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Treatment of pulmonary hypertension during initial hospitalization in a multicenter cohort of infants with congenital diaphragmatic hernia (CDH)

Abstract

Objective

Describe inpatient pulmonary hypertension (PH) treatment and factors associated with therapy at discharge in a multicenter cohort of infants with CDH.

Methods

Six years linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used to describe associations between prenatal/perinatal factors, clinical outcomes, echocardiographic findings and PH medications (PHM), during hospitalization and at discharge.

Results

Of 1106 CDH infants from 23 centers, 62.8% of infants received PHM, and 11.6% of survivors were discharged on PHM. Survivors discharged on PHM more frequently had intrathoracic liver, small for gestational age, and low 5 min APGARs compared with those discharged without PHM (p < 0.0001). Nearly one-third of infants discharged without PHM had PH on last inpatient echo.

Conclusions

PH medication use is common in CDH. Identification of infants at risk for persistent PH may impact ongoing management. Post-discharge follow-up of all CDH infants with echocardiographic evidence of PH is warranted.

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Fig. 1: Percentage of patients treated with each medication by year.

Data availability

The data set used for this study is derived from the Children’s Hospital Neonatal Database (CHND), and is not publicly available due to data use agreement restrictions from the member institutions. Data are however available from the authors upon reasonable request and with permission of the CHND.

References

  1. 1.

    Badillo A, Gingalewski C. Congenital diaphragmatic hernia: treatment and outcomes. Semin Perinatol. 2014;38:92–96.

    PubMed  Google Scholar 

  2. 2.

    Lally KP. Congenital diaphragmatic hernia - the past 25 (or so) years. J Pediatr Surg. 2016;51:695–8.

    PubMed  Google Scholar 

  3. 3.

    Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J, Stolar CJH, et al. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr. 2013;163:114–119.e111.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Petroze RT, Caminsky NG, Trebichavsky J, Bouchard S, Le-Nguyen A, Laberge JM, et al. Prenatal prediction of survival in congenital diaphragmatic hernia: an audit of postnatal outcomes. J Pediatr Surg. 2019;54:925–31.

    PubMed  Google Scholar 

  5. 5.

    Dillon PW, Cilley RE, Mauger D, Zachary C, Meier A, Altman RP, et al. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:307–12.

    PubMed  Google Scholar 

  6. 6.

    Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller RL. Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J Pediatr. 2015;166:251–256.e251.

    PubMed  Google Scholar 

  7. 7.

    Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics. 2014;134:e413–e419.

    PubMed  Google Scholar 

  8. 8.

    Ameis D, Khoshgoo N, Keijzer R. Abnormal lung development in congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26:123–8.

    PubMed  Google Scholar 

  9. 9.

    Mous DS, Kool HM, Wijnen R, Tibboel D, Rottier RJ. Pulmonary vascular development in congenital diaphragmatic hernia. Eur Respir Rev. 2018;27:170104.

    PubMed  Google Scholar 

  10. 10.

    Finer NM. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997;99:838–5.

    Google Scholar 

  11. 11.

    Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6:38.

    PubMed Central  Google Scholar 

  12. 12.

    Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Systematic Rev. 2017;2017:CD005494.

    Google Scholar 

  13. 13.

    Gao XF, Zhang JJ, Jiang XM, Ge Z, Wang ZM, Li B, et al. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials. Patient Preference Adherence. 2017;11:871–85.

    PubMed  Google Scholar 

  14. 14.

    Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir. J. 2019;53:1801916.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gien J, Kinsella JP. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. J Perinatol. 2016;36:S28–S31.

    PubMed  Google Scholar 

  16. 16.

    Pierro M, Thébaud B. Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014;19:357–63.

    CAS  PubMed  Google Scholar 

  17. 17.

    Murthy K, Dykes FD, Padula MA, Pallotto EK, Reber KM, Durand DJ, et al. The children’s hospitals neonatal database: an overview of patient complexity, outcomes and variation in care. J Perinatol. 2014;34:582–6.

    CAS  PubMed  Google Scholar 

  18. 18.

    Lakshminrusimha S, Keszler M, Kirpalani H, Van Meurs K, Chess P, Ambalavanan N, et al. Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices. Matern Health Neonatol Perinatol. 2017;3:27.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kumar VHS, Dadiz R, Koumoundouros J, Guilford S, Lakshminrusimha S. Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia. Pediatr Surg Int. 2018;34:735–42.

    PubMed  Google Scholar 

  20. 20.

    Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC, Girgis RE, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179:615–21.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Malowitz JR, Hornik CP, Laughon MM, Testoni D, Cotten CM, Clark RH, et al. Management practice and mortality for infants with congenital diaphragmatic hernia. Am J Perinatol. 2015;32:887–94.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Putnam LR, Tsao K, Morini F, Lally PA, Miller CC, Lally KP, et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatrics. 2016;170:1188–94.

