Neonatal palliation

Patients with functionally univentricular hearts often require palliation as neonates for obstructions in the systemic outflow tract or the aortic arch, or because or diminished flow of blood to the lungs. Patients in the latter category will require creation of a shunt, such as the modified Blalock–Taussig shunt, but are less likely to have ventricular dysfunction prior to surgery. Neonates with lesions such as hypoplasia of the left heart, however, often have some degree of ventricular dysfunction prior to surgery. This preoperative condition has been associated with increased mortality, with the qualitative assessment of right ventricular function prior to the Norwood operation found to be the best predictor of survival at 18 months of age.¹ Additionally, patients presenting as neonates with right ventricular dysfunction are twice as likely to die early compared to those that present with normal right ventricular function.² A variety of aetiologies can contribute to ventricular dysfunction, including volume overload from pulmonary overcirculation, tricuspid valvar regurgitation, coronary arterial insufficiency, and metabolic acidosis.³

As the pulmonary vascular resistance falls after birth, the resulting overcirculation of the lungs can lead to hypoperfusion of the systemic circulation and metabolic acidosis. Additionally, the diastolic runoff into the pulmonary circulation can lead to low diastolic blood pressures, decreased pressures for coronary arterial perfusion, and myocardial ischemia.⁴ Use of inotropic agents that increase heart rate, and thus myocardial consumption of oxygen, can further exacerbate this precarious myocardial perfusion. This state can exist both prior to and after surgery in patients with hypoplasia of the left heart, and strategies to limit the flow of blood to the lungs, to maximize systemic flow by reducing systemic vascular resistance, and to improve coronary arterial perfusion, are critical in the perioperative management.

One strategy to limit pulmonary overcirculation, and the resultant volume overload and ventricular dysfunction, is to manipulate the pulmonary vasculature and its flow. The pulmonary vasculature is sensitive to acidosis and hypoxia. These conditions lead to vasoconstriction and increased pulmonary vascular resistance. Increasing pulmonary vascular resistance can decrease the flow of blood into the lungs, and improve the ratio of pulmonary to systemic flows.⁵ In the intubated patient, permissive hypoventilation to achieve a partial pressure of carbon dioxide of 40–50 millimeters of mercury can help to increase pulmonary vascular resistance.⁶ Subambient oxygen to induce alveolar hypoxia has also been used, but this use remains controversial.⁷ Inspiration of around 3% of carbon dioxide, to achieve a mild respiratory acidosis, can also be used. The use of hypercarbia was found to decrease the ratio of pulmonary to systemic flows, to decrease difference in arterial and mixed venous saturations, to increase the mean arterial blood pressure, and to improve cerebral oxygenation.^{8, 9} Alternatively, it is possible to perform the Norwood procedure earlier, before the development of marked pulmonary overcirculation and ventricular dysfunction with systemic underperfusion.

More recently, there has been an appreciation of the deleterious effects postoperatively of elevated systemic vascular resistance in neonates with functionally univentricular hearts. Hoffman et al.^{10, 11} demonstrated high systemic vascular resistance in such patients to be a postoperative risk factor for cardiovascular collapse. Parameters such as increasing base deficit and rising lactates can identify anaerobic metabolism, and thus identify patients at high-risk for death. These methods, however, have a low sensitivity in detecting periods of high systemic vascular resistance. Conversely, measurement of the mixed venous saturation, and the difference between arterial and mixed venous saturations, were effective in detecting periods of elevated systemic vascular resistance and low systemic output prior to cardiovascular collapse. Monitoring mixed venous saturation of oxygen, and the use of phenoxybenzamine, a blocker of alpha receptors, to lower systemic vascular resistance have led to improved survival and a lower incidence of sudden cardiovascular collapse after the Norwood procedure.¹²

It is imperative to rule out residual anatomic defects, especially obstruction of the aortic after the Norwood operation, with echocardiography or cardiac catheterization. If there are no residual anatomic defects in need of correction, and low cardiac output persists despite adequate inotropic support, the use of additional pharmacological agents may be considered.

One potentially useful pharmacological agent is milrinone, an inhibitor of phosphodiesterase with inotropic, lusitropic, and vasodilatory properties.¹³ The use of milrinone postoperatively leads to decreased systemic and pulmonary vascular resistance, increased cardiac output, and decreased filling pressures. In a large randomized multicenter trial, milrinone was found to decrease low cardiac output syndrome after surgery.¹⁴ Milrinone, however, has not been systematically studied in patients with functionally univentricular hearts who have perioperative ventricular dysfunction.

