Hypoplastic left heart syndrome: Prognosis and management options

Abstract

Few congenital heart malformations have raised as many surgical, ethical, social and economic issues as the therapy for infants diagnosed with hypoplastic left heart syndrome. Before the 1980s, this complex malformation was associated with 95% mortality within the first month of life. In the past two decades, palliative surgery and cardiac transplantation have become management options, in addition to comfort care for the infant. These innovations have forced parents and physicians to make difficult decisions because the long term results of the additional treatment options are not known. This article describes the current risk factors, diagnosis, treatment and outcome of infants with hypoplastic left heart syndrome. Prenatal diagnosis provides families with time for counselling and for becoming more informed about management options. Surgical therapy provides hope for the survival of these infants, but their long term outcomes are not well defined. Comfort care in either the home or hospital remains an acceptable management option. More investigations to determine the long term outcome following palliative surgery and transplantation are needed before they become the standards of care.

Few congenital heart malformations have raised as many surgical, ethical, social and economic issues as the therapy for infants born with hypoplastic left heart syndrome (HLHS) (1,2). HLHS was first described by Lev in 1952 (3) and named in 1958 by Noonan and Nadas (4). It has been reported to occur in approximately 0.016% to 0.036% of live births in Canada and the United States (5–9). Thus, each year approximately 56 to 126 infants in Canada and 640 to 1440 infants in the United States are born with HLHS (10,11). HLHS represents 2% to 9% of congenital heart disease cases and accounts for 23% of neonatal deaths from congenital heart malformations (6,12–14).

HLHS is a clinically useful description of a constellation of cardiac malformations, all characterized by underdevelopment or absence of the left ventricle (2). Features of HLHS include varying degrees of hypoplasia of the left ventricle, mitral valve and aortic valve atresia or stenosis, and hypoplasia of the ascending aorta (13) (Figure 1). Coarctation of the aorta occurs in 67% to 80% of cases (6,15,16). Most often, the newborn is otherwise healthy, with the prevalence of serious, associated noncardiac conditions being relatively low (2,5). Untreated, the prognosis for the infant is certain death (2).

Figure 1).

Illustration of the essential anatomical and physiological derangements when a hypoplastic left ventricle is associated with aortic and mitral atresia. There is an imperforate aortic orifice and a hypoplastic ascending aorta (Asc ao). The mitral orifice is imperforate and the left ventricular (LV) cavity is slitlike. Blood leaves the obstructed left atrium (LA) through a restrictive interatrial communication that is usually represented by a foramen ovale. The right ventricle (RV) supplies the pulmonary and systemic circulations. The systemic bed is reached through a patent ductus arteriosus (PDA) that also provides retrograde flow into the hypoplastic ascending aorta and the coronary arteries. RA Right atrium; PT Pulmonary trunk; Desc ao Descending aorta. Reproduced with permission from reference 48

Before the 1980s, this complex malformation was associated with 95% mortality within the first month of life (12,13,17,18). In the past two decades, there has been remarkable progress in the management of children born with HLHS (19). In the 1970s, Fontan and Baudet (20) introduced an operative procedure that is now being applied to a variety of cardiac lesions involving one functional ventricle, including HLHS (20). In 1980, Norwood et al (21) reported the first palliative reconstructive surgery for HLHS (18,21). In 1986, Bailey et al completed the first successful infant heart transplant for HLHS, offering an alternative to the palliative reconstructive approach (19,22). However, many infants die while awaiting a donor heart for transplantation (13,19). The option of palliative or comfort care without aggressive surgical intervention remains, either at home or in hospital (13,17–19). Parents and physicians face difficult decisions regarding the appropriate therapeutic intervention for individual infants with HLHS (13). This paper will review the risk factors, diagnosis, treatment and outcome of infants with HLHS.

RISK FACTORS

HLHS occurs predominantly in males (23). It is well known that there is a genetic predisposition for HLHS in some families, but a complete understanding of the genetic causes is unknown (19). Approximately 12% of infants with HLHS have associated extracardiac anomalies (5,8). Genetic disorders associated with HLHS include Turner syndrome, Holt-Oram syndrome, Smith-Lemli-Opitz syndrome, Noonan syndrome, trisomy 13, trisomy 18 and trisomy 21 (6,8,23,24). Further investigations are needed to determine specific risk factors for HLHS which could lead to better prenatal screening and diagnosis.

