Part 5. Management of Patients with Cardiovascular Disease

Heart failure is a complex condition with many potential causes, but with the end result that the heart is unable to meet the metabolic demands of the body (including growth in children). Many believe that there must also be a component of systemic or pulmonary congestion. However, some patients with heart failure may have no significant congestion at rest, but only develop congestion with exertion or other forms of increased oxygen demand. Heart failure is generally precipitated by an insult to the cardiovascular system, either acquired or congenital. In adults, the most common insult is ischemic coronary artery disease with resultant left ventricular dysfunction. In children, heart failure is rarely ischemic, and the causes are quite varied and age dependent; refer to Chapters 483 and 484 for specific lesions associated with heart failure in children of different ages. Although infants with large left-to-right shunts and pulmonary overcirculation are commonly referred to as being in heart failure, their ventricular performance is usually normal, and their “heart failure” is usually a manifestation of pulmonary overcirculation with or without elevated ventricular filling pressures. They may have decreased systemic blood flow as well. Severe left-sided obstructive lesions (eg, hypoplastic left heart syndrome) often present with heart failure in the newborn period because the left ventricle cannot adequately eject blood to the systemic circulation. Both of these groups of lesions are generally managed by surgery or transcatheter intervention, but symptomatic therapy is often needed prior to surgical correction

Once the body has sensed a low cardiac output, a complex neurohormonal cascade is activated that includes the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (Fig. 497-1). This adaptive process causes fluid retention and stimulates release of vasopressive neurohormones such as norepinephrine in order to maintain or increase circulating blood volume and blood pressure. However, this cascade soon becomes maladaptive because it increases preload and afterload in an already overstressed system. Cellular responses are also initiated. For example, the augmentation of beta-adrenergic activity increases intracellular calcium which in turn increases myocardial inotropy and chronotropy. These adaptive mechanisms also soon become maladaptive, as prolonged beta-adrenergic stimulation of the heart leads to apoptosis and fibrosis.

The American Heart Association and the American College of Cardiology have divided heart failure into 4 stages: stage A: at risk for heart failure; stage B: structural heart disease without signs or symptoms; stage C: structural heart disease with previous or current symptoms; stage D: refractory heart disease requiring special interventions.1 The diagnosis and management of each of these stages in adults requires different modalities and approaches. Pediatric heart failure can also be considered in a similar light, although many of the proposed treatment strategies are different.2

Infants and young children present with poor feeding, failure to thrive, respiratory distress, diaphoresis, irritability or lethargy, and pallor. Older children frequently complain of poor appetite, abdominal pain, nausea, and vomiting, and occasionally present with chest pain, palpitations or syncope. Signs of heart failure include tachycardia, tachypnea, pallor, cool extremities, and peripheral edema. Young infants may have periorbital or facial edema. Jugular venous distension can be noted in older children. Cardiac examination reveals a prominent precordium with displacement of the apical impulse, frequently distant heart tones, and a gallop rhythm. Rales, particularly at the bases, and wheezing are heard in older children with pulmonary edema. Breath sounds may be diminished because of collapse of the left lower lobe as a result of compression of the left main bronchus by a dilated left atrium or as a result of pleural effusions. Tender hepatomegaly and ascites are not uncommon.

Chest radiography usually reveals cardiomegaly, pulmonary venous congestion or frank pulmonary edema (Fig. 497-2), although children with acute myocarditis may not have cardiomegaly at initial presentation. In addition there may be pleural effusions and left lower lobe atelectasis.

An electrocardiogram (EKG) may be useful. Children with fulminant myocarditis frequently have an abnormal EKG with low voltages, global ST segment elevation, or a wide complex rhythm (Fig. 497-3). It can also be diagnostic in infants with anomalous left coronary artery from the pulmonary artery (ALCAPA) where an anterolateral infarction pattern is frequently seen. EKG may also reveal arrhythmias such as supraventricular tachycardia, ventricular arrhythmias, or rarely heart block.

Heart failure is a clinical diagnosis, but echocardiography provides valuable supportive information regarding cardiac function and the details of anatomy.

A majority of children with heart failure are decompensated on initial presentation. Symptoms of decompensation include breathlessness with minimal activity, orthopnea (inability to lie flat and/or use of multiple pillows), feeling faint or lightheaded, and gastrointestinal symptoms such as poor appetite, abdominal discomfort, nausea, and vomiting. Abdominal pain and nausea are ominous symptoms and should prompt further evaluation. A variety of clinical and laboratory parameters may help estimate the adequacy of cardiac output and oxygen delivery in the child. Peripheral pulse volume, capillary refill, blood pressure, urine output, and blood gas analysis indirectly assess cardiac output and oxygen delivery. In children, cardiac output is rarely directly measured, and is usually estimated using surrogate markers of oxygen delivery such as mixed venous oxygen saturation and serum lactate concentration.

Mixed venous oxygen saturation directly correlates with systemic oxygen extraction and thus is an excellent index of the adequacy of systemic blood flow. In patients without an intracardiac left-to-right shunt, the pulmonary artery oxygen saturation is the true “mixed” venous oxygen saturation. However, it is not easily accessed in young infants and children and cannot be used in patients with left-to-right shunting. The saturation in the superior vena cava (SVC) is also well mixed and approximates mixed venous saturation, though it is usually slightly lower due to the greater oxygen extraction of the upper body compared to that of the lower body. It is a very good surrogate for the mixed venous saturation in small children or older children with left-to-right shunting. Because an elevated serum lactate level indicates anaerobic metabolism, it is another good index of the adequacy of oxygen delivery, Several studies have demonstrated the usefulness of serum lactate in predicting outcome in adults and children after cardiac surgery, trauma, and similar events.

Near infrared spectroscopy (NIRS) is a noninvasive technique which measures wavelength-specific absorption of light. It is used to measure oxyhemoglobin and deoxyhemoglobin in specific tissues. NIRS is now being used by many centers in the postoperative period to monitor cerebral and splanchnic oxygen saturations in order to assess the adequacy of oxygen delivery at the tissue level.

Biomarkers of Heart Failure

Serum B-type natriuretic peptide (BNP) is a neurohormonal peptide secreted in response to ventricular dilatation. Normal serum BNP level is less than 100 pg/mL. Rising BNP levels are usually seen with worsening heart failure. In patients with heart failure, serum BNP level is usually significantly elevated, and is frequently greater than 1000 pg/mL. On the other hand, a decline in serum BNP level can indicate clinical improvement. Thus it is useful to follow serial serum BNP levels both while escalating therapy for worsening heart failure, and during weaning from inotropic support and afterload reduction.

Treatment of Acute Decompensated Heart Failure

Factors that influence cardiac output such as preload, afterload, myocardial contractility, heart rate and rhythm must be assessed and manipulated.3

Preload versus Fluid Overload

Patients with acute decompensated heart failure and low cardiac output syndrome (LCOS) are usually fluid overloaded; thus fluid boluses should be avoided or small aliquots (5–10 mL/kg) should be used with careful monitoring of vital signs. Rapid infusion of large volume of fluid may suddenly distend the heart and cause bradycardia, hypotension, and cardiac arrest. Most of these patients require intravenous diuretics such as furosemide. In fact, many patients will have a remarkable clinical improvement with this simple therapy, and may not need additional pharmacologic support.

Pharmacologic Support

Patients presenting with decompensated heart failure frequently require agents that provide inotropy and/or afterload reduction (Table 497-1). The treatment of choice for many centers is the use of inodilators (inotropes with afterload reducing properties) such as milrinone.4 It has replaced catecholamines such as dopamine, dobutamine, and epinephrine as first line of therapy in children with low cardiac output syndrome (LCOS). Milrinone is a nonglycoside, noncatecholamine inotropic agent with additional vasodilatory and lusitropic properties. It inhibits phosphodiesterase type III, increasing intracellular cyclic adenosine monophosphate (AMP) and intracellular calcium, thus enhancing myocardial contractility. It also enhances diastolic relaxation of the myocardium by increasing the rate of reuptake of calcium after systole. It may also act synergistically with a beta-adrenergic agonist such as dopamine and has fewer side effects. Phosphodiesterase type III inhibitors have been used extensively in adults and more recently introduced to pediatric practice. Milrinone lowers filling pressures, systemic and pulmonary artery pressures, and systemic and pulmonary vascular resistances, while improving cardiac index. Milrinone is usually initiated at 0.25 μ/kg/minute and can be titrated gradually to 1 μ/kg/minute based on clinical response.5 It is prudent to avoid a bolus of milrinone in patients with LCOS, who are either normotensive or hypotensive at presentation. Milrinone has also replaced amrinone because of the relatively high incidence of thrombocytopenia associated with the latter. Catecholamines, either endogenous (eg, dopamine or epinephrine) or synthetic (eg, dobutamine) act by stimulating myocardial surface beta-adrenergic receptors, leading to increased adenylate cyclase and intracellular cyclic adenosine monophosphate (cAMP).

In patients with heart failure, down-regulation and desensitization of beta-adrenergic receptors as a result of either antecedent congestive heart failure or sustained use of catecholamines, can decrease the efficiency of these agents. Deleterious effects of catecholamines, as a result of their nonspecific actions on adrenergic receptors include (1) excessive chronotropy, which increases myocardial oxygen consumption; (2) atrial and ventricular dysrhythmias; and (3) increase in afterload by activating peripheral alpha-adrenergic receptors, leading to increased impedance and decreased cardiac output. Additional noncardiac side effects of catecholamines include electrolyte and glucose derangements, increase in pulmonary vascular resistance, depression of ventilatory response to hypoxemia and hypercarbia, and limb ischemia.

Other Agents

Nesiritide is a synthetic intravenous form of brain natriuretic peptide (BNP) that has recently been used to treat decompensated heart failure in adults based on its beneficial effects on the renal, neurohormonal and cardiovascular systems. Exogenous administration causes natriuresis, diuresis, vasodilatation and increased renal blood flow, increased cardiac output and urine output, as well as improved symptomatology in the adult heart failure patient.6,7 The dose used in infants and children has ranged from 0.005 to 0.03 μ/kg/minute.8

Levosimendan is a recent treatment for low cardiac output syndrome (LCOS). It is a calcium-sensitizing agent with inotropic and afterload reducing effects. It binds to troponin C and improves the efficiency of the contractile apparatus. The most appealing aspect of this medication is its ability to do this without increasing intracellular calcium levels or cAMP. In adults, early studies have suggested benefit through its ability to increase cardiac output, decrease filling pressures, and allow the use of lower doses of catecholamines and thus potentially mitigate the adverse effects of high dose catecholamines.9 It is usually given as a bolus of 6 to 12 μ/kg/minute followed by an infusion of 0.05 to 0.1 μ/kg/minute over 24 to 48 hours. Pharmacokinetic studies have shown active metabolites up to 72 hours, and the dose can be repeated weekly. Levosimendan may have a role as adjunctive therapy in refractory heart failure unresponsive to the currently available inotropic and afterload reducing agents.10

Role of Mechanical Ventilation

Patients with low cardiac output syndrome (LCOS) may require mechanical ventilation for worsening cardiorespiratory failure. Positive pressure ventilation provides afterload reduction to the failing heart, and decreases respiratory effort and oxygen consumption. However, intubation can precipitate cardiopulmonary decompensation due to a transient decrease in endogenous catecholamines, decrease in preload, and decrease in functional residual capacity. These patients should be appropriately premedicated and resuscitative medications should be readily available.

Supportive Measures

In children with low cardiac output syndrome (LCOS), maintaining a hematocrit level greater than or equal to 35% increases the oxygen carrying capacity of blood. Children with heart failure are also prone to have fever, which increases oxygen consumption. High core temperature with cool extremities may be caused by peripheral vasoconstriction, but could also be of viral etiology in children with myocarditis, or due to catheter-related infections in children with central lines. These children often decompensate due to a persistent fever, so that aggressive fever control is necessary while searching for its etiology.

Mechanical Circulatory Support

Mechanical circulatory support is an essential component of pediatric cardiac intensive care. Although conventional therapy with inotropic support and afterload reduction remains the mainstay of treatment for the failing heart, mechanical circulatory support is being increasingly used in the pediatric population.11,12 When combined with an active heart transplantation program, mechanical circulatory support can significantly improve survival.13 Most of the pediatric experience is limited to the use of extracorporeal membrane oxygenation (ECMO). However, ventricular assist devices (VAD) are now being used in infants, children, and young adults as a bridge to transplantation.

Indications for mechanical support are

• Inability to wean off cardiopulmonary bypass
• Severe ventricular dysfunction of all etiologies
• Cardiopulmonary arrest
• Pulmonary hypertension refractory to medical therapy
• Intractable arrhythmias with hemodynamic compromise
• Occluded systemic-to-pulmonary artery shunt
• Respiratory failure

Extracorporeal Membrane Oxygenation (ECMO)

There is a large pediatric experience with the use of extracorporeal membrane oxygenation (ECMO) for cardiopulmonary failure. Venous-arterial ECMO is necessary for cardiac dysfunction unresponsive to conventional pharmacologic therapy or in patients with coexisting pulmonary disease. Patients must be considered to have “reversible” or “correctable” cardiac or pulmonary disease to be considered candidates for ECMO support. The pediatric experience with rapid resuscitation ECMO after cardiopulmonary arrest is growing.13 Many centers now can rapidly deploy mechanical support and current survival for this indication is 40% to 50%. Rapid institution of circulatory support with modified ECMO systems can be lifesaving with excellent short-term preservation of end-organ function in these patients.

