistulas between the left ventricle and the coronary circulation with concerning coronary circulation (Figures 2 and 3, and Videos 1 and 2).

2 patients presented with cardiogenic shock (one with incessant arrhythmia and one requiring extracorporeal membrane oxygenation).

2 patients presented with heart failure and severe atrioventricular valvar regurgitation (Figure 4 and Video 3).

1 patient presented with heart failure with associated end organ dysfunction.

Table 1 documents the clinical characteristics, indications for support, procedural details, and outcomes of these 9 neonates and infants with functionally univentricular heart and ductal-dependent systemic circulation and no prior cardiac surgery who were supported with HYBRID + VAD (8 with HLHS and 1 with HLHS-related malformation). Six of these 9 patients with functionally univentricular ductal-dependent systemic circulation were intubated and mechanically ventilated prior to HYBRID + VAD and at the time they entered the hybrid operating theater for HYBRID + VAD, and the remaining 3 were receiving noninvasive ventilatory support.

Table 1.

Clinical Characteristics, Indications for Support, Procedural Details and Outcomes of 9 Patients With Functionally Univentricular Heart and Ductal-Dependent Systemic Circulation Supported With HYBRID + VAD.

VAD implant year	Diagnosis	Indication for VAD	Surgery prior to VAD implant	Age at VAD implant (days)	Weight at VAD implant (kg)	Transplant vs death	Length of VAD support (days)	Days in hospital prior to VAD implant	Intubation > 10 days after VAD implant
Survivors
2017	HLHS^V: (MA + AA)	Cardiogenic shock with incessant arrhythmia	None	20	3.8	Transplant	64	20	No
2018	HLHS^NV: (MS + AA) Large coronary sinusoids/fistulas	Unfavorable anatomy (large coronary sinusoids/fistulas)	None	20	2.43	Transplant	162	20	Yes
2020	HLHS^V: (MS + AA)	Cardiogenic shock needing ECMO	None	14	4	Transplant	101	13	No
2020	HLHS^V: (MS + AA) Large coronary sinusoids/fistulas	Unfavorable anatomy (large coronary sinusoids/fistulas with coronary stenoses confirmed on catheterization)	None	25	3.1	Transplant	225	24	No
2020	HLHS^NV: (MS + AA) Large coronary sinusoids/fistulas	Unfavorable anatomy (large coronary sinusoids/fistulas)	None	19	3.19	Transplant	226	19	No
2021	Tricuspid atresia^V: severe aortic coarctation + hypoplastic aortic arch, VSD, hypoplastic right ventricle, subvalvar aortic valve stenosis, pulmonary valve stenosis	Moderately severe mitral regurgitation combined with subvalvar aortic valve stenosis, pulmonary valve stenosis	None	34	2.99	Transplant	134	28	No
Nonsurvivors
2017	HLHS^V: (MA + AA) Severe tricuspid regurgitation	Late referral with heart failure and associated end organ dysfunction	None	143	3.85	Death from sepsis and MODS. End organ function made marginal improvement on VAD	138	111	Yes
2018	HLHS^NV: (MS + AA) Large coronary sinusoids/fistulas	Unfavorable anatomy (large coronary sinusoids/fistulas)	None	18	3.25	Withdrawal of support secondary to severe liver dysfunction	56	13	Yes
2018	HLHS^V: (MA + AS) Severe tricuspid regurgitation	Heart failure and severe tricuspid regurgitation	None	30	2.9	Bowel infarct in SMA territory	98	23	No

Abbreviations: ECMO, extracorporeal membrane oxygenation; HLHS^NV, hypoplastic left heart syndrome in patient who was not intubated and ventilated before hybrid approach and ventricular assist device insertion; HLHS^V, hypoplastic left heart syndrome in patient who was intubated and ventilated before hybrid approach and ventricular assist device insertion; MA + AA, mitral atresia and aortic atresia; MA + AS, mitral atresia and aortic stenosis; MODS, multiple organ dysfunction syndrome; MS + AA, mitral stenosis and aortic atresia; SMA, superior mesenteric artery; Tricuspid atresia^V, Tricuspid atresia in patient who was intubated and ventilated before hybrid approach and ventricular assist device insertion; VAD, ventricular assist device; and VSD, ventricular septal defect.