DIAGNOSIS

Prenatal diagnosis:

An increasing number of infants are being diagnosed prenatally with high resolution ultrasonography. The specificity and predictive value of ultrasonography have been reported to be greater than 95% (25). Some defects, however, evolve or progress during the latter half of pregnancy, which limits definitive diagnosis early in gestation (19,26–28).

Prenatal diagnosis of HLHS in fetal life offers to families the opportunity for counselling about the diagnosis and their options, such as pregnancy termination, planned delivery in a health centre (with the appropriate specialty services available and alerted) and postnatal management options (27,29). Prenatal diagnosis of HLHS could possibly decrease donor waiting time if the neonate is placed on a transplant list before birth (30).

Postnatal diagnosis:

Most infants with HLHS are recognized soon after birth. The normal physiological changes that occur after birth lead to serious or lethal hemodynamic disturbances in the neonate with HLHS (19). The three major determinants of the hemodynamic disturbances are the gradual decrease in pulmonary vascular resistance, the spontaneous constriction of the ductus arteriosus and the inadequacy of the interatrial connection (31). Coarctation of the aorta may impede retrograde blood flow to a diminutive ascending aorta and, thus, decrease the adequacy of coronary blood flow (32,33). As these changes occur, systemic and coronary perfusion are decreased, leading to tissue hypoxia, metabolic acidosis and, eventually, vascular shock and death (31,32). Although the structural defects of HLHS may be variable among individual infants, the associated pathophysiology is similar (31).

The clinical presentations of HLHS occur most frequently between days 1 and 3 of life, and include respiratory distress with tachypnea and mild cyanosis, shock, and less commonly, severe cyanosis (31). Most infants die within the first two weeks of life, with an average age at death of 4.5 days (31,33,34). Some patients with HLHS, however, can survive beyond sixty days, without any surgical intervention through the development of pulmonary hypertension (8,33). Morris et al (8) found that 15%±4% of infants died on the first day of life, 70%±5% died within the first week of life and 91%±3% died within 30 days.

Survival of infants with HLHS requires meticulous attention to balance the systemic and pulmonary circulation, especially during the hemodynamic changes in the newborn period (Table 1). While the ductus arteriosus is patent, the majority of infants are able to maintain a precarious balance between the pulmonary and systemic resistance, resulting in a satisfactory pulmonary and systemic perfusion (31). Therefore, immediate therapy of infants with HLHS is aimed at maintaining the patency of the ductus arteriosus with an intravenous prostaglandin E₁ infusion (32). Diuretic infusion, inotropic support, sodium bicarbonate infusion, mechanical ventilation and sedation may be necessary to treat the respiratory and cardiac insufficiency complicated by metabolic acidemia (33).

TABLE 1:

Factors unfavorable for survival with hypoplastic left heart syndrome

Partial pressure of arterial oxygen greater than 60 mmHg

Interatrial communication 3 mm or less in width

Mitral atresia

Aortic atresia

Significant noncardiac congenital anomalies

Higher arterial oxygen pressure is paradoxically an unfavourable sign, indicating pulmonary overcirculation with progressive congestive failure and consequent systemic undercirculation and poor peripheral perfusion (31,35). Less commonly, there may be a persistance of high pulmonary arteriolar resistance that does not diminish in the postnatal period or when there is marked restriction at the interatrial septum (31). There is a significant correlation of survival with smaller interatrial communications; however, severe intractable hypoxemia also limits survival (33). An interatrial flow jet width 3 mm or less, measured by colour flow Doppler, is thought to be associated with a greater risk of death (36). A study from Japan suggested that an interatrial communication of less than 5 mm without severe hypoxemia may have a better long term survival (33). Limited balloon dilatation may, therefore, be beneficial to those infants who develop progressive hypoxemia and metabolic acidosis. Optimal medical management is critical if these infants are to survive (19).