Long-Term Ventricular Assist Devices

The pediatric experience with several long-term pulsatile devices has been growing. Advantages of these devices include their ability to support the circulation for a long period of time as a bridge to transplantation, ease of use, mobility for cardiac rehabilitation, need for low-level anticoagulation, and pulsatile flow (with the pulsatile devices). Disadvantages include a propensity to have thromboembolic complications, risk of infection, increased risk of human leukocyte antigen-sensitization, and size limitation especially with biventricular support.

When low cardiac output syndrome (LCOS) persists despite escalation of inotropic support and afterload reduction, early institution of mechanical circulatory support should be considered before the child sustains irreversible end organ damage. The choice of device should be based on urgency of need for support, patient size, need for short-term versus long-term support, and institutional resources.

In adults with diffuse inoperative myocardial disease, whether ischemic or not, few agents have produced any increase in survival and there is no reason to think that they would do better in children with comparable diffuse myocyte dysfunction. This is not surprising, because most therapies do not address the intrinsic myocyte dysfunction. On the other hand, symptomatic improvement is also an important goal, particularly in children who might then go on to surgical repair.

The management of chronic heart failure can be divided into two main areas: pharmacologic and electrophysiologic. Pharmacologic therapy primarily consists of diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), aldosterone antagonists, and beta-adrenergic receptor antagonists (beta-blockers). Electrophysiologic therapy primarily consists of cardiac resynchronization therapy (CRT) and implantable cardioverters/defibrillators (ICDs).

Diuretics

Most patients with heart failure have some fluid overload. At the time of presentation or during acute exacerbations, fluid overload may be more apparent than during the stable chronic phase of heart failure. Although diuretic therapy is intuitive for treating someone with systemic or pulmonary venous congestion, there are surprisingly little data to support its benefit. Diuretics can exacerbate the activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, thus potentially perpetuating or worsening the maladaptive neurohormonal imbalance.14 This and other concerns about the effectiveness of diuretics have led investigators to explore other methods of reducing fluid overload in adults with congestive heart failure, including ultrafiltration.15 The most commonly used diuretics are loop diuretics (eg, furosemide) and thiazide diuretics (hydrochlorothiazide and metolazone). These medications, used alone or in combination, increase urinary sodium and water excretion, thus reducing the congestion associated with heart failure.

Digoxin

Digoxin is a sodium-potassium ATPase inhibitor with positive inotropy, negative chronotropy, and inhibition of neurohormonal activation.16,17 Traditional thinking was to dose digoxin to achieve relatively high serum digoxin concentrations, while avoiding toxicity. However, more recent information suggests that lower digoxin serum concentrations may actually be preferable to higher levels due to the ability of digoxin to block neurohormonal activation at lower levels while avoiding its inotropic effects and possible toxicities at higher levels.18-21 Current recommendations in adults are for using 0.125 mg to 0.25 mg daily in most patients, a much lower dose than had traditionally been recommended.1 The role of digoxin in pediatric heart failure is not defined. In patients with pulmonary overcirculation due to large left-to-right shunts at the ventricular level, there is conflicting evidence of the utility of digoxin. Some reports have demonstrated benefit, whereas others have shown either no benefit, or actually worsening hemodynamics when administered acutely in the catheterization laboratory.22-26 In adults with heart failure, digoxin has never been shown to improve survival, only symptoms. One retrospective analysis has shown a higher mortality in a group of adults who had higher serum digoxin concentrations compared with those with lower concentrations or placebo23 (Fig. 497-4). In children with heart failure due to systemic ventricular dysfunction, there is no evidence to either support or refute the role of digoxin. Thus, one can choose to use digoxin for the same indications as in adults with heart failure (eg, symptoms), but should consider using lower doses to achieve lower serum digoxin concentrations.

Angiotensin-Converting Enzyme (ACE) Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve symptoms and survival in adults with heart failure. ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II which is a potent vasoconstrictor, enhances release of norepinephrine from sympathetic nerve endings, and induces cardiac hypertrophy, apoptosis, and fibrosis.27-30 ACE inhibitors have both systemic effects of vasodilation, and intramyocardial effects that aid in reverse remodeling in heart failure. ACE is identical to kininase II, an enzyme that breaks down bradykinin. It is this inhibition of kininase II that it is thought to be responsible for the well-known side effect of cough seen with ACE inhibitors. Side effects also include angioedema, hypotension, hyperkalemia, and renal dysfunction. The medications are generally very well tolerated and are now considered a Class I recommendation for the treatment of heart failure in adults.1 The role of ACE inhibitors in pediatric heart failure is much less clear. They may be useful in children with dilated cardiomyopathy. ACE inhibitors have also been used in cardiomyopathy after anthracycline treatment for cancer in childhood, but evidence of long-term improvement from enalapril is lacking.31-39 A more recent report in adults with acute increases in troponin I levels after anthracyline administration demonstrated significantly fewer cardiac events (eg, heart failure, arrhythmias) in those treated with enalapril compared to placebo.40 In those children with large left-to-right shunts at the ventricular level who are unable to undergo surgical correction, ACE inhibitors may be beneficial.

Angiotensin Receptor Blockers (ARBs)

Angiotensin receptor blockers (ARBs) are similar to angiotensin-converting enzyme (ACE) inhibitors, but are selective and competitive, nonpeptide angiotensin II receptor antagonists. As such, they do not have any effect on bradykinin, and therefore avoid some of the side effects of ACE inhibitors. Their use in children has been limited, and published reports have been primarily in the treatment of hypertension.41 It may be reasonable to consider ARBs to treat heart failure in children.

Aldosterone Antagonists

Aldosterone antagonists have been shown to provide a survival benefit in adults in 2 separate randomized clinical trials: Low-dose spironolactone in adults with moderate to severe heart failure,42 and eplerenone in adults with heart failure after acute myocardial infarction.43 Spironolactone has long been used by pediatric cardiologists as a potassium-sparing diuretic, and it seems reasonable to continue using this medication in children with heart failure. Eplerenone, a selective blocker of the mineralocorticoid receptor, and not glucocorticoid, progesterone, or androgen receptors, may have additional benefits over spironolactone due to its lack of the side effect of gynecomastia. However, there is very little experience with this drug in children.

Beta-Adrenergic Receptor Blockers (Beta-Blockers)

The mechanism of effect of beta-adrenergic receptor blockers (beta-blockers) in heart failure is multifactorial, but is at least partially mediated through the ability of beta-blockers to decrease beta-adrenergic receptor stimulation. Although beta-adrenergic stimulation is a positive adaptive process acutely in heart failure or other types of stress, chronic stimulation ultimately becomes maladaptive and harmful in the failing heart.44-47 Other potential mechanisms of action include negative chronotropic effects, upregulation of beta-adrenergic receptors (although many beta-blockers do not upregulate beta-adrenergic receptors), coronary vasodilatory effects, and possibly antioxidant effects of beta-blockers such as carvedilol, The two large randomized clinical trials of carvedilol in adults with mild-moderate heart failure and one with severe heart failure conclusively showed a survival benefit.47,48 Subsequent to this, both metoprolol and bisoprolol were also shown to have a survival benefit over placebo in the treatment of chronic heart failure in adults.48,49

Third-generation beta-blockers (eg, carvedilol, bucindolol) are either selective or nonselective for beta-1 or beta-2 blockade, but have important ancillary properties: alpha-receptor blockade (carvedilol) and direct systemic vasodilatory properties (bucindolol) that may add to their efficacy in the treatment of congestive heart failure. Carvedilol was actually shown to have a survival benefit over metoprolol in a group of adults with heart failure followed during a 5-year period (Fig. 497-5).50,51 More recently, it has been suggested that the variable response to bucindolol (and possibly other beta-blockers) may be due to single nucleotide polymorphisms within the beta-1 adrenergic receptor.52,53

There have been many retrospective reports of the use of beta-blockers in children with heart failure that suggested possible benefit effects on left ventricular performance and symptoms.54-59 However, a recent multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial of carvedilol in children with heart failure failed to show a benefit in the primary endpoint, which was a composite endpoint of heart failure outcomes—worse, better, or unchanged over an 8-month period (Fig. 497-6). However, the trend of improvement with carvedilol in children with a systemic left ventricle was positive, while the opposite was found in those with a systemic ventricle that was not a left ventricle (P < 0.02) (Fig. 497-7). It may be reasonable to consider the use of beta-blockers in those with a systemic left ventricle.

Electrophysiologic Therapy in Heart Failure

The two main therapies consist of cardiac resynchronization therapy (CRT) and implantable cardioverters/defibrillators (ICDs). CRT began in response to the observation that cardiac dyssynchrony is a common, but disadvantageous phenomenon in heart failure. In adults, this is usually manifested electrocardiographically as a left bundle branch block pattern, which results in late activation of the left ventricular free wall. This late activation alters regional loading conditions, myocardial blood flow and myocardial metabolism.60,61 There are also regional alterations in gene expression and protein production involved with mechanical function and stress. These alterations ultimately lead to derangement of both contractile and noncontractile elements, with the end result of ventricular remodeling, dilatation and pump failure. Early studies with the use of CRT demonstrated improvements in symptoms, quality of life, exercise capacity and ejection fraction.62 More recently, CRT has been shown to improve survival in adults with heart failure.63 The definition of dyssnchrony has been evolving since the introduction of this concept. CRT appears to have limited value in adults with heart failure and a narrow QRS, despite the presence of mechanical dyssynchrony by echocardiography.64,65 Interestingly, CRT may also benefit papillary muscle function and thus mitral valve function in patients with heart failure.66 The indications and risk/benefit balance of CRT in children with heart failure is not well defined. There have been reports of the use of CRT acutely after surgery for congenital heart disease in children.67 There have also been reports of successful use in children with congenital heart disease more chronically.68 One large multicenter retrospective report showed possible benefit in children with a variety of heart diseases, although the indications and predictors of beneficial effect are still not clear.69 Attempts at using biventricular pacing to treat right bundle branch block have been limited, but may have some benefit in selected children.70,71 The use of CRT and/or ICDs in children is complicated by the small size of children. In the very young, a thoracotomy is usually required. Even in older children, these devices can be placed transvenously, but growth can complicate the longevity of the leads, and using the only supracardiac venous access can limit future needs for transvenous access to the heart.

Death from heart failure can result from either end organ damage from heart failure or from sudden death. Sudden death due to arrhythmias is usually (but not always) due to ventricular tachycardia or fibrillation. Implantable cardioverters/defibrillators (ICDs) can be used as either secondary prevention or primary prevention. Secondary prevention is used in those with previous cardiac arrest or documented sustained ventricular tachycardia. ICDs are indicated in this group of adults with heart failure, who also have a reasonable chance of prolonged survival.

As with all other heart failure therapies, the indications for the use of ICDs in children with heart failure are not well defined. There have been descriptions of the successful use of ICDs in children, although the complication rate (including inappropriate discharges) is significant.72-74 In the very young (as stated above), transvenous placement may not be an option, and the used of complex subcutaneous arrays are being explored. Clearly, increased study and experience is needed in the use of ICDs in children in order to determine the indications and complications of this potentially life-saving therapy.

Single ventricle or univentricular heart refers to a limited number of congenital heart lesions from a strict anatomic perspective. Anatomically, single ventricle lesions can be either a single left ventricle, due to agenesis of the right ventricular inlet (there is often a small component of the right ventricular outlet present), or a single right ventricle, secondary to agenesis of the left ventricle.1,2 In both, the atria drain through one or two atrioventricular valves into the only ventricular chamber (Fig. 498-1). These lesions are rare, and do not include common lesions such as tricuspid atresia and hypoplastic left-heart syndrome.

In practice the concept of “single ventricle” expands beyond the strict anatomic definition, and refers to all congenital heart lesions that share a single ventricle physiology, regardless of the underlying structural variant.3,4 This expanded functional definition includes all those lesions in which the patient lacks a second ventricle that can independently support the pulmonary circulation. In most such lesions, components of a second ventricle exist.

In single ventricle physiology the circulations mix at the atrial and/or ventricular level. The surgical approach typically consists of various staging procedures which result in a complete separation, or “bypass,” of the pulmonary circulation from the heart. The final surgical stage that fully separates the pulmonary circulation is known as the modified Fontan operation. The “single ventricle” then becomes the systemic pumping chamber, and the systemic venous return flows passively through the pulmonary circulation without interposition of a ventricular pump.3

Thus, the single ventricle from a physiologic perspective includes patients with

• single right ventricle
• single left ventricle
• unbalanced complete atrioventricular (AV) canal (a common AV valve is more aligned to one ventricle than the other, typically associated with asymmetry in the development of the two ventricular chambers)
• tricuspid atresia (eFig. 498.1)
• hypoplastic tricsupid valve and right ventricle, frequently with intact ventricular septum and pulmonary atresia
• mitral atresia
• hypoplastic left heart syndrome and its variants (eFig. 498.2)

In addition, single ventricle physiology also exists in patients with complex intracardiac anatomy such that surgical septation of the ventricles cannot be performed, thus, they are managed in the same pathway as those with more traditional forms of single ventricle physiology. Examples are double outlet right ventricle and straddling atrioventricular valves, noncommitted ventricular septal defects, and complex multiple ventricular septal defects, for which surgical septation is not feasible. In such patients, following a Fontan procedure, two ventricles function together as the systemic ventricle.