In 2020, one additional infant with HLHS was supported with our HYBRID + VAD approach; although we previously reported this infant in a prior publication of our HYBRID + VAD approach,⁶ we did not include this infant in this current analysis of 83 neonates and infants with HLHS and HLHS-related malformations undergoing initial palliation at our institution because this patient underwent initial surgical palliation at another institution. This patient had the diagnosis of HLHS with aortic atresia and mitral atresia along with severe pulmonary venous obstruction, cor triatriatum, and restrictive atrial septum. The patient underwent initial palliation with a Hybrid Stage 1 procedure at another institution, was transferred to our institution with heart failure, and underwent revision of the Hybrid procedure combined with Berlin Heart VAD insertion at 100 days of age (weight at Hybrid revision + VAD insertion = 4.2 kg). This patient was hospitalized at our institution for 25 days prior to VAD insertion for pre-VAD optimization, was not mechanically ventilated prior to VAD insertion, and was extubated within 10 days of VAD insertion. Unfortunately, this patient died secondary to multiple organ dysfunction syndrome after being supported with VAD for 287 days. Important differences exist between patients whose initial surgical palliation is HYBRID + VAD and patients who undergo HYBRID + VAD as a bailout of failing prior staged palliation.

Bridge to transplantation with prostaglandin: Early in this series, during the initial evolution of our HYBRID + VAD approach, 3 patients with cardiac risk factors who were not candidates for staged palliation were bridged to transplantation with prostaglandin. These patients would be bridged with HYBRID + VAD today. Consequently, Figure 1, which shows our current algorithm for treatment, does not include the option of supporting a neonate or infant with prostaglandin while awaiting primary cardiac transplantation.

For patients with functionally univentricular ductal-dependent systemic circulation and major cardiac risk factors, initial palliation with HYBRID + VAD is now utilized because of the potential for prolonged time on the wait list for a donor heart. VAD facilitates survival on the transplant waiting list during prolonged wait times; allows these patients to be extubated, enterally nourished, and optimized for transplantation; and also allows survival through potential crises while on the waiting list, including episodes of hemodynamic instability and sepsis.

Surgical Technique and Anticoagulation Protocol

Our surgical techniques for HYBRID + VAD and our protocols for anticoagulation for HYBRID + VAD have been previously published.^6,7 For HYBRID + VAD for univentricular neonates with ductal-dependent systemic circulation, during the first 24 h after VAD insertion, no anticoagulation is given. The following anticoagulation protocol is then initiated:

Bivalirudin: During hours 24 to 72, bivalirudin is titrated to a partial thromboplastin time (PTT) of 50 to 70. After 72 h, bivalirudin is titrated to a PTT of 70 to 100.

Aspirin: Aspirin is started on day 5 after VAD implantation at a dose of 5 mg/kg/day (divided into 2 daily doses), and aspirin is increased each week until a dose of 30 mg/kg/day is reached by week 4.

Dipyridamole: Dipyridamole is started on week 5 after VAD implantation at a dose of 2.5 mg/kg/day, and dipyridamole is increased twice each week until a dose of 15 mg/kg/day is reached by week 6.

Omega-3 fatty acid: Omega-3 fatty acid is typically started at 3 to 4 months after VAD implantation.

For Norwood (Stage 1) Operation, we utilize a Sano right ventricle to pulmonary artery conduit for patients with a dominant morphological right ventricle (n = 59) and a modified Blalock-Taussig-Thomas (BTT) systemic-to-pulmonary artery shunt for patients with a dominant morphological left ventricle (n = 3). Cardiopulmonary bypass is established with one right atrial venous cannula and 2 arterial cannulas (for Norwood with Sano: one arterial cannula in the patent arterial duct and one arterial cannula directly in the innominate artery, for Norwood with BTT shunt: one arterial cannula in the patent arterial duct and one arterial cannula perfusing the innominate artery via the BTT shunt). Circulatory arrest is not utilized and instead, sucker bypass is briefly utilized during atrial septectomy and continuous antegrade cerebral perfusion via the innominate artery is utilized during arch construction and aortopulmonary amalgamation. Prior to arch construction and aortopulmonary amalgamation, a single dose of cold potassium-based blood cardioplegia is administered either directly into the ascending aorta or into the side arm of the innominate artery cannula. After separation from cardiopulmonary bypass, modified ultrafiltration and delayed sternal closure are utilized on all patients.

