Ann Thorac Surg 2007;83:e11-e13
© 2007 The Society of Thoracic Surgeons
Case Reports
Oral Sildenafil Ameliorates Impaired Pulmonary Circulation Early After Bidirectional Cavopulmonary Shunt
Shintaro Nemoto, MD, PhD*,
Eitaro Umehara, MD,
Tadashi Ikeda, MD, PhD,
Tatsuya Itonaga, MD,
Masashi Komeda, MD, PhD
Department of Cardiovascular Surgery, Kyoto University Hospital, Kyoto University, Graduate School of Medicine, Kyoto, Japan
Accepted for publication January 30, 2007.
* Address correspondence to Dr Nemoto, Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, Osaka, 569-8686 Japan (Email: snemoto{at}poh.osaka-med.ac.jp).
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Abstract
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We report a case of successful administration of oral sildenafil (ie, a phosphodiesterase-5 inhibitor) in an infant for impaired pulmonary circulation that caused early clinical deterioration after a bicavopulmonary shunt. The transpulmonary pressure gradient (ie, a clinical indicator of pulmonary circulation) was initially normalized by inhaled nitric oxide; however, an increase in transpulmonary pressure gradient and oxygen desaturation occurred after extubation and discontinuation of inhaled nitric oxide on postoperative day 1. Subsequent administration of oral sildenafil in stepwise doses resulted in normalization of transpulmonary pressure gradient and improved oxygen saturation with successful discontinuation of intravenous vasodilators. Our results suggest that oral sildenafil may be a potent adjunctive therapy for impaired postoperative pulmonary circulation after right heart bypass surgery.
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Introduction
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It is widely known that pulmonary circulation plays an important role in mortality and morbidity after right heart bypass surgery, including the Fontan-type procedure and bidirectional cavopulmonary shunt (BCPS) [1, 2]. Severe impairment of the pulmonary circulation only occurs infrequently after right heart bypass surgery, but such impairment causes increased central venous pressure and decreased left-heart preload leading to severe congestion in the major organs and low cardiac output syndrome, respectively.
There are various options for treatment of impaired pulmonary circulation, including intravenous trinitroglycerine (TNG), prostaglandin E1 [3], intravenous or oral prostacyclin [4, 5], and inhaled nitric oxide (NO) [3, 4, 6, 7]. Sildenafil citrate (Viagra [Pfizer, Japan, Tokyo]) has recently been used to treat various types of pulmonary hypertension [6–11], because it produces a strong pulmonary vasodilative response by increasing the intracellular cGMP concentration through inhibition of phosphodiesterase-5 (an enzyme that degrades cGMP) [8, 9, 12].
Here we report the case of successful administration of oral sildenafil to treat an infant with impaired pulmonary circulation that caused early clinical deterioration after BCPS.
A 1-year-old boy was diagnosed by echocardiography as having a concordant criss-cross heart with a hypoplastic left ventricle, transposition of the great arteries, coarctation of the aorta, patent ductus arteriosus, a ventricular septal defect, and a secundum atrial septal defect. During the neonatal period he had undergone coarctation repair by end-to-end anastomosis and pulmonary artery banding. At 9 months of age the patient underwent a right BCPS using cardiopulmonary bypass concomitantly with a second pulmonary artery banding surgery, and pulmonary artery (PA) reconstruction by resection and end-to-end direct anastomosis for stenosis at the right PA origin, which was caused by distal migration of the earlier PA band. Although the postoperative course was uneventful, echocardiography 1 month postoperatively showed residual stenosis at the PA bifurcation, which caused unbalanced pulmonary flow (i.e., flow from the BCPS predominantly draining into the right PA and excessive antegrade flow through the banded main PA draining into the left PA). Cardiac catheterization showed that the mean pressures of the right and left PA were 17 mm Hg and 30 mm Hg, respectively. The calculated total pulmonary vascular resistance was 4.8 Wood units x m2 and the ratio of pulmonary-to-systemic flow was 1.95 with a PaO2 of 57 mm Hg on room air. Although angiography showed that both PA branches were well developed, with a Nakata index of 385 [13], the pulmonary hemodynamics were unsuitable for future Fontan completion. Redirection of BCPS flow into both PA branches with an ideal PA pressure was indicated. Accordingly, at the age of 1 year, the boy underwent repeated PA reconstruction with fresh autologus pericardium on cardiopulmonary bypass with transection of the main PA and enlargement of intraatrial communication.
After admission to the intensive care unit after surgery, the patient was sedated with intravenous morphine chloride and infusion of midazolam (Fig 1). The mean pressure of the superior vena cava, which is equivalent to the mean PA pressure (PAP), was well maintained at 11 mm Hg with TNG and prostaglandin E1 infusion. His systemic blood pressure and the mean common atrial pressure (CAP) were 94/44 (mean, 61) and 6 mm Hg, respectively. However, the mean PAP gradually increased and the transpulmonary pressure gradient (TPG; mean PAP-mean CAP), which is a clinical indicator for pulmonary circulation, increased by more than 10 mm Hg in the early morning on postoperative day (POD) 1, despite TNG and prostaglandin E1 infusion (Fig 2). Inhaled NO was initiated and the patient’s TPG normalized at 3 mm Hg. He was successfully extubated with maintenance of stable hemodynamics, and inhaled NO was discontinued after extubation. However, TPG gradually increased again and reached 20 mm Hg, despite high-dose TNG infusion, and a high oxygen flow of 7 L/min (delivered by a face mask) was required to maintain SaO2 of 75%.
