CASE REPORTS
Sildenafil for Pulmonary Hypertension After Heart Transplantation Aparna Kulkarni, MD,a Tajinder P. Singh, MD,a Ashok Sarnaik, MD,b Henry L. Walters, MD,c and Ralph Delius, MDc Patients with increased pulmonary vascular resistance may experience acute pulmonary hypertension after heart transplantation. Pulmonary vasodilator drugs usually are delivered by the intravenous or the endotracheal route during acute pulmonary hypertensive crisis. Oral pulmonary vasodilators have a potential role in less acutely ill patients with increased pulmonary artery pressure after heart transplantation. We describe the 1st successful post-operative use of oral sildenafil for pulmonary vasodilation in a patient after heart transplantation. J Heart Lung Transplant 2004;23:1441-4. Copyright © 2004 by the International Society for Heart and Lung Transplantation.
Patients with chronic heart failure who are receiving medical management often develop pulmonary vascular changes and a gradual increase in pulmonary vascular resistance (PVR) that correlates in a linear fashion with mortality after heart transplantation.1 Pulmonary vascular resistance ⬎3 to 5 Wood units and transpulmonary gradients of ⬎15 mm Hg have accounted for a 3- to 5-fold increased risk of mortality within the initial 30 days after heart transplantation.2,3 Pulmonary hypertension usually presents as right heart failure after heart transplantation. Vasodilators including sodium nitroprusside, nitroglycerine, prostacyclin, and phosphodiesterase inhibitors such as enoximone are delivered as intravenous infusions. Inhaled nitric oxide typically is delivered to mechanically ventilated patients in the intensive care setting for acute pulmonary hypertensive crisis. An oral pulmonary vasodilator may be a better alternative in a less acutely ill patient with increased pulmonary artery (PA) pressure after heart transplantation. This report describes the 1st successful post-operative use of oral sildenafil for pulmonary vasodilation in a patient after heart transplantation. CASE REPORT A 4-year-old girl underwent heart transplantation for dilated cardiomyopathy. She was born with a doubleoutlet right ventricle, a hypoplastic aortic arch, and
From the aDivisions of Cardiology and bCritical Care Medicine, Department of Pediatrics, and cDepartment of Cardiovascular Surgery, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan. Submitted June 13, 2003; revised September 9, 2003; accepted September 11, 2003. Reprint requests: Tajinder P. Singh, MD, Division of Cardiology, Children’s Hospital of Michigan, 3901, Beaubien Blvd. Detroit, Michigan. Telephone: 313-745-0154. Fax: 313-993-0894. E-mail:
[email protected] Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ j.healun.2003.09.024
coarctation of the aorta. She underwent complete surgical repair (closure of the ventricular septal defect and repair of the coarctation) as a neonate. She had recurrence of the aortic coarctation at 2 months of age and underwent successful balloon dilation of the involved segment. At follow-up, she had progressive left ventricular systolic dysfunction and congestive heart failure that was treated with maximum-tolerated doses of digoxin, captopril, furosemide, aldactone, carvedilol, and aspirin. Her heart failure progressed, and she was hospitalized several times during acute exacerbations to receive intravenous inotrope therapy. She underwent cardiac catheterization for hemodynamic assessment at 3.5 years of age, before listing for cardiac transplantation. Her PA pressure (40/25 mm Hg; mean, 31 mm Hg) and PVR (4.4 Wood units) were increased in room air with wedge pressures of 17/18/10 mm Hg. The cardiac output, using the Fick method, was 4.5 liter/min (indexed). The PA pressure (38/15 mm Hg; mean, 28 mm Hg), PVR (3.1 Wood units) decreased in response to hyperoxia (100% oxygen). The pulmonary capillary wedge pressures were 22/21/14 mm Hg during hyperoxia. The cardiac output remained unchanged. The patient underwent heart transplantation at 4 years of age. She had a brief period of cardiopulmonary arrest after induction of anesthesia in the operating room and required resuscitation for 30 seconds. The transplantation was completed without any further complications. The graft ischemic time was 260 minutes, and the total time on cardiopulmonary bypass was 215 minutes. Her post-operative inotropic regimen included dopamine (3 g/kg/min), dobutamine (3 g/ kg/min), and milrinone (0.5 g/kg/min). Sodium nitroprusside infusion was used for after-load reduction. She also received anti-thymocyte gamma globulin, an equine anti– human-thymocyte immune globulin preparation, high-dose methylprednisolone, azathioprine, and oral cyclosporine according to institutional immune suppression protocol. A transthoracic echocardiogram 24 hours after the transplantation demonstrated moderate tricuspid regurgitation, and PA 1441
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Figure 1. Central venous pressure and urine output 48 hours before and 24 hours after initiation of sildenafil therapy. The arrows represent the timing of the 1st sildenafil dose. CVP, central venous pressure.