    PubMed  Google Scholar 

  23. 23.

    Campbell BT, Herbst KW, Briden KE, Neff S, Ruscher KA, Hagadorn JI. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics. 2014;134:e420–e426.

    PubMed  Google Scholar 

  24. 24.

    Murthy K, Pallotto EK, Gien J, Brozanski BS, Porta NFM, Zaniletti I, et al. Predicting death or extended length of stay in infants with congenital diaphragmatic hernia. J Perinatol. 2016;36:654–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Cauley RP, Potanos K, Fullington N, Bairdain S, Sheils CA, Finkelstein JA, et al. Pulmonary support on day of life 30 is a strong predictor of increased 1 and 5-year morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2015;50:849–55.

    PubMed  Google Scholar 

  26. 26.

    Carpentier E, Mur S, Aubry E, Pognon L, Rakza T, Flamein F, et al. Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension. J Pediatr Surg. 2017;52:1480–3.

    CAS  PubMed  Google Scholar 

  27. 27.

    Lawrence KM, Hedrick HL, Monk HM, Herkert L, Waqar LN, Hanna BD, et al. Treprostinil improves persistent pulmonary hypertension associated with congenital diaphragmatic hernia. J Pediatrics. 2018;200:44–49.

    CAS  Google Scholar 

  28. 28.

    Olson E, Lusk LA, Fineman JR, Robertson L, Keller RL. Short-term treprostinil use in infants with congenital diaphragmatic hernia following repair. J Pediatrics. 2015;167:762–4.

    Google Scholar 

  29. 29.

    Lawrence KM, Berger K, Herkert L, Franciscovich C, O’Dea CLH, Waqar LN, et al. Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia. J Pediatr Surg. 2019;54:55–59.

    PubMed  Google Scholar 

  30. 30.

    Bialkowski A, Moenkemeyer F, Patel N. Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. Eur J Pediatric Surg. 2013;25:171–6.

    Google Scholar 

  31. 31.

    Kipfmueller F, Schroeder L, Berg C, Heindel K, Bartmann P, Mueller A. Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia. Pediatr Pulmonol. 2018;53:452–60.

    PubMed  Google Scholar 

  32. 32.

    Lawrence KM, Monos S, Adams S, Herkert L, Peranteau WH, Munson DA, et al. Inhaled nitric oxide is associated with improved oxygenation in a subpopulation of infants with congenital diaphragmatic hernia and pulmonary hypertension. J Pediatr. 2020;219:167–72.

    CAS  PubMed  Google Scholar 

  33. 33.

    Fliman PJ, deRegnier RA, Kinsella JP, Reynolds M, Rankin LL, Steinhorn RH. Neonatal extracorporeal life support: impact of new therapies on survival. J Pediatr. 2006;148:595–9.

    PubMed  Google Scholar 

  34. 34.

    Harting MT, Lally KP. The congenital diaphragmatic hernia study group registry update. Semin Fetal Neonatal Med. 2014;19:370–5.

    PubMed  Google Scholar 

  35. 35.

    Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol. 2005;29:123–8.

    PubMed  Google Scholar 

  36. 36.

    Mous DS, Buscop-van Kempen MJ, Wijnen RMH, Tibboel D, Rottier RJ. Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy. Respir Res. 2017;18:187.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kinsella JP, Steinhorn RH, Mullen MP, Hopper RK, Keller RL, Ivy DD, et al. The left ventricle in congenital diaphragmatic hernia: implications for the management of pulmonary hypertension. J Pediatr. 2018;197:17–22.

    PubMed  Google Scholar 

  38. 38.

    Patel N, Lally PA, Kipfmueller F, Massolo AC, Luco M, Van Meurs KP, et al. Ventricular dysfunction is a critical determinant of mortality in congenital diaphragmatic hernia. Am J Respir Crit Care Med. 2019;220:1522–30.

    Google Scholar 

  39. 39.

    Patel N, Massolo AC, Paria A, Stenhouse EJ, Hunter L, Finlay E, et al. Early postnatal ventricular dysfunction is associated with disease severity in patients with congenital diaphragmatic hernia. J Pediatr. 2018;203:400–407.e401.

    PubMed  Google Scholar 

  40. 40.

    Keller RL, Tacy TA, Hendricks-Munoz K, Xu J, Moon-Grady AJ, Neuhaus J, et al. Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity. Am J Respir Crit Care Med. 2010;182:555–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Mourani PM, Sontag MK, Younoszai A, Ivy DD, Abman SH. Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics. 2008;121:317–25.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    American Academy of Pediatrics Section on Surgery. American Academy of Pediatrics Committee on Fetus and Newborn Lally KP, Engle W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121:627–32.

    Google Scholar 

  43. 43.

    Hollinger LE, Harting MT, Lally KP. Long-term follow-up of congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26:178–84.