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Fig 1. Postoperative time course of hemodynamic measurements during the intensive care unit stay. (mean BP = mean blood pressure; mean CAP = mean common atrial pressure equivalent to the pressure of the inferior vena cava; mean PAP = mean pulmonary arterial pressure equivalent to the pressure of the superior vena cava; NO = inhaled nitric oxide; NTG = intravenous nitroglycerine infusion; PGE1 = intravenous prostaglandin E1 infusion; SIL = oral sildenafil administration;  = µg/kg/min.)
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Fig 2. Changes in the postoperative transpulmonary pressure gradient (TPG). The TPG increased after discontinuation of inhaled nitric oxide (NO), but normalized after administration of oral sildenafil (SIL) without use of inhaled NO or other vasodilators. The TPG (mm Hg) was calculated as mean pulmonary arterial pressure (PAP)—mean common atrial pressure (CAP), in which the mean PAP is equivalent to the pressure of the superior vena cava and the mean common atrial pressure is equivalent to the pressure of the inferior vena cava.
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Because respiration was well maintained, nasal NO delivery [14] was indicated for the elevated TPG, but it was not available in our hospital. Therefore, after obtaining consent from the patient’s parents, sildenafil was administered through a nasogastric tube at a starting dose of 0.5 mg/kg. With careful monitoring of hemodynamics, the dose of sildenafil was increased stepwise by 0.5 mg/kg every 4 hours up to a maximum dose of 1.5 mg/kg. This protocol was approved by the Human Ethics Committee for clinical trials at Kyoto University, Graduate School of Medicine. Two hours after the first dose, TPG began to decrease and then normalized at the maximum dose. Oxygen saturation improved dramatically and reached 81% in room air, and TNG infusion was discontinued uneventfully without a rise in TPG. The patient was discharged from the intensive care unit 3 days after surgery. The dose of sildenafil was gradually reduced during the next 5 days (ie, 1.5 mg/kg every 6 hours on POD 3, 1.5 mg/kg every 8 hours on POD 4, 0.75 mg/kg every 8 hours on POD 5, once a day on POD 6, with completion of dosing on POD 7). Postoperative radionuclide pulmonary perfusion scanning showed equivalent uptake of 99mTc macroaggregated human serum albumin in both lungs, and the patient was discharged from the hospital on POD 15.
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Comment
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There are three major findings in this report: (1) conventional endothelial-dependent vasodilators (ie, prostaglandin E1 and TNG) failed to treat impaired pulmonary circulation early after BCPS; (2) oral sildenafil normalized TPG very effectively, similar to inhaled NO; and (3) sildenafil caused no major side effects and no "rebound" deterioration in pulmonary circulation after discontinuation.
It is well known that endothelial dysfunction occurs during and after cardiopulmonary bypass, with particular effects on the pulmonary circulation [15, 16]. In addition, despite upregulation of NO synthetase activity [17], actual NO production from the pulmonary endothelium is strongly suppressed after a Fontan procedure [18, 19] and pulmonary flow is reduced and becomes pulseless; such effects are also seen after BCPS. In the present case, pulmonary hypertension in the left PA due to excess blood flow from the banded main PA caused additional pulmonary endothelial damage, which may explain the limited effect of endothelium-dependent intravenous vasodilation therapy in this patient. Therefore our experience suggests that endothelium-independent pulmonary vasodilators may be indicated for treatment of impaired pulmonary circulation after right heart bypass surgery. Currently two such vasodilators are available (ie, inhaled NO [which involves direct NO delivery to medial smooth muscle of the PA, causing enhancement of local cGMP production] and sildenafil [which is a phosphodiesterase-5 inhibitor that results in maintenance of the serum and local cGMP concentrations]).
Both inhaled NO and sildenafil were very effective in normalizing pulmonary circulation and oxygen saturation in this case; however there are several disadvantages of inhaled NO. First, although NO can be delivered to patients through an endotracheal tube and a specially designed nasal cannula [14], an appropriate scavenging system for harmful oxidants is also required. Second, discontinuation of inhaled NO often causes acute deterioration of the pulmonary circulation; a so-called "rebound" effect [4, 20]. These disadvantages often result in an extended intensive care unit stay, and in our case the pulmonary circulation became impaired (as indicated by the increased TPG) soon after extubation and discontinuation of inhaled NO, suggesting a rebound to the treatment. In contrast, with sildenafil there is no need for a special delivery system, rebound after discontinuation has not been reported, and there are no apparent major hemodynamic side effects; in particular, there is no evidence that sildenafil causes hypotension, which often occurs with infusion of an intravenous vasodilator.