Within the group of patients with heterotaxy (variable and often discordant situs of the viscera and cardiac segments), single ventricle variants are frequent, especially in the asplenia group (right atrial isomerism), in which a common atrioventricular valve drains into a main ventricle, with hypoplasia of a secondary ventricle. D-malposition of the aorta, severe stenosis or atresia of the pulmonary outflow tract, and anomalous pulmonary venous connections are frequent associated findings.5

Single ventricle physiology is an evolutionary step backward. The right ventricle appeared in reptiles and birds 165 million years ago to allow adaptation to air breathing, aerobic exercise, and flying. Patients with single ventricle physiology therefore lack an important mechanism of adaptation to aerobic exercise, so that exercise limitation is frequent in this group of patients, even after the final surgical palliation.6

Utilizing the segmental approach, each anatomic level can be analyzed.7-10

1. 1. Atria: solitus, inversus, or ambiguous (heterotaxy). The situs of the atria typically coincides with the situs of the viscera (if there is situs inversus of the viscera and the stomach is on the right side, then it is likely that the right atrium will also be inverted, on the left side). In solitus, the right atrium is right sided, receiving the systemic venous return, whereas the left atrium is left sided. When there is neither situs solitus nor inversus, the patient is said to have situs ambiguus.

   2. Atrioventricular connections: In addition to normal atrioventricular connections, there may be double-inlet connections in which the mitral and tricuspid valves enter a single ventricle, a common inlet (complete common atrioventricular valve), or atresia of the mitral or tricuspid valve.

   3. Ventricles: The ventricles may have a normal D-loop, in which the right ventricle is to the right of the left ventricle or an L-loop, in which the right ventricle is to the left of the left ventricle.

   4. Conotruncus or outflow: The normal relationship of the aorta to the pulmonary artery is rightward, lower, and posterior, with fibrous continuity of the aortic valve with the atrioventricular valves. The D-malposed aorta is anterior and to the right of the pulmonary artery, whereas the L-malposed aorta is anterior and to the left of the pulmonary artery

The normal segmental description of situs solitus based upon the above considerations is {S,D,S}. Many different segmental combinations can be found in single ventricles. Among the “anatomic” single ventricles, single left ventricle is more common2,10 (eFig. 498.3), with the vast majority having an infundibular outlet chamber and discordant ventriculoarterial connections (transposition). Inverted ventricular loop (L-loop) with transposition and left outlet chamber is slightly more frequent than ventricular D-loop. A small percentage has normally related great vessels, with a right sided infundibular outlet chamber (Holmes heart) ({S,D,S}).11

In addition to this segmental description, the presence or absence of obstruction at any level within the heart or great arteries is determined (eTable 498.1). For example, in double inlet left ventricle, the opening between the left ventricle and the hypoplastic right ventricular outflow chamber may be restrictive. This causes subaortic obstruction in the setting of transposition, or subpulmonary stenosis if the vessels are not transposed (Holmes heart). Coarctation of the aorta is often present in those patients with subaortic obstruction.

Overall, patients with single ventricle preoperatively tend to have complete mixing of pulmonary and systemic venous returns within the heart (Fig. 498-2). Blood leaving the heart goes both to the pulmonary and systemic circulations; therefore, the aortic and pulmonary oxygen saturations are usually equal but sometimes streaming of blood within the heart causes differences in aortic and pulmonary oxygen saturations. The single ventricle is volume overloaded, as it supplies both circulations. This parallel circulation is relatively inefficient because some previously oxygenated blood from the lungs returns to the pulmonary circulation and some systemic venous blood is shunted into the systemic arterial circulation (Fig. 498-2, eFig. 498.4).3

The balance between the systemic and the pulmonary circulations depends on multiple factors, including anatomic obstruction as well as relative vascular resistances and perfusion pressure.Assuming no lung disease, and a constant arteriovenous oxygen difference, based on the systemic oxygen saturation, one can estimate the Qp/Qs, or relationship between the pulmonary and systemic blood flows (eFig. 498.5). Ideally, the (Qp/Qs) should be kept at least at 1:1, which typically is achieved in the presence of complete mixing when the systemic arterial oxygen saturation is around 75%, in the absence of lung disease and with a normal cardiac output. Some cardiologists recommend maintaining aortic oxygen saturation over 85% with a QP/QS of 1.5 to 2, to improve growth potential.

Qp/Qs can be calculated by the simplified formula

where Spv is the hemoglobin oxygen saturation of blood in the pulmonary veins, Spa is the saturation in the pulmonary artery, Ssa is the saturation in the systemic artery, and Ssv is the mixed saturation in the systemic veins.

In the absence of obstruction at any level, the relationship between pulmonary and systemic blood flow depends on the relative resistances of the two vascular beds. At birth, Qp/Qs is only modestly increased as pulmonary vascular resistance falls from in utero levels, so that systemic arterial oxygen saturation is generally in the mid 70s. As pulmonary vascular resistance decreases in the first few weeks of life, pulmonary blood flow and systemic arterial oxgyen saturation increase greatly because the vascular resistance of the pulmonary vascular bed is much lower than that of the systemic bed. Saturations greater than 85% are associated with such high pulmonary blood flow and in some of these patients heart failure may develop, with respiratory distress, diaphoresis, and failure to thrive. Providing supplemental oxygen to infants with single ventricle to increase saturations when the oxygen levels are above 80% can be detrimental, as oxygen acts as a pulmonary vasodilator, decreasing pulmonary vascular resistance, increasing the pulmonary blood flow, altering the Qp/Qs relationship such that the systemic output decreases.3

However, many patients with single ventricle physiology have various levels of obstruction within the heart and great vessels, so that Qp/Qs depends on factors other than relative vascular resistances. The levels of obstruction include

• Pulmonary or subpulmonary stenosis or atresia: This may lead to a marked decrease in systemic arterial oxygen saturation, as the ductus arteriosus closes over the first hours of life. The degree of cyanosis is determined by the severity of the obstruction. In patients with severe pulmonary stenosis or pulmonary atresia, severe cyanosis can occur rapidly, and is a life-threatening event. In that situation, the infant is considered to be “ductal dependent.” Prostaglandin E1 is started immediately to reverse the problem. The typical hemodynamic status once the PDA is opened is illustrated in eFigure 498.6.

• Systemic (aortic) obstruction: This can be below the aortic valve (subaortic stenosis), at the valve, in the aortic arch (hypoplasia or aortic arch interruption), or in the aortic isthmus between the left subclavian artery and ductus arteriosus (coarctation of the aorta). When the obstruction is critical, newborns are ductal dependent, meaning that patency of the ductus arteriosus is necessary to maintain adequate systemic blood flow.
• Atrioventricular obstruction: With a stenotic or atretic atrioventricular valve, restriction of flow between the two atria can be very deleterious. In the hypoplastic left heart syndrome, for example, restriction at the foramen ovale causes severe left atrial and pulmonary venous hypertension. Severe pulmonary edema necessitates an emergency intervention to decompress the left atrium. This is done either via a balloon atrial septostomy, or more commonly now, placement of an interatrial stent. Restriction across the atrial septum is less common in right sided lesions but it can occur. If it does, the patient presents with low cardiac output and systemic venous hypertension.

The vast majority of the patients with single ventricle variants develop symptoms in the newborn period and early infancy. Patients with ductal dependent lesions need emergency intervention. Those with increased pulmonary blood flow may show signs of heart failure as the pulmonary vascular resistance drops, whereas those with decreased pulmonary blood flow have severe cyanosis. If not treated, death occurs in infancy in more than 50% of patients,12-14 more than half occurring during the neonatal period.

Patients with increased pulmonary blood flow may develop irreversible pulmonary vascular changes after the first year of life, leading to a decrease in the Qp/Qs. As pulmonary blood flow decreases the symptoms of heart failure resolve, but progressively severe cyanosis appears. Typical complicating features related to cyanosis and polycythemia include stroke, renal dysfunction, scoliosis, and endocarditis. Patients eventually develop progressive ventricular dysfunction, arrhythmias, and worsening heart failure.

Most adult survivors without intervention are those with a systemic left ventricle with 2 well-functioning atrioventricular valves, situs solitus, and pulmonary stenosis of moderate degree, protecting the pulmonary bed and no subaortic or aortic obstruction. Approximately a quarter will have developed pulmonary hypertension with various levels of vascular hypertensive pulmonary arteriopathy. Most survivors have signs of congestive heart failure. Complete heart block can develop in patients with discordant ventricular loop {S,L,L}variants, requiring a pacemaker.13 Progressive insufficiency of the atrioventricular valves is poorly tolerated in patients with single ventricle, especially with a single or dominant right ventricle. Patients with heterotaxy have a worse prognosis, due to the frequency of severe pulmonary stenosis or atresia, or to a dominant anatomically right ventricle and associated insufficiency of the atrioventricular valves, which can predispose to the development of ventricular dysfunction.15

Patients with single ventricle have variable physical examinations, depending on the presence or absence of associated pathology, particularly pulmonary or systemic obstruction.15

• Pulmonary stenosis (decreased pulmonary blood flow): Variable cyanosis is present. Patients with significant pulmonary stenosis develop similar clinical manifestations as patients with tetralogy of Fallot, and cyanosis will be the most remarkable feature on examination. Patients with mild stenosis may be acyanotic. As patients get older, clubbing becomes evident. Patients rarely have thoracic deformities. Their precordium is commonly normoactive. There may be a left superior parasternal palpable lift in patients with l-transposition. The peripheral pulses are usually normal. On auscultation, there is a systolic ejection murmur of intensity and duration directly correlating with the amount of pulmonary blood flow, and inversely correlated with the severity of the pulmonary stenosis and level of cyanosis. The absence of a systolic ejection murmur may suggest pulmonary stenosis. A continuous murmur from a patent ductus or aortopulmonary collateral vessels may be present. The second heart sound is commonly loud and single (aortic component), particularly in the patients with l-transposition.
• No pulmonary stenosis (increased pulmonary blood flow): With no pulmonary stenosis, patients tend to present with heart failure due to increased pulmonary blood flow, manifested by respiratory distress, diaphoresis, and poor weight gain. Cyanosis is minimal or absent. Patients more commonly have thoracic deformities and a hyperdynamic precordium. A soft systolic ejection murmur in the midprecordium with radiation to the axilla and to the back represents relative pulmonary stenosis. The second heart sound is loud, in the base, with simultaneous aortic and pulmonary components. An S3 gallop and a mitral valve middiastolic rumble can be auscultated in the apex.
• Systemic outflow or aortic obstruction: In newborns, systemic obstruction presents typically with signs of hypoperfusion, including decreased peripheral pulses, duskiness, and, eventually, cardiovascular collapse. Findings specific to the level of obstruction may be found, particularly in the older infant with adequate systemic output. When a systolic thrill in the base and suprasternal notch appears, subaortic stenosis should be suspected. On auscultation, there is a harsh, loud systolic ejection murmur in the base and mid precordium with radiation to the neck. When the obstruction is valvar, a prominent systolic ejection click is audible in the retrosternal area. When coarctation of aorta is present, the peripheral pulses and blood pressures are unequal.
• Pulmonary venous obstruction: The presence of more severe pulmonary edema and congestion than expected from the amount of pulmonary blood flow or ventricular dysfunction suggests severe obstruction of the left atrioventricular valve with a restrictive atrial septal defect, or anomalous pulmonary venous connections with obstruction, the latter particularly common in patients with heterotaxy syndromes.

The signs of chronic cyanosis and polycythemia are obvious in older palliated patients but tend to be subtle in the infant and young child. As surgical staged palliation leads to near normalization of oxygen saturations, the detrimental effects of chronic cyanosis are rarely seen in patients with single ventricle nowadays, except for those who are not good candidates for palliation or who have failed the procedures already.

Following surgical palliation cardiac examination depends on the procedure performed and the underlying anatomy. An aortopulmonary shunt is associated with a continuous murmur at the site of the shunt. The second heart sound is single after a modified Norwood procedure.16 Murmurs are frequently absent after the bidirectional Glenn and modified Fontan procedures, A blowing systolic murmur occurs in the setting of systemic atrioventricular valve regurgitation, whereas a systolic ejection murmur may indicate subvalvar or valvar aortic stenosis, or anterograde flow across the pulmonary valve into the pulmonary arteries in certain anatomic variants. A diastolic murmur is typically due to semilunar valve regurgitation (which happens quite commonly in patients in whom the anatomic pulmonary valve becomes the neoaortic valve after a Norwood palliation).

During evaluation and follow-up, patients with single ventricle variants regularly undergo an electrocardiogram, echocardiogram, chest x-ray, and pulse oximetry. The results vary depending on the underlying anatomic variant. Some electrocardiographic and radiographic findings are pathognomonic of the condition. When children are over 7 years of age, cardiopulmonary stress testing is also performed. Holter monitors are obtained every other year to evaluate the presence of silent arrhythmias. Cardiac magnetic resonance is ordered more and more often to evaluate anatomic and functional features in these patients. Cardiac catheterization continues to be generally performed prior to surgical procedures, and it is especially indicated when complications arise during follow-up with possible interventional transcatheter therapy to address specific abnormalities encountered (Table 498-1).

Electrocardiography

The electrocardiographic findings are very variable in single ventricle patients, and depend on the underlying anatomy. Occasionally they may be pathognomonic. For example, patients with tricuspid atresia frequently have a superior axis with counterclockwise loop and decreased right ventricular forces. Ventricular inversion is indicated by inverted initial activation with Q waves in the right precordial leads (qRS or qR in V1) in association with the absence of Q waves in the left precordial leads (RS in V6). This is important to appreciate because such patients are at risk of developing complete atrioventricular block over time.13

Patients with hypoplastic left ventricle show diminished left ventricular forces and dominant right-sided forces, but this may be subtle enough that it is indistinguishable from the normal newborn electrocardiogram (ECG). Unlike the normal newborn, the right ventricular hypertrophy persists and is often associated with ST-T wave changes, reflecting strain pattern (eFig. 498.7). Patients with hypoplastic right heart variants such as pulmonary atresia with intact ventricular septum show diminished right-sided forces, with relative left-axis deviation for a newborn. Ischemic changes can also be present in those patients who have this condition associated with severe coronary abnormalities. Patients with single right ventricle have signs of right ventricular hypertrophy. With unbalanced ventricles there typically is an underlying endocardial cushion defect, there is an associated left anterior hemiblock pattern with signs of left ventricular hypertrophy when the left ventricle is dominant, or right ventricular hypertrophy if the right ventricle is dominant.

