Fontan circulation provides very good medium-term palliation for patients with a single ventricle. Nonetheless, the physiology is severely altered from normal including persistent low cardiac output state, high systemic vascular resistance and pulmonary vascular resistance, elevated central venous pressure, systolic and diastolic ventricular dysfunction, and abnormal arterial and venous haemodynamics.Reference Redington1 A significant number of Fontan patients will develop early or late complications including ventricular dysfunction, arrhythmias, persistent hypoxaemia, protein-losing enteropathy, bronchial casts, prolonged pleural effusions, thromboembolism, and stroke.Reference Gewillig2–Reference Rychik5 Hosein et alReference Hosein, Clarke and McGuirk6 showed in their study that elevated pulmonary artery pressure preoperatively has an adverse influence on Fontan outcome.
The creation of a Fontan circulation causes loss of pulsatile pulmonary blood flow. This results in endothelial dysfunction with a decrease in the sheer stress-mediated release of endothelium-derived nitric oxide and causes an increase in pulmonary vascular resistance.Reference Khambadkone, Li, de Leval, Cullen, Deanfield and Redington7 On the basis of growing experience with oral sildenafil in the treatment of persistent pulmonary hypertension of the newborn and pulmonary arterial hypertension in children,Reference Baquero, Soliz, Neira, Venegas and Sola8, Reference Humpl, Reyes, Holtby, Stephens and Adatia9 we postulated that sildenafil would be of benefit in patients with failing Fontan circulation.
Patients and methods
This study included 13 consecutive patients with severe Fontan complications presenting to either Birmingham Children’s Hospital, or to the Department of Paediatric Cardiology, University Hospital Wales, Cardiff, over a period of 30 months from January, 2006 to July, 2008. The mean age at the completion of the Fontan circulation was 4.5 (2.6–10) years. The mean interval between Fontan completion and the onset of complications was 2.5 (0.1–13) years. Sildenafil was given at a dose of 1–2 milligrams per kilogram 3–4 times per day. Treatment duration was between 2 months and 2 years and was weaned off gradually according to clinical response.
Four patients presented with bronchial casts, three patients suffered from protein-losing enteropathy, two had severe cyanosis after fenestrated Fontan, two had prolonged chylous effusions, one had previous failure of Fontan and take-down, and one had arrhythmias and end-stage cardiac failure and required conversion to an extra-cardiac Fontan.
Results
All four patients with bronchial casts improved significantly on sildenafil treatment. Two of these underwent concomitant catheter creation of a fenestration. One patient (no. 1) had previous stenting of a Fontan fenestration for bronchial casts with good effect. He later developed progressive right-ventricular dysfunction and the bronchial casts recurred. Sildenafil treatment was commenced and the casts improved but recurred early after successful cardiac transplantation. Sildenafil therapy was re-initiated with good effect and could be stopped some 3 months after transplantation.
In all three patients with protein-losing enteropathy, the serum albumin levels and the stool α-1-antitrypsin levels improved significantly on sildenafil treatment. Patient no. 5 initially was treated conservatively with a high-protein and medium-chain triglyceride diet, steroids and heparin, but developed significant side effects including osteoporosis. When referred to our unit, she was found to have a restriction to pulmonary venous return and thus underwent atrial septectomy and conversion to a fenestrated Fontan circulation. She was left with marked cyanosis and underwent partial catheter device occlusion of the fenestration. The protein-losing enteropathy recurred and she was commenced on sildenafil treatment with good effect.
Patient no. 6 underwent total catheter device occlusion of a large fenestration 6 months after the completion of an extracardiac, fenestrated Fontan procedure. He had a poor functional result and was diagnosed late with florid protein-losing enteropathy – albumin 19 grams per decilitre and α-1-antitrypsin 17.6 milligrams per gram. He underwent concomitant commencement of sildenafil treatment and transcatheter stent fenestration of his Fontan circulation with good result. Subsequently, he underwent dual-chamber epicardial pacing with complete resolution of protein-losing enteropathy. Patient no. 7 is stable on sildenafil treatment and high-protein diet.
Sildenafil was used in two patients for severe persistent chylous effusions early after Fontan completion in conjunction with stent augmentation of the Fontan fenestration with good result. In two patients with severe cyanosis after fenestrated Fontan procedure, sildenafil was used with an observed rise in resting and exercise saturations and clinical improvement. One went on to undergo partial Fontan fenestration closure and one had surgical resection of a restrictive atrial septum.
Sildenafil was used perioperatively in two patients having creation/conversion of an extracardiac Fontan with good effect Details of all patients are included in Table 1.
