Pediatr Cardiol (2007) 28:465471 DOI 10.

1007/s00246-007-9007-0

Medical Management of the Failing Fontan

N. S. Ghanayem S. Berger J. S. Tweddell

Published online: 31 August 2007 Springer Science+Business Media, LLC 2007

Abstract The Fontan operation accomplishes complete separation of systemic venous blood from pulmonary venous circulation in patients with single ventricle anatomy. Operative survival since the rst description of the Fontan operation is excellent in the current era through modications in surgical techniques, identication of patient-specic risk factors, and advances in postoperative care. Improved early outcomes have also resulted in a decline in late mortality for patients who have undergone staged palliation with the Fontan operation. As the number of late survivors from the Fontan operation increases, caregivers will be evermore faced with the challenge of recognizing and managing the patient with failing Fontan physiology. Even after excellent early results, patients with single ventricle lesions remain at risk of progressive ventricular dysfunction, dysrhythmias, progressive hypoxemia, elevated pulmonary vascular resistance, and protein-losing enteropathy, which can result in morbidities including but not limited to, myocardial failure, thromboembolism, and stroke. Consequently, continued long-term survival of patients who undergo the Fontan operation is

dependent upon preservation of single ventricle function, avoidance of late complications, and, in the patient with a failing Fontan, recognition and treatment of the underlying pathophysiologic process that has resulted in Fontan failure. Keywords Fontan Single ventricle Palliation Protein-losing enteropathy Fontan failure Late outcomes Separation of systemic venous blood from pulmonary venous circulation for patients with single ventricle anatomy was rst described more than three decades ago. Since that time, the Fontan operation has undergone a series of surgical revisions that have reduced early postoperative mortality from 20% to less than 2% [14, 29]. Given the increasing number of early survivors who have undergone single ventricle palliation, caregivers are now faced with the challenge of lifelong optimization of single ventricle function as well as the challenge of treating patients with failing Fontan physiology. Incidence and Risk Factors

N. S. Ghanayem (&) Department of Pediatrics, Division of Critical Care, Childrens Hospital of Wisconsin and Medical College of Wisconsin, 9000 West Wisconsin Avenue, MS 681, Milwaukee, WI 53226, USA e-mail: nghanayem@aol.com S. Berger Department of Pediatrics, Division of Cardiology, Childrens Hospital of Wisconsin and Medical College of Wisconsin, 9000 West Wisconsin Avenue, MS 681, Milwaukee, WI 53226, USA J. S. Tweddell Department of Surgery, Division of Cardiothoracic Surgery, Childrens Hospital of Wisconsin and Medical College of Wisconsin, 9000 West Wisconsin Avenue, MS 681, Milwaukee, WI 53226, USA

In a 25-year retrospective series published by Mair et al. [29], late results after Fontan palliation were evaluated by era. With improvements in management, late death (range, 4 months to 18 years) has diminished dramatically from 25% early in the experience to 5% in the recent era. Late deaths have been attributed to progressive myocardial failure, dysrhythmias, and thromboembolism. In a followup of survivors, 11% were found to have clinically signicant morbidity, including atrial dysrhythmias, proteinlosing enteropathy (PLE), liver dysfunction, congestive heart failure, progressive ventricular dysfunction, or stroke, at a median age of 8 years (range, 125).

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Choussat and Fontan rst described ten commandments, which were selection criteria for patients undergoing atriopulmonary connection for tricuspid atresia. Although indications for successful Fontan have been modied over the ensuing decades, these criteria remain as physiologic risk factors for a failing Fontan [9]. The notable risk factors take into account ventricular performance, atrioventricular and aortic valve function, and pulmonary circulation. Small pulmonary artery size, pulmonary vascular resistance [4 wood units, preoperative pulmonary artery pressure [15 mmHg, or the presence of venovenous collaterals constitute a higher risk group of patients [4, 9, 21]. Poor functional outcome is a timerelated phenomenon and increases in frequency with longer duration of follow-up. Furthermore, more complex anatomy as indicated by the use of main pulmonary artery ascending aorta anastomoses or ventricular septal defect enlargement, both indicators of ventricular outow obstruction, has been identied as a risk factor for the failing Fontan. Interestingly, neither better early postoperative hemodynamics nor a bafe fenestration were protective against diminished late functional outcome [12].