Low pressures of coronary arterial perfusion resulting from diastolic runoff into the pulmonary arteries in neonates with functionally univentricular hearts and systemic-to-pulmonary arterial shunts can lead to myocardial ischemia, ventricular dysfunction, and cardiovascular collapse. This is particularly important postoperatively, and has been identified as the cause of death in around one-quarter of patients that died after the Norwood procedure.⁴ Strategies to maintain coronary arterial perfusion include maintenance of an adequate hemoglobin, and inotropic support, such as dopamine or epinephrine, at low dosage to maintain diastolic blood pressure greater than 25 millimeters of mercury. An alternative strategy employed by some centers is to place a conduit from the right ventricle to the pulmonary arteries, rather than constructing a systemic-to-pulmonary arterial shunt. This may lead to a more stable initial postoperative course, with improved diastolic blood pressures and a decrease in the ratio of pulmonary to systemic flows.¹⁵ Additionally, interim mortality has been lower in some centers using the conduit from the right ventricle to pulmonary arteries as part of the Norwood sequence when compared to those patients that received a Blalock–Taussig shunt.¹⁶ The long-term consequences on ventricular function and arrhythmias that might results from the ventriculotomy needed for placement of the conduit, however, remain important unanswered questions.¹⁷

There is considerable controversy over the ideal inotropic agent or agents for use perioperatively in neonates undergoing the first stage of the Norwood sequence. The ideal agent would increase systemic cardiac output without increasing the flow of blood to the lungs, would avoid excessive tachycardia, and improve delivery of oxygen. Using piglets as a model for the hypoplastic left heart syndrome, Riordan et al.¹⁸ compared the effects of infusions of epinephrine, dopamine, dobutamine, and epinephrine on pulmonary and systemic flows and delivery of oxygen (Fig. 1). Only epinephrine at 0.1 micrograms per kilogram per minute decreased the ratio of pulmonary to systemic flows and improved the delivery of oxygen. In a different animal model, Reddy et al.¹⁹ evaluated the use of epinephrine, sodium bicarbonate, and calcium carbonate before and after cardiopulmonary bypass. All of the medications increased systemic blood flow, and decreased the ratio of pulmonary to systemic flows. They showed that a continuous infusion of epinephrine at low dosage was useful, but bolus doses could be deleterious. A combination of epinephrine in low doses, and milrinone at low or moderate dosage, is reasonable in the perioperative period for the neonate with hypoplastic left heart syndrome and ventricular dysfunction, albeit that the particular choice of inotropes, and their dosages, needs to be individualized to the patient.

Figure 1. Inotropic Medication relative to ratios of pulmonary to systemic flows. Reproduced with permission from: Riordan CJ, Randsbaek F, Storey JH, Montgomery WD, Santamore WP, Austin III EH. Inotropes in the hypoplastic left heart syndrome: effects in an animal model. Ann Thorac Surg 1996; 62: 83–90.

Shore et al.²⁰ evaluated retrospectively the use of steroids in infants with high inotropic requirements late after initial presentation or cardiac surgery. After the administration of steroids, there was a significant decrease in the dose of epinephrine, the inotrope score, and heart rate, while mean arterial blood pressure increased. We are currently undertaking a prospective trial on the use of steroids in postoperative neonates with low cardiac output in the setting of high inotropes.

In patients with functionally univentricular hearts and low cardiac output in spite of maximal medical therapy, consideration for mechanical support should also be given. Such mechanical support has been used successfully in neonates both preoperatively and postoperatively. The early experience²¹ with extracorporeal membrane oxygenation found the presence of a functionally univentricular heart to be a risk factor for nonsurvival. More recent studies^{22, 23} have reported improved survival in patients with functionally univentricular hearts, even in patients with hypoplastic left heart syndrome. Extracorporeal membrane oxygenation has been used successfully in neonates with hypoplastic left heart syndrome preoperatively, intraoperatively, and postoperatively for low cardiac output or after cardiac arrest.²⁴ The routine postoperative use of mechanical support with a left ventricular assist device has also been used as a strategy of management for patients undergoing the Norwood procedure, with Ungerleider et al.²⁵ reporting stable hemodynamics and good neurologically intact survival with this approach.