systolic pressure was estimated at 32 to 36 mm Hg. She received a nitroglycerine infusion, and the inspired oxygen concentration was increased to 50%. She was extubated the following day. Because of drug-induced hypertension (steroids, inotropes, and cyclosporine), dobutamine and dopamine were weaned during the next 24 hours, and oral diltiazem was substituted for intravenous sodium nitroprusside to treat systemic hypertension. By post-operative Day 3, her central venous pressures had gradually increased from 15 to 18 cm H2O to 28 to 30 cm H2O. She experienced progressive azotemia despite a urine output of 1.5 cc/kg/hr (blood urea nitrogen, 58 mg/dl; serum creatinine, 1.3 mg/dl). A transthoracic echocardiogram demonstrated moderate
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dilatation of the right atrium and the right ventricle, severe tricuspid regurgitation, and an underfilled left heart with good left ventricular systolic function. The systolic PA pressure was estimated as 45 to 47 mm Hg. Milrinone (0.4 g/kg/min), nitroglycerine (5 g/kg/ min), and oxygen (50%) were continued for their pulmonary vasodilatory effect. Oral sildenafil therapy was added to the regimen for its additional vasodilatory effect at a dosage of 0.25 mg/kg every 4 hours and was increased to 0.5 mg/kg every 4 hours after 2 doses. Within 12 hours after initiation of sildenafil, the central venous pressure decreased rapidly to 12 to 15 cm H2O (Figure 1). She had profuse diuresis (Figure 1) and improved renal function within 24 hours (blood urea nitrogen, 39 mg/dl; creatinine, 0.7 mg/dl). An echocardiogram at post-operative Day 4 showed decreased right atrial and right ventricular dilation, improved tricuspid regurgitation (Figure 2), and normal-size left ventricle. The PA systolic pressure was estimated at 30 to 34 mm Hg. Intravenous milrinone and nitroglycerine were weaned during the next 24 hours. Sildenafil dosage was weaned to 0.5 mg/kg every 8 hours during the next 4 days. A right heart catheterization performed at the time of a biopsy 10 days after transplantation, at 2 liter/min oxygen by nasal cannula, demonstrated normal PA pressure (25/13 mm Hg; mean, 18 mm Hg), PVR (1.8 Wood units), and transpulmonary gradient (7 mm Hg). We found no evidence of rejection at this biopsy. She was discharged home 2 weeks after transplantation, receiving sildenafil, oxygen, immunosuppression medications, diuretics, and diltiazem. Oxygen and sildenafil were weaned during the next 6 weeks and discontinued by 8 weeks after transplantation. We
Figure 2. Comparison of tricuspid regurgitation by color-Doppler echocardiography before (left panel) and 24 hours after (right panel) the initiation of oral sildenafil therapy. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.