Chest X-Ray

Chest x-ray findings also vary considerably with variations in the anatomy of single ventricle patients, as noted below.13,14

In patients with pulmonary stenosis the cardiac silhouette is of normal size and there are diminished pulmonary vascular markings. In the absence of pulmonary stenosis there is usually cardiomegaly and increased pulmonary vascular markings, either due to high flow (increased active vascularity) or pulmonary venous congestion (increased passive vascularity).

With abnormal ventricular looping and ventriculoarterial relationships, it is common to see abnormal mediastinal densities, related to the different great vessel anatomy and orientation. A narrow mediastinum is commonly seen in patients with associated d-transposition of the aorta. In the presence of pulmonary atresia an acute angle may be seen at the left heart border because of the absence of a normal main pulmonary artery contour.

Chest X-ray can be particularly helpful in patients with heterotaxy (eFig. 498.8), in whom radiographic evidence of abnormal visceral and bronchial situs, cardiac position, and lung segmentation can be elucidated. An unbalanced complete atrioventricular canal is suspected in patients with associated cardiac malpositions on chest X-ray, such as isolated dextrocardia, levocardia with situs inversus, or ambiguous, or mesocardia.

Excessive cardiomegaly suggests the onset of ventricular dysfunction, often associated with severe regurgitation of the atrioventricular valves, or systemic outflow obstruction.

Signs of pulmonary venous hypertension out of proportion compared to the amount of pulmonary blood flow are seen when there is insufficiency or stenosis of the left atrio-ventricular valve with a restrictive atrial septum, or when there is anomalous pulmonary-venous connection with obstruction.

Echocardiography

Definitive diagnosis is usually made by echocardiography, which allows sequential determination of (1) thoracoabdominal situs; (2) systemic venous and pulmonary venous connections; (3) atrioventricular and ventriculoarterial alignments and connections17-19 (eFig. 498.8); (4) morphology and function of the single ventricle or dominant ventricle, and the atrioventricular valves (eFigs. 498.9 and 498.10); (5) conotruncal anatomy (position of the infundibular outlet chamber and size of the bulboventricular foramen, if present);18,19 (6) aortic arch and pulmonary arterial anatomy; and (7) the presence of a ductus arteriosus or other aortopulmonary connection.15

Each anatomic variant has specific echocardiographic features that characterize the lesion. Rarely, the anatomy cannot be elucidated in detail and angiography or magnetic resonance is required. Echocardiography is a routine essential test in the management of these patients at all times throughout their lives. In the teenager and young adult, transesophageal echocardiogram may be necessary to delineate the anatomy well.

Cardiac Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT)

Cardiac magnetic resonance imaging (MRI) and/or computed tomography (CT) angiography can these days elucidate the anatomic features of most complex heart defects accurately. CT has the disadvantage of requiring significant ionizing radiation exposure. Gadolinium-enhanced three-dimensional magnetic resonance angiography can demonstrate the anatomy beautifully, especially for pulmonary arterial or arch abnormalities (eFig. 498.11). In addition, MRI is the best methodology to assess ventricular dynamics, especially when the underlying anatomy is that of a single right ventricle.20,21 In small children, heart-rate-gated studies to obtain high-quality images of intracardiac anatomy and coronary arteries can be difficult to succeed, given the baseline tachycardia.

Catheterization and Angiography

There are very few conditions for which diagnostic cardiac catheterization and angiography continues to be performed prior to an initial surgical intervention. Anatomic definition of cardiac and vascular structures usually can be determined by echocardiography or if necessary, cardiac magnetic resonance imaging (MRI)21 or computerized tomography (CT) angiography. Patients with pulmonary atresia and small central pulmonary arteries continue to undergo diagnostic angiography in many centers, to delineate the anatomy of major aortopulmonary collateral vessels prior to staged repair. These patients rarely have single ventricle physiology, however. Patients with asplenia syndrome sometimes have mixed pulmonary venous connection which may require diagnostic cardiac catheterization to fully define. In addition, patients with pulmonary atresia and intact ventricular septum usually undergo diagnostic cardiac catheterization prior to surgical intervention to determine the presence of right ventricle-dependent coronary arterial circulation.

Following the early staged surgical procedures, cardiac catheterization continues to be performed routinely in most patients prior to the next stage, as well as in those patients who have postoperative complications potentially requiring intervention.22 Anatomic features of the single ventricle can be demonstrated nicely on angiography (eFig. 498.12).23 However, the main purpose of the study usually is to assess residual lesions and intervene as necessary (eFig. 498.13 A,B). For example, pulmonary artery stenosis is sometimes seen at the site of a previous shunt or pulmonary artery banding. Venocameral or pulmonary arteriovenous fistulas may develop after a bidirectional Glenn procedure, residual left to right shunts, or aortopulmonary collateral vessels may require embolization.22,24,25

Some consider that patients who are at low risk may be assessed with noninvasive methods and defer diagnostic cardiac catheterization unless a potential problem is found (ie, postoperative coarctation of aorta seen on MRI.21 Others recommend performing routine preoperative diagnostic cardiac catheterization for all patients with single ventricle variants outside of the neonatal period.

Diagnostic evaluation will help identify risk factors for surgical palliation (Table 498-2). Information important for decision making from a hemodynamic standpoint includes systemic and pulmonary blood flow, pulmonary arterial pressure and vascular resistance, and ventricular end-diastolic pressure.15,22 Patients with elevated pulmonary vascular resistance are not candidates for a Fontan procedure.

The management algorithm typically followed for patients with single ventricle variants is illustrated in eFigure 498.14. Graphics illustrating the various surgical interventions that can be performed on these patients are shown in eFigures 498.15, 498.16, 498.17, 498.18, 498.19, 498.20, 498.21, 498.22, 498.23, and 498.24.27,34

Medical Management

Prior to surgical intervention, newborns with ductal-dependent lesions are placed on prostaglandin E1 until surgery is performed. Newborns who do not have a ductal-dependent lesion but have pulmonary stenosis may have a good balance between systemic and pulmonary blood flow once the ductus arteriosus closes, and may be discharged without an initial surgical intervention. In the absence of an adequate degree of pulmonary stenosis, heart failure may develop, as discussed above. These patients may be managed with diuretics and afterload reduction, or pulmonary artery banding, particularly those patients without any pulmonary outflow obstruction.35,36

In order to balance pulmonary and systemic blood flow in the intensive care unit, the intensivist typically manipulates pulmonary vascular resistance, increasing it to minimize pulmonary blood flow and maintain systemic perfusion.12,37 This may be achieved either by using a closed hood to increase inspired and pulmonary vascular resistance, or by using a hypoxic or hypercarbic mixture, or by hypoventilation utilizing mechanical ventilation, sedation and paralysis. Supplemental oxygen and hyperventilation should be avoided, as well as any other factor that could lower the pulmonary vascular resistance. Additional medical management in the intensive care unit prior to surgery depends upon the patient’s condition. Common drugs used for inotropic support in the perioperative period include milrinone, low-dose dopamine, and epinephrine.12

Following Surgical Intervention

Significant alteration in physiology may occur with the surgical intervention, although the initial neonatal palliative procedures typically retains the same physiologic model of complete mixing and circulations in parallel. After stage II, the circulation is in series for the upper half of the body, but will not be completely in series until after stage III, the modified Fontan procedure. If the stage I palliation includes an aortopulmonary shunt, the patient is placed on low dose aspirin (3–5 mg/kg/day) as antiplatelet agent.15,16 Because a volume load persists after stage I palliation, the patient commonly receives diuretics, occasionally an afterload reducing agent (such as captopril), and occasionally digoxin to maximize ventricular function. Infants at this stage are typically in need of high-calorie formula, with very careful monitoring of weight gain.16 They have a fragile hemodynamic condition and little reserve, and may require hospitalization during minor systemic illnesses. Respiratory syncytial virus (RSV) vaccination is warranted.

After stage II (bidirectional Glenn procedure) and stage III (Fontan procedure) patients are typically continued on afterload reduction and sometimes digoxin, but diuretics are often discontinued. Following stage II patients typically improve in growth parameters, and can be weaned from high-calorie feeds because of a more stable and efficient circulation—the single ventricle is volume downloaded because pulmonary blood flow is directly provided to the lungs, passively. However, other medical problems can present. For example, chronic hypertension of the upper-body venous circulation may cause pleural effusions and upper-body edema.

There is significant variability in the medical management of patients with single ventricle.38,39 For instance, some cardiologists use afterload reducing agents in all single ventricle patients, and others only when there is evidence of ventricular dysfunction, or only in patients who have a systemic right ventricle. Some surgeons recommend warfarin use following Fontan procedure initially, whereas others do not. Similarly, differences in management are seen at every stage both in the medical and surgical arenas. However, in general, some form of anticoagulation is always used, and there is general consensus on the overall management approach with regards to goals of interventions and approximate timing of surgery.

Interventional Cardiac Catheterization

Patients with single ventricle variants may require transcatheter interventions early at presentation and prior to the initial palliative procedure. Such is true for of patients with a restrictive atrial-septal defect and left atrial outlet atresia or stenosis.22 Transcatheter creation of a new atrial septal defect with septostomy and balloon septoplasty may be life saving.

Newborn patients with single ventricle and ductal-dependent lesions can sometimes be considered candidates for ductal stenting. In particular, patients with hypoplastic left heart syndrome have been managed by some with what is called a hybrid procedure, where the ductus is stented by the interventional cardiologist12,27 (eFig. 498.25), while the surgeon places bilateral pulmonary artery bands to decrease the pulmonary blood flow and protect the pulmonary vascular bed. This becomes the initial palliative procedure or stage I, followed by a comprehensive stage II surgical procedure, when the patient undergoes arch reconstruction, removal of bands, pulmonary artery plasty, and bidirectional Glenn procedure.

Following each palliative surgical stage, interventional cardiac catheterization plays a significant role in optimizing hemodynamics and treating potential causes of hemodynamic disturbances (Table 498-1).22 Sometimes, emergency cardiac catheterization in the immediate postoperative period to create a new or augment a fenestration, to close residual defects, or balloon dilate/stent stenotic vessels is required in a severely compromised patient.22 At other times, interventions are performed later in the postoperative period in patients with chronic symptoms.

Interventions during cardiac catheterization are common in patients with single ventricle and these include coil embolization of venous anomalies24 or aortopulmonary collaterals,25 balloon dilation and/or stenting of branch pulmonary artery stenosis, pulmonary valvotomy or balloon dilation of coarctation of the aorta, closure of a prior surgical shunt, transcatheter closure of residual anterograde flow through the pulmonary valve, transcatheter closure of fenestration or baffle leaks, and so on (Table 498-1).

Surgical Management

Historic Perspective

The pioneer surgical contributions to the care of these patients have historically opened new horizons to patients who lacked therapeutic options previously. The Blalock-Taussig (BT) shunt was introduced in 1945 to augment pulmonary blood flow.31 This is now performed frequently during infancy in a modified fashion using a Gore-Tex tube, in patients with single ventricle who have pulmonary stenosis or atresia as the initial surgical palliation. eFigure 498.20 illustrates various types of surgical shunts used to provide pulmonary blood flow.

In 1958, William Glenn created a direct anastomosis between the superior vena cava and the right pulmonary artery, and proved that the pulmonary vasculature can accommodate the systemic venous return passively, without interposition of a ventricular pump.40,41 This was an extraordinary concept at the time, and the procedure continues to be done today, in a modified fashion (a bidirectional Glenn procedure, with blood flow from the superior vena cava to both pulmonary arteries), but still with the same physiologic consequences. The bidirectional Glenn shunt physiologically is a bypass of the ventricles, creating a more efficient circulation by imposing less volume work on the ventricles (eFig. 498.21).

The next major step towards proving that a pulmonary ventricle is not essential for survival in humans was the performance of the Fontan procedure in the early 1970s, demonstrating that in patients with tricuspid atresia, a complete bypass of the ventricles can be achieved successfully by anastomosing the right atrium to the pulmonary artery (eFig. 498.22).42-44 Some patients who underwent that original surgery in the 1970s are still alive today.45

The next major step was an aggressive neonatal surgical approach, the Norwood procedure for patients with hypoplastic left-heart variants (eFig. 498.16).46 It became clear that patients could not only survive long-term without a right ventricle with normal oxygen levels following the modified Fontan procedure, but they could do so without a left ventricle. It was this advance of neonatal cardiac surgery, hand in hand with improvements in postoperative care and the progress in interventional pediatric cardiology in the 1980s that management pathways were developed for neonates and infants with hypoplastic left ventricle, aimed at preserving their candidacy for Fontan palliation or heart transplantation.12,32

There are patients with single ventricle variants who still may not be candidates for single ventricle palliation, and for whom the only option is transplantation. Such is true for some severe forms of pulmonary atresia and intact ventricular septum with severe coronary arteriopathy, as well as patients with single ventricle variants and dysplastic atrioventricular valves with significant regurgitation or those with more than moderate ventricular dysfunction. Stenting of the ductus can be performed pretransplant to avoid the need for chronic use of prostaglandins while waiting for an organ. In addition there are a few centers in the country who electively offer transplantation as a first line therapy for single ventricle variants which require a Norwood procedure otherwise.38 Intermediate and long-term survival of either approach is comparable, but there are not enough organs available to allow transplantation to be the major option for these patients, so that most consider transplant should be reserved for patients at higher risk or who have failed single ventricle palliation.