One difficulty with sildenafil is that the drug is absorbed systemically and its plasma concentration is unpredictable immediately after surgery. Therefore sildenafil was administered in stepwise dose increments with careful monitoring of hemodynamics and adverse events in our protocol, and we observed no side effects after sildenafil administration. However, careful continued surveillance of our patient and a clinical cohort will be required to confirm the safety and efficacy of oral sildenafil for treatment of impaired pulmonary circulation after right heart bypass surgery.
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Acknowledgments
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We are grateful to Sumiko Yokoyama and Dr Kenichi Inui, Department of Pharmacy, Kyoto University Hospital, for their preparation of oral sildenafil. We are also indebted to Dr Hiraku Doi, Department of Pediatrics, Kyoto University Hospital, for his careful follow-up of this patient.
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References
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- Gentles TL, Meyer Jr JE, Gauvreau K, et al. Fontan operation in five hundred consecutive patients: factors influencing early and late outcome J Thorac Cardiovasc Surg 1997;114:376-391.[Abstract/Free Full Text]
- Knott-Craig CJ, Danielson GK, Schaff HV, et al. The modified Fontan operation: an analysis of risk factors for early postoperative death and takedown in 702 consecutive patients from one institution J Thorac Cardiovasc Surg 1995;109:1237-1243.[Abstract/Free Full Text]
- Schmid ER, Burki C, Engel MH, Schmidlin D, Tornic M, Seifert B. Inhaled nitric oxide versus intravenous vasodilators in severe pulmonary hypertension after cardiac surgery Anesth Analg 1999;89:1108-1115.[Abstract/Free Full Text]
- Miyaji K, Nagata N, Miyamoto T, Kitahori K. Combined therapy with inhaled nitric oxide and intravenous epoprostenol (prostacyclin) for critical pulmonary perfusion after the Fontan procedure J Thorac Cardiovasc Surg 2003;125:437-439.[Free Full Text]
- Takahashi K, Mori Y, Yamamura H, Nakanishi T, Nakazawa M. Effects of beraprost sodium on pulmonary vascular resistance in candidate for a Fontan procedure: a preliminary study Pediatr Int 2003;45:671-675.[Medline]
- Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomized trial in infants after cardiac surgery Intensive Care Med 2003;29:1996-2003.[Medline]
- Leuchte HH, Schwaiblmair M, Baumgartner RA, Neurohr CF, Kolbe T, Behr J. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension Chest 2004;125:580-586.[Medline]
- Reffelmann T, Kloner RA. Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease Circulation 2003;108:239-244.[Free Full Text]
- Schlze-Neick I, Hartenstein P, Li J, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease Circulation 2003;108(Suppl II):II-67-II-73.
- Atz AM, Lefler AK, Fairbrother DL, Uber WE, Bradley SM. Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crisis J Thorac Cardiovasc Surg 2002;124:628-629.[Free Full Text]
- Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal Anestheology 1999;91:307-310.
- Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension Am J Respir Crit Care Med 2002;165:1098-1102.[Abstract/Free Full Text]
- Nakata S, Imai Y, Takanashi Y, et al. A new method of the quantitative standardization of cross-sectional areas of the pulmonary arteries in congenital heart diseases with decreased pulmonary blood flow J Thorac Cardiovasc Surg 1984;88:610-619.[Abstract]
- Kitamukai O, Sakuma M, Takahashi T, Nawata J, Ikeda J, Shirato K. Hemodynamic effects of inhaled nitric oxide using pulse delivery and continuous delivery systems in pulmonary hypertension Intern Med 2002;41:429-434.[Medline]
- Morita K, Ihnkem K, Buckberg GD, Sherman MP, Ignarro LJ. Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass Ann Thorac Surg 1996;61:1775-1780.[Abstract/Free Full Text]
- Glavind-Kristensen M, Brix-Kristensen V, Toennesen E, et al. Pulmonary endothelial dysfunction after cardiopulmonary bypass in neonatal pigs Acta Anaesthesiol Scand 2002;46:853-859.[Medline]
- Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation Circulation 2003;107:3204-3208.[Abstract/Free Full Text]
- Levy M, Danel C, Leval AM, Leca F, Vouhe PR, Israel-Biet D. Nitric oxide synthetase expression by pulmonary arteries: a predictive marker of Fontan procedure outcome? J Thorac Cardiovasc Surg 2003;125:1083-1090.[Abstract/Free Full Text]
- Mahle WT, Todd K, Fyfe DA. Endothelial function following the Fontan operation Am J Cardiol 2003;91:1286-1288.[Medline]
- Atz AM, Adatia I, Wessel DL. Rebound pulmonary hypertension after inhalation of nitric oxide Ann Thorac Surg 1996;62:1759-1764.[Abstract/Free Full Text]
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S. Nemoto
Reply
Ann. Thorac. Surg.,
February 1, 2008;
85(2):
694 - 695.
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T. Soueide and I. Rassi
Oral Sildenafil After Bidirectional Cavopulmonary Shunt
Ann. Thorac. Surg.,
February 1, 2008;
85(2):
693 - 694.
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Abstract
Introduction
