Oral Sildenafil to Control Pulmonary Hypertension after Congenital Heart Surgery Farah Peiravian, Ahmad A Amirghofran, Mohammad Borzouee,

Gholam H Ajami, Mohammad R Sabri and Sara Kolaee Asian Cardiovasc Thorac Ann 2007;15:113-117

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ORIGINAL CONTRIBUTION

Oral Sildenal to Control Pulmonary Hypertension after Congenital Heart Surgery

Farah Peiravian, MD, Ahmad A Amirghofran, MD1, Mohammad Borzouee, MD1, Gholam H Ajami, MD1, Mohammad R Sabri, MD1, Sara Kolaee, MD
Department of Pediatric Cardiac Surgery Dena Hospital Kazerun Islamic Azad University Faculty of Medicine 1 Department of Pediatric Cardiac Surgery and Cardiology Faghihi Hospital Shiraz University of Medical Sciences Shiraz, Iran

This study investigates the role of oral sildenal in decreasing pulmonary pressure after congenital heart surgery. Between September 2002 and September 2004, among a group of postoperative children with large septal defects, moderate to severe pulmonary hypertension [pulmonary artery (PA) to aortic (Ao) pressure ratio of 0.76 0.17] and systemic desaturation (Ao Sat = 0.89 0.11), oral sildenal (0.3 mgkg-1, every 3 hours) was administered for a period of 2448 hours (sildenal group). These patients were compared to a group of 22 children with similar pathologies who did not receive sildenal (control group). Postoperative PA pressure (28.61 7.80 vs 39.40 10.80 mm Hg) and PA/Ao pressure (0.28 0.08 vs 0.41 0.11) were signicantly lower in the sildenal group ( p = 0.001 and 0.001 respectively). Pulmonary hypertensive crisis was detected in 4 patients in the control group, but none in the sildenal group ( p = 0.02). There was no signicant rise in PA pressure following discontinuation of the drug (26.30 6.66 vs 28.49 10.93 mm Hg, p = 0.366). No signicant complications were noticed regarding sildenal use. Low doses of oral sildenal appear to be effective and safe to control postoperative PA pressure in children. Absence of rebound pulmonary hypertension, availability, and low cost of the drug are considered as its major advantages.
(Asian Cardiovasc Thorac Ann 2007;15:1137)

ABSTRACT

Pulmonary hypertension (PH) and pulmonary hypertensive crisis remain a major problem after surgical correction of congenital heart diseases with pre-existing significant PH.1,2 Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, remains the drug of choice for control of pulmonary hypertension after cardiac surgery, but life-threatening events are seen with abrupt discontinuation of iNO.3 The vasodilator effect of NO is due to activation of soluble guanylate cyclase, which converts guanine triphosphate to cyclic guanosine monophosphate (cGMP) which

INTRODUCTION

leads to activation of protein kinases and subsequent vascular relaxation. While cGMP is destroyed by phosphodiesterase 5 (PDE-5), sildenafil is a potent and selective inhibitor of PDE-5.4 It has been used in adults and children with primary and secondary pulmonary hypertension, either as monotherapy, or in combination with inhaled prostacyclin or NO.3,58 This study was performed to investigate the effect of oral sildenafil (as monotherapy) in controlling postoperative PH, following congenital cardiac surgery.

For reprint information contact: Farah Peiravian, MD Tel: 98 711 624 9134 Fax: 98 711 635 1218 Email: fpeiravian@hotmail.com Department of Pediatric Cardiac Surgery, Dena Hospital, Sattar Khan Street, Shiraz, Iran. 2007, VOL. 15, NO. 2 113 ASIAN CARDIOVASCULAR & THORACIC ANNALS Downloaded from asianannals.ctsnetjournals.org by on July 6, 2009

Sildenal in Congenital Heart Surgery

Peiravian

Table 1. Demographic and Preoperative Cardiac Catheterization Data in the Sildenal Group Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Sex M M F M M F F M M F M M M M F M M M F M Age (yr) 1 2 16 8 2 9 12 7 2 14 1.5 3 2 1.5 9 1 1 7 4 2 Weight (kg) 9 8 27 16 10 25 20 21 13 26 7 12 9 6.7 22 8 10 17 12 8 Cardiac diagnosis VSD, APW VSD, SAW VSD VSD, PDA VSD VSD, PDA VSD VSD, PDA VSD VSD, ASD, PDA VSD, PDA VSD, PDA VSD, ASD VSD VSD VSD, PDA VSD VSD, SAW VSD, PDA VSD, APW Sat (%) 90 89 87 85 92 92 85 91 86 94 89 84 86 86 95 82 81 93 86 84 PA/Ao Pressure 0.75 0.86 0.83 0.95 0.82 0.82 1.00 0.9 0.75 0.81 0.89 1.06 0.96 0.92 0.76 0.97 0.83 0.92 1.16 0.95 Qp/Qs 1.34 1.75 2.00 0.83 4.00 4.00 0.93 1.75 1.18 4.20 1.86 0.92 1.68 2.40 1.26 1.08 2.28 3.14 1.10 3.05