Prior Publications

Our previous analysis⁶ examined 9 patients with HLHS managed with HYBRID + VAD: 8 of these 9 previously reported patients had not undergone prior surgical intervention and are included in this current analysis with updated follow-up provided for each of these patients (Table 1), while, as discussed above, 1 of these 9 previously reported patients had undergone prior hybrid procedure at another institution and is not included in this current analysis, although updated follow-up information about this patient is provided in this study. This current study therefore reports 83 total patients, including 75 patients not previously reported and 8 patients who were previously reported.⁶ This current manuscript provides updated follow-up on these 8 previously reported patients with HLHS supported with HYBRID + VAD and also presents one new patient not previously reported with HLHS-related malformation, who was supported with HYBRID + VAD. Our rationale for this approach is that this current analysis allows assessment of all 83 patients with HLHS or HLHS-related malformations who underwent evaluation for initial surgery at our institution from 2015 to 2021, inclusive, and therefore allows for complete assessment and analysis of our comprehensive approach to the management of these challenging patients. Furthermore, although our surgical techniques and protocols for anticoagulation have been previously reported,^6,7 the overall outcomes of this entire cohort have not been published until this current study.

Database and Institutional Review Board

Data were sourced from a registry and database that uses software certified by the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) and has been prospectively maintained on all patients undergoing pediatric and congenital cardiac surgery at our institution (a component of the CardioAccess International Clinical Outcomes Database: Comprehensive Cardiovascular and Thoracic Module, CardioAccess Inc, Saint Petersburg, Florida, and Fort Lauderdale, Florida: http://www.cardioaccess.com). This study was approved by the University of Florida Institutional Review Board with waiver of the need for consent.

In this study, the same definition of Operative Mortality is used that is used in all databases of STS.^9,10 Operative mortality is defined in all STS databases as (1) all deaths, regardless of cause, occurring during the hospitalization in which the operation was performed, even if after 30 days (including patients transferred to other acute care facilities); and (2) all deaths, regardless of cause, occurring after discharge from the hospital but before the end of the 30th postoperative day.

Results

Outcomes Stratified by Treatment Pathway

Standard-risk patients: Standard-risk patients (n = 62) underwent initial Norwood (Stage 1) Operation with an Operative Mortality of 2 patients or 3.2%. Median postoperative length of hospital stay after Norwood Stage 1 was 23 days. A total of 60 out of 62 (96.72%) patients survived Norwood (Stage 1) Operation; of these 60 Norwood (Stage 1) survivors, zero patients died during Interstage One (between Norwood [Stage 1] and Stage 2), and:

57 underwent successful bidirectional superior cavopulmonary connection;

2 underwent successful biventricular repair; and

1 underwent successful heart transplantation, was discharged home, and died 853 days after Norwood (Stage 1) from multiple organ dysfunction syndrome.

Fifty-seven patients underwent Stage 2 superior cavopulmonary connection with zero Operative Mortality. Two patients died during Interstage Two (between Stage 2 Superior Cavopulmonary Connection and Stage 3 Total Cavopulmonary Connection); 1 died secondary to vomiting and dehydration and 1 died from sudden cardiac death. Ten patients underwent Fontan operation with zero Operative Mortality, and 45 patients are awaiting Fontan. Table 2 documents the mortality timing for patients who underwent Norwood (Stage 1).

Table 2.

Mortality Timing for Patients Who Underwent Norwood (Stage 1).

Mortality timing for patients who underwent Norwood (Stage 1)
Time period	Mortality	Percentage (%)
Mortality reported as a percentage of patients at risk in the time period under analysis
Mortality within 30 days of Norwood (Stage 1)	0/62	0.0
Mortality more than 30 days after Norwood (Stage 1), but before hospital discharge from Norwood (Stage 1)	2/62	3.2
Mortality Interstage One (between Norwood [Stage 1] and Stage 2)	0/60	0.0
Mortality before discharge to home from Stage 2 Superior Cavopulmonary Connection	0/57	0.0
Mortality Interstage Two (between Stage 2 Superior Cavopulmonary Connection and Stage 3 Total Cavopulmonary Connection)	2/57	3.5
Mortality late after heart transplant after Norwood (Stage 1) and posttransplant discharge home	1/1	100.0
Mortality before discharge to home from Stage 3 Total Cavopulmonary Connection	0/10	0.0
Total mortality	5/62	8.1
Mortality reported as a percentage of all 62 patients undergoing Norwood Stage 1
Mortality within 30 days of Norwood (Stage 1)	0/62	0.0
Mortality more than 30 days after Norwood (Stage 1), but before hospital discharge from Norwood (Stage 1)	2/62	3.2
Mortality Interstage One (between Norwood [Stage 1] and Stage 2)	0/62	0.0
Mortality before discharge to home from Stage 2 Superior Cavopulmonary Connection	0/62	0.0
Mortality Interstage Two (between Stage 2 Superior Cavopulmonary Connection and Stage 3 Total Cavopulmonary Connection)	2/62	3.2
Mortality late after heart transplant after Norwood (Stage 1) and posttransplant discharge home	1/62	1.6
Mortality before discharge to home from Stage 3 Total Cavopulmonary Connection	0/62	0.0
Total mortality	5/62	8.1

