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Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart diseaseOpen access

Alain Fraisse| Ghazwan Butrous| Mary B. Taylor| Michael Oakes| Maria Dilleen| David L. Wessel
Original
Volume 37, Issue 3 / March , 2011

Pages 502 - 509

Abstract

Purpose

To evaluate the efficacy and safety of intravenous sildenafil for immediate postoperative pulmonary hypertension (PH) in pediatric patients undergoing congenital heart surgery.

Methods

A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group trial was conducted. Patients were randomized to one of three doses of intravenous sildenafil, or placebo, for a minimum of 24 h.

Results

The study was heavily underpowered. Whereas enrollment of 228 patients (57 per treatment arm) was required to achieve the sample size estimate to detect difference between arms, the sponsor terminated the study after 15 months owing to slow patient accrual. Seventeen patients (median age 5 months) experiencing postoperative PH were randomized and treated, five with placebo and four each with low-, medium-, and high-dose sildenafil. In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy (p = 0.330). Median time to extubation (3 versus 8 days, p = 0.023) and intensive care unit stay (6 versus 15 days, p = 0.008) were shorter for sildenafil patients. Mean ± standard deviation systolic pulmonary artery pressure was reduced with sildenafil (46 ± 11 to 35 ± 6 mmHg, p = 0.027 versus placebo). No adverse events or systemic hypotension were attributed to sildenafil.

Conclusion

Intravenous sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative PH.

Keywords

References

  1. Wessel DL (2006) Postoperative treatment of pulmonary hypertension. In: Beghetti M, Barst RJ, Naeije R, Rubin LJ (eds) Pulmonary arterial hypertension related to congenital heart disease. Munich, Elsevier, Urban & Fischer, pp 143–176
  2. Hopkins RA, Bull C, Haworth SG, de Leval MR, Stark J (1991) Pulmonary hypertensive crises following surgery for congenital heart defects in young children. Eur J Cardiothorac Surg 5:628–634
    • View reference on publisher's website
    • View reference on PubMed
  3. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ (1993) Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation 88:2128–2138
    • View reference on PubMed
  4. Wessel DL (2001) Current and future strategies in the treatment of childhood pulmonary hypertension. Prog Pediatr Cardiol 12:289–318
    • View reference on publisher's website
  5. Barnett CF, Machado RF (2006) Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag 2:411–422
    • View reference on publisher's website
    • View reference on PubMed
  6. Atz AM, Adatia I, Wessel DL (1996) Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg 62:1759–1764
    • View reference on publisher's website
    • View reference on PubMed
  7. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM (1998) Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 159:2164–2171
    • View reference on publisher's website
    • View reference on PubMed
  8. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD (1998) Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr Res 43:163–168
    • View reference on publisher's website
    • View reference on PubMed
  9. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157
    • View reference on publisher's website
    • View reference on PubMed
  10. Atz AM, Lefler AK, Fairbrother DL, Uber WE, Bradley SM (2002) Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. J Thorac Cardiovasc Surg 124:628–629
    • View reference on publisher's website
    • View reference on PubMed
  11. Atz AM, Wessel DL (1999) Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 91:307–310
    • View reference on publisher's website
    • View reference on PubMed
  12. Nichols DJ, Muirhead GJ, Harness JA (2002) Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 53:5S–12S
    • View reference on publisher's website
    • View reference on PubMed
  13. Lammers AE, Haworth SG, Pierce CM (2006) Intravenous sildenafil as an effective treatment of pulmonary hypertensive crises during acute intestinal malabsorption. Cardiol Young 16:84–86
    • View reference on publisher's website
    • View reference on PubMed
  14. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, Butrous G, Petros A, Lange P, Redington AN (2003) Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 108:II167–II173
    • View reference on publisher's website
    • View reference on PubMed
  15. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS (2003) Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med 29:1996–2003
  16. Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wessel DL (1995) Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 92:2226–2235
    • View reference on PubMed
  17. Mukherjee A, Dombi T, Wittke B, Lalonde R (2009) Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther 85:56–63
    • View reference on publisher's website
    • View reference on PubMed
  18. Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, Wessel DL (2009) Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 155:841–847 (e841)
    • View reference on publisher's website
  19. Lindberg L, Olsson AK, Jogi P, Jonmarker C (2002) How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 123:1155–1163
    • View reference on publisher's website
    • View reference on PubMed
  20. Bando K, Turrentine MW, Sharp TG, Sekine Y, Aufiero TX, Sun K, Sekine E, Brown JW (1996) Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg 112:1600–1607; discussion 1607–1609
    • View reference on publisher's website
    • View reference on PubMed
  21. Ma M, Gauvreau K, Allan CK, Mayer JE, Jenkins KJ (2007) Causes of death after congenital heart surgery. Ann Thorac Surg 83:1438–1445
    • View reference on publisher's website
    • View reference on PubMed
  22. Nagdyman N, Fleck T, Bitterling B, Ewert P, Abdul-Khaliq H, Stiller B, Hubler M, Lange PE, Berger F, Schulze-Neick I (2006) Influence of intravenous sildenafil on cerebral oxygenation measured by near-infrared spectroscopy in infants after cardiac surgery. Pediatr Res 59:462–465
    • View reference on publisher's website
    • View reference on PubMed

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