SURGICAL TREATMENT AND THEIR OUTCOMES

The Norwood staged procedures:

The ability to make a precise diagnosis in the neonate using echocardiography, combined with the introduction of prostaglandin E₁ to maintain ductal patency, paved the way for Norwood et al (21) to develop the palliative, staged reconstructive procedures that have altered the outlook of HLHS in the past decade (2,19). Refinements in operative techniques, diagnostic imaging and perioperative management have futher improved survival following these palliative procedures (2,30).

The initial phase of the Norwood procedure is the construction of an unobstructed systemic blood flow from the right ventricle to the aorta, and restricted pulmonary blood flow through a systemic to pulmonary artery shunt (2) (Figure 2a; Stage 1). Subsequent procedures are designed to facilitate the transition to a physiologically normal circulation with the connection of the superior vena cava (SVC) (Hemi-Fontan; Stage 2) and inferior vena cava (IVC) (Fenestrated Fontan; Stage 3) to the undivided pulmonary arteries (2,27,30) (Figure 2b,c). The last stage involves the closure of the fenestration, which is performed in the cardiac catheterization laboratory (Figure 2d; Stage 4). The final result is that the right ventricle pumps oxygenated blood through a reconstructed aorta and venous blood returns directly to the lungs (13).

Figure 2).

Illustration of the staged palliative surgery for hypoplastic left heart syndrome. a) Norwood procedure; b) Hemi-Fontan procedure; c) Fenestrated Fontan procedure; d) Closure of the fenestration. The final result is that the right ventricle (RV) pumps blood through a reconstructed aorta (Ao) and venous blood returns through the superior (SVC) and inferior vena cava (IVC) directly to the lungs. BT Shunt Blalock-Taussig Shunt; LA Left atrium; RA Right atrium

The perioperative survival rates reported for the Norwood operation have ranged from 47% to 85% (2,18,37). Survival has been shown to be worse in patients with significant noncardiac congenital anomalies, low birth weight and severe obstruction to pulmonary venous return (2,34). Hospital survival rates reported are 94% to 98% following the hemi-Fontan procedure and 86% to 94% following the Fontan procedure (2,38–40). Actuarial survival for all infants with combined staged procedures has been reported to be 63% to 80% at one year of age and 58% to 72% at five years of age (2,39,41–43). In a large multi-institutional study on neonates with aortic atresia, the actuarial survival of all infants with HLHS placed in the palliative surgery pathway was 50% at one year of age and 47% at three years of age (34).

Morbidity associated with the cardiovascular system was reported in 10% of patients including dysrhythmias, coarctation, right ventricular dysfunction, left pulmonary artery occlusion and pulmonary artery hypertension (2).

The central nervous system (CNS) of infants with HLHS has been an area of concern, especially because more and more infants are surviving palliation. Bove and Lloyd (2) noted neurological conditions in 6% of patients including thromboembolic strokes and developmental delays. Razzouk et al (12) noted that 10% of patients had neurological abnormalities following reconstructive procedures. Glauser et al (35) found that postmortem, 45% of infants had hypoxic-ischemic lesions and intracranial hemorrhages. Furthermore, an association between HLHS and congenital brain anomalies has been proposed because of the high prevalence of major and minor CNS abnormalities postmortem, with frequencies ranging from 3% to 29% (24).

Rogers et al (17) reported that at a mean age of 38 months, 73% of infants had microcephaly and 45% were underweight following interventions. Sixty-four per cent of these infants had varying degrees of mental retardation and 73% had substantial functional disability. However, Kern et al (44) noted that in their cohort, the median full scale IQ was 88 and only 8.3% of their patients met the diagnostic criteria for mental retardation. They found that although the results were not statistically significant, all HLHS patients scored lower on average on neurodevelopmental tests compared with matched controls (44). The cause of a high prevalence of developmental disabilities remains unclear, illustrating the need to evaluate these patients continuously to assess their quality of life (2,17).

Concerns about the long term outcome of infants with HLHS include the adequate preservation of the right ventricle and valvular function when exposed to systemic pressure (32). In addition, resources and expertise that are required for staged repair of HLHS may not be readily available in many centres (32). Results from institutions treating fewer than 16 patients/year have reported mortality rates as high as 91% (32).