High-risk patients with risk factors other than major cardiac risk factors: High-risk patients with risk factors other than major cardiac risk factors (n = 9) underwent initial Hybrid Stage 1 palliation (without VAD) with an Operative Mortality of Zero but with 1 death after Comprehensive Stage 2. A total of 9 out of 9 (100%) survived Hybrid Stage 1 operation (without VAD); of these 9 Hybrid Stage 1 survivors:

4 underwent successful heart transplantation,

1 is awaiting heart transplantation,

3 underwent Comprehensive Stage 2 with 1 Operative Mortality after Comprehensive Stage 2, and

1 underwent successful biventricular repair.

High-risk patients with major cardiac risk factors: High-risk patients with major cardiac risk factors (n = 9) underwent initial HYBRID + VAD: 6 patients (67%) underwent successful cardiac transplantation and are alive today and 3 patients (33%) died while awaiting transplantation on VAD. The cause of death of these 3 nonsurvivors is documented in Table 1. All 6 survivors of HYBRID + VAD are at home doing well after successful cardiac transplantation. Length of VAD support was similar among survivors and nonsurvivors, with a maximal length of VAD support of 226 days:

Median length of VAD support of all 9 patients supported with HYBRID + VAD was 134 days (mean = 134 days, range = 56-226 days).

Median length of VAD support of all 6 survivors supported with HYBRID + VAD was 148 days (mean = 152 days, range = 64-226 days).

Median length of VAD support of all 3 nonsurvivors supported with HYBRID + VAD was 98 days (mean = 97 days, range = 56-138 days).

Only 1 of 6 survivors (16.7%) required intubation more than 10 days after HYBRID + VAD, but 2 of 3 nonsurvivors (66.7%) required intubation more than 10 days after HYBRID + VAD. Only 1 of 9 patients supported with HYBRID + VAD experienced stroke, after 150 days on VAD. This stroke was not life threatening, did not necessitate VAD removal, and this patient ultimately underwent successful cardiac transplantation.

Bridge to transplantation with prostaglandin: Early in this series, 3 patients with cardiac risk factors were bridged to primary cardiac transplantation with prostaglandin: 2 underwent successful heart transplantation after 52 and 120 days of prostaglandin therapy, and 1 died while awaiting transplantation after 293 days of prostaglandin therapy.

Overall Outcomes

Table 3 provides the Operative Mortality and outcomes at one year for all 83 patients. Of note, Operative Mortality after Norwood (Stage 1) Operation is 3.2% (2/62) and one-year survival in all 83 patients is 90.4% (75/83).

Table 3.

Overall Outcomes.

		Operative mortality	Operative mortality	Mortality at 1 year	Mortality at 1 year
Initial approach	Number	(n)	(%)	(n)	(%)
Norwood	62	2	3.2	3	4.8
Hybrid No VAD^a	9	0	0.0	1^a	11.1
HYBRID + VAD	9	3	33.3	3	33.3
TX from PGE^b	3	0	0.0	1^b	33.3
Total—all patients	83	5	6.0	8	9.6

PGE, prostaglandin; VAD, ventricular assist device; TX, transplant

1 death at Comprehensive Stage 2.

1 death while awaiting transplantation after 293 days of prostaglandin therapy.

Figure 5 is a Kaplan-Meier survival curve that documents longitudinal survival with 95% confidence intervals in patients who underwent Norwood (Stage 1) operation (n = 62), HYBRID Stage 1 without VAD (n = 9), and HYBRID + VAD (n = 9).

Figure 6 is a flow diagram that documents the initial and longitudinal outcomes of all 83 patients, after their initial palliation and after any subsequent operations.

