Asian Cardiovasc Thorac Ann 2007;15:113-117
© 2007 Asia Publishing EXchange Ltd
Oral Sildenafil 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
For reprint information contact: Farah Peiravian, MD Tel: 98 711 624 9134 Fax: 98 711 635 1218 Email: fpeiravian{at}hotmail.com, Department of Pediatric Cardiac Surgery, Dena Hospital, Sattar Khan Street, Shiraz, Iran.
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ABSTRACT
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This study investigates the role of oral sildenafil 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 sildenafil (0.3 mg·kg–1, every 3 hours) was administered for a period of 24–48 hours (sildenafil group). These patients were compared to a group of 22 children with similar pathologies who did not receive sildenafil (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 significantly lower in the sildenafil group ( p = 0.001 and 0.001 respectively). Pulmonary hypertensive crisis was detected in 4 patients in the control group, but none in the sildenafil group ( p = 0.02). There was no significant rise in PA pressure following discontinuation of the drug (26.30 ± 6.66 vs 28.49 ± 10.93 mm Hg, p = 0.366). No significant complications were noticed regarding sildenafil use. Low doses of oral sildenafil 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.
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INTRODUCTION
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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 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.3,5–8 This study was performed to investigate the effect of oral sildenafil (as monotherapy) in controlling postoperative PH, following congenital cardiac surgery.
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PATIENTS AND METHODS
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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 flow 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 first group (sildenafil group) consisted of 20 patients aged 1 to 16 years who received sildenafil (Viagra, Pfizer laboratory, NY, USA) after the operation. Sildenafil was given to these patients through nasogastric tube or via the oral route every three hours with a dose of 0.3 mg·kg–1. It was initiated at the commencement of cardiopulmonary bypass and continued for 24–48 hours after surgery. The second group (control group) consisted of 22 patients aged 1–14 years who did not receive sildenafil. 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 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 2–3 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 significant.
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RESULTS
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The mean age in the sildenafil group was 5.25 ± 4.70 years, and 3.97 ± 3.20 years in the control group ( p = 0.308). Fourteen patients in the sildenafil group and 10 patients in the control group were male. The mean weight in the sildenafil group was 14.33 ± 6.86 kg (range: 6.70–27 kg) versus 12.88 ± 5.40 kg (range 5–25 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 sildenafil 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 cases, PDA, in one case ASD, and in two cases SAW was seen other than VSD. Table 3 demonstrates no statistically significant 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 sildenafil group, this ratio was significantly 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 significantly lower in the sildenafil group ( p = 0.047, 0.001, 0.001 respectively). Figures 1–3 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 sildenafil 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).
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Figure 1. Comparison of systolic PA pressure between the sildenafil group and the control group during first 24 hours after surgery.
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Figure 2. Comparison of diastolic PA pressure between the sildenafil group and the control group during first 24 hours after surgery.
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Figure 3. Comparison of mean PA pressure between the sildenafil group and the control group during first 24 hours after surgery.
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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 sildenafil group ( p = 0.02). No significant systemic hypotension was detected in the sildenafil group. The only complications related to sildenafil were short lived erections in 3 males, transient nasal stuffiness 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 sildenafil group, and hemothorax (1), pneumonia (1), gastric hemorrhage (1), and aborted cardiac arrest accompanied with pulmonary hypertensive crisis (2) in the control group.
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DISCUSSION
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Currently, inhaled NO is the gold standard treatment for residual pulmonary hypertension after congenital cardiac surgery. However, there are some limitations, namely 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, sildenafil was added to iNO,1,3,6–9 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 sildenafil by increasing intracellular and circulating cGMP prevents rapid depletion of cGMP when iNO is withdrawn, and potentiates the pulmonary vasodilatory effect of the agent.1,3–4 Atz and Wessel in 1999 confirmed the doubling of circulating cGMP in 2 of 3 cases following administration of oral sildenafil.3 The efficacy of sildenafil in the treatment of primary pulmonary hypertension has also been shown in several studies.8,10–12 Schulze-Neick et al showed that intravenous sildenafil was a selective pulmonary vasodilator and as effective as iNO.4 Experience with oral sildenafil in postoperative PH is limited to some case reports with difficulty in weaning or suboptimal efficacy of iNO. In all of these studies, sildenafil was added to iNO or other pulmonary vasodilators.1,3,6–9,13 In our study, although a low dose of oral sildenafil 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 efficacy, safety, and optimal dosing of sildenafil in children.
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ACKNOWLEDGMENTS
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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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REFERENCES
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- Atz AM, Lefler 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;124:628–9.[Free Full Text]
- 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; 95:171–6.[Medline]
- Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91:307–10.[Medline]
- Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003;108 Suppl I:II167–73.
- Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003;88:827–8.[Abstract/Free Full Text]
- Garcia Martinez E, Ibarra de la Rosa I, Perez Navero JL, Tejero Mateo I, Exposito Montes JF, Suarez de Lezo, et al. Sildenafil in the treatment of pulmonary hypertension. An Pediatr (Barc) 2003;59:110–3.
- Laquay N, Levy ML, Vaccaroni L, Mauriat P, Carli P. Use of oral sildenafil (Viagra) in pulmonary hypertension after cardiac pediatric surgery. Ann Fr Anesth Reanim 2003;22:140–3.[Medline]
- Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002; 54:404–9.[Medline]
- Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, et al. Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 2005;79:194–7.[Abstract/Free Full Text]
- Fraisse A, Habib G. Treatment of pulmonary arterial hypertension in children. Arch Pediatr 2004; 11:945–50.[Medline]
- Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84:E4.[Medline]
- Laupland KB, Helmersen D, Zygun DA, Viner SM. Sildenafil treatment of primary pulmonary hypertension. Can Respir J 2003; 10:48–50.[Medline]
- Bentlin MR, Saito A, De Luca AK, Bossolan G, Bonatto RC, Martins AS, Rugolo LM. Sildenafil for pulmonary hypertension treatment after cardiac surgery. J Pediatr (Rio J) 2005; 81:175–8.
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ABSTRACT
INTRODUCTION