Ao = aorta, APW = aortopulmonary window, ASD = atrial septal defect, F = female, M = male, PA = pulmonary artery, PDA = patent ductus arteriosus, Qp = pulmonary blood ow, Qs = systemic blood ow, Sat = aortic saturation, SAW = subaortic web, VSD = ventricular septal defect.

Table 2. Demographic and Preoperative Cardiac Catheterization Data in the Control Group Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Sex M F M M F F F F M F M F M M F F M F F M M F Age (yr) 14 7 3 3 4 9 5 4 4 4 2 2 1.5 1.5 8 1.5 1.5 6 3 1 1.5 1 Weight (kg) 25 18 16 12.5 12 22 22 15 12 13 15 6 10 10 15 7.5 8.5 15 8 8 8 5 Cardiac Diagnosis VSD VSD, PDA VSD VSD, SAW VSD, PDA VSD VSD, PDA VSD, PDA VSD, PDA, SAW VSD, PDA VSD, PDA VSD VSD, PDA VSD, PDA VSD, ASD VSD, PDA VSD VSD, PDA VSD, PDA VSD VSD VSD, PDA Sat (%) 90 89 89 90 92 90 95 85 88 88 93 79 91 86 90 86 90 66 84 88 76 82 PA/Ao pressure 0.99 1.00 0.71 0.96 0.86 0.76 0.77 0.86 0.77 0.80 0.85 0.94 0.76 0.78 1.10 0.84 0.84 0.88 1.30 0.76 0.77 0.97 Qp/Qs 1.12 3.40 1.55 1.36 1.50 1.38 1.84 1.74 1.10 1.06 2.07 0.65 3.30 1.10 1.33 2.79 4.49 0.46 0.53 1.66 0.90 1.08

Ao = aorta, ASD = atrial septal defect, F = female, M = male, PA = pulmonary artery, PDA = patent ductus arteriosus, Qp = pulmonary blood ow, Qs = systemic blood ow, Sat = aortic saturation, SAW = subaortic web, VSD = ventricular septal defect.

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Peiravian

Sildenal in Congenital Heart Surgery

Table 3. Comparison of Preoperative Variables between the Sildenal Group and the Control Group Sildenal group Age (yr) Weight (kg) PA Pressure (mm Hg) Ao Pressure (mm Hg) PA/Ao Pressure Systemic Saturation (%) 5.25 4.70 14.33 6.86 76.8 17.4 85.9 18.7 0.89 0.10 86.26 9.77 Control group 3.97 3.20 12.88 5.40 81.7 16.3 92.6 10.7 0.87 0.13 86.70 6.36 p-Value 0.308 0.450 0.346 0.158 0.611 0.861

Table 4. Comparison of Postoperative Variables between the Sildenal Group and the Control Group Sildenal group PA/Ao Pressure Maximum systolic PA pressure (mm Hg) Minimum systolic PA pressure (mm Hg) Mean systolic PA pressure (mm Hg) Mechanical ventilation time (hrs) ICU stay (hrs) Hospital stay (days) 0.28 0.08 43.55 16.36 18.40 7.84 28.61 7.80 13.75 12.12 72.65 29.97 7.20 2.14 Control group 0.41 0.10 52.81 12.84 27.72 8.87 39.40 10.80 22.60 9.50 86.28 93.94 7.80 3.78 p-Value 0.001 0.047 0.001 0.001 0.013 0.539 0.533

