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Anesthesiology:
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Sildenafil for Pulmonary Hypertension in Pregnancy?

Lynch, Tadhg D. M.B., B.Ch., B.A.O.*; Laffey, John G. M.D.

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To the Editor:—

We read with interest the comprehensive series presented by Bonnin et al.1 Their report of the treatment of severe pulmonary hypertension (PHTN) during pregnancy in their institution from 1992 to 2002 is a timely reminder of the high maternal and fetal mortality from this condition. We would like to draw the readers’ attention to the emerging role of phosphodiesterase inhibitors (PDEs), such as sildenafil, in the treatment of PHTN. Clinical trials have demonstrated that oral sildenafil is effective in the treatment of both acute and chronic PHTN2–4 of a variety of etiologies.5,6 In addition, several recent reports exist of its successful use in pregnant patients with this devastating disease process.7,8
Phosphodiesterase inhibition has been demonstrated to treat PHTN by reducing cyclic guanosine monophosphate breakdown, making pulmonary vascular smooth muscle more sensitive to endogenous and administered nitric oxide.9 This reduces ventilation perfusion mismatch and hypoxia.3,10 Of the PDE5 inhibitors studied, sildenafil has the greatest selectivity for the pulmonary circulation and arterial oxygenation.11 The use of PDE inhibitors seems safe in both ischemic heart disease12 and heart failure.13 The effect of PDEs on pulmonary vasculature and pulmonary artery pressure has been studied in comparison to and in combination with inhaled iloprost and inhaled nitric oxide,14–16 and it augments their vasodilatory effects.17,18 In fact, sildenafil is at least as effective as inhaled nitric oxide in relaxing the pulmonary vasculature and may have fewer side effects.19 Coadministration of sildenafil with nitric oxide also leads to less rebound PHTN, a major problem with nitric oxide administration, caused by down-regulation of nitric oxide synthetase.15
Sildenafil has other potentially beneficial effects in this context. It causes uterine artery vasodilation and has been shown to improve uterine muscle wall thickness in in vitro fertilization patients with previous poor endometrial response.20 In addition, sildenafil and nitric oxide are being used successfully to treat preterm and term neonatal and childhood PHTN.21,22
The therapeutic potential of sildenafil in the treatment of PHTN during pregnancy awaits definitive demonstration in the form of a clinical trial. However, its proven effectiveness and safety in other forms of pulmonary hypertension, coupled with ease of oral administration and its apparent lack of teratogenicity, mean that it is a highly promising therapy for severe pulmonary hypertension in pregnant patients.
Tadhg D. Lynch, M.B., B.Ch., B.A.O.,*
John G. Laffey, M.D.
*University College Hospital Galway, Galway, Ireland. tadhglynch@hotmail.com
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References

1. Bonnin M, Mercier FJ, Sitbon O, Roger-Christoph S, Jais X, Humbert M, Audibert F, Frydman R, Simonneau G, Benhamou D: Severe pulmonary hypertension during pregnancy: Mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 2005; 102:1133–7

2. Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW, Hill NS: Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med 2005; 99:1501–10

3. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F: Sildenafil for treatment of lung fibrosis and pulmonary hypertension: A randomised controlled trial. Lancet 2002; 21:360:895–900

4. Sastry BK, Narasimhan C, Reddy NK, Raju BS: Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43:1149–53

5. Richalet JP, Gratadour P, Robach P, Pham I, Dechaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J: Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005; 171:275–81

6. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR: Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104:424–8

7. Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K: Eisenmenger’s syndrome in a 27 week pregnancy-management with bosentan and sildenafil. Ir Med J 2005; 98:87–8

8. Lacassie HJ, Germain AM, Valdes G, Fernandes MS, Allamand F, Lopez H: Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol 2004; 103:1118–20

9. Zhao L, Mason NA, Morrell NM, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR: Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104:424–8

10. Dishy V, Sofowora G, Harris PA, Kandcer M, Zhan F, Wood AJ, Stein CM: The effect of sildenafil on nitric oxide mediated-vasodilation in healthy men. Clin Pharmacol Ther 2001; 70:270–9

11. Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissmann N, Seeger W, Grimminger F: Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study. J Am Coll Cardiol 2004; 44:1488–96

12. Bush HS: Safe use of sildenafil in patients with coronary artery disease. Cleveland Clin J Med 2001; 68:349–52

13. Shakar SF, Bristow MR: Low level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic heart failure receiving beta-blocking agents. Curr Cardiol Rep 2001; 3:224–31

14. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW: Effect of inhaled iloprost plus oral sildenafil in patients in patients with primary pulmonary hypertension. Circulation 2001; 104:1218–22

15. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F: Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136:515–22

16. Michelakis E, Tymchak W, Lein 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

17. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, Semigran MJ: Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: Combined administration with inhaled nitric oxide. Chest 2005; 127:1647–53

18. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Weissmann N, Schudt C, Tenor H, Seeger W, Grimminger F: Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase type 3 and 4 inhibition in severe pulmonary hypertension. Crit Care Med 2002; 30:2489–92

19. Mychaskiw G, Sachdev V, Heath BJ: Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth 2001; 13:218–20

20. Sher G, Fisch JD: Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril 2002; 78:1073–6

21. Karatza AA, Bush A, Magee AG: Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005; 100:267–73

22. Travadi JN, Patole SK: Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: A review. Pediatr Pulmonol 2003; 36:529–35

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