Skip to main content
SpringerLink
Log in

Administration of Inhaled Pulmonary Vasodilators to the Mechanically Ventilated Neonatal Patient

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Pulmonary hypertension is a life-threatening condition that affects people of all ages that can occur as an idiopathic disorder at birth or as part of a variety of cardiovascular and infectious disorders. It is commonly treated with inhaled pulmonary vasodilators such as nitric oxide and less frequently using formulations and analogs of prostacyclin. To minimize systemic effects and preserve pulmonary vasodilation, vasodilators are often administered directly into the airway. Nitric oxide is the only USA Food and Drug Administration-approved inhaled pulmonary vasodilator that can be used during mechanical ventilation. Over the past two decades, interest has grown in the use of aerosolized prostacyclin and prostacyclin analogs for the treatment of pulmonary hypertension during mechanical ventilation. Clinicians who administer inhaled prostacyclin may not have a clear understanding of its risks because of the lack of data from large clinical trials examining safety and efficacy; moreover, its safe use remains poorly documented. The off-label use of drugs is legitimate, but prescribers must recognize the potential complications and liability in doing so. This manuscript aims to address potential problems related to the aerosol administration of pulmonary vasodilators in the mechanically ventilated neonatal patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

(Drawn by David White, with permission)

Fig. 2

(Drawn by David White, with permission)

Similar content being viewed by others

References

  1. Hill NS, Farber HW. Pulmonary hypertension. Totowa: Springer; 2008.

    Book  Google Scholar 

  2. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105:14–20.

    Article  CAS  PubMed  Google Scholar 

  3. INOmax®. Nitric oxide gas. 2015. http://inomax.com/wp-content/uploads/2016/02/INOmax-PI-web-2015-10.pdf. Accessed 30 Mar 2016.

  4. American Academy of Pediatrics Committee on Drugs. Unapproved uses of approved drugs: the physician, the package insert, and the Food and Drug Administration: subject review. Pediatrics 1996;98:143–5.

  5. Off-label use of drugs in children. Pediatrics. 2014;133(3):563–7.

    Article  Google Scholar 

  6. Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database Syst Rev. 2010:CD005089.

  7. Rabinovitch M. Morphology of the developing pulmonary bed: pharmacologic implications. Pediatr Pharmacol (New York). 1985;5:31–48.

    CAS  Google Scholar 

  8. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr. 1978;92:805–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kitagawa M, Hislop A, Boyden EA, Reid L. Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery, and alveolar development. Br J Surg. 1971;58:342–6.

    Article  CAS  PubMed  Google Scholar 

  10. Naeye RL, Shochat SJ, Whitman V, Maisels MJ. Unsuspected pulmonary vascular abnormalities associated with diaphragmatic hernia. Pediatrics. 1976;58:902–6.

    CAS  PubMed  Google Scholar 

  11. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S–24S.

    Article  CAS  PubMed  Google Scholar 

  12. Philips JB 3rd, Lyrene RK, Godoy G, Graybar G, Barefield E, Sams JE, et al. Hemodynamic responses of chronically instrumented piglets to bolus injections of group B streptococci. Pediatr Res. 1988;23:81–5.

    Article  PubMed  Google Scholar 

  13. Shankaran S, Farooki ZQ, Desai R. beta-hemolytic streptococcal infection appearing as persistent fetal circulation. Am J Dis Child. 1982;136:725–7.

    CAS  PubMed  Google Scholar 

  14. Gersony WM, Duc GV, Sinclair JC. “PFC” syndrome (persistence of the fetal circulation). Circulation 1969;40:Suppl III-87.

  15. Grover RF, Reeves JT, Blount SG Jr. Tolazoline hydrochloride (Priscoline): an effective pulmonary vasodilator. Am Heart J. 1961;61:5–15.

    Article  CAS  PubMed  Google Scholar 

  16. Ward RM. Pharmacology of tolazoline. Clin Perinatol. 1984;11:703–13.

    CAS  PubMed  Google Scholar 

  17. Goetzman BW, Sunshine P, Johnson JD, Wennberg RP, Hackel A, Merten DF, et al. Neonatal hypoxia and pulmonary vasospasm: response to tolazoline. J Pediatr. 1976;89:617–21.

    Article  CAS  PubMed  Google Scholar 

  18. Stevens DC, Schreiner RL, Bull MJ, Bryson CQ, Lemons JA, Gresham EL, et al. An analysis of tolazoline therapy in the critically-ill neonate. J Pediatric Surg. 1980;15:964–70.

    Article  CAS  Google Scholar 

  19. Stevenson DK, Kasting DS, Darnall RA Jr, Ariagno RL, Johnson JD, Malachowski N, et al. Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr. 1979;95:595–9.