Manifestations and Medical Management The approach to the failing Fontan should begin with the search for anatomic abnormalities or arrhythmias that may be amenable to surgical or interventional therapies. Specically, one should rule out high venous pressures due to atrioventricular valve insufciency, pulmonary venous obstruction, pulmonary artery stenoses, or obstruction within the Fontan bafe. Similarly, the presence of aortopulmonary collaterals should be ruled out. In addition, the Fontan fenestration should be assessed. It is conceivable that catheter enlargement of a small fenestration, either by balloon dilatation or stent implantation, might result in improved cardiac output, albeit at the expense of arterial saturation [18, 32]. Atrioventricular synchrony is essential to optimal Fontan function, and therefore sinus node dysfunction or lack of atrioventricular synchrony should be identied and pacemaker therapy initiated. In the absence of structural complications or arrhythmias, management of the failing Fontan can prove to be exceedingly difcult. Patients may present with ventricular dysfunction, progressive hypoxemia, and/or protein-losing enteropathy all challenging entities that frequently coexist.

Ventricular Dysfunction Ideally, the volume unloading provided by staged palliation results in reduction in ventricular size and wall thickness

that in turn increases contractility and ventricular performance both short term and long term. However, even with the ideal candidate, ventricular dilatation may persist due to the lasting impact of previous volume overload, as well as the presence of aortopulmonary collaterals that are common in patients with chronic cyanosis. As a result, late ventricular dysfunction and subsequent failure of Fontan circulation as manifested by lower functional class, exercise intolerance, dyspnea, fatigue, and syncope may ensue. In a failing Fontan, abnormalities in systolic and/or diastolic function exist [7, 26, 30, 40]. Systolic dysfunction is characterized by reduced contractility and an ejection fraction of less than 50%. Diastolic dysfunction is more difcult to dene but is evident by increased ventricular end diastolic pressure and the rate of ventricular relaxation [2, 28]. If severe enough, ventricular dysfunction is treated with intravenous inotropes. Phosphodiesterase inhibitors provide inotropy, lusiotropy, and vasodilatory properties that would appear benecial to the failing Fontan patient. Phosphodiesterase inhibition with milrinone has been successful in treating and preventing early postoperative low cardiac output syndrome [17]. After Fontan palliation, phosphodiesterase inhibition with amrinone has also been shown to improve early postoperative hemodynamics by increasing cardiac index and stroke volume index [42]. A few studies as well as anecdotal experience with chronic intravenous milrinone therapy have suggested that symptomatic relief may be obtained in patients with congestive heart failure. However, the impact of milrinone therapy on chronic ventricular dysfunction is unknown [5, 25]. The hemodynamic prole of phosphodiesterase inhibitors is well suited to the patient with a failing Fontan; thus, chronic intravenous therapy with milrinone is used despite the absence of supportive data. Angiotensin-converting enzyme (ACE) inhibition is frequently used for patients with failing Fontan circulation, although the benets are again unproven in this group. In a study of adult patients with asymptomatic left ventricular dysfunction, ACE inhibitor therapy reduced both morbidity and mortality [35]. Numerous studies have demonstrated elevated levels of hormones that modulate uid homeostasis including elevated levels of antidiuretic hormone, aldosterone, renin, and angiotensin, in patients with Fontan circulation [16, 27, 43]. In addition, persistently elevated levels of renin and angiotensin were found in Fontan patients with prolonged effusions and presumed low cardiac output. Activation of the reninangiotensin system and subsequent increased angiotensin II causes vasoconstriction of both systemic and pulmonary vasculature, which results in higher ventricular end diastolic pressure and progressive low cardiac output. ACE inhibition may therefore be effective therapy for patients with failing

