medical management fontan

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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 venouscirculation in patients with single ventricle anatomy. Opera-

tive survival since thefirst description of the Fontanoperation

is excellent in the current era through modifications in sur-

gical techniques, identification of patient-specific risk factors,

and advancesin postoperativecare. Improved earlyoutcomes

have also resulted in a decline in late mortality for patients

who have undergone staged palliation with the Fontan oper-

ation. 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 pro-gressive 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, thrombo-

embolism, 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 afailing 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 anat-

omy was first described more than three decades ago. Since

that time, the Fontan operation has undergone a series of

surgical revisions that have reduced early postoperativemortality 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

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 follow-

up of survivors, 11% were found to have clinically sig-

nificant morbidity, including atrial dysrhythmias, protein-

losing enteropathy (PLE), liver dysfunction, congestive

heart failure, progressive ventricular dysfunction, or stroke,

at a median age of 8 years (range, 125).

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, USAe-mail: [email protected]

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

123

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DOI 10.1007/s00246-007-9007-0


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Choussat and Fontan first described ten command-

ments, which were selection criteria for patients

undergoing atriopulmonary connection for tricuspid atre-

sia. Although indications for successful Fontan have been

modified over the ensuing decades, these criteria remain as

physiologic risk factors for a failing Fontan [9]. The

notable risk factors take into account ventricular perfor-

mance, atrioventricular and aortic valve function, andpulmonary circulation. Small pulmonary artery size, pul-

monary 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 time-

related phenomenon and increases in frequency with longer

duration of follow-up. Furthermore, more complex anat-

omy as indicated by the use of main pulmonary artery

ascending aorta anastomoses or ventricular septal defect

enlargement, both indicators of ventricular outflow

obstruction, has been identified as a risk factor for the

failing Fontan. Interestingly, neither better early postoper-ative hemodynamics nor a baffle 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. Spe-

cifically, one should rule out high venous pressures due to

atrioventricular valve insufficiency, pulmonary venous

obstruction, pulmonary artery stenoses, or obstruction

within the Fontan baffle. Similarly, the presence of aorto-

pulmonary 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 dys-

function or lack of atrioventricular synchrony should be

identified and pacemaker therapy initiated. In the absence

of structural complications or arrhythmias, management of

the failing Fontan can prove to be exceedingly difficult.

Patients may present with ventricular dysfunction, pro-

gressive 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 perfor-

mance 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, exer-cise intolerance, dyspnea, fatigue, and syncope may ensue.

In a failing Fontan, abnormalities in systolic and/or dia-

stolic 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

difficult to define 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 pro-

vide inotropy, lusiotropy, and vasodilatory properties that

would appear beneficial 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 symp-

tomatic 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 profile 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 benefits 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 fluid homeo-

stasis 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 car-

diac output. Activation of the reninangiotensin system and

subsequent increased angiotensin II causes vasoconstric-

tion 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 benefit 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 withchronic 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 determineif beta blockers will be of benefit 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 fluid 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 ven-

tricular myocytes in response to wall stretch and has been

shown to play a role in regulation of vascular tone and fluid

homeostasis. BNP causes arterial and venous dilatation

without reflex tachycardia, vasodilates coronary vascula-

ture, 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 nesiri-

tides therapeutic benefit 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/perfu-

sion imbalances within the lung. Desaturation at rest and

with exercise commonly occurs in patients with residual

anatomic shunts, such as persistent atrial level shunt/bafflefenestration 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 col-

lateral 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 venove-

nous 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 investi-

gated 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 hyp-

oalbuminemia through intestinal protein loss, is a

troublesome complication after successful Fontan com-

pletion. Despite modifications 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 proce-

dure [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 identifi-

cation 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 eleva-

tion in abdominal venous pressures presumably leads tointestinal 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 pres-

sures, 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. Not-

withstanding these plausible explanations in the

pathogenesis of PLE, not all cases of PLE have concomi-tant elevation in systemic venous pressures [9, 32].

Inflammation 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 preoper-

ative ventricular end diastolic pressure were risk factors for

the development of PLE. Other large single center cohorts

have identified heterotaxy, polysplenia, anomalies of sys-

temic 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 findings in

patients who develop PLE. Interestingly, longer cardiopul-

monary bypass time at Fontan palliation has also been

identified 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 difficult operation due to anatomic issues that make for

a higher risk patient.

Fluid retention that occurs as a result of reduced vas-

cular 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 sub-

sequent thromboembolic complications. Similarly, chronic

loss of immunoglobulin can lead to infection from acquiredimmunodeficiency. 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 pre-

sentation. Unfortunately, PLE may manifest even with

optimal Fontan palliation and in the absence of residual

structural abnormalities. When structural abnormalitiesand/or opportunity for either catheter or surgical interven-

tion 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 albuminreplacement 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 specifically 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 inflammatory processes, such as systemic lupus ery-

thematosus, sarcoidosis, and allergic gastroenteropathy

[41, 42, 45, 46]. These findings suggest that some cases of

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PLE may be due to an inflammatory response. When sig-

nificant hemodynamic derangements are absent or

minimal, this inflammation-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 concentrationshave 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 lym-

phatic 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 fromhigh 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 deficiency 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 pres-

sure 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

benefit 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 con-

gestion with a decrease in enteric protein losses.

Hypocalcemia, another finding in PLE, is attributed to

hypoproteinemia and subsequent decrease in serum cal-

cium. In addition, hypocalcemia may result from vitamin D

deficiency due to the fat malabsorption also seen with PLE.

Administration of calcium replacement as an adjunct

therapy with and without concomitant vitamin D supple-

mentation has been shown to alleviate symptoms from PLE

[20]. Although calcium deficiency is explainable, the

mechanism through which calcium supplementation has

been shown to attenuate enteric protein loss is unclear.

Immunodeficiency due to lymphocyte and immuno-

globulin loss is a reported complication of PLE with the

potential for chronic immune deficiency leading to further

mucosal damage. Given that gastrointestinal mucosa serves

as a portal of entry for pathogens, the immunologic con-sequences 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 PLE-

induced immunodeficiency.

Elevated Pulmonary Vascular Resistance

Elevated pulmonary vascular resistance after the Fontanoperation has been reported in patients who have failed

Fontan physiology despite the presence of acceptable pul-

monary 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 uncer-

tain but likely due to the absence of pulsatile flow after the

Fontan operation. Pulsatile flow 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 findings, Levy

et al. [24] demonstrated overexpression of nitric oxide

synthase via immunostaining from the pulmonary vascu-

lature of patients with failing Fontan physiology. Similarly,

elevated endothelin-1 expression, a potent endothelium-

derived vasoconstrictor, was also found by immunostaining

[38]. Although unstudied, pharmacologic management

with pulmonary vasodilator agents such as bosentan,

prostacyclin, or sildenafil may play a role in attenuating the

deleterious effects of high pulmonary vascular resistance in

the failing Fontan patient.

Conclusion

Modifications 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 cir-

culation. 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 onproposed pathophysiologic mechanisms. Medical therapy

includes strategies borrowed from the treatment of con-

gestive 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.

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