PATIENTS AND METHODS

From September 2002 to September 2004, 42 patients with large septal defects and moderate to severe preoperative PH (PA/Ao pressure more than 0.7), were enrolled in this study. All of the patients underwent cardiac catheterization in the two months before surgery. Aortic and PA pressures and saturations were measured directly during cardiac catheterization. Preoperative PA to aortic pressure ratio and pulmonary to systemic blood ow ratios were calculated, but pulmonary vascular resistance could not be determined due to inability to measure oxygen consumption. The patients were randomly assigned to two groups. The rst group (sildenal group) consisted of 20 patients aged 1 to 16 years who received sildenal (Viagra, Pzer laboratory, NY, USA) after the operation. Sildenal was given to these patients through nasogastric tube or via the oral route every three hours with a dose of 0.3 mgkg-1. It was initiated at the commencement of cardiopulmonary bypass and continued for 2448 hours after surgery. The second group (control group) consisted of 22 patients aged 114 years who did not receive sildenal. No vasodilator was administered in the control group, except for the cases with pulmonary hypertensive crisis, when intravenous nitroglycerin was administered. Demographic data, cardiac diagnoses, and
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preoperative cardiac catheterization values of all patients in each group are summarized in Tables 1 and 2. After the operation, systemic and pulmonary pressures were measured hourly for 23 days via arterial and PA lines. The recorded PA pressures, PA/Ao ratio, duration of mechanical ventilation, ICU and hospital stays were compared between the two groups. Results were statistically analyzed using chi-square and t tests, and a p-value less than 0.05 was considered signicant.

RESULTS

The mean age in the sildenal group was 5.25 4.70 years, and 3.97 3.20 years in the control group ( p = 0.308). Fourteen patients in the sildenal group and 10 patients in the control group were male. The mean weight in the sildenal group was 14.33 6.86 kg (range: 6.7027 kg) versus 12.88 5.40 kg (range 525 kg) in the control group ( p = 0.450). The major congenital defect in both groups was ventricular septal defect (VSD), but 13 patients in the sildenal group suffered from other concomitant anomalies including 2 aortopulmonary windows, 8 PDAs (patent ductus arteriosus), 2 ASDs (arterial septal defect) and subaortic web (SAW) in two patients. In the control group; in 13

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Sildenal in Congenital Heart Surgery

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sildenafil group control group

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Table 5. PA Pressure before and after Discontinuation of Sildenal With Sildenal After D/C Sildenal p-Value

40

mm Hg

35

30

Mean systolic PA Pressure (mm Hg) 26.30 6.66 28.49 10.93 0.366

25

20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Time(hr)

Figure 1. Comparison of systolic PA pressure between the sildenal group and the control group during rst 24 hours after surgery.
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cases, PDA, in one case ASD, and in two cases SAW was seen other than VSD. Table 3 demonstrates no statistically signicant differences between the two groups regarding preoperative variables including age, weight, PA pressure, Ao pressure, PA/Ao pressure, and systemic saturation. After surgery, PA/Ao pressure dropped in both groups, but in the sildenal group, this ratio was signicantly lower (0.28 0.08 vs 0.41 0.10, p = 0.001). As shown in Table 4, after surgery, maximum, minimum, and mean recorded systolic PA pressures were signicantly lower in the sildenal group ( p = 0.047, 0.001, 0.001 respectively). Figures 13 show mean systolic and diastolic pressures, in addition to the mean values of recorded PA pressure during the 24 hours after surgery in both groups. All of these values were lower in the sildenal group. Although there was no difference in duration of ICU and hospital stays between the two groups, mechanical ventilation time was significantly shorter in the sildenafil group (13.75 12.12 vs 22.60 9.50 hours) ( p = 0.013). As shown in Table 5, there was no significant rise in PA pressure after discontinuation of sildenafil (26.30 6.66 vs 28.49 10.93 mm Hg) ( p = 0.366). Four patients in the control group experienced pulmonary hypertensive crisis compared to none in the sildenal group ( p = 0.02). No signicant systemic hypotension was detected in the sildenal group. The only complications related to sildenal were short lived erections in 3 males, transient nasal stufness in 5 and gastrointestinal upset in 2. All complications reversed after discontinuation of the drug. There was no death in either group. Postoperative complications were hemothorax (1), pneumonia (1), and left sided pleural effusion (1) in the sildenal group, and hemothorax (1), pneumonia (1), gastric hemorrhage (1), and aborted cardiac arrest accompanied with pulmonary hypertensive crisis (2) in the control group.

sildenafil group control group

30

25

20

mm Hg

15

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Time(hr)

Figure 2. Comparison of diastolic PA pressure between the sildenal group and the control group during rst 24 hours after surgery.

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sildenafil group control group

35

30

mm Hg

25

20

15

10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Time (hr)

Figure 3. Comparison of mean PA pressure between the sildenal group and the control group during rst 24 hours after surgery.