Surgical Management

Staged Surgical Palliation

The goals in the management of patients with single ventricle variants include protection of the pulmonary vasculature by avoiding elevation in pulmonary arterial blood flow and pressure, and preservation of ventricular function by minimizing volume and pressure overload.

First-Stage Palliation

The first stage palliative procedure is typically performed in a newborn or soon thereafter. The reported early operative mortality for an aortopulmonary shunt in neonates can be as high 17%32; however, this value continues to decrease as the years go by. If performed after the neonatal period, the mortality is significantly lower. The early operative mortality in the newborn with single ventricle ranges from 8% to 25%, and depends on the specific lesion, the presence of hemodynamic compromise or organ dysfunction prior to surgery, and associated cardiac malformations.33 It is highest in patients who require complex surgery, such as aortic arch reconstruction or resection of subaortic stenosis, and in those with complex lesions such as patients with heterotaxy and associated anomalous pulmonary venous connections. Over the years the surgical mortality for stage I palliation in the form of Norwood procedure has continued to improve, as low as 12% for some centers and patient populations.42 However, there is a significant interstage mortality of up to 15%, mostly represented by sudden death.12

Stent implantation in the patent ductus is becoming more popular as an alternative to a surgical shunt, although the intermediate and long-term results of this procedure are unknown.12

Some single ventricle lesions either have subaortic obstruction at birth or are at risk of developing it, particularly when the ventricle is unloaded by the bidirectional Glenn shunt.47,48 These patients may benefit from a Damus-Kaye-Stansel anastomosis as part of their staged palliation (eFig. 498.23). Patients with hypoplastic left heart syndrome undergo a modified Norwood procedure, which includes ascending aortic enlargement via modification of the Damus-Kaye-Stansel procedure, aortic arch augmentation, atrial septectomy, and either a Blalock-Taussig shunt or a right ventricle-to-pulmonary artery conduit (eFig. 498.16).3,46 The latter is a recent modification and is commonly referred to as the Sano modification34 (eFig. 498.25). It is thought to minimize the risk of interstage death because aortic diastolic pressure is higher, putatively decreasing the risk of coronary ischemia.

The circulation resulting from the initial palliation is only left in place for a short period of time (3–6 months), as ventricular dysfunction may become significant over time. This relates to the inherent volume overload of a shunted single ventricle physiology (the systemic ventricle is providing both the systemic and the pulmonary blood flow). Due to this volume load the ventricle over time acquires more spherical shape, which leads to an increase in the end-systolic stress (afterload), and reductions in ventricular function.

Second Stage Palliation: The Bidirectional Glenn Procedure

Around 4 to 6 months of age, a bidirectional cavopulmonary anastomosis, or Glenn procedure, is performed.3,49 Risk factors are similar to those for the Fontan procedure, although patients with risk factors are more likely to tolerate a bidirectional Glenn rather than a Fontan. Following this procedure, there is more effective pulmonary blood flow, as only desaturated upper body blood passes into the lungs. Pulmonary blood flow decreases substantially but systemic O2 saturation is usually quite adequate, at about 80 to 85%. In addition, venous return to the heart is markedly decreased, leading to a reduction in atrial-filling pressures (eFig. 498.21). There is an immediate change in ventricular geometry following a bidirectional Glenn because of the decrease in ventricular volume and increase in the ventricular mass/volume ratio).This can lead to subaortic stenosis in certain single ventricle variants.47,48 A bidirectional Glenn circulation is essentially nonpulsatile. However, there are specific instances when it is pulsatile, such as when there is additional pulmonary blood flow from either a shunt or anterograde flow across the pulmonary valve. In these patients, the systemic oxygen saturation tends to be higher as there is increased amount of pulmonary blood flow. Currently the surgical mortality following bidirectional Glenn procedure is less than 5%.

Third Stage Palliative Surgery: Fontan Procedure

Complete separation of systemic venous return from the heart (total cavopulmonary bypass) is commonly called a modified Fontan procedure. Many modifications of the initial Fontan procedure have been proposed and performed. Originally, the anastomosis was created between the atrial appendage and the pulmonary artery, directly or by interposition of a conduit43,44 (Fig. 498-3). Later, the anastomosis was made at the roof of the right atrium medial to the entry point of the superior vena cava.50 Subsequently, the entry point of the superior vena cava was used at the site of anastomosis to the pulmonary artery and a baffle was used to direct blood within the right atrium to the superior vena cava and the pulmonary arteries (lateral tunnel)3,51 (eFig. 498.25). Currently, the extracardiac conduit is the preferred technique used in most centers3,52 (eFig. 498.19 and Fig. 498-3). Many surgeons prefer to add a fenestration or small hole (4 mm) within the Fontan pathway allowing right-to-left shunting to serve as a pop-off, lowering postoperative venous pressures.30 Patients with a fenestrated Fontan circulation typically have oxygen saturation in the high 80s to low 90s range. If the Fontan is unfenestrated, then the oxygen saturations are almost normal (the only source of desaturation comes from coronary venous return). Generally the Fontan procedure is performed in patients between ages 2 and 5 years, depending on the preference of the center.49

The surgical mortality of the Fontan procedure has improved significantly over the past 2 decades, to less than 5% currently.3,42,52-55 Unfortunately, recent reports suggest that a total cavopulmonary bypass, or the Fontan circulation, is not without long-term consequences.54,55 Estimated freedom from Fontan failure at 5 and 10 years has been reported in the order of 90% and 87%, respectively,42,53 with a continued risk of death of about 1% to 3% per year.

Morbidity after Single Ventricle Palliation

Postoperative Aortopulmonary Shunt

Infants following stage I palliation are in compensated heart failure, have difficulty in gaining weight, and have a limited reserve in case of any concurrent illness. This limited reserve is associated with a relatively high incidence of sudden death during this interstage period, as discussed above. If the second stage is not feasible, these patients tend to develop cardiomyopathy over time, and the chronic cyanosis and polycythemia lead to a significant long- term risk of cerebrovascular accident. They are also at high risk for endocarditis and arrhythmias.12,16,42,56

The total right heart bypass, or Fontan circulation, may become dysfunctional for various reasons:

1. 1. Postoperative bidirectional Glenn procedure

   Patients palliated with a bidirectional Glenn procedure have persistent cyanosis, so that they too are at risk from the deleterious effect of chronic polycythemia. In addition, they are at risk of developing pulmonary arteriovenous malformations which cause intrapulmonary shunting of deoxygenated blood directly into the pulmonary veins, leading to further desaturation.56,57 This complication is reversible once the Fontan is completed,58 presumably due to flow of hepatic venous blood into the pulmonary circulation. The elevated upper body venous pressures also leads to formation of venovenous and venocameral collateral vessels, which also exacerbates the cyanosis,24 Last, chronic cyanosis leads to the development of aortopulmonary collateral flow, which increases the volume work of the single ventricle.

   Exercise stress testing in these patients demonstrates that even when the systemic saturation is adequate at rest (> 85%), there is marked desaturation during exercise.59 Patients with partial right heart bypass, either pulsatile or not, have markedly depressed exercise capacity (48% of the estimated functional capacity), directly in relationship with the level of systemic saturation. The chronotropic response is normal, similar to what occurs with cyanotic congenital heart defects.

   2. Postoperative Fontan

   a. Increase in the transpulmonary gradient: The difference between pulmonary arterial and pulmonary venous pressure is the transpulmonary pressure gradient and it should not exceed about 8 mmHg. Over time, it tends to increase in the Fontan patient due to deficient pulmonary arterial growth, pulmonary artery branch stenosis,60 chronic pulmonary micro or macro thromboembolism,61 or a progressive increase in pulmonary vascular resistance. This typically translates into increase in pulmonary arterial and systemic venous pressures. In these patients, oral anticoagulants should be routinely prescribed. The clinical manifestations of elevated systemic venous pressures are described below.

   b. Myocardial failure: An increase in the systemic ventricular end diastolic pressure due to myocardial failure leads to an elevation in pulmonary venous pressure and subsequently in pulmonary arterial and systemic venous pressure. This can occur in hand with atrioventricular valve insufficiency.

   c. Pulmonary venous obstruction: Pulmonary venous stenosis or extrinsic compression, or obstruction between the left and right atrium (in patients with hypoplastic left heart syndrome) can also lead to elevated pulmonary venous and, subsequently, pulmonary arterial and systemic venous pressures.

   d. Systemic venous pathway obstruction: If there is obstruction within the Fontan baffle or conduit, systemic venous hypertension will occur proximal to the obstruction.

Clinical manifestations of Fontan failure include peripheral edema, chronic pleural effusions, protein-losing enteropathy,62 decreased exercise tolerance, chronic atrial arrhythmias, and chronic cyanosis

Sometimes there are mechanical problems related to the specific type of Fontan procedure performed, which can be solved or improved greatly with Fontan redo. Such occurs in patients who develop a giant right atrium after an atriopulmonary anastomosis, or conduit obstruction in extracardiac conduits. They may benefit from either redo or conversion to a different type of Fontan.63

Peripheral Edema and Chronic Effusions

As manifestations of venous hypertension, extravascular fluid may respond to anticongestive management. Cardiac catheterization may be indicated to evaluate hemodynamics with a particular focus on a possible, intervention to relieve right- or left-sided obstruction. Protein losing enteropathy occurs in up to 11% of the patients.62 They present with chronic diarrhea, hypoproteinemia, hypoalbuminemia, chronic edema, pleural effusions, ascites, pericardial effusions, and increase of the fecal alpha-1 antitrypsin. This problem is thought to be related to venous hypertension, although hemodynamic correlation is not always present. Medical management includes maximization of anticongestive therapy, and use of anticoagulation, steroids, all with limited success. The prognosis is poor, and thus, intervention is required. Creation of a Fontan fenestration is an option, to lower venous pressures. Heart transplantation may be indicated, but it is of increased risk.

Cyanosis

Cyanosis can develop in the Fontan patient due to development of a right-to-left shunt within the baffle or decompressing venous collaterals to pulmonary veins or cardiac chambers. Other possibilities include ventilation-perfusion (VQ) mismatch due to either parenchymal lung disease or to the effects of chronic pulmonary thromboembolism. Right-to-left shunting can often be resolved in the catheterization laboratory by coil or device closure (eFig. 498.26).

Following staged surgical palliation sinus node dysfunction is reported to be as high as 37%.64 Arrhythmias may occur in the early postoperative period, particularly in patients with high risk factors and poor postoperative hemodynamics. Among these, atrial arrhythmias, junctional ectopic tachycardia, and even ventricular arrhythmias may develop. Junctional ectopic tachycardia can occur in the immediate postoperative period after total right heart bypass,particularly in patients of less than age 3 years, and is a sign of poor prognosis.

Supraventricular tachycardia in the form of atrial flutter is a serious problem following the Fontan procedure.65 In the long-term follow-up, it seems to be less frequent in patients with total cavopulmonary connection (external conduit Fontan) than in those with atriopulmonary connection, although the follow-up periods are not comparable. Management includes antiarrhythmic drugs, pacemakers, and radiofrequency ablation, as well as Fontan redo.66 Fontan redo is offered to those patients with an old-style Fontan connection and severely dilated atria.

Patients with a Fontan circulation have mildly diminished functional capacity by ergometry to about 70% of the estimated functional capacity in association with mild desaturation and subnormal chronotropic response.59

Pregnancy in Single Ventricle Patients

Although limited reported experience demonstrated feasibility of a successful pregnancy in single ventricle mothers, there is significant morbidity and potential mortality related to it. Forty-five percent of pregnancies resulted in live births in a study of 33 pregnancies.67

As the diagnostic role of cardiac catheterization has diminished over the years, its role as a mode of primary therapy has exponentially increased. In most large congenital cardiac centers today more than 70% of all children undergoing cardiac catheterization have an interventional therapy as part of the procedure. Interventional cardiac catheterization has become the standard of care for treating an increasing number of congenital heart lesions, while in others it remains investigational (Table 499-1). Common interventional procedures include balloon septostomy in neonates with d-transposition of the great arteries, balloon valvoplasty in valvar pulmonic or aortic stenosis, balloon angioplasty with or without stent repair of branch pulmonary artery stenosis or coarctation of the aorta, device closure of a patent ductus arteriosus, atrial septal defect, muscular ventricular septal defect, and embolization of abnormal venous or arterial vessels. Investigational interventional catheter based treatments include stented valve implant for pulmonary insufficiency, ductal stenting for first stage treatment of infants with hypoplastic left heart syndrome or pulmonary atresia, and fetal intervention for critical aortic or pulmonic stenosis to promote ventricular growth in utero.

Interventional procedures are directed at avoiding, postponing, or complementing surgery with its attendant risks, scars, and lengthy hospitalization and recovery times. Occasionally there is no suitable surgical procedure. Most patients treated with interventional catheterization go home the same day as the procedure and can return to full activity within 5 days. The therapeutic procedures performed in pediatric populations are dilatations, valve implants, or closures. Dilatations are performed using balloons alone or in combination with stents, valve implants use specially designed valved stents, whereas closures are done with embolization coils or specially designed devices or plugs.

An unrestrictive atrial septal defect may be necessary for patients with certain cardiac abnormalities. Adequate mixing through an atrial septal defect is essential for survival in neonates with d-transposition of the great arteries (dTGA) as well as in patients with a functional single ventricle who have a severe mitral stenosis or atresia, tricuspid atresia, or total anomalous pulmonary venous connection. Balloon atrial septostomy (Rashkind procedure) involves passing a balloon-tipped catheter through the foramen ovale into the left atrium (LA), inflating the balloon, and then pulling it back rapidly across the atrial septum. The resulting tear in the atrial septum usually improves mixing. In most centers, this procedure is performed under echocardiographic guidance and moderate sedation at the bedside (Fig. 499-1). Although balloon catheters successfully tear the thin valve of the foramen ovale of neonates with dTGA, the thicker septum in neonates with left-heart obstruction, or in older infants is not usually amenable to balloon septostomy. Techniques used to open the septum in these patients include static balloon dilatation with high pressure or cutting balloons, and atrial septal stenting (Fig. 499-2).