Discussion

Our analysis of 83 patients with HLHS (n = 73) or physiologically equivalent HLHS-related malformations (n = 10) reveals that, to date, our comprehensive approach to the management of patients with HLHS and HLHS-related malformations is associated with an Operative Mortality after Norwood (Stage 1) Operation of 3.2% (2/62) and, more importantly, a one-year survival in all 83 patients of 90.4% (75/83). Our comprehensive approach is based on the principle that some patients with HLHS or HLHS-related malformations are very high-risk for Norwood (Stage 1) palliation or hybrid palliation secondary to important cardiac risk factors. Although primary cardiac transplantation offers the best option for survival of these challenging neonates, waitlist mortality must be minimized. Median length of VAD support of all 9 patients supported with HYBRID + VAD was 134 days, with a maximum length of support of 226 days. These wait list times for neonates in need of a new heart are certainly long, and these prolonged times are manageable because of the VAD. Our data demonstrate that high-risk functionally univentricular neonates with ductal-dependent systemic blood flow who are suboptimal candidates for Norwood palliation can be successfully stabilized with pulsatile VAD insertion along with their initial surgical palliation while awaiting transplantation; these patients may be extubated, enterally nourished, and optimized for transplantation while on VAD.

Between January 1, 2014 and December 31, 2017, 2737 Norwood (Stage 1) Operations were performed and captured in STS CHSD, and the aggregate rate of Operative Mortality was 15.0%.¹¹ Meanwhile, the Single Ventricle Reconstruction Trial, funded by the National Institutes of Health of the United States of America (USA), documented a one-year survival of 64% in patients undergoing Norwood (Stage 1) Operation with modified Blalock-Taussig-Thomas systemic-to-pulmonary artery shunt and 74% in patients undergoing Norwood (Stage 1) Operation with Sano right ventricle to pulmonary artery conduit.^12,13 These data can contextualize the results reported in this manuscript (an Operative Mortality after Norwood (Stage 1) Operation of 3.2% [2/62] and a one-year survival in all 83 patients of 90.4% [75/83]).

In the final analysis, our comprehensive approach to neonates with HLHS and HLHS-related malformations maximizes survival and optimizes the utilization of donor hearts. High-risk patients with HLHS and HLHS-related malformations who are poor candidates for Norwood palliation can be successfully stabilized with pulsatile VAD insertion along with hybrid palliation while awaiting cardiac transplantation. VAD facilitates survival during prolonged wait times, which can exceed 6 months. In patients with functionally univentricular hearts, we prefer pulsatile VAD rather than continuous flow VAD because we believe that (1) pulsatile VAD is more physiologic, (2) the management of patients on pulsatile VAD is more intuitive for the healthcare team, (3) pulsatile VAD is associated with decreased risk of pulmonary overcirculation, and (4) pulsatile VAD is associated with improved renal function.

It is a fact that not nearly enough donor hearts are available to offer cardiac transplantation to all patients with HLHS.⁶ Between 2014 and 2020, between 111 and 133 neonatal heart transplants were performed per year in the United States of America,¹⁴ while, as discussed above, an average of 684.25 Norwood (Stage 1) Operations were performed annually in the United States of America between January 1, 2014 through December 31, 2017.¹¹ However, a subset of high-risk patients with functionally univentricular circulation may be best served with primary cardiac transplantation. The strategy reported in this study can facilitate safe prolonged bridge to cardiac transplantation in high-risk neonates with functionally univentricular circulation.

A recent analysis of the STS CHSD examined 1135 patients who underwent Fontan revision (n = 598) or transplantation secondary to Fontan failure (n = 537) at 100 centers.¹⁵ Transplantation increased from 34 in 2010 to 76 in 2017, largely owing to an increase in patients with HLHS (18 in 2010 to 49 in 2017). In these patients with Fontan failure, Operative Mortality and composite major morbidity and mortality associated with transplantation was 7.6% and 35%, respectively. Because cardiac transplantation in the setting of failed staged palliation is associated with high morbidity and mortality, it is reasonable to consider primary transplantation for the subset of functionally univentricular patients who are at high-risk for failing conventional staged palliation. Strategies to optimize survival while on the wait list are critical in this setting. Although support with VAD optimizes survival while on the wait list in high-risk patients, the utilization of prolonged VAD support in neonates and infants with functionally univentricular circulation is uncommon.^16–20

Value of This Analysis

This study presents a comprehensive approach to the management of neonates with HLHS and HLHS-related malformations that is based on the principle that some patients with HLHS or HLHS-related malformations are very high-risk for Norwood (Stage 1) palliation or hybrid palliation secondary to important cardiac risk factors. Although primary cardiac transplantation offers the best option for survival of these challenging neonates, waitlist mortality must be minimized. Published literature clearly documents the lack of available donor hearts for neonates and infants.^6,11,14 VAD support can stabilize neonates and infants during prolonged times on the wait list and therefore maximize utilization of donor hearts and improve overall survival of patients with HLHS and HLHS-related malformations.

