Download PDF
Am J Perinatol 2019; 36(03): 262-267
DOI: 10.1055/s-0038-1667378
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Sildenafil Exposure in the Neonatal Intensive Care Unit

Elizabeth J. Thompson
1   Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
,
Krystle Perez
2   Department of Pediatrics, University of Washington, Seattle, Washington
,
Christoph P. Hornik
3   Department of Pediatrics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
,
P. Brian Smith
3   Department of Pediatrics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
,
Reese H. Clark
4   Pediatrix-Obstetrix Center for Research and Education, Sunrise, Florida
,
Matthew Laughon
2   Department of Pediatrics, University of Washington, Seattle, Washington
5   Division of Neonatal-Perinatal Medicine, UNC Hospital, Chapel Hill, North Carolina
,
on behalf of the Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee › Author Affiliations Funding This work was funded under the National Institute of Child Health and Human Development contract HHSN2752010000031 for the Pediatric Trials Network. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Hornik receives salary support for research from the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001117). Dr. Smith receives salary support for research from the National Institutes of Health and the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001117), the National Institute of Child Health and Human Development (HHSN275201000003I and 1R01-HD081044–01), and the Food and Drug Administration (1R18-FD005292–01); he also receives research support from Cempra Pharmaceuticals (subaward to HHS0100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Laughon receives support from the U.S. government for his work in pediatric and neonatal clinical pharmacology (NHLBI R34 HL124038, PI: Laughon and Government Contract HHSN267200700051C, PI: Benjamin under the Best Pharmaceuticals for Children Act) and from the National Institute of Child Health and Human Development (K23HD068497). The other authors have nothing to disclose.
Further Information

Publication History

02 May 2018

02 July 2018

Publication Date:
06 August 2018 (online)

    Permissions and Reprints

Abstract

Objective Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants.

Study Design Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016.

Results Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge.

Conclusion The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.

Keywords

premature infant - sildenafil - pulmonary hypertension - bronchopulmonary dysplasia - neonate
 