Balloon pulmonary valvoplasty is safe and highly successful in reducing the transvalvar gradient while producing little pulmonary insufficiency. With large balloons that exceed the size of the pulmonary valve annulus by 20% to 40%, pulmonary valve gradients are typically reduced to less than 15 mmHg. The residual obstruction and insufficiency are similar to that seen after surgery. It has become the standard procedure for valvar pulmonic stenosis because the mortality and morbidity are extremely low, it is an outpatient procedure, and there is no sternotomy, cardiopulmonary bypass, blood transfusions, general anesthetic, or scar (Fig. 499-3). Only very thick dysplastic valves, as occur in Noonan syndrome, and supravalvar stenosis may respond poorly to balloon dilatation and require surgery. Even neonates with pulmonary atresia and intact ventricular septum can undergo successful balloon valvoplasty after the atretic valve is perforated by a radio frequency or laser-tipped wire.

For similar reasons balloon aortic valvoplasty is the treatment of choice in patients with valvar aortic stenosis and can be performed with low mortality, good relief of aortic obstruction, and variable but usually mild aortic insufficiency. Patients with calcific aortic stenosis, moderate to severe aortic insufficiency, or annular hypoplasia are not good candidates for valvoplasty. Early and medium-length follow-up studies show results comparable to primary surgery; usually there is less aortic regurgitation but occasionally severe aortic regurgitation necessitates valve replacement. Longer-term studies suggest the durability or repair with balloon dilatation may be less than that with surgery. The risks of valvoplasty include arrhythmias, emboli, neurologic events, and injury to access vessels. In contrast, surgical risks include mortality, risks of anesthesia, cardiopulmonary bypass, blood products, the disadvantages of a long hospitalization, an undesirable scar, and greater cost. Both balloon aortic valvoplasty and surgical valvotomy are palliative. Longer-term follow-up suggests that repeat treatment for either recurrent stenosis or worsening insufficiency occurs in 50% of patients within 8 years of valvoplasty. In some patients who develop restenosis after surgical or balloon procedures, balloon valvoplasty has been used as a means of deferring valve replacement; such delays are particularly important in small children who would otherwise require multiple valve replacements.

Balloon mitral valvoplasty has been performed via a transseptal approach in a few children in the United States, and a larger number in Asia and the Middle East. Preliminary results indicate very good relief of obstruction with minimal resulting mitral insufficiency in children with rheumatic mitral stenosis. Results for congenital mitral stenosis are variable, with a greater propensity for developing mitral insufficiency. Balloon dilatation in this situation is used sparingly, usually reserved for children in whom surgical repair carries an unusually high risk.

Angioplasty of obstructed vessels in children has been performed since 1982. Relief of obstruction is achieved by tearing the intimal and medial layers. The most commonly involved vessels are arteries, specifically the pulmonary arteries and aorta, though some postoperative venous obstructions are amenable to dilatation as well. Recent advances in balloon catheter technology, allowing for smaller balloon catheters that can be inflated to extremely high pressures (25 atm), have made these procedures safe and more effective. Balloons with tiny surgical blades attached, called cutting balloons, are now available. They allow dilatation of even the most resistant vessel stenosis. For some lesions, such as distal pulmonary artery stenosis, direct surgical relief is extremely difficult, making angioplasty clearly the treatment of choice.

Stenosis of the branch pulmonary arteries may be congenital, acquired, or postsurgical (ie, at shunt insertion sites, bands, or conduits). Examples of congenital pulmonary artery branch stenosis (PABS) include tetralogy of Fallot with pulmonary atresia, Williams syndrome, Alagille syndrome, and congenital rubella. Stenosis caused by scarring from previous Blalock-Taussig or other aortopulmonary shunts is usually amenable to balloon palliation. Native stenoses or hypoplastic pulmonary arteries can be less responsive, although with the current improved balloon technology success rates are greater than 90% (Fig. 499-4). In some patients there may be modest initial improvement in the size of the pulmonary arteries, which then show significant growth thereafter. A combined surgical-transcatheter approach to patients with complex pulmonary artery stenosis has now become commonplace. Surgery to proximal stenoses and any intracardiac defects is used in conjunction with transcatheter therapy of distal pulmonary stenosis and recurrent obstruction improves short- and long-term outcomes.

Balloon dilatation of native aortic coarctation in neonates and children is successful in 80% of patients but has been associated with significant complications, including aortic rupture and death (< 1%) as well as late aneurysm formation at the site of the previously torn vessel (7%). Recurrence of coarctation following dilatation in neonates occurs in up to 75% of patients, and for this reason most cardiac centers recommend surgical treatment of neonatal coarctation. The role of this procedure for native coarctation in older children is unsettled, with equivalent immediate efficacy and complications, shorter hospitalization, but what appears to be a higher late recoarctation rate. Most centers offer dilatation as an alternative treatment to surgery in toddlers and preteens. For teenagers endovascular stent repair has become the treatment of choice (see below). On the other hand, recoarctation angioplasty has achieved wide acceptance because the surrounding scar from the previous surgery makes repeat surgical repair more difficult. The late results of recoarctation balloon angioplasty appear to be at least as good as reoperation.

Balloon-expandable stents (metallic mesh tubes) are now used to treat many lesions that are not amenable to balloon dilatation alone. Lesions with significant elastic recoil that resist tearing can often be treated with endovascular stents.

The largest experience in pediatrics is with stenting for branch pulmonary artery stenosis. Results have shown an increase in vessel diameter, a fall in peak systolic gradient across the obstruction, an increase in flow to the stented lung, and a decrease in right ventricular pressure. Restenosis is rare, occurring in only 3% of patients, and redilatation has been effective. Similar success has been reported with stents in postoperative right ventricular to pulmonary artery conduit stenosis, and stent placement has become the treatment of choice for systemic venous obstruction. Stent placement as primary treatment of coarctation of the aorta, both native and recurrent, has become a preferred therapy for adolescent patients in most centers (Fig. 499-5). Procedural success is excellent in over 95% of patients with no significant restenosis at mid-term follow-up. Serious complications are seen in 1% of patients including death, stroke, and aneurysm formation requiring surgical repair.

Aortopulmonary collaterals, arteriovenous malformations, Blalock-Taussig shunts, venous collaterals, coronary artery fistulas, and small patent ductus arteriosus (PDA) have all been successfully occluded by coil or vascular plug embolization (Fig. 499-6). The embolization coils consist of a straight metal wire, either stainless steel, platinum, or Inconel (nickel–chromium alloy) with or without Dacron strands, available in multiple sizes, lengths, and shapes, that coil into a helix when extruded from the catheter. Vascular plugs are Nitinol (nickel–titanium alloy) wire mesh that when extruded from the catheter expand into the shape of a plug. Although PDA or coronary artery fistula embolization may obviate the need for surgery, most embolizations serve either to reduce the cardiac workload by decreasing the amount of shunting or to simplify a planned surgical procedure.

The technique for coil or vascular plug closure of collaterals or other communications is straightforward. A catheter is placed in the vessel to be occluded, and a selective angiogram is done to delineate the anatomy and diameter of the vessel to be closed. Coils or plugs are chosen that are slightly larger than the diameter of the vessel, as the vessel will distend when the coil or plug is deployed. With a long wire the coil or plug is pushed through the catheter and deployed in the vessel (Fig. 499-7). Repeat angiography is performed to confirm complete closure. If residual flow remains, additional coils or plugs are placed. Coils can be placed through smaller catheters so they are particularly good if the lesion is difficult to get to with a tortuous catheter course. Larger vessels or lesions are best closed with plugs.

Patent ductus arteriosus (PDA) coil, vascular plug, or device occlusion have become standard therapy for closure of PDA in infants, children, and adults. Equipment is still too large for use in premature infants although technical development is underway to meet this challenge. Recent reports have demonstrated closure rates of nearly 100% with PDAs measuring up to 6 mm diameter. The coil is deployed with one loop of coil in the pulmonary artery and the rest in the ductal ampulla. Because the ductus is often funnel shaped, this arrangement anchors the coil in the ductus and prevents embolization to the pulmonary bed or lower body. If a single coil does not completely close the PDA, multiple coils can be placed until no residual shunting exists. The coils can be placed either anterograde from the femoral vein or retrograde from the femoral artery (Fig. 499-8). The latter is technically less challenging and therefore more common. Larger PDAs are typically closed with vascular plugs especially designed for the PDA. These are delivered anterograde from the femoral vein and close PDAs up to 14 mm in diameter (Fig. 499-9). Complications are exceedingly rare and most often consist of coil embolization to the pulmonary artery; the coil can be retrieved and removed from the patient in the catheterization laboratory with minimal effort and risk. Larger plugs or devices pose the risk of left pulmonary artery stenosis or coarctation of the aorta due to extension into these areas. This is quite rare, and seen only with closure of a very large ductus in a very small child. Pulse loss is a risk for small infants but can be minimized by a venous approach. Rarely recanalization of the PDA after coil closure, documented by color flow Doppler, has been reported.

Surgical closure of atrial and ventricular septal defects requires cardiopulmonary bypass with its attendant risks. Transcatheter closure of secundum atrial septal defects is safe and effective in greater than 96% of patients, with no mortality and complications in less than 3% of patients, and has become the treatment of choice at most centers worldwide. Patients with associated anomalies requiring surgical treatment, such as partial anomalous pulmonary venous return, or patients with extremely large or asymmetric defects, those extending too close to the atrioventricular (AV) valves or pulmonary veins, still undergo surgical closure. Over the past 5 years at the University of California, San Fransisco, over 97% of children with isolated secundum atrial septal defects have been successfully closed nonsurgically with device placement.

The procedure is performed under moderate sedation and takes approximately 3 hours. Placement of the device is guided by both fluoroscopy and echocardiography.(eFig. 499-1A,B). In smaller children surface echocardiography is used, in school-age children most centers use intravascular ultrasound, a catheter is placed from the femoral vein to the right atrium with a small echo transducer on the tip (eFig. 499.2). Patients usually go home the same day or morning after and resume full activities within 5 days. Complications are extremely rare with no reports of death, stroke, need for blood transfusion, thrombus, or significant arrhythmia in children.

There are currently two devices in common use in the United States and several others in development around the world (eFig. 499.3). All are similar in that they have two patches consisting of a flexible metal frame with a fabric or mucosal covering connected centrally. The device is compressed into a catheter or sheath and advanced to the left atrium where the distal patch is pushed out of the catheter and expanded. The system is brought back to the atrial septum and held in place. The sheath is then withdrawn over the proximal patch allowing it to expand in the right atrium. The two patches hold themselves in place by clamping onto the atrial septal tissue surrounding the hole. The device is then released and over the next 4 to 6 months the endocardium of the atrium grows over the device (several cells thick) to finalize closure (eFig. 499.4).

Ventricular septal defects (VSDs) can also be closed with device placement but the procedure is much more complex and at present limited primarily to muscular defects (Fig. 499-10). This procedure usually requires general anesthesia and transesophageal guidance of the device placement. The children stay a single night in the hospital and can resume full activity within 5 days. Success rates are high, greater than 97% with low complication rates, although higher than with ASD closure. Late complications are rare. Perimembranous ventricular septal defects, the most common type of VSD, are very close to the aortic valve and the conducting system, the AV node, posing additional challenges for device closure. Specially designed devices have been used successfully but with a significant incidence of complete heart block that presents unpredictably late requiring at times urgent pacemaker placement. Because of these issues, new devices are in development for closure of perimembranous VSD. Currently only patients with either extremely high surgical risk or an associated ventricular septal aneurysm that eliminates the risk for either aortic valve injury or atrioventricular (AV) nodal injury are closed by device (Fig. 499-11).

Pulmonary insufficiency with right ventricular dilatation is common in adolescents after repair of tetralogy of Fallot or truncus arteriosus. Although initially thought to be well tolerated, it has become clear that severe chronic pulmonary insufficiency in children leads to right ventriclar failure, exercise intolerance, and shortened life span in adults. In an attempt to minimize the need for repeat surgeries, and their inherent complications, a catheter deliverable stented valve has been developed. It is currently available for general use in Europe and is in phase 2 clinical trials in the United States. Due to the large size of the introducing system (22 Fr) it is limited to use in adolescent and adult patients.The procedure can be performed under moderate sedation taking only 3 hours with both fluoroscopic and intravascular ultrasound guidance for placement. A Bovine jugular venous valve is sewn inside a platinum metal balloon expandable stent. The stent valve is then compressed onto a dilatation balloon and the system threaded anterograde from the femoral vein to the pulmonary valve area. The stented valve is expanded and the delivery system removed (Fig. 499-12).

The procedure is successful in 95% of implants with significant reduction in RV systolic pressures and of the pressure gradient across the right ventricular outflow tract (RVOT). Pulmonary insufficiency, severe in all before implant, is absent in over 60% and trivial or mild in 38% of patients in 18-month follow-up. Procedural complications included acute surgery for RVOT or existing homograft dissection in 5% with no associated mortality. Late complications included endocarditis, and reobstruction due to sternal compression or stent fracture. Repeat stent dilatation or stent implantation inside the existing stent is needed in up to 12% of patients due to late stenosis or fracture. Freedom from reoperation is 84% at 5 years. Percutaneous valve implant results in resolution of RV dilatation and improved exercise tolerance at 1 year. The hope is that this procedure may be extended to younger children with improvements in stent valve technology.