Limitations and Future Directions

The major challenge of prolonged VAD support of neonates and infants is the prevention of thromboembolic complications and stroke. Strategies must be developed to prevent stroke in neonates and infants supported with VAD for prolonged periods of time. Our program continues to explore strategies to minimize strokes during VAD support and manage strokes during VAD support. We are considering augmentation of our current protocol of anticoagulation while on VAD, including the possible addition of Clopidogrel after 120 days on VAD support.

Conclusion

A comprehensive approach to the management of 83 neonates and infants with HLHS or HLHS-related malformation is associated with an Operative Mortality after Norwood (Stage 1) Operation of 3.2% (2/62) and a one-year survival of 90.4% (75/83). A subset of 9 out of these 83 patients (11%) was felt to be very high-risk for Norwood (Stage 1) palliation or hybrid palliation secondary to important cardiac risk factors. These 9 high-risk neonates and infants were stabilized with VAD insertion along with initial palliation while awaiting transplantation. These patients were extubated, enterally nourished, and optimized for transplantation while on VAD. VAD facilitates survival on the transplant waiting list during prolonged wait times. VAD support allows survival through potential crises while on the waiting list, including episodes of hemodynamic instability and sepsis. Our comprehensive approach to patients with functionally univentricular ductal-dependent systemic circulation improves the overall survival of these challenging patients and provides a pathway for salvage of the highest risk subset of these neonates.

Supplemental Material

sj-mov-1-pch-10.1177_21501351221088030 - Supplemental material for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021)

Supplemental material, sj-mov-1-pch-10.1177_21501351221088030 for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021) by Mark S. Bleiweis, Giles J. Peek, Joseph Philip, James C. Fudge, Kevin J. Sullivan, Jennifer Co-Vu, Curt DeGroff, Himesh V. Vyas, Dipankar Gupta, Renata Shih, Biagio “Bill” A. Pietra, Frederick Jay Fricker, Susana C. Cruz Beltran, Michael A. Arnold, Mark C. Wesley, Andrew D. Pitkin, Jose F. Hernandez-Rivera, Dalia Lopez-Colon, Wendy E. Barras, Yuriy Stukov, Omar M. Sharaf, Dan Neal, Connie S. Nixon and Jeffrey P. Jacobs in World Journal for Pediatric and Congenital Heart Surgery

Supplemental Material

sj-mov-2-pch-10.1177_21501351221088030 - Supplemental material for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021)

Supplemental material, sj-mov-2-pch-10.1177_21501351221088030 for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021) by Mark S. Bleiweis, Giles J. Peek, Joseph Philip, James C. Fudge, Kevin J. Sullivan, Jennifer Co-Vu, Curt DeGroff, Himesh V. Vyas, Dipankar Gupta, Renata Shih, Biagio “Bill” A. Pietra, Frederick Jay Fricker, Susana C. Cruz Beltran, Michael A. Arnold, Mark C. Wesley, Andrew D. Pitkin, Jose F. Hernandez-Rivera, Dalia Lopez-Colon, Wendy E. Barras, Yuriy Stukov, Omar M. Sharaf, Dan Neal, Connie S. Nixon and Jeffrey P. Jacobs in World Journal for Pediatric and Congenital Heart Surgery

Supplemental Material

sj-mp4-3-pch-10.1177_21501351221088030 - Supplemental material for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021)

Supplemental material, sj-mp4-3-pch-10.1177_21501351221088030 for A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021) by Mark S. Bleiweis, Giles J. Peek, Joseph Philip, James C. Fudge, Kevin J. Sullivan, Jennifer Co-Vu, Curt DeGroff, Himesh V. Vyas, Dipankar Gupta, Renata Shih, Biagio “Bill” A. Pietra, Frederick Jay Fricker, Susana C. Cruz Beltran, Michael A. Arnold, Mark C. Wesley, Andrew D. Pitkin, Jose F. Hernandez-Rivera, Dalia Lopez-Colon, Wendy E. Barras, Yuriy Stukov, Omar M. Sharaf, Dan Neal, Connie S. Nixon and Jeffrey P. Jacobs in World Journal for Pediatric and Congenital Heart Surgery

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Yuriy Stukov

Jeffrey P. Jacobs

Supplemental Material

Supplemental material for this article is available online.

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