Construction of the bidirectional cavopulmonary anastomosis

Infants with functionally univentricular hearts may have progressive cardiac dysfunction from a variety of mechanisms as discussed above. These patients have a volume-loaded ventricle, which may lead to concomitant and progressive atrioventricular valvar regurgitation. This volume-load on the heart activates the neurohormonal cascade evident in patients with congestive heart failure. Performing a bidirectional superior cavopulmonary anastomosis, such as the bidirectional Glenn anastomosis or Hemi–Fontan procedure, prior to completing the Fontan circulation may help to preserve ventricular function, decrease ventricular size, and increase the ratio of ventricular mass to volume ratio.²⁶ This effect has been clearly demonstrated in younger children, but may be of limited value in children over 3 years of age.²⁷ Additionally, the volume unloading with the bidirectional Glenn anastomosis many not persist over time. One study found no difference 6–9 months after surgery in end-diastolic volume, mass, ventricular output, or centroid motion.²⁸

When comparing patients that have undergone a primary total cavopulmonary connection to those that have undergone a superior bidirectional cavopulmonary anastomosis prior to completion of the Fontan circulation, the staged patients have better contractility and improved ventricular efficiency (Fig. 2).²⁹

Figure 2. Cardiac performance comparing patients undergoing a staged approach, with an interim bidirectional cavopulmonary anastomosis, as opposed to direct conversion to the Fontan circulation: (a) shows that the proportional decreased in end-diastolic volume (EDV) was greater in those converted directly to the Fontan ciruit; (b) shows that the end-systolic elastance (Ees) increased in the setting of both staged and primary strategies; (c) shows that the arterial elastance (Ea) also increased in both strategies, but the increment of Ea was greater in those converted directly to the Fontan circuit; and (d) shows that the ratio of Ea to Ees, the ventriculoarterial coupling, decreased in those having a staged conversion, while it increased after direct conversion. Reproduced with permission from: Tanoue Y, Sese A, Ueno Y, et al. Bidirectional Glenn procedure improves the mechanical efficiency of total cavopulmonary connection in high-risk Fontan candidates. Circulation 2001; 103: 2176–2180.

Limited data exists regarding the perioperative management of the patients having construction of a bidirectional Glenn anastomosis in the setting of a poorly functioning ventricle. Recent work demonstrated that a mild respiratory acidosis postoperatively, with levels of carbon dioxide between 45 and 55 millimeters of mercury, leads to an increased cardiac output, decreased consumption of oxygen, and improved arterial saturations. With this strategy, there was a significant decrease in oxygen consumption and lactate levels and an increase in arterial oxygen saturations.^{30, 31} No change was found in the ratio of pulmonary to systemic flows, suggesting that selective vasodilation of the cerebral vasculature did not account for the findings. Rather, the primary effect was an increase in systemic cardiac output through a decrease in systemic vascular resistance.

There is also a paucity of data on pharmacological therapy for the failing ventricle after the bidirectional Glenn anastomosis. Many inotropes, such as catecholamines, will stimulate alpha-adrenergic receptors in the lungs and increase pulmonary vascular resistance. This may be counterproductive as increased pulmonary pressures have been predictive of postoperative complications and mortality.^{32, 33} The use of milrinone, which causes vasodilation, increased contractility, and lusitropy, is likely to be beneficial, albeit that this has yet to be proven in this population of patients.

Mechanical support has also been used for patients after a bidirectional Glenn anastomosis. Survival, however, is less than with congenital cardiac malformations.³⁴

Completion of the Fontan circulation

Many patients with a functionally univentricular heart will eventually proceed to completion of the Fontan circulation. Such patients are at increased risk for myocardial dysfunction for a variety of reasons, including years of volume and pressure overload, chronic hypoxemia, multiple episodes of cardiopulmonary bypass, increased wall stress and hypertrophy, and myocardial disarray and increased collagen (Fig. 3).³⁵ The increased ratio of ventricular mass to volume evident after construction of the bidirectional Glenn anastomosis can lead to a stiff ventricle and diastolic dysfunction. This decrease in ventricular relaxation was predictive of postoperative length of stay after the Fontan procedure.³⁶ Additionally, in patients with a dominant morphologically left ventricle, the ventricular geometry changes from ellipsoidal to spherical over time.³⁷ Postoperatively, the patient will experience an increase in afterload, decrease in preload, and may experience a progressive decrease in functional status.³⁸