    PubMed  Google Scholar 

Download references

Acknowledgements

Jeanette Asselin, Beverly Brozanski, David Durand (ex officio), Francine Dykes (ex officio), Jacquelyn Evans (Executive Director), Theresa Grover, Karna Murthy (Chair), Michael Padula, Eugenia Pallotto, Anthony Piazza, Kristina Reber and Billie Short are members of the Children’s Hospitals Neonatal Consortium, Inc. For more information, please contact: support@thechnc.org.

We are indebted to the following institutions that serve the infants and their families, and these institutions also have invested in and continue to participate in the Children’s Hospital’s Neonatal Database (CHND). The site sponsors/contributors for the CHND are also included: Anthony Piazza, Children’s Healthcare of Atlanta, Atlanta, GA; Gregory Sysyn, Children’s Healthcare of Atlanta at Scottish Rite; Carl Coghill, Children’s Hospital of Alabama, Birmingham, AL; Ajay Talati, Le Bonheur Children’s Hospital, Memphis, TN; Anne Hansen, Tanzeema Houssain, Children’s Hospital Boston, Boston, MA; Karna Murthy, Gustave Falciglia, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Beth Haberman, Cincinnati Children’s Hospital, Cincinnati, OH; Kristina Reber, Nationwide Children’s Hospital, Columbus, OH; Rashmin Savani, Children’s Medical Center, Dallas, TX; Theresa Grover, Children’s Hospital Colorado, Aurora, CO; Girija Natarajan, Children’s Hospital of Michigan, Detroit, MI; Annie Chi, Yvette Johnson, Cook Children’s Health Care System, Fort Worth, TX; Gautham Suresh, Texas Children’s Hospital, Houston, TX; William Engle, Riley Children’s Hospital, Indianapolis, IN; Eugenia Pallotto, Children’s Mercy Hospitals & Clinics, Kansas City, MO; Robert Lyle, Becky Rogers, Arkansas Children’s Hospital, Little Rock, AR; Rachel Chapman, Children’s Hospital Los Angeles, Los Angeles, CA; Jamie Limjoco, American Family Children’s Hospital, Madison, WI; Priscilla Joe, Children’s Hospital & Research Center Oakland, Oakland, CA; Jacquelyn Evans, Michael Padula, David Munson, The Children’s Hospital of Philadelphia, Philadelphia, PA; Suzanne Touch, St. Christopher’s Hospital for Children, Philadelphia, PA; Beverly Brozanski, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; Rakesh Rao, Amit Mathur, St. Louis Children’s Hospital, St Louis, MO; Victor McKay, All Children’s Hospital, St. Petersburg, FL; Mark Speziale, Laurel Moyer, Rady Children’s Hospital, San Diego, CA; Billie Short, Children’s National Medical Center, Washington, DC; Kevin Sullivan, AI DuPont Hospital for Children, Wilmington, DE; Con Yee Ling, Primary Children’s Medical Center, Salt Lake City, UT; Michael Uhing, Ankur Datta, Children’s Hospital of Wisconsin, Milwaukee, WI; Lynne Willett, Nicole Birge, Children’s Hospital of Omaha; Rajan Wadhawan, Florida Hospital for Children; Elizabeth Jacobsen-Misbe, Robert DiGeronimo, Seattle Children’s Hospital, Seattle, WA; Kyong-Soon Lee, Hospital for Sick Children, Toronto, ON; Michel Mikhael, Children’s Hospital Orange County, Los Angeles, CA.

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Contributions

RBS helped design the study, analyze data, and drafted the initial manuscript. TRG, NR, MW, SK, BH, HH, JG, HAH, NFMP, and KM helped design the study, analyze data, and reviewed and edited manuscript. BB, RD, and NA helped conceptualize the study and reviewed and edited manuscript. RC helped design the study and reviewed and edited the manuscript. JD helped analyze data and reviewed and edited the manuscript. YJ and MU helped conceptualize the study and reviewed and edited the manuscript. IZ performed primary data curation and analysis, and reviewed and edited the manuscript.

Corresponding author

Correspondence to Ruth B. Seabrook.

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Conflict of interest

BB, TG, and KM are board members of the Children’s Hospitals Neonatal Consortium, 501(c)(3) non-profit organization that manages and owns the Children’s Hospitals Neonatal Database, a data source used in this study. None of the remaining authors have any financial or other conflicts of interest as described in the author instructions.

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Members of the Children’s Hospitals Neonatal Consortium Congenital Diaphragmatic Hernia Focus Group are listed below acknowledgements.

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Seabrook, R.B., Grover, T.R., Rintoul, N. et al. Treatment of pulmonary hypertension during initial hospitalization in a multicenter cohort of infants with congenital diaphragmatic hernia (CDH). J Perinatol 41, 803–813 (2021). https://doi.org/10.1038/s41372-021-00923-z

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