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Fontan physiology. However, in staged univentricular palliation, few limited studies of ACE inhibition exist with no clear benet to this patient population [15, 34]. Increased sympathetic nervous system activity due to chronic heart failure further deteriorates cardiovascular function through prolonged adrenergic activation that leads to myocardial hypertrophy and apoptosis. Beta-blocking agents inhibit this neurohumoral activation. In adults with chronic heart failure, beta blockers have been used in combination with ACE inhibition and result in improved left ventricular ejection fraction, diminished symptoms of heart failure, and lower mortality [22]. Data on the use of beta blockers for treatment of congestive heart failure in the pediatric age group are limited. A multicenter review of beta blocker therapy with carvedilol in pediatric heart failure demonstrated clinical improvement in two-thirds of patients (range, 3 months19 years); however, only 20% of these patients had congenital heart disease and only 5 of 46 patients (11%) had undergone a Fontan procedure [3]. Although promising, further study is required to determine if beta blockers will be of benet to the patient with failing Fontan physiology. Although pharmacologic augmentation of cardiac output can be effective in improving organ function, diuretic therapy is also needed for uid homeostasis. Activation of the reninangiotensinaldosterone axis has been observed in cavopulmonary anastomoses even in the absence of heart failure. Aldosterone antagonism with spironolactone appears to be well suited for management of the patient with failing Fontan physiology. However, spironolactone is a weak diuretic and generally not used alone but, rather, with a loop diuretic. Furosemide is most commonly used and acts on the distal loop of Henle, inhibiting chloride reabsorption and passive reabsorption of sodium and water. Thiazide diuretics such as chlorothiazide are also used in heart failure and act through sodium reabsorption at the distal convoluted tubule. Aggressive combination diuretic therapy is often necessary in the patient with failing Fontan circulation; however, this can pose a challenge because electrolyte derangements and dehydration may result that may further deteriorate existing organ dysfunction. Brain natriuretic peptide (BNP) is produced by ventricular myocytes in response to wall stretch and has been shown to play a role in regulation of vascular tone and uid homeostasis. BNP causes arterial and venous dilatation without reex tachycardia, vasodilates coronary vasculature, and possesses lusiotropic properties, all of which result in improved cardiac output. In addition, BNP has a direct effect on renal function through afferent arteriole vasodilation, efferent arteriole vasoconstriction, and direct tubular effects resulting in natriuresis and diuresis [11]. Nesiritide, a recombinant B-type natriuretic peptide that is structurally and functionally identical to BNP, is currently

used with success in acute decompensated heart failure in adults. Only anecdotal experience demonstrating nesiritides therapeutic benet has been reported in pediatric patients with acute heart failure, with no data on the effect in chronic heart failure [31]. Nevertheless, the known physiologic properties of nesiritide make a compelling argument for its use in the patient with failing Fontan physiology.

Hypoxemia Slight hypoxemia with arterial saturations in the low 90s is common after Fontan completion, even when residual atrial level shunts are absent [9, 13]. This desaturation is thought to result from coronary sinus return to the pulmonary venous atrium, arteriovenous shunts, or ventilation/perfusion imbalances within the lung. Desaturation at rest and with exercise commonly occurs in patients with residual anatomic shunts, such as persistent atrial level shunt/bafe fenestration or venovenous collateral, and is often more pronounced in the presence of progressive ventricular dysfunction. Venovenous collateral blood vessels have a larger impact on the single ventricle patient after bidirectional cavopulmonary anastomosis. Since most venovenous collateral vessels tend to decompress from the upper body circulation into the inferior vena cava, their impact on arterial saturation after the completion of the Fontan operation is minimal. However, it is possible for venovenous collateral vessels to decompress directly into the left atrium or pulmonary venous circulation. This could serve as a source of arterial desaturation and should be investigated in the excessively hypoxemic patient post-Fontan. Catheter embolization of these blood vessels should be considered. Supplemental oxygen may be helpful in the treatment of moderate to severe hypoxemia.

Protein-Losing Enteropathy Protein-losing enteropathy (PLE), a phenomenon of hypoalbuminemia through intestinal protein loss, is a troublesome complication after successful Fontan completion. Despite modications in Fontan palliation, PLE continues to occur at an incidence of 315%, with a reported mortality of 30% at 2 years and 50% at 5 years after diagnosis [10, 36, 39]. PLE remains quite variable in presentation, from clinically asymptomatic to chronically debilitating. Onset of PLE can be as early as 1 month to nearly two decades after Fontan palliation, but it occurs most commonly 2 or 3 years following the Fontan procedure [32].