    Article  CAS  PubMed  Google Scholar 

  20. Ward RM, Daniel CH, Kendig JW. Oliguria and tolazoline pharmacokinetics in the newborn. Pediatrics. 1986;77:307–15.

    CAS  PubMed  Google Scholar 

  21. Andrews AF, Roloff DW, Bartlett RH. Use of extracorporeal membrane oxygenators in persistent pulmonary hypertension of the newborn. Clin Perinatol. 1984;11:729–35.

    CAS  PubMed  Google Scholar 

  22. Beck R, Anderson KD, Pearson GD, Cronin J, Miller MK, Short BL. Criteria for extracorporeal membrane oxygenation in a population of infants with persistent pulmonary hypertension of the newborn. J Pediatric Surg. 1986;21:297–302.

    Article  CAS  Google Scholar 

  23. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA. 1987;84:9265–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987;61:866–79.

    Article  CAS  PubMed  Google Scholar 

  25. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–6.

    Article  CAS  PubMed  Google Scholar 

  26. Kinsella JP, Abman SH. Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr. 1995;126:853–64.

    Article  CAS  PubMed  Google Scholar 

  27. Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep. 2008;60:3–11.

    CAS  PubMed  Google Scholar 

  28. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663–5.

    Article  CAS  PubMed  Google Scholar 

  29. Van Heerden PV, Webb SA, Hee G, Corkeron M, Thompson WR. Inhaled aerosolized prostacyclin as a selective pulmonary vasodilator for the treatment of severe hypoxaemia. Anaesth Intensive Care. 1996;24:87–90.

    PubMed  Google Scholar 

  30. Davis MD, Hunt J. Exhaled breath condensate pH assays. Immunol Allergy Clin N Am. 2012;32:377–86.

    Article  Google Scholar 

  31. United States Food and Drug Administration Center for Drug Evaluation and Research Approval Package for Iloprost. Submission Number 21779. 2004.

  32. United States Food and Drug Administration Center for Drug Evaluation and Research Approval Package for Treprostinil. Submission Number 22387. 2009.

  33. Actelion. Ventavis prescribing information. South San Francisco: Actelion; 2013

  34. United Therapeutics Corp. Tyvaso prescribing information. Research Triangle Park: United Therapeutics Corp; 2016.

    Google Scholar 

  35. Horen B, Montastruc JL, Lapeye-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002;54(6):665–70.

    Article  PubMed  PubMed Central  Google Scholar 

  36. GSK. Flolan prescribing information. Research Triangle Park: GSK; 2008.

  37. Yilmiz O, Kahyeci Zeybek C, et al. Inhaled iloprost in preterm infants with severe respiratory distress syndrome and pulmonary hypertension. Am J Perinatol. 2014;31:321–6.

    Article  Google Scholar 

  38. Tissot C, Beghetti M. Review of inhaled iloprost for the control of pulmonary artery hypertension in children. Vasc Health Risk Manag. 2009;5:325–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Brown A, Gillespie J, Miquel-Vergas F, et al. Inhaled epoprostenol therapy for pulmonary hypertension: Improves oxygenation index more consistently in neonates than in older children. Pulmon Circ. 2012;2:61–6.

    Article  Google Scholar 

  40. Cosa N, Costa E. Inhaled pulmonary vasodilators for persistent pulmonary hypertension of the newborn: safety issues relating to drug administration and delivery devices. Med Dev Evid Res. 2016;9:45–51.

    Article  Google Scholar 

  41. Institute for Safe Medication Practices (IMSP). ISMP list of high-alert medications in acute care settings. 2014. https://www.ismp.org/tools/institutionalhighAlert.asp. Accessed 30 Mar 2016.

  42. Kingman MS, Tankersley MA, Lombardi S, Spence S, Torres F, Chin KS, et al. Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey. J Heart Lung Transplant. 2010;29:841–6.

    Article  PubMed  Google Scholar 

  43. Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. Ann Pharmacother. 2013;47:790–6.

    Article  PubMed  Google Scholar 

  44. Siobal MS, Kallet RH, Pittet JF, Warnecke EL, Kraemer RW, Venkayya RV, et al. Description and evaluation of a delivery system for aerosolized prostacyclin. Respir Care. 2003;48:742–53.

    PubMed  Google Scholar 

  45. Actelion. Veletri prescribing information. South San Francisco: Actelion; 1995.

  46. Luk CK, Dulfano MJ. Effect of pH, viscosity and ionic-strength changes on ciliary beating frequency of human bronchial explants. Clin Sci (Lond). 1983;64:449–51.

    Article  CAS  Google Scholar 

  47. Ricciardolo FL, Gaston B, Hunt J. Acid stress in the pathology of asthma. J Allergy Clin Immunol. 2004;113:610–9.

    Article  CAS  PubMed  Google Scholar 

  48. Holma B, Lindegren M, Andersen JM. pH effects on ciliomotility and morphology of respiratory mucosa. Arch Environ Health. 1977;32:216–26.