Investigational Procedures

Fetal Intervention

There is currently much interest and activity in fetal cardiac intervention in fetuses developing left heart or right heart hypoplasia. These babies are born with only a single ventricle and have significant morbidity and mortality. Because cardiac structures develop along lines of flow in utero it is thought that severe aortic or pulmonic stenosis/atresia in early gestation may be a major factor in the development of hypoplastic left or right heart syndromes. The hypothesis is that early interventional opening of the stenotic or atretic aortic or pulmonic valve will allow improved flow into the ventricles, preventing hypoplasia and allowing a normal two-ventricle circulation postpartum. This is an area of intense controversy but successful fetal cardiac aortic balloon valvuloplasty has been performed with resultant improvement in left ventricular development.

Single Ventricle Palliation

Currently patients with aortic atresia and hypoplastic left heart syndrome (HLHS) or pulmonary atresia with right ventricular hypoplasia are palliated with neonatal surgery to establish a stable source of systemic (for HLHS) or pulmonic (for pulmonary atresia) blood flow. Due to the associated morbidity, mortality, and prolonged hospitalization associated with neonatal cardiac surgery an interest in catheter palliation has developed. Stent placement in the ductus arteriosus to maintain patency allows for a stable source of systemic flow in HLHS and of pulmonary flow in pulmonary atresia with RV hypoplasia. Advances in coronary and peripheral stent technology have led to effective tools for stenting the ductus arteriosus even in neonates (eFig. 499.5A,B). The acute complications and long-term results are yet to be determined; however, this catheter-based palliative approach may play an increasing role in the management of infants with ductal dependent blood flow in the future.

Single Ventricle Total Cavopulmonary Connection

The final surgical stage in the treatment of patients with single ventricle physiology is connection of the inferior vena cava (IVC) to the pulmonary arteries, most commonly done with an extra-cardiac Gore-Tex tube, to assure that all desaturated venous blood flows passively to the lungs. In an attempt to eliminate the need for this final surgery investigators have been attempting interventional creation of this connection by implanting a covered stent from the IVC to the pulmonary arteries. This requires some surgical preparation at the time of the second-stage Glenn surgery to prepare the area to exclude the covered stent. Although still in its infancy this technique may allow nonsurgical completion of the total cavopulmonary connection in the future.

Hybrid Procedures

The term hybrid refers to procedures in which the surgeon and interventional cardiologist work together, combining techniques from both arenas to optimize results. These procedures are performed in a modified operating room or catheterization laboratory with angiographic equipment, operating lighting and equipment, and cardiopulmonary bypass. This is a rapidly evolving field. Current examples include (1) stage 1 palliation of hypoplastic left heart syndrome with simultaneous ductal stenting (interventional) and bilateral pulmonary artery banding (surgical); (2) valved stent implant (direct surgical access of the catheter through the right ventricle) in small high risk children with obstructed insufficient RV-to-pulmonary artery conduits (eFig. 499.6); (3) transventricular muscular VSD device closure in infants with direct surgical exposure of the RV; (4) intraoperative stent placement for treatment of branch pulmonary artery stenosis with surgical central pulmonary artery reconstruction; and (5) carotid surgical cutdown exposure for critical aortic stenosis dilatation or ductal stent placement in premature infants. It is unclear at this time which of these hybrid procedures will have significant advantage and truly evolve into new therapeutic strategies for these children with complex congenital heart disease.1-14

The number of people living with congenital heart disease is rising yearly. Approximately 1 in 300 children is born with significant heart disease that requires intervention in the first month of life. In the United States, there are approximately 35,000 children born with heart disease each year. Secondary to advances in surgery, medicine, and intensive care unit (ICU) care, most of these children live into adult life. There are now as many adults with congenital heart disease as there are children. Long-term considerations for their care and well-being need to be considered too. This section will deal with some of the day-to-day issues that face these patients.

Medical insurance and insurance eligibility issues remain problematic in the current US health care system. The financial stresses and strains placed on families with children with congenital heart disease can be enormous. Health care costs vary internationally but in the United States these issues can be challenging and may negatively impact upon care. In the current system, children, adolescents, and some young adults are covered under their parents’ private insurance group contracts. Dependent care continues until age 18, 21, or 25, depending upon such things as academic or dependent status and the parent’s contract with his or her employer. Some insurance contracts will allow young adults with disability to continue under the parent’s coverage. Even with some form of private health insurance, families still face significant financial hardships with the costs of medicines and needed services. Parents and older patients may decide when, where, and how much to work to simply have access to a certain level of insurance. Families without private health insurance may qualify for state or federal programs. There are many regulations for both initially receiving and maintaining eligibility, and the bureaucratic intricacies can be overwhelming. The children may easily have gaps in their health care coverage.

One major problem relates to adolescents and young adults as they try to transition to independence. Some will simply need continuous financial help from their parents in regard to medical issues. Others, with more severe lesions who can be classified as disabled, may qualify for Medicare and Social Security Disability (SSI). A Web site that may be helpful is www.disabilitysecrets.com/advice.html.

Most children with congenital heart disease can expect to live to be adults; as survival has increased, attention has been diverted towards some of the other important aspects of care, including neurodevelopmental, behavioral, emotional, and psychosocial issues. Improving quality of life issues starts with the fetus. Prenatal diagnosis of ductal-dependent lesions has been shown to improve not only survival but also neurodevelopmental outcomes, as these neonates are less likely to have preoperative metabolic acidosis. At the initial diagnosis of the complex heart disease, the family is overwhelmed; indeed, most if not all families cannot absorb the majority of the information proffered at that time. Prenatal diagnosis gives the family time to prepare and anticipate such things as health insurance, time off work, and childcare. They can have all their support systems in place, and dealing with the issues prior to delivery can significantly lessen the emotional and financial impact on the family and let them concentrate on the more immediate postdelivery issues. The parents and family members are integral parts of the care team. Their emotional wellbeing is important for both short- and long-term care. Several studies have shown that although IQ scores of children with congenital heart disease are generally within the average range, they tend to be lower than in age-matched controls in the normal population. Term newborns with cyanotic heart disease and complex single-ventricle physiology have widespread brain abnormalities before they undergo heart surgery. These abnormalities are not associated with known genetic defects/disabilities that are common in children with congenital heart disease. These genetic issues are additional burdens that affect neurodevelopmental outcomes. It is only recently that a change in hematocrit levels during bypass surgery on infants was found to affect neurodevelopmental outcome. Lower hematocrit levels as part of hemodilution strategies for bypass were associated with lower IQ scores. Children with congenital heart disease tend to have learning difficulties with attention deficit disorder, visual spatial issues, expressive language, or behavior. For patients with hypoplastic left heart syndrome, motor scores appeared to be more effective than cognitive scores at age 1 year.

The main focus at the toddler/preschool age is to anticipate issues in preparation for school and physical activities. As the children enter school, questions regarding the type of learning strategies and the areas of education that need to be stressed become important. The use of medicines for attention deficit hyperactivity disorder (ADHD) must be scrutinized, as these medicines are sympathomimetic and carry a risk of arrhythmia. This is an excellent time to try to steer a child to the appropriate level of physical activities and sports. The concept of health-related quality of life (HRQOL) has been explored in several studies, and many children and parents rate their quality of life in a similar manner to age and gender-match controls. Several predictors have been identified that may be important determinants of HRQOL including the diagnosis of cyanotic heart disease, reduced physical capacity, the use and duration of deep hypothermia and circulatory arrest, and early prenatal distress. Interestingly, in some of these studies, the parents of children with congenital heart disease rated HRQOL lower than their children. As many of these children have been through frequent medical and/or surgical procedures, there is a tendency of parents to be overprotective. Although this is certainly a natural reaction as the child grows and develops, this can have psychologically deleterious effects. It is therefore important to solicit information on activities and to avoid unnecessary restrictions. As children age, body image is also a consideration, as surgical scars and other morphologic differences can be associated with a negative impact on self-esteem. Studies have also shown an increased incidence of depressive symptoms in children with surgically corrected congenital heart disease, compared to their age matched controls. Once again, developing a rational, achievable exercise routine that may involve other family members can be helpful.

As children grow into adolescence and adulthood, concerns other than school performance predominate. These include peer relationships, fear of death, employment, insurance, marriage, contraception, the ability to have children, and the risk of transmission of congenital heart disease. Adolescents becoming independent have their own challenges. A study of heart transplant patients, ages 15 to 31, revealed that more than half of respondents admitted to missing medications or follow-up appointments. In a study of young adults (ages 19 and 20) and adolescents (ages 16–18) with congenital heart disease, more than half of the young adults and more than one-quarter of adolescents reported that in the past 30 days they had either smoked cigarettes, used marijuana or other drugs, or had an episode of binge drinking. More than one-third of adults with congenital heart disease have met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition criteria for either a depressive episode or general anxiety disorder. Adolescents and adults with congenital heart disease do not always tell their doctors the extent of their problems or limitations; in fact, they tend to be ambivalent. One study concluded that they have a strong wish to be healthy, and they may hide their symptoms from the healthcare personnel and sometimes even from themselves. In my own experience, this is very true. Only after one of my teenage patients died did we find out that he had a syncopal episode 2 weeks prior to his sudden death that was witnessed by his siblings, whom he had sworn to secrecy.

Specific screening and testing for children with known heart disease will be covered under the section “Exercise Considerations in Congenital Heart Disease.” In addition, this section will focus more on the high school and college athletes including club sports, as sports participation at this age and level is truly competitive and training is pushed beyond normal endurance. The section will also be limited to cardiac issues and will not include hemoglobinopathies (sickle cell variants), clotting abnormalities, pulmonary causes, or neurologic causes such as cardiovascular accidents (CVAs), and seizures.

Pregnancy and Contraception

Risk stratification for maternal outcomes for pregnancy are limited. Table 500-1 provides our best current practical guidelines for counseling patients regarding risks. Collaborative management by a pediatric cardiologist, or adult cardiologist with experience in congenital heart disease, and a perinatologist is optimal.

Prevention of pregnancy with steroidal birth control increases the risk of thromboembolic events and is contraindicated in patients with residual right-to-left shunts, pulmonary hypertension, and single ventricles with passive pulmonary blood flow. Alternative approaches should be utilized.

Exercise

Physical exertion at some level is beneficial for almost all people, including those with congenital heart disease. The goal is to balance the beneficial effects of increased cardiac work associated with exercise with the risk of disease progression or serious injury and death, which may occur. Making recommendations for the type or extent of physical activity for children with congenital heart disease is quite difficult and secondary to the heterogeneity within defects. In addition, secondary to changes in surgical techniques and the timing of interventions, there is a lack of data in making recommendations for various lesions for which we have not necessarily had enough time to know the long-term risks.

The 36th Bethesda Conference, published in 2005, deals with eligibility recommendations for competitive athletes with cardiovascular abnormalities.1 As such, it does not deal with recreational activities or physical education at school. Generally, sports are broken down into categories based upon the amount of dynamic and static activity (eTable 500.1). All exertion and physical activity can be broken down into these components. Restrictions for patients with congenital heart disease vary depending on the actual increase on myocardial oxygen demands and the physiologic stress placed on the underlying cardiac conditions. For instance, wrestling, a sport with a high static component, is not recommended for patients with moderate or severe aortic insufficiency, as it potentially will increase the amount of leakage. It should also be noted that the exact classification of some sports varies in the amount of dynamic and static components from training to competition. Many sports not considered to have a high static component during competition include training sessions with weightlifting. Training regimens may need to be modified. Different positions in different sports also have very different physical demands. Examples would include goalie versus a midfielder in soccer, a catcher versus first-base player in baseball, and an offensive lineman versus wide receiver in football. In addition, bicycling will vary on whether a ride is level or up hill with an increasing static component as the grade or slope increases. Exercise activities are also classified as to whether there is a collision risk or increased risk secondary to dizziness or momentary loss of coordination. For instance, patients with pacemakers and patients who take anticoagulation agents such as Coumadin or enoxaparin will have restrictions that are not related to myocardial demands.

Patients with cyanotic heart lesions usually restrict themselves, because they become more cyanotic with increasing physical effort. They may participate in physical education at school but must be allowed to rest or stop, and they should not be forced or induced to do any competitive activity, such as running a mile for time or performing so many push-ups or sit-ups. Most children with repaired lesions can participate in all sports. The timing after repair will depend on the type of surgery or intervention. Patients with atrial and ventricular septal defects that are repaired surgically must wait 3 to 6 months before full participation in sports. They should have an echocardiogram and EKG to make sure that they do not have any arrhythmias, pulmonary hypertension, or ventricular dysfunction. Patients with atrial septal defects, especially those closed after childhood, may have tachyarrhythmias as long-term sequelae and should be followed for this possibility. Small atrial septal defects/patent foramen ovales and ventricular septal defects with QP/QS ratios of less than 1.5:1 are not always repaired. These patients are cleared for all activity, except for patients with atrial septal defects and patent foramen ovales who should not scuba dive, secondary to the risk of embolic stroke. Moderate-to-large atrial septal defects, ventricular septal defects, and patent ductus arteriosus are usually repaired either by surgery or interventional catheterization once they are found in children old enough to compete competitively (approximately age 12 years). They can participate in routine exercise, as long as they are allowed to rest and limit their exertion until they are repaired.

Tetralogy of Fallot patients should not compete in any sports until after they are repaired. Their postrepair recommendations depend on right ventricular function, volume and pressure, and on the presence or absence of atrial or ventricular arrhythmias. The right ventricular volume should be normal or only mildly enlarged, and the right ventricular pressure should be less than one-half systemic. They should have exercise stress tests to specifically look for ventricular arrhythmias, because many have had a ventriculotomy as part of the repair.

