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Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

  • Christoph P. Hornik (a1), Nikolas J. Onufrak (a2), P. Brian Smith (a1), Michael Cohen-Wolkowiez (a1), Matthew M. Laughon (a3), Reese H. Clark (a4) and Daniel Gonzalez (a2)...



The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.


The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.


We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model.


We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL.


We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted.


Corresponding author

Correspondence to: C. P. Hornik, MD, MPH, Duke Clinical Research Institute, Box 17969, Durham, NC 27715, United States of America. Tel: 919 668 8935; Fax: 919 668 7058; E-mail:


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1. Steinhorn, RH. Pharmacotherapy for pulmonary hypertension. Pediatr Clin North Am 2012; 59: 11291146.
2. Porta, NF, Steinhorn, RH. Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 2012; 39: 149164.
3. Buxton, N, Flannery, T, Wild, D, Bassi, S. Sildenafil (Viagra)-induced spontaneous intracerebral haemorrhage. Br J Neurosurg 2001; 15: 347349.
4. Samada, K, Shiraishi, H, Aoyagi, J, Momoi, MY. Cerebral hemorrhage associated with sildenafil (Revatio) in an infant. Pediatr Cardiol 2009; 30: 998999.
5. Baquero, H, Soliz, A, Neira, F, Venegas, ME, Sola, A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatr 2006; 117: 10771083.
6. Steinhorn, RH. Diagnosis and treatment of pulmonary hypertension in infancy. Early Hum Dev 2013; 89: 865874.
7. Steinhorn, RH, Kinsella, JP, Pierce, C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155: 841847 e1.
8. Mourani, PM, Sontag, MK, Ivy, DD, Abman, SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr 2009; 154: 379384. e1-2.
9. Limjoco, J, Paquette, L, Ramanathan, R, Seri, I, Friedlich, P. Changes in mean arterial blood pressure during sildenafil use in neonates with meconium aspiration syndrome or sepsis. Am J Ther 2015; 22: 125131.
10. Vassalos, A, Peng, E, Young, D, et al. Pre-operative sildenafil and pulmonary endothelial-related complications following cardiopulmonary bypass: a randomised trial in children undergoing cardiac surgery. Anaesthes 2011; 66: 472480.
11. Ahsman, MJ, Witjes, BC, Wildschut, ED, et al. Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed 2010; 95: F109F114.
12. Mukherjee, A, Dombi, T, Wittke, B, Lalonde, R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther 2009; 85: 5663.
13. Laughon, MM, Benjamin, DK Jr, Capparelli, EV, et al. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol 2011; 4: 643652.
14. Laughon, MM, Benjamin, DK Jr. Mechanisms to provide safe and effective drugs for children. Pediatr 2014; 134: e562e563.
15. Spitzer, AR, Ellsbury, DL, Handler, D, Clark, RH. The Pediatrix BabySteps Data Warehouse and the Pediatrix QualitySteps improvement project system – tools for “meaningful use” in continuous quality improvement. Clin Perinatol 2010; 37: 4970.
16. Olsen, IE, Groveman, SA, Lawson, ML, Clark, RH, Zemel, BS. New intrauterine growth curves based on United States data. Pediatr 2010; 125: e214e224.
17. Samiee-Zafarghandy, S, Smith, PB, van den Anker, JN. Safety of sildenafil in infants. Pediatr Crit Care Med 2014; 15: 362368.
18. McLaughlin, VV, McGoon, MD. Pulmonary arterial hypertension. Circulation 2006; 114: 14171431.
19. Galie, N, Ghofrani, HA, Torbicki, A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 21482157.
20. Shekerdemian, LS, Ravn, HB, Penny, DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res 2004; 55: 413418.
21. Farrow, KN, Groh, BS, Schumacker, PT, et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 2008; 102: 226233.
22. Vargas-Origel, A, Gomez-Rodriguez, G, Aldana-Valenzuela, C, et al. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27: 225230.
23. Kearns, GL. Selecting the proper pediatric dose: it is more than size that matters. Clin Pharmacol Ther 2015; 98: 238240.
24. Holford, N. Dosing in children. Clin Pharmacol Ther 2010; 87: 367370.
25. Thakkar, N, Gonzalez, D, Cohen-Wolkowiez, M, et al. An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants. J Perinatol 2016; 36: 744747.
26. Barst, RJ, Beghetti, M, Pulido, T, et al. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129: 19141923.
27. Barst, RJ, Ivy, DD, Gaitan, G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation, 125: 324334.
28. US Food and Drug Administration. Revatio (sildenafil): Drug Safety Communication-Recommendation against use in children. Retrieved April 20, 2016, from
29. US Food and Drug Administration. Medical, statistical, and clinical pharmacology reviews of pediatric studies conducted under Section 505A and 505B of the Federal Food, Drug, and Cosmetic Act, as amended by the FDA Amendments Act of 2012 (FDASIA). Retrieved May 3, 2016, from
30. Dodgen, AL, Hill, KD. Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension. Drug Healthc Patient Saf 2015; 7: 175183.
31. Kraemer, U, Wildschuth, E, Tibboel, D. “Out of the blue”-safety and efficacy of pulmonary hypertension treatment in childhood. Pediatr Crit Care Med 2014; 15: 377378.
32. England, A, Wade, K, Smith, PB, Berezny, K, Laughon, M. Optimizing operational efficiencies in early phase trials: the Pediatric Trials Network experience. Contemp Clin Trials 2016; 47: 376382.


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