Table 1 Details of patients.
There were no significant side effects requiring sildenafil withdrawal over the treatment period. Medium treatment duration was 8 months, with a range of 2–25 months, with 6 of the 13 (46%) patients continuing on sildenafil treatment.
Discussion
The Fontan procedure provides high-grade palliation for patients with functionally univentricular hearts. Many of the immediate and long-term problems after a Fontan procedure, such as prolonged pleural effusions, persistent hypoxaemia, protein-losing enteropathy, and bronchial casts are pathophysiologically not fully understood and remain a challenge for treatment.Reference Redington1
Potentially treatable residual anatomic or haemodynamic lesions should be excluded meticulously. Steroids and heparin have been used with varying degrees of success in the management of protein-losing enteropathy and plastic bronchitis.Reference Ghanayem, Berger and Tweddell3–Reference Rychik5, Reference Haseyama, Satomi, Yasukochi, Matsui, Harada and Uchita10 In addition, various interventions including pacemaker implantation, transcatheter Fontan fenestration, and stent fenestration of the atrial septum have been reported in the management of patients with Fontan complications.Reference Stümper, Gewillig and Vettukattil11
Even though the pathophysiology of protein-losing enteropathy and plastic bronchitis is speculative,Reference Mertens, Hagler, Sauer, Somerville and Gewillig4, Reference Rychik5 we based our treatment strategy with sildenafil on the concept that the lack of pulsatile flow within the Fontan circulation contributes to pulmonary endothelial dysfunction and an increase in the overall pulmonary vascular resistance.Reference Khambadkone, Li, de Leval, Cullen, Deanfield and Redington7
Sildenafil is a selective inhibitor of cyclic guanosine–monophosphate-specific phosphodiesterase type 5. It is effective even in the absence of a functional endothelium. Phosphodiesterase 5 inhibitors cause pulmonary vasodilatation by promoting an enhanced and sustained level of cyclic guanosine monophosphate. Sildenafil was successfully used in the treatment of a case of plastic bronchitis after the Fontan procedure.Reference Haseyama, Satomi, Yasukochi, Matsui, Harada and Uchita10 In addition, sildenafil was shown to have a direct effect on mesenteric vascular resistance, leading to a normalisation of the mesenteric Doppler flow and resolution of protein-losing enteropathy in a case of a failing Fontan circulation.Reference Uzun, Wong, Bhole and Stumper12 There are several animal and human studies with specific phosphodiesterase type 5 inhibitors and they have an effect on mesenteric and portal circulation. Sildenafil and vardenafil have been shown to reduce portal venous pressure and increase mesenteric blood flow.Reference Teixeira, Priviero and Webb13, Reference Colle, De Vriese, Van Vlierberghe, Lameire and DeVos14
Sildenafil has a list of side effects occurring in up to 5% of patients. These unwanted effects include headache, dizziness flushing, dyspepsia, penile erection, nasal congestion, abnormal vision, diarrhoea, and hypersensitivity reaction including rash and priapism. Sildenafil drug level increases significantly if used concomitantly with erythromycin and cimetidine. None of our patients had significant side effects.
There were 13 patients with significant early or late Fontan problems who were treated with sildenafil in our study. Although the mechanism of protein-losing enteropathy or bronchial casts is not fully understood, we argued that an elevated systemic venous pressure, together with increased pulmonary and mesenteric vascular resistance, may be key elements in the pathophysiology, and thus the use of an oral pulmonary vasodilator should be of benefit. As a number of the patients in this study were very unwell at the time of presentation, 5 of 13 patients underwent concomitant catheter interventions in the form of stent enlargement or the creation of a fenestration combined with stenting of a narrow left pulmonary artery in two patients. Thus, strictly speaking, the individual contribution of either sildenafil treatment or catheter intervention to the clinical improvement in these cases cannot be fully ascertained. In addition, serial measurements of the semi-quantitative data, such as a 6-minute walk distance, cardiac output, or measurements of systemic venous pressures or pulmonary vascular resistance could not be obtained. A recent study by Giardini et alReference Giardini, Balduci, Specchia, Gargiulo, Bonvicini and Picchio15 showed that oral administration of a single dose of sildenafil in Fontan patients improved exercise capacity and haemodynamic response to exercise.
Conclusion
Sildenafil can be used safely and effectively in patients with failing Fontan circulation. It should be considered as an adjunct to the treatment of patients presenting with severe Fontan complications, which may be related to increased pulmonary vascular resistance. Prospective randomised controlled trials of sildenafil treatment in patients with Fontan circulation should be undertaken.