    Article  CAS  PubMed  Google Scholar 

  49. Le Brun PP, de Boer AH, Heijerman HG, Frijlink HW. A review of the technical aspects of drug nebulization. Pharm World Sci. 2000;22:75–81.

    Article  PubMed  Google Scholar 

  50. Van Heerden PV, Blythe D, Webb SA. Inhaled aerosolized prostacyclin and nitric oxide as selective pulmonary vasodilators in ARDS—a pilot study. Anaesth Intensive Care. 1996;24:564–8.

    PubMed  Google Scholar 

  51. Berlinski A, Willis JR. Albuterol delivery by 4 different nebulizers placed in 4 different positions in a pediatric ventilator in vitro model. Respir Care. 2013;58:1124–33.

    Article  PubMed  Google Scholar 

  52. Cancado JE, Mendes ES, Arana J, Horvath G, Monzon ME, Salathe M, et al. Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol. BMC Pharmacol Toxicol. 2015;16:9.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Clary-Meinesz C, Mouroux J, Cosson J, Huitorel P, Blaive B. Influence of external pH on ciliary beat frequency in human bronchi and bronchioles. Eur Respir J. 1998;11:330–3.

    Article  CAS  PubMed  Google Scholar 

  54. Horvath G, Schmid N, Fragoso MA, Schmid A, Conner GE, Salathe M, et al. Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway. Am J Respir Cell Mol Biol. 2007;36:53–60.

    Article  CAS  PubMed  Google Scholar 

  55. Shin HW, Shelley DA, Henderson EM, Fitzpatrick A, Gaston B, George SC. Airway nitric oxide release is reduced after PBS inhalation in asthma. J Appl Physiol. 2007;102:1028–33.

    Article  CAS  PubMed  Google Scholar 

  56. Hunt JF, Fang K, Malik R, Snyder A, Malhotra N, Platts-Mills TA, et al. Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med. 2000;161:694–9.

    Article  CAS  PubMed  Google Scholar 

  57. Eichelbronner O, Reinelt H, Wiedeck H, Mezody M, Rossaint R, Georgieff M, et al. Aerosolized prostacyclin and inhaled nitric oxide in septic shock—different effects on splanchnic oxygenation? Intensive Care Med. 1996;22:880–7.

    Article  CAS  PubMed  Google Scholar 

  58. Davis MD, Walsh BK, Dwyer ST, et al. Safety of an alkalinizing buffer designed for inhaled medications in humans. Respir Care. 2013;58(7):1226–32.

    Article  PubMed  Google Scholar 

  59. Siobal M. Aerosolized prostacyclins. Respir Care. 2004;49:640–52.

    PubMed  Google Scholar 

  60. Sun FF, Taylor BM. Metabolism of prostacyclin in rat. Biochemistry. 1978;17:4096–101.

    Article  CAS  PubMed  Google Scholar 

  61. Rosenkranz B, Fischer C, Frolich JC. Prostacyclin metabolites in human plasma. Clin Pharmacol Ther. 1981;29:420–4.

    Article  CAS  PubMed  Google Scholar 

  62. Nephron Pharmaceuticals. Albuterol sulfate prescribing information. Orlando: Nephron Pharmaceuticals.

  63. Nephron Pharmaceuticals. Ipratropium bromide prescribing information. Orlando: Nephron Pharmaceuticals.

  64. AstraZeneca. Pulmicort Respule prescribing information. Sodertalji: AstraZeneca; 2010.

  65. Hospira, Inc. Acetylcysteine prescribing information. Lake Forest: Hospira, Inc; 2004.

  66. Genentech, Inc. Pulmozyme prescribing information. South San Francisco: Genentech, Inc; 2014.

Download references

Author information

Authors and Affiliations

  1. Physiology and Biophysics, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Hermes A. Kontos Medical Sciences Building Room 215, Richmond, VA, 23298, USA

    Michael D. Davis

  2. Division of Neonatal-Perinatal Medicine, C.S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI, USA

    Steven M. Donn

  3. Professor Emeritus, Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    Robert M. Ward

Authors
  1. Michael D. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven M. Donn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert M. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael D. Davis.

Ethics declarations

Conflict of interest

Robert Ward, MD, Steven Donn, MD, and Michael D. Davis have served as paid consultants to Mallinckrodt Pharmaceuticals (formally Ikaria, Inc.). Mallinckrodt Pharmaceuticals had no input into the content of this review and had no editorial involvement with the content of this manuscript. None of the authors own stock or serve as employees of companies with an interest in this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Davis, M.D., Donn, S.M. & Ward, R.M. Administration of Inhaled Pulmonary Vasodilators to the Mechanically Ventilated Neonatal Patient. Pediatr Drugs 19, 183–192 (2017). https://doi.org/10.1007/s40272-017-0221-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-017-0221-9

Keywords

Search

Navigation