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observed no adverse effects of sildenafil. The pulmonary vascular resistance (2.9 Wood units) and transpulmonary gradient (11 mm Hg) measured 8 weeks after transplantation, although higher than those during oxygen and sildenafil therapy, were well tolerated clinically by the patient. The patient has not had any rejection episodes and currently is doing well. DISCUSSION Pulmonary hypertension is a significant cause of morbidity and mortality after heart transplantation.1 Patients with chronic heart failure often have an increased left ventricular end-diastolic pressure and may have pulmonary hypertension caused by transmission of the increased distal pressure to the lung vasculature. The early structural change in the pulmonary arterioles is that of medial hypertrophy and results in a reactive increase in PA pressure and PVR. With time, however, collagen deposition in the pulmonary veins and arteries leads to irreversible structural changes so that the increased PVR and PA pressure become non-reactive to pulmonary vasodilators.4 Increased PVR before transplantation, with assessment of its reversible component, has been helpful in predicting the response of the pulmonary vasculature after transplantation, and a favorable outcome is associated with reversibility of the PVR index.5 Right heart failure after heart transplantation has been associated with prolonged graft ischemic time, increased PVR, and tricuspid regurgitation after endomyocardial biopsies.6 High-risk transplant recipients treated prophylactically for right heart failure with vasodilators such as prostaglandin E1, phosphodiesterase III inhibitor enoximone, and alkalinization during the first 48 hours of post-operative care seem to have improved outcome.7 Oxygen, nitric oxide, prostacyclin, nitroglycerine, and sodium nitroprusside have been used with varying success to treat right heart failure secondary to pulmonary hypertension.8 The use of oral sildenafil has not been described previously in treating pulmonary hypertension after heart transplantation. Our patient had signs of right heart failure while receiving after-load reduction therapy (milrinone), a vasodilator (nitroglycerine), and oxygen. The use of an efficacious oral pulmonary vasodilator, such as sildenafil, may have a role in this clinical setting because it may allow weaning of intravenous pulmonary vasodilator support and may be administered conveniently for several days or weeks. This after-load reduction would support right ventricular function, allowing time for the resolution of pulmonary vascular medial hypertrophy (the reversible component) and for the gradual development of right ventricular hypertrophy to compensate for the irreversible component of the increased PVR.
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Sildenafil is a pulmonary vasodilator that enhances and prolongs the action of cyclic guanosine monophosphate (cGMP), a primary mediator of vasodilation, by selective inhibition of the cGMP-specific PDE 5 isoenzyme. Inhibition of cGMP breakdown may be efficacious particularly in achieving pulmonary vasodilation in patients with pulmonary hypertension.9 Sildenafil has been shown to augment the effects of nitric oxide and inhaled prostacyclin in adults with primary pulmonary hypertension.10,11 Oral sildenafil was comparable to inhaled nitric oxide in patients with primary and secondary pulmonary hypertension.12 Chronic oral sildenafil therapy also improved exercise performance and clinical condition in a case series of 14 patients with pulmonary hypertension that included 5 patients with congenital heart disease.13 In summary, this report describes the clinical and hemodynamic effects of oral sildenafil therapy in a child with right heart failure after heart transplantation. A systematic evaluation of the use of this oral pulmonary vasodilator in patients after heart transplantation should be considered. REFERENCES 1. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official report—2000. J Heart Lung Transplant 2000;19:909 –31. 2. Murali S, Kormos RL, Uretsky BF, et al. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: the Pittsburgh experience. Am Heart J 1993;126:896 –904. 3. Chen JM, Levin HR, Michler RE, Prusmack CJ, Rose EA, Aaronson KD. Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality. J Thorac Cardiovasc Surg 1997;114:627–34. 4. Iijima T, Doi M, Kamma H, Horiguchi H, Yazawa T, Ogata T. Pulmonary vasculature in idiopathic dilated cardiomyopathy: a morphometric study. Acta Pathol Jpn 1993;43: 28 –35. 5. Zales VR, Pahl E, Backer CL, Crawford S, Mavroudis C, Benson DW, Jr. Pharmacologic reduction of pretransplantation pulmonary vascular resistance predicts outcome after pediatric heart transplantation. J Heart Lung Transplant 1993;12:965–72. 6. Williams MJ, Lee MY, DiSalvo TG, et al. Biopsy-induced flail tricuspid leaflet and tricuspid regurgitation following orthotopic cardiac transplantation. Am J Cardiol 1996;77: 1339 –44. 7. Bauer J, Dapper F, Demirakca S, Knothe C, Thul J, Hagel KJ. Perioperative management of pulmonary hypertension after heart transplantation in childhood. J Heart Lung Transplant 1997;16:1238 –47. 8. Stobierska-Dzierzek B, Awad H, Michler RE. The evolving
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management of acute right-sided heart failure in cardiac transplant recipients. J Am Coll Cardiol 2001;38:923–31. 9. Bogdan M, Humbert M, Francoual J, et al. Urinary cGMP concentrations in severe primary pulmonary hypertension. Thorax 1998;53:1059 –62. 10. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677–80. 11. Wilkens H, Guth A, Konig J, et al. Effect of inhaled
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iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218 –22. 12. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398 –403. 13. Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002;54:404 –9.