Figure 3. Pressure–volume loops in patients with volume overload of their dominant ventricle. The upper diagram illustrates the normal pressure– volume relationship (loop A) and that of the chronic volume overloaded but compensated ventricle (loop B). Loop C represents the pressure–volume loop after removal of the chronic volume overload but with different characteristics. The lower diagram shows a decompensated ventricle and its pressure–volume loop (loop D). Loop E illustrates the dilated dominant ventricle with high end-diastolic pressures even after removal of the volume overload. Reproduced with permission from: Lawrenson J, Gewillig M. The ventricle in the functionally univentricular heart. In: Redington A, Brawn WJ, Deanfield JE, Anderson RH (eds). The Right Heart in Congenital Heart Disease. Greenwich Medical Media, London, 1998.

In the normal functionally biventricular heart, there are shared superficial myocardial fibres that encircle the ventricles.³⁹ This allows for interactions between the right and left ventricle to augment cardiac function. Much of the mechanical work of the right ventricle is generated by left ventricular contraction. In the setting of a functionally single ventricle, this augmentation is not present. In patients with hypoplasia of the left heart, the abnormal left ventricular structure leads to abnormalities in regional wall motion and strain of the right ventricle.⁴⁰

In an animal model of the Fontan circulation, postoperative subjects were evaluated using pressure–volume conduction catheters to evaluate ventricular energetics.⁴¹ After the Fontan procedure there was a decrease in the end-systolic elastance and an increase in the arterial elastance, leading to a decrease in the ventriculoarterial coupling. Additionally, stroke work decreased while the total mechanical energy remained relatively unchanged, resulting in a significant decrease in mechanical efficiency. This is likely to contribute to the limited cardiac functional reserve observed after the Fontan procedure.

In addition to mechanical inefficiency, there is evidence for a decrease in diastolic function after the Fontan procedure.⁴² These findings are consistent with the concept of decreased ventricular compliance and abnormal relaxation persisting late after surgery.

In the current era, nonetheless, the Fontan circulation can be completed with a very low mortality. One large center⁴³ reported only two deaths after completing the Fontan procedure in a large cohort of patients between 1994 and 1999. Certain surgical and perioperative strategies may improve morbidity and mortality. For example, the use of a fenestration in the Fontan circuit, and the use of modified ultrafiltration, have both been associated with decreased mortality.⁴⁴

There is limited data regarding the optimal vasoactive medication for the poorly functioning ventricle after completion of the Fontan circulation.⁴⁵ With the pulmonary and systemic vascular beds in series, agents that increase pulmonary vascular resistance may have an adverse effect on cardiac output and oxygen delivery. Dopamine and nitroprusside, when used separately or in combination, increase cardiac output and decrease pulmonary vascular resistance.⁴⁶ For the postoperative patient with ventricular dysfunction after completion of the Fontan circuit, therefore, dopamine or epinephrine alone or in combination with milrinone are good choices. Again, medications and appropriate dosages should be individualized to the physiological state of the patient.

Mechanical support has also been used in patients with a failing Fontan circulation, with survival after extracorporeal membrane oxygenation being better in patients with a Fontan circulation than subsequent to a bidirectional Glenn anastomosis.³⁴ The future care of this latter group of patients, which is a growing population, will require novel strategies for management.

The management of the patient with ventricular dysfunction after completion of the Fontan circulation is often more complicated over the long-term than during the immediate perioperative period. For reasons as listed above, ventricular dysfunction is common, and many patients will have symptoms of congestive heart failure. It is likely that traditional medications used in adults with congestive heart failure, such as beta-blockers and inhibitors of angiotensin converting enzyme, will also benefit those with the Fontan circulation. Studies of inhibitors of angiotensin converting enzyme in patients with the Fontan circuit, however, found no effect of these medications on resting cardiac index, diastolic function, systemic vascular resistance, exercise capacity, or cardiac autonomic nervous activity.^{47, 48} The patient with a failing ventricle in the setting of an atriopulmonary circuit can undergo conversion to the lateral tunnel or extracardiac Fontan with improved function, but some require orthotopic cardiac transplantation.