  • References

  • 1 Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed 2012; 97 (03) F223-F228
    CrossrefPubMedGoogle Scholar
  • 2 Iacovidou N, Syggelou A, Fanos V, Xanthos T. The use of sildenafil in the treatment of persistent pulmonary hypertension of the newborn: a review of the literature. Curr Pharm Des 2012; 18 (21) 3034-3045
    CrossrefPubMedGoogle Scholar
  • 3 Porta NF, Steinhorn RH. Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 2012; 39 (01) 149-164
    CrossrefPubMedGoogle Scholar
  • 4 Khemani E, McElhinney DB, Rhein L. , et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007; 120 (06) 1260-1269
    CrossrefPubMedGoogle Scholar
  • 5 Trembath A, Laughon MM. Predictors of bronchopulmonary dysplasia. Clin Perinatol 2012; 39 (03) 585-601
    CrossrefPubMedGoogle Scholar
  • 6 König K, Barfield CP, Guy KJ, Drew SM, Andersen CC. The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. J Matern Fetal Neonatal Med 2014; 27 (05) 439-444
    CrossrefPubMedGoogle Scholar
  • 7 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. Pediatrics 2006; 117 (04) 1077-1083
    CrossrefPubMedGoogle Scholar
  • 8 Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2011; 2011 (08) CD005494
    PubMedGoogle Scholar
  • 9 Jain A, McNamara PJ. Persistent pulmonary hypertension of the newborn: Advances in diagnosis and treatment. Semin Fetal Neonatal Med 2015; 20 (04) 262-271
    CrossrefPubMedGoogle Scholar
  • 10 Goodman G, Perkin RM, Anas NG, Sperling DR, Hicks DA, Rowen M. Pulmonary hypertension in infants with bronchopulmonary dysplasia. J Pediatr 1988; 112 (01) 67-72
    CrossrefPubMedGoogle Scholar
  • 11 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 2012; 125 (02) 324-334
    CrossrefPubMedGoogle Scholar
  • 12 Galiè N, Ghofrani HA, Torbicki A. , et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
    CrossrefPubMedGoogle Scholar
  • 13 Steinhorn RH, Kinsella JP, Pierce C. , et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155 (06) 841-847
    CrossrefPubMedGoogle Scholar
  • 14 Nyp M, Sandritter T, Poppinga N, Simon C, Truog WE. Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?. J Perinatol 2012; 32 (01) 64-69
    CrossrefPubMedGoogle Scholar
  • 15 Al Omar S, Salama H, Al Hail M. , et al. Effect of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. A feasibility study. J Neonatal Perinatal Med 2016; 9 (03) 251-259
    PubMedGoogle Scholar
  • 16 Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2017; 8: CD005494
    Google Scholar
  • 17 Perez KM, Laughon M. Sildenafil in term and premature infants: a systematic review. Clin Ther 2015; 37 (11) 2598-2607
    CrossrefPubMedGoogle Scholar
  • 18 Hilgendorff A, Apitz C, Bonnet D, Hansmann G. Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart 2016; 102 (Suppl. 02) ii49-ii56
    CrossrefPubMedGoogle Scholar
  • 19 Tan K, Krishnamurthy MB, O'Heney JL, Paul E, Sehgal A. Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety. Eur J Pediatr 2015; 174 (08) 1109-1115
    CrossrefPubMedGoogle Scholar
  • 20 Trottier-Boucher MN, Lapointe A, Malo J. , et al. Sildenafil for the treatment of pulmonary arterial hypertension in infants with bronchopulmonary dysplasia. Pediatr Cardiol 2015; 36 (06) 1255-1260
    CrossrefPubMedGoogle Scholar
  • 21 Samiee-Zafarghandy S, Smith PB, van den Anker JN. Safety of sildenafil in infants*. Pediatr Crit Care Med 2014; 15 (04) 362-368
    CrossrefPubMedGoogle Scholar
  • 22 Wardle AJ, Wardle R, Luyt K, Tulloh R. The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. Arch Dis Child 2013; 98 (08) 613-617
    CrossrefPubMedGoogle Scholar
  • 23 Vargas-Origel A, Gómez-Rodríguez G, Aldana-Valenzuela C, Vela-Huerta MM, Alarcón-Santos SB, Amador-Licona N. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol 2010; 27 (03) 225-230
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Caputo S, Furcolo G, Rabuano R. , et al. Severe pulmonary arterial hypertension in a very premature baby with bronchopulmonary dysplasia: normalization with long-term sildenafil. J Cardiovasc Med (Hagerstown) 2010; 11 (09) 704-706
    CrossrefPubMedGoogle Scholar
  • 25 Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003; 88 (09) 827-828
    CrossrefPubMedGoogle Scholar
  • 26 Hon KL, Cheung KL, Siu KL. , et al. Oral sildenafil for treatment of severe pulmonary hypertension in an infant. Biol Neonate 2005; 88 (02) 109-112
    CrossrefPubMedGoogle Scholar
  • 27 Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005; 111 (24) 3274-3280
    CrossrefPubMedGoogle Scholar
  • 28 Karatza AA, Bush A, Magee AG. Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005; 100 (02) 267-273
    CrossrefPubMedGoogle Scholar
  • 29 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 (03) 379-384
    CrossrefPubMedGoogle Scholar
  • 30 Balasubramanian H, Strunk T, Kohan R. Arterial hypotension and prerenal failure in an extremely preterm infant associated with oral sildenafil. J Perinatol 2015; 35 (06) 458-459
    CrossrefPubMedGoogle Scholar
  • 31 Fang AY, Guy KJ, König K. The effect of sildenafil on retinopathy of prematurity in very preterm infants. J Perinatol 2013; 33 (03) 218-221
    CrossrefPubMedGoogle Scholar
  • 32 Leibovitch L, Matok I, Paret G. Therapeutic applications of sildenafil citrate in the management of paediatric pulmonary hypertension. Drugs 2007; 67 (01) 57-73
    CrossrefPubMedGoogle Scholar
  • 33 Marsh CS, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Br J Ophthalmol 2004; 88 (02) 306-307
    CrossrefPubMedGoogle Scholar
  • 34 Pierce CM, Petros AJ, Fielder AR. No evidence for severe retinopathy of prematurity following sildenafil. Br J Ophthalmol 2005; 89 (02) 250
    PubMedGoogle Scholar
  • 35 Kehat R, Bonsall DJ, North R, Connors B. Ocular findings of oral sildenafil use in term and near-term neonates. J AAPOS 2010; 14 (02) 159-162
    CrossrefPubMedGoogle Scholar
  • 36 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 (03) 413-418
    CrossrefPubMedGoogle Scholar
  • 37 Kahveci H, Yilmaz O, Avsar UZ. , et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatr Pulmonol 2014; 49 (12) 1205-1213
    Google Scholar
  • 38 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 (02) 125-131
    CrossrefPubMedGoogle Scholar
  • 39 Samiee-Zafarghandy S, van den Anker JN, Laughon MM, Clark RH, Smith PB, Hornik CP. ; Pharmaceuticals for Children Act – Pediatric Trials Network Administrative Core Committee. Sildenafil and retinopathy of prematurity risk in very low birth weight infants. J Perinatol 2016; 36 (02) 137-140
    CrossrefPubMedGoogle Scholar
  • 40 Trembath A, Hornik CP, Clark R, Smith PB, Daniels J, Laughon M. ; Best Pharmaceuticals for Children Act—Pediatric Trials Network. Comparative effectiveness of surfactant preparations in premature infants. J Pediatr 2013; 163 (04) 955-960
    CrossrefPubMedGoogle Scholar
  • 41 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 (07) 1723-1729
    Google Scholar
  • 42 FDA Drug Safety Communication. FDA recommends against the use of Revatio (sildenafil) in children with pulmonary hypertension. August 30, 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm . Accessed October 10, 2014
    PubMedGoogle Scholar
  • 43 Barst RJ, Beghetti M, Pulido T. , et al; STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129 (19) 1914-1923
    CrossrefPubMedGoogle Scholar
  • 44 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 (02) 226-233
    CrossrefPubMedGoogle Scholar