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Unfortunately, increased knowledge of univentricular physiology has not lent itself to full understanding of the pathogenesis of PLE, nor has it allowed for clear identication of risk factors for PLE. Chronically elevated systemic venous/right atrial pressures with subsequent increased inferior vena caval and portal vein pressures have been implicated as the primary cause of PLE. This elevation in abdominal venous pressures presumably leads to intestinal congestion, lymphatic obstruction, and enteric protein loss [32]. Despite the volume unloading that results from staged palliation of univentricular anatomy, the single ventricle often develops poor compliance and diastolic dysfunction that subsequently results in low cardiac output. Low cardiac output in the face of elevated venous pressures, or even with venous pressures considered normal for Fontan physiology (\15 mmHg), predisposes the patient to mesenteric ischemia and subsequent intestinal mucosal injury leading to the onset of enteric protein losses. Notwithstanding these plausible explanations in the pathogenesis of PLE, not all cases of PLE have concomitant elevation in systemic venous pressures [9, 32]. Inammation due to infection or unexplained etiologies can result in epithelial membrane injury that results in PLE despite acceptable Fontan hemodynamics [23]. To better understand the pathogenesis of PLE, a greater awareness of predictive risk factors is needed. In a large retrospective multicenter study including more than 3000 patients, of whom 3.7% developed PLE, ventricular anatomy other than dominant left ventricle and an elevated preoperative ventricular end diastolic pressure were risk factors for the development of PLE. Other large single center cohorts have identied heterotaxy, polysplenia, anomalies of systemic venous drainage, and increased pulmonary arteriolar resistance as risk factors for the development of PLE [9, 10]. Conversely, elevated total pulmonary vascular resistance and right atrial pressures have not been uniform ndings in patients who develop PLE. Interestingly, longer cardiopulmonary bypass time at Fontan palliation has also been identied as a risk factor for late development of PLE. The mechanism of prolonged bypass increasing the risk of PLE is unclear given that similarly long bypass times in other forms of congenital heart surgery have not been associated with PLE [36]. This supports the speculation that prolonged bypass in association with perioperative elevated systemic venous pressures typical of the single ventricle patient results in intestinal epithelial membrane injury that predisposes the patient to PLE. Prolonged bypass may also be a marker for a more difcult operation due to anatomic issues that make for a higher risk patient. Fluid retention that occurs as a result of reduced vascular oncotic pressure due to ongoing enteric protein loss is the most common clinical presentation. The diagnosis is made in the presence of hypoalbuminemia,

hypoproteinemia, and stool a1 antitrypsin clearance. Often, peripheral edema, ascites, chronic diarrhea, hypocalcemia, or respiratory distress resulting from pleural effusions are manifestations that prompt the initial assessment. In more severe forms of PLE, chronic loss of anticoagulant proteins can result in an acquired hypercoagulable state and subsequent thromboembolic complications. Similarly, chronic loss of immunoglobulin can lead to infection from acquired immunodeciency. Furthermore, the development of intestinal lymphangiectasia may result in lymphocyte depletion [32, 39]. Finally, chronic malnutrition and somatic growth retardation may be found with PLE. Treatment of PLE continues to be problematic and therapy is not always successful in reversing enteric protein losses. Prior to embarking on a management strategy, full evaluations of the existing anatomy, hemodynamics, and the conduction system are imperative regardless of presentation. Unfortunately, PLE may manifest even with optimal Fontan palliation and in the absence of residual structural abnormalities. When structural abnormalities and/or opportunity for either catheter or surgical intervention are absent, medical management with pharmacologic and nutritional support is employed. Medical intervention for PLE is threefold and includes therapy directed at improving ventricular dysfunction, membrane stabilization, and improving protein homeostasis through nutritional support and protein replacement therapy. Hemodynamic management is often directed at diuresis and augmentation of cardiac output with afterload reduction and/ or inotropic support, as mentioned previously. In fact, many aspects of medical management of the failing Fontan parallel those of ventricular dysfunction with the use of ACE or phosphodiesterase inhibition and, potentially, nesiritide or beta blockade. In Mertens series of Fontan survivors with PLE, medical management with afterload reduction, diuretics, digoxin, and albumin replacement led to resolution or partial improvement in 54% of patients; however, the remaining 46% of patients died [32]. Aldosterone receptor antagonists increase sodium and water retention and have become important adjunct therapy for congestive cardiomyopathy. Studies in animal models of PLE have shown that aldosterone receptor antagonist therapy also reduces proteinuria. Multiple case reports of patients with PLE have specically shown attenuation of intestinal protein losses with spironolactone therapy. Whether this is secondary to changes in intravascular volume or pressure, or through direct mineralocorticoid receptor antagonism of renal and intestinal epithelial cells, is unknown [37, 44]. PLE has been described in patients with autoimmune and inammatory processes, such as systemic lupus erythematosus, sarcoidosis, and allergic gastroenteropathy [41, 42, 45, 46]. These ndings suggest that some cases of