Cardiac transplantation:

Cardiac transplantation offers the potential for a normal cardiovascular physiology over the limitations of the single ventricle physiology achieved after multi-stage reconstruction (12). Infants who survive stage 1 palliation may not be suitable for the next procedures and, therefore, may need cardiac transplantation (30). Infants with certain anatomical subtypes (mitral atresia or aortic atresia) face significant early mortality after reconstruction and perhaps are best treated with cardiac transplantation (12). The major limitations of transplantation are a shortage of donors and size matching from donor to recipient (12). Management during the waiting period can also be challenging (12); one study had a waiting period ranging from zero to 100 days (30). HLHS infants are prone to the development of intractable heart failure or systemic organ dysfunction as the waiting period lengthens and, thus, pretransplant mortality is 20% to 40% (12). Longer waiting times also increase the risk of postoperative pulmonary hypertension (30).

During the waiting period, infants are stabilized using continuous intravenous infusions of prostaglandin E₁ at the minimum rate necessary to maintain ductal patency (12,45). Mechanical ventilation, inotropic support, intermittent infusion of sodium bicarbonate and diuretics may be necessary (45). Once stabilized, many neonates can be weaned off ventilatory and cardiac support (45). If systemic perfusion is compromised due to a restrictive duct, infants may require percutaneous or open placement of a ductal stent (12).

Moderate hypoxemia is far better tolerated than hyperoxia in infants with HLHS, which results in hypoperfusion acidosis (45). Pulmonary overcirculation and oxygen saturations of more than 90% may be the result of the decrease in pulmonary vascular resistance that accompanies birth (45). This is best treated with diuretic infusions and decreased inspired oxygen concentration by blending in nitrogen and carbon dioxide (16,45). These measures will selectively increase pulmonary resistance while maintaining systemic resistance and, hence, balance the two circulations (16). The balance between the pulmonary and systemic circulations is critical for these infants to survive to receive a transplant.

Although atrial mixing of blood is essential for survival, some degree of obstruction to pulmonary venous return is desirable to limit pulmonary overcirculation (45). Some infants may develop progressive hypoxemia due to an absent or severely restrictive interatrial communication (12,45). These infants may require intervention, such as a balloon or blade atrial septostomy, or open, surgical septectomy (12,45).

Operative mortality of neonatal cardiac transplantation has been reported to be in the range of 9% to 20% (12,45). Actuarial survival for infants who received transplants was 76% at five years and 70% at seven years (12). Actuarial survival for all infants listed for transplant has been reported to be 60% to 65% at two years and 55% to 60% at seven years (12,45). Jacobs et al (34) reported an overall survival of 48% at two years and 47% at three years.

Rejection is the major cause of death following paediatric cardiac transplantation because early diagnosis is challenging (12,30,45). Routine surveillance by endomyocardial biopsy in infants is not very practical, and, in the absence of cardiac symptoms, it has not been very helpful (12). Clinical evaluation and noninvasive testing, therefore, have been the primary means of rejection surveillance for the infants (6). Rejection is most commonly seen during the first three to six months following transplant, but many late deaths have been due to rejection (12,46). The incidence of rejection has been reported to be 0.52 to 1.05/patient/year (6,12). Razzouk et al (12) reported that actuarial freedom from rejection was 30% at three months, 28% at one year and 15% at seven years.

Infection is most prevalent during the early post-transplantation period and during treatment for rejection, periods corresponding to the most intense immunosuppression (12,45). Approximately 50% to 70% of patients will have a significant infection during the first year after transplantation (12,45). Appropriate management requires vigilance and early, aggressive antibiotic treatment (45). In the early postoperative period, infections are usually bacterial and involve the lungs, urinary tract and sepsis (45). During the next several months, cytomegalovirus and Pneumocystis carinii are more problematic (45).

Accelerated graft coronary vasculopathy is a major limitation of long term survival after transplantation (12,30,45). The incidence in paediatric heart transplant recipients ranges from 2% to 43% at five years post-transplant (45,47). The etiology of graft coronary vasculopathy is still unclear, although most investigators support an immunological basis (12). Cardiac retransplantation is the only effective therapy for the vasculopathy, and close and long term follow-up of all patients is indicated (12).