Asymptomatic patients with aortic stenosis, including subvalvar and supravalvar stenosis, who have mild stenosis, defined as a mean gradient of less than 25 mmHg by echocardiogram or as a peak gradient of 30 mmHg in the catheterization lab, can participate in all sports as long as they have a normal ECG. Asymptomatic moderate aortic stenosis defined as a catheterization gradient of 30 to 50 mmHg or a mean gradient of 25 to 40 mmHg on echocardiogram may participate in some sports, but they will need an echocardiogram/exercise testing prior to approval. Patients with severe aortic stenosis should not participate in competitive sports or in physical education at school, and their level of exercise should be adjusted by a cardiologist. Because all forms of subvalvar, valvar, and supravalvar aortic stenosis tend to progress with time, these patients will need serial follow-up every 1 to 2 years with the possibility of a change in recommendations.

Pulmonic stenosis is very well tolerated, and as long as the right ventricular pressures are less than one-half systemic and the right ventricular function is normal, patients should not have any restrictions. Patients with a peak gradient by echocardiogram of more than 50 mmHg undergo intervention, usually by catheterization. Following intervention, if they have right ventricular pressures less than one-half systemic, good right ventricular function, and only mild pulmonary insufficiency, they can participate in all sports 2 weeks postcatheterization intervention and 3 months postsurgical intervention.

D transposition (simple transposition) patients at present will almost all have had arterial switch repairs. The important caveat to remember here is that their coronary arteries were moved as part of the operation. They should all undergo exercise stress testing prior to approval for competitive sports. Additional sequelae that may affect their ability to participate are supravalvar pulmonic stenosis or supravalvar aortic stenosis and dilation of the neoaortic root. Fontan patients are such a heterogeneous group, that it is difficult to predict how they will react to physical exertion.

Coarctation patients also have their own set of considerations.The first is to remember that they often have other associated lesions, including subaortic stenosis, bicuspid aortic valve, aortic stenosis, and dilated aortic roots that must also be factored into exercise participation. Patients after repair will sometimes have mild residual gradients at rest, a recurrence of a gradient with exercise, left ventricular hypertrophy or systemic hypertension. Patients repaired by stent or balloon angioplasty should have magnetic resonance imaging (MRI) to look for aneurysms prior to competitive sports participation.

Kawasaki disease is now the most common type of acquired heart disease. Aneurysms will develop in 4% of those patients treated with high-dose gamma globulin in the acute phase. The risks of exercise in individuals depend on the degree of coronary involvement. There are two avenues for the development of coronary ischemia from Kawasaki disease. Coronary thrombi may form in large aneurysms and spread distally if the aneurysms do not resolve. Second, since coronary aneurysms represent a vasculitis and damage to the coronary wall, progressive coronary artery stenosis may develop. The limitations are varied, and the most important piece of information to remember is that patients who develop aneurysms need stress testing with myocardial perfusion imaging to delineate their safe exercise levels.

Effects of Altitude

Oxygen delivery to tissues is equal to the oxygen content of the blood times the cardiac output. Exposure to higher altitudes where the partial pressure of oxygen (PO2) and inspired oxygen (PIO2) are reduced, decreases alveolar oxygen (PaO2) as can be calculated from the alveolar gas equation: PaO2 = PIO2 – PaCO2/R + F R is the respiratory quotient, normally about 0.8, and F is the correction factor, usually less than 2 mmHg. The normal PIO2 is about 150 mmHg and is equal to 21% of 760 mmHg (barometric pressure minus 47 mmHg) water vapor pressure. The partial pressure of oxygen (PO2) is determined by barometric pressure, and the barometric pressure decreases as altitude increases. Because the oxygen dissociation curve is S-shaped, it does not show a significant decrease in oxygen saturation until the PO2 is about 60 mmHg.

When there is normal cardiopulmonary function, alveolar oxygen PaO2 is about 100 mmHg. The difference between alveolar and arterial oxygen (AaDO2) is normally less than 15 mmHg, producing arterial PaO2 of at least 85 mmHg and oxygen saturation in the high 90s. In practical terms, up to a level of 3000 feet, there is no response to altitude because there is essentially no change in oxygenation. The oxygen dissociation curve is almost horizontal at this point. The PaO2 at 5000 feet is 82 mmHg, and the oxygen dissociation curve starts to become more vertical at this point, although the slope is shallow. Between 5000 to 10,000 feet (moderate elevation) the slope of the curve is still not steep, but there will be changes of oxygen saturation and initiation of physiologic responses to the decreased oxygen saturation (hypoxia). An elevation of 10,000 feet corresponds to a PaO2 of 62 mmHg. Above 10,000 feet, high altitude, the oxygen dissociation curve is much more vertical, and increases in altitude cause much more precipitous falls in PaO2 and O2 saturation and stronger physiologic responses.

The heart lesions which do not tolerate the physiologic increase in pulmonary vasoconstriction caused by hypoxia (increased altitude) include single ventricles with Fontan circulation, as these patients do not have a ventricle to pump blood to the pulmonary circulation. In general, Fontan circulation patients will tolerate increased altitude if they have an atrial fenestration, but this improved toleration depends on the reason for the presence or continued presence of the fenestration (eg, some centers only fenestrate high-risk Fontans, and these high-risk patients would be expected to do poorly with any added stress). Other patients who have the potential to be affected at moderate altitudes include patients with pulmonary hypertension from pulmonary vascular disease and patients with either severe tricuspid regurgitation (eg, Ebstein anomaly), severe pulmonary insufficiency (eg, tetralogy of Fallot status posttransanular patch repair or with longstanding homograft valves), or both. This intolerance to altitude will be increased if exertional activity is involved, as the reduced alveolar oxygen tension created by exercise may increase pulmonary vasoconstriction.

Patients with cyanotic heart disease and those with Fontan physiology should live below 5000 feet (low altitude) so that there will not be a significant compromise of O2 delivery to the body or a significant increase in pulmonary vasoconstriction. They usually will be able to visit moderate elevations, 5000 to 10,000 feet for short periods, such as airline flights without sequelae. The longer they stay at elevation and the closer the elevation is to 10,000 feet, the more likely they are to develop symptoms and distress. Trips to relatives who live at moderate elevation or family ski vacations should have contingency plans that allow the patient to return to low altitude quickly. Even if they are not symptomatic at rest, their exercise tolerance will likely be affected. Supplemental oxygen will be helpful in alleviating symptoms.

All commercial airlines carry supplemental oxygen, but they have differing policies on the use of supplemental oxygen, and it is wise to contact and arrange ahead of time the O2 delivery system to be used. (In this day and age, expect to be charged a handsome supplemental fee.) Commercial aircraft can maintain a cabin pressure equivalent to sea level or local ground level up to an altitude of 22,500 feet. Above that altitude, cabin pressure will start to decrease, inducing lower arterial saturation/PO2 in the travelers. The maximum altitude allowed is roughly 9000 feet, but at usual cruising altitudes, the cabin pressure is usually 7000 to 8000 feet. Because most flights are of short duration (less than 6 hours) and there is little physical activity, commercial flights are well tolerated. Special consideration for layovers at altitude must be considered in planning travel.

Another travel consideration is the actual altitude to be visited. Most major US cities are listed at elevations near or below 5000 feet (low altitude). Unfortunately, some of the cities at around 5000 feet are situated in mountain valleys, and some of their greater metropolitan areas may be at much higher elevation. For example, Albuquerque is listed at an elevation of 4945 feet, and Salt Lake is listed at an elevation of 4390 feet, but both cities have associated areas of between 7000 and 8000 feet of elevation. Long-term plans for higher education and job selection will also be affected by altitude. In the western United States, some schools are located at high altitudes, and school performance and the possibility of having to be more self-sufficient while away at school can be quite demanding.

Patients with severe tricuspid regurgitation, severe pulmonary insufficiency, tricuspid regurgitation and pulmonary insufficiency, or right ventricular dysfunction will be increasingly affected at increasing moderate elevation. They can be expected to have the same problems as Fontan circulation patients at moderate elevations when they live at high elevations, and they should live below 10,000 feet in elevation. Every patient will vary in their clinical response, so recommendations in medications need to be customized. Most effects of elevation are reversible over time, although subsequent response to hypoxia may be more vigorous.

Patients who should remain at low altitude also include unrepaired tetralogy of Fallot and unrepaired tetralogy of Fallot physiology patients (eg, tricuspid atresia, ventricular septal defect, pulmonic stenosis, and transposition ventricular septal defect pulmonic stenosis, because they are at risk of hypoxic (hypercyanotic episodes). They should not fly or visit moderate or high altitude until they are repaired. The patient with an absent pulmonary artery on the side opposite the aortic arch (a rare condition) should not spend time in elevations above 5000 feet because of the risk of acute pulmonary edema.

Besides supplemental oxygen, there are now other medical options to aid patients who are planning visits to moderate and high altitudes or who have pulmonary vasoconstriction. Phosphodiesterase type-5 inhibitors, such as sildenafil, have a rapid onset of action, and they may be started a few days prior to the expected change in altitude. The endothelin blocker bosentan would not be a good choice, since it does not achieve its maximal effect for weeks or months after institution of therapy. There is also a much higher risk of side effects. Inhaled (nebulized) iloprost a stable analog of prostacyclin is another alternative. Because it is inhaled, side effects are uncommon and include headache, flushing, and most importantly hypotension. The major limitations are the frequency of application, up to 6 times per day, and the need for a nebulizer. The L type calcium channel blocker, nifedipine, is also effective at treating pulmonary edema caused by acute pulmonary hypertension.2-6

Exercise increases oxygen consumption, cardiac output, heart rate, and systemic blood pressure and therefore increases cardiac work. Children are becoming heavier, and there is an increase in childhood obesity in Western cultures. There are many studies linking childhood obesity to adult coronary heart disease. For the vast majority of children, strenuous exercise would be extremely beneficial.

There are approximately 3000 to 5000 sudden-death episodes per year in children and adolescents in the United States. There are between 5 and 10 million children and adolescents participating in organized sports activities, so the percentage of athletes dying suddenly is quite small. Highly trained athletes are thought to represent the most fit and healthy members of our society, so these tragic, early, and unexpected deaths make a deep impression on us. The majority, approximately 40% to 50% of sudden deaths, are caused by hypertrophic cardiomyopathy. Between 10% and 20% will be caused by coronary abnormalities (usually the left or right coronary artery arising from the wrong sinus origin or a single-coronary artery origin). The remaining 30% will be caused by such lesions as myocarditis, dilated cardiomyopathy including noncompaction, ion channelopathies (long QT) syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia (AVRD), Wolff-Parkinson-White (WPW) syndrome, previous Kawasaki disease with undiagnosed coronary involvement, commotio cordis, and connective tissue disorders with dilated aortic roots (eg, Marfan’s). The incidence in the population of these disorders is at most 0.3%. The percentage presenting for screening would be thought to be even less, secondary to self-selection not to participate in sports.

The pediatrician often has to verify that a child can play competitive sports, and there is great concern about the occasional child who dies suddenly during or just after strenuous exercise.

There is no consensus as to what should be included in cardiovascular screening. There is no standardization of state or federal regulations, nor is there a medical entity that establishes the precise requirements of exercise testing. There is no screening regimen that would abolish the risk of cardiovascular induced death. The European Society of Cardiology recommendation of screening ECGs for all participants is based mainly on the Italian state subsidized national program. This program mandates that all individuals from age 12 to 35 years participating in organized team sports or individual sports must obtain annual medical clearance by accredited sports medicine physicians. This medical clearance is by history, physical examination, and ECG.

At present, the American Heart Association guidelines from 2007 do not include an ECG as part of the screening process. Some of the reasons listed for not requiring ECG include the financial resources, manpower, and logistics needed to implement such a program. It seems doubtful that consensus could be reached to implement a screening ECG program secondary to the conflicting interests of the various groups involved and the competition for money with other issues and priorities in public health. There is also the additional problem of borderline or false-positive ECGs. Past screening programs have included at least 10% false-positive tests, which far outnumber the true-positives. This requirement for further testing and the possibility for exclusion from sports without cause would produce both short and long-term emotional and financial burdens on families and athletes. This does not mean that ECGs should not be performed after someone has been identified by the AHA screening guidelines. The 2007 AHA guidelines are listed in Table 501-1.

A positive family history includes sudden death, syncope, chest pain, arrhythmias, or heart disease. It is particularly likely in hypertrophic cardiomyopathy, right ventricular dysplasia, mitral valve prolapse, long QT syndrome, premature atherosclerosis, and Marfan syndrome.

A positive personal history includes syncope, chest pain, arrhythmias, murmurs, Kawasaki disease or heart disease in general.

Positive signs include left ventricular enlargement or hypertrophy, specific murmurs, and Marfanoid body habitus. There are no abnormal signs with anomalous aortic origin of a coronary artery, coronary arterial aneurysms after Kawasaki syndrome, or the long QT syndrome.

At the discretion of the examiner, a positive response or finding in any one or more of the 12 items may be judged sufficient to trigger referral for cardiovascular evaluation.

Comprehensive screening evaluations should be administered every 2 years through high school. At the collegiate level, the testing should be performed upon entry and then a more selective interim history with blood pressure measurements every year. If the interim history suggests changes, then a more thorough examination and possible referral should be performed.

Many of the causes of sudden death in young athletes are congenital in origin. Structural abnormalities such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia (AVRD) are inherited, and closer evaluation and genetic testing may be warranted in primary relatives. Other structural abnormalities, such as coronary abnormalities and myocarditis, do not merit further familial investigation. For causes where no abnormalities are found, the deaths are most likely to be arrhythmogenic in nature. The ability now exists to perform postmortem genetic testing to look for ion channelopathies, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). This new modality offers the ability to further identify relatives of the deceased who are at risk for sudden death, as well as to better understand the natural history of these diseases.1-9