Novel strategies of management for patients with dysfunctioning ventricles

With the recent advances in the medical and surgical care of patients with functionally univentricular hearts, more are surviving to adolescence and adulthood. These patients, for reasons as listed above, are at a high-risk of developing congestive heart failure. Acute decompensation is a common cause of death in adults with congestive heart failure. Traditional strategies of management, using inotropic agents such as dobutamine and milrinone, have been shown to increase mortality in adults.⁴⁹ New paradigms will be likely be necessary optimally to treat the failing myocardium in patients with functionally univentricular hearts. The ideal strategy would be to promote venous, arterial, and coronary arterial vasodilation, not to increase heart rate or cause arrhythmias, not to increase myocardial demand for oxygen, have no tachyphylaxis, provide neurohormonal suppression, promotes diuresis and natriuresis, and have minimal side effects.

Levosimendan

Levosimendan is a promising new calcium sensitizer (Fig. 4). Calcium regulation in the failing myocardium is abnormal, with prolonged intracellular calcium transients, and a decreased ability to restore low levels in diastole.⁵¹ There is a reduced expression of calcium channels in the sacroplasmic reticulum, and myocardial contraction and relaxation depends primarily on fluxes of calcium between the cytosol and the extracellular fluid.⁵² Traditional inotropic agents that increase intracellular calcium are associated with increased consumption of oxygen, impaired myocardial relaxation, and arrhythmias.⁵³ Levosimendan is novel in that it increases both inotropy and vasodilation without increasing levels of calcium levels or myocardial demand for oxygen.⁵⁴ The agent has been used safely and effectively in adults, while there are isolated reports of its use in children with severe postoperative heart failure,⁵⁵ and in the setting of a dilated cardiomyopathy.⁵⁶

Figure 4. Site of action of various inotropic agents. Most of the conventional inotropes increase cyclic adenosine monophosphate (cAMP), with a subsequent increase in intracellular concentrations of calcium ions, which enhances contraction. Such increased concentrations, however, may promote arrhythmias, particularly during ischemia and reperfusion. Calcium sensitizers such as levosimendan, pimobendan, and EMD 53998, may enhance myocardial contraction without increasing intracellular concentrations of calcium ions, thus avoiding the associated risk of increased arrhythmias. AMP: adenosine monophosphate; ATP: adenosine triphosphate; PDE: phosphodiesterase. Reproduced with permission from: du Toit E, Hoffmann D, McCarthy J, Pineda C. Effect of levosimendan on myocardial contractility coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model. Heart 2001; 86: 81–87.

Mechanical support

Mechanical support in children is currently used as a bridge to either recovery or transplantation. In adults, the use of mechanical support as definitive therapy was found to be superior to optimal medical management in terms of both symptoms and survival.⁵⁷ Devices such as the DeBakey VAD^® Child, an axial flow system, have now been used in three children at our institution as a bridge to transplantation (Fig. 5). Two of three patients survived to transplantation and are currently doing well at home. Conceivably, such a device could be placed into the caval veins to augment flow from the systemic venous circulation into the lungs in patients with a Fontan circulation. This has been performed successfully in an animal model, and could potentially be used for long-term support for the patients with poor ventricular function in the setting of a functionally univentricular heart.⁵⁸

Figure 5. The Debakey VAD® Child device. The inducer/impeller is the only moving part of the pump. It has six blades with eight magnets hermetically sealed in each blade. The components are fully enclosed in a titanium flow tube. The pump is driven by a brushless, direct current motor stator that is contained in the stator housing. The pump is attached to a titanium inlet cannula that is placed into the left ventricle. A graft is connected to the pump outlet and anastomosed to the aorta. Reproduced with permission from Micromed Technology, Inc., Houston, Texas, USA.

Conclusions

Patients with functionally univentricular hearts are at high-risk for developing ventricular dysfunction, and require individualized perioperative management. Initial inotropic support with low dose epinephrine and milrinone seems to be a good strategy for those with hypoplasia of the left heart, with administration of phenoxybenzamine in the operating room for alpha-adrenergic antagonism. There is a myriad of pathophysiological abnormalities after construction of cavopulmonary anastomoses, such as suboptimal ventriculoarterial coupling, impaired contractility, and altered ventricular geometry. Future medical therapy will include human recombinant B-type naturetic peptide and calcium sensitizing agents. Surgical therapy will involve use of miniaturized axial pump devices.