There is also the need for lifelong immunosuppressive therapy following cardiac transplantation (12). Chronic immunosuppressive therapy brings concerns associated with renal dysfunction, hypertension and the increased risk of lymphoproliferative disease (45). Renal impairment is related to cyclosporine toxicity as well as the pretransplant low perfusion state of the recipient (45); it has been reported in approximately 11% of cases (6). Most of the lymphomatous lesions have been shown to be associated with Epstein-Barr virus as well as more intense immunosuppressive therapy (12,45). Immunosuppressed infants have a 3% to 16% risk of developing a malignant tumour and a 5% to 10% risk of developing lymphoproliferative disease (45,46). Avoidance of the use of chronic steroids in infants and maintaining the immunosuppression at as low a level as possible for good allograft function may reduce the incidence of neoplasms, hypertension and renal dysfunction (12,45).

As institutions, neonatologists and cardiologists develop more experience, possibly expand the donor pool, and improve the diagnosis and treatment of rejection, graft vasculopathy and immunomodulations, there may be an increase in the survival from cardiac transplantation (12). It may be beneficial to discuss both surgical options of cardiac transplantation and staged palliative surgeries with the families of these children following the diagnosis of hypoplastic left heart syndrome (19). If a family were to select cardiac orthotransplantation and if no donor were available, the Norwood operation could provide an appropriate initial alternative (19). The costs and benefits of surgical therapy, however, continue to be debated.

Comfort care:

Palliative or comfort care continues to be a common option chosen by the parents of HLHS infants (19). In one institution, 63% of parents opted for termination or declined intervention postnatally, suggesting that many are not prepared to have their children undergo multiple operations with an uncertain long term outcome (29). Caplan et al (13) performed a survey to determine the practice, patterns and perceptions of outcome for infants with HLHS. Of the institutions studied, 36% offered comfort care only, 26% offered surgery only and 38% offered both (13). Of the neonatologists who answered the questionnaires, 24% recommended comfort care only, 64% recommended surgery only (44 palliative versus 33 transplant), and 12% recommended comfort care or surgery (13). Thus, comfort care for HLHS remains a common option for physicians and institutions. Physician reluctance to recommend palliative surgeries may change if the long term intact survival improves. Likewise, neonatal or infant cardiac transplantation may be a more viable option if intact long term survival increases and if mortality while on the waiting list for a donor heart can be decreased (13). Surgical therapy provides hope for survival with this condition, but the long term prognosis is still unknown and more investigations on long term outcomes are warranted (12).

CONCLUSIONS

Nearly 1500 to 2000 infants in Canada and the United States are born with HLHS each year (12). It has been reported to occur in approximately 0.016% to 0.036% of live births in Canada and the United States (5–9). Although the incidence of HLHS is low in the neonatal population, it has a very high mortality rate and is responsible for approximately 23% of neonatal deaths (6,11–14). Opinions on optimal therapy range from no intervention to the surgical options of staged palliation or cardiac transplantation (12,30). Palliative or comfort care remains the option for many parents and physicians with the expectation of early death. With palliative procedures, infants retain their hearts and avoid long term immunosuppression and possible side effects, but they have a high operative mortality and long term morbidity (17). Cardiac transplantation has a higher operative survival, but there are problems associated with severe rejection, graft coronary artery disease and uncertain long term outcomes (30).

Because of developing techniques, the outlook for children with HLHS at some centres has improved dramatically from an expected mortality of 95% by one month of age without treatment to an actuarial survival of 58% at five years after staged surgical palliation intervention and 55% to 60% at seven years after cardiac transplantation (12,19). Progress still needs to be made to increase the availability of donor hearts for cardiac transplantation to be a viable therapeutic option (19).

Although prognosis for HLHS is no longer one of certain death, many issues surrounding surgical treatment remain poorly defined (2). Great variation exists in HLHS cardiac morphology, which is a major determinant of successful surgical intervention (2). The long term outcomes and quality of life following surgery remain poorly defined. More information on the natural history of HLHS, its antenatal diagnosis, operative strategies and long term outcome are essential to determine the optimal management for individual infants with HLHS.