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PLE may be due to an inammatory response. When signicant hemodynamic derangements are absent or minimal, this inammation-mediated epithelial membrane injury may be the most important factor in the development of intestinal protein loss. Multiple case reports have described success in attenuating PLE with administration of corticosteroids. Along with improved serum protein and albumin levels, elevated immunoglobulin G concentrations have correlated with steroid therapy in PLE [32, 46]. The mechanism through which steroids reduce PLE is unclear; however, steroids have been shown, with biopsy, to reduce intestinal lymphangiectasia. This implies that steroids may act through stabilization of intestinal capillary and lymphatic membranes [38, 45, 46]. Reported prednisone dosages administered range from 2 mg/kg/day in children to 2560 mg/day in adolescents over several months. Unfortunately, the effectiveness of this therapy has been limited by return of symptoms with tapering of the steroids [18]. Chronic intestinal vascular congestion that results from high venous pressures in Fontan physiology is speculated to interfere with production and distribution of heparin sulfate. These sulfated glycosaminoglycans have been shown to regulate albumin losses and hence can explain the enteric heparin sulfate deciency seen in patients with PLE [33]. Consequently, limited case reports of heparin therapy have demonstrated dramatic improvement in symptoms as well as a marked elevation in serum protein with reduction in enteric protein losses [1, 8]. The use of fractionated heparin has not been adequately studied in this population. Hypoproteinemia and subsequent reduced oncotic pressure are hallmarks of PLE. Exogenous albumin therapy with aggressive diuretic administration is often necessary for symptomatic relief of peripheral edema, pleural effusions, and intestinal edema that potentiates ongoing protein losses. However, administration of albumin provides no nutritional benet to the failing Fontan patient, and replacement therapy should therefore be combined with a high-protein diet. Besides enteric protein losses, the patient with PLE may also have fat malabsorption from intestinal lymphatic dilatation. For this reason, in addition to a high-protein diet, a diet high in medium-chain triglycerides may enhance the nutritional state given that they are directly absorbed into intestinal veins bypassing lymphatic circulation [39]. Perhaps this strategy might also lead to a reduction in lymphatic congestion with a decrease in enteric protein losses. Hypocalcemia, another nding in PLE, is attributed to hypoproteinemia and subsequent decrease in serum calcium. In addition, hypocalcemia may result from vitamin D deciency due to the fat malabsorption also seen with PLE. Administration of calcium replacement as an adjunct therapy with and without concomitant vitamin D supplementation has been shown to alleviate symptoms from PLE

[20]. Although calcium deciency is explainable, the mechanism through which calcium supplementation has been shown to attenuate enteric protein loss is unclear. Immunodeciency due to lymphocyte and immunoglobulin loss is a reported complication of PLE with the potential for chronic immune deciency leading to further mucosal damage. Given that gastrointestinal mucosa serves as a portal of entry for pathogens, the immunologic consequences of PLE may be severe. Attenuation of infectious risks with administration of intravenous immunoglobulins as replacement therapy in PLE has been reported, although the results are temporary [6]. Consequently, vaccination, close monitoring, and rapid detection/intervention of and for acute infection is the mainstay of therapy for PLEinduced immunodeciency.

Elevated Pulmonary Vascular Resistance Elevated pulmonary vascular resistance after the Fontan operation has been reported in patients who have failed Fontan physiology despite the presence of acceptable pulmonary artery pressure and pulmonary vascular resistance index (PVRI) at the time of Fontan palliation. Clinical manifestations may include any of the previously reported problems: low cardiac output, excessive hypoxemia, or PLE. The mechanism through which this occurs is uncertain but likely due to the absence of pulsatile ow after the Fontan operation. Pulsatile ow is necessary for shear stress-mediated release of endogenous nitric oxide and subsequent regulation of pulmonary vasculature tone. In a study of basal PVRI responsiveness late after Fontan operation, Khambadkone et al. [19] reported a decrease in basal PVRI with exogenous nitric oxide, suggesting the presence of endothelial dysfunction in the patient with Fontan circulation. Consistent with these ndings, Levy et al. [24] demonstrated overexpression of nitric oxide synthase via immunostaining from the pulmonary vasculature of patients with failing Fontan physiology. Similarly, elevated endothelin-1 expression, a potent endotheliumderived vasoconstrictor, was also found by immunostaining [38]. Although unstudied, pharmacologic management with pulmonary vasodilator agents such as bosentan, prostacyclin, or sildenal may play a role in attenuating the deleterious effects of high pulmonary vascular resistance in the failing Fontan patient.

Conclusion Modications in staged surgical intervention for patients with single ventricle anatomy have resulted in improved survival, and with increasing longitudinal experience, there

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is greater recognition of patients with failing Fontan circulation. The challenge bestowed upon caregivers in the current era is twofold: (1) to preserve single ventricle function with an aim to prevent late complications and (2) in the patient with a failing Fontan, to reverse or, more realistically, limit the progressive deterioration of single ventricle function. To date, medical management of the failing Fontan has been generally anecdotal and based on proposed pathophysiologic mechanisms. Medical therapy includes strategies borrowed from the treatment of congestive heart failure and membrane stabilization. These efforts should be part of a management strategy that includes revision of surgically amenable obstruction, optimization of rhythm, fenestration, and ultimately, if necessary, replacement therapy. References
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