DISCUSSION

Currently, inhaled NO is the gold standard treatment for residual pulmonary hypertension after congenital cardiac surgery. However, there are some limitations, namely
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Peiravian incomplete elimination of pulmonary hypertensive crisis and fatal rebound PH after discontinuation of iNO.1,3,4 In addition, a special device is required for administration of the drug. In order to overcome such shortcomings, sildenal was added to iNO,1,3,69 or used alone.5 Negative feedback inhibition of production of endogenous NO by exogenous nitric oxide has been postulated as the mechanism of rebound PH after iNO withdrawal.3 PDE-5 inhibition by sildenal by increasing intracellular and circulating cGMP prevents rapid depletion of cGMP when iNO is withdrawn, and potentiates the pulmonary vasodilatory effect of the agent.1,34 Atz and Wessel in 1999 conrmed the doubling of circulating cGMP in 2 of 3 cases following administration of oral sildenal.3 The efcacy of sildenal in the treatment of primary pulmonary hypertension has also been shown in several studies.8,1012 Schulze-Neick et al showed that intravenous sildenal was a selective pulmonary vasodilator and as effective as iNO.4 Experience with oral sildenal in postoperative PH is limited to some case reports with difculty in weaning or suboptimal efcacy of iNO. In all of these studies, sildenal was added to iNO or other pulmonary vasodilators.1,3,69,13 In our study, although a low dose of oral sildenal was used without concomitant pulmonary vasodilators, it was successful in reducing pulmonary pressure and eliminating the risk of pulmonary hypertensive crisis after congenital cardiac surgery, without the hazard of rebound PH. In conclusion, sildenafil can be considered as an attractive and effective oral therapy for postoperative pulmonary hypertension. It is safe, easily applied, and inexpensive. However, further studies are necessary to determine the efcacy, safety, and optimal dosing of sildenal in children.

Sildenal in Congenital Heart Surgery

REFERENCES
1. Atz AM, Leer AK, Fairbrother DL, Uber WE, Bradley SM. Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. J Thorac Cardiovasc Surg 2002;124:6289. Polderman FN, Cohen J, Blom NA, Delhaas T, Helbing WA, Lam J, et al. Sudden unexpected death in children with a previously diagnosed cardiovascular disorder. Int J Cardiol, 2004; 95:1716. Atz AM, Wessel DL. Sildenal ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91:30710. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, et al. Intravenous sildenal is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003;108 Suppl I:II16773. Carroll WD, Dhillon R. Sildenal as a treatment for pulmonary hypertension. Arch Dis Child 2003;88:8278. Garcia Martinez E, Ibarra de la Rosa I, Perez Navero JL, Tejero Mateo I, Exposito Montes JF, Suarez de Lezo, et al. Sildenal in the treatment of pulmonary hypertension. An Pediatr (Barc) 2003;59:1103. Laquay N, Levy ML, Vaccaroni L, Mauriat P, Carli P. Use of oral sildenal (Viagra) in pulmonary hypertension after cardiac pediatric surgery. Ann Fr Anesth Reanim 2003;22:1403. Kothari SS, Duggal B. Chronic oral sildenal therapy in severe pulmonary artery hypertension. Indian Heart J 2002; 54:4049. Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, et al. Oral sildenal reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 2005;79:1947.

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10. Fraisse A, Habib G. Treatment of pulmonary arterial hypertension in children. Arch Pediatr 2004; 11:94550. 11. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84:E4. 12. Laupland KB, Helmersen D, Zygun DA, Viner SM. Sildenal treatment of primary pulmonary hypertension. Can Respir J 2003; 10:4850. 13. Bentlin MR, Saito A, De Luca AK, Bossolan G, Bonatto RC, Martins AS, Rugolo LM. Sildenal for pulmonary hypertension treatment after cardiac surgery. J Pediatr (Rio J) 2005; 81:1758.

ACKNOWLEDGMENTS

We would like to thank Dr. Ali Akbar Nekouian and Dr. Davood Mehrabani at the Center for Development of Clinical Studies in Nemazee Hospital for editorial and statistical assistance.

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Oral Sildenafil to Control Pulmonary Hypertension after Congenital Heart Surgery Farah Peiravian, Ahmad A Amirghofran, Mohammad Borzouee, Gholam H Ajami, Mohammad R Sabri and Sara Kolaee Asian Cardiovasc Thorac Ann 2007;15:113-117 This information is current as of July 6, 2009
Updated Information & Services References including high-resolution figures, can be found at: http://asianannals.ctsnetjournals.org/cgi/content/full/15/2/113 This article cites 10 articles, 3 of which you can access for free at: http://asianannals.ctsnetjournals.org/cgi/content/full/15/2/113#BIB L This article, along with others on similar topics, appears in the following collection(s): Cardiac - pharmacology http://asianannals.ctsnetjournals.org/cgi/collection/cardiac_pharma cology Requests to reproduce this article in parts (figures, tables) or in its entirety should be submitted via email to: info@asiapex.com For ordering reprints, please email: info@asiapex.com

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