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Increasing the dose of ibuprofen with postnatal age to close a hemodynamically significant patent ductus arteriosus in very preterm infants

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Abstract

Patent ductus arteriosus (PDA) is associated with neonatal morbidities in high-risk preterm infants. Early neonatal treatment by ibuprofen induces the ductus arteriosus (DA) closure in approximatively 60% of infants. Dose escalation of ibuprofen according to postnatal age has been suggested for improving the DA closure rate. The aim of this study was to assess the efficacy and tolerance of an increasing dose regimen of ibuprofen. This single-center retrospective cohort study involved infants hospitalized from 2014 to 2019 in our neonatal unit. Selection criteria were gestational age < 30 weeks, birth weight < 1000 g, and treatment by ibuprofen. Three dose levels were used and consisted of a daily intravenous injection of ibuprofen-tris-hydroxymethyl-aminomethane (ibuprofen-THAM) for three consecutive days: (i) 10 −5 −5 mg/kg before the 70th h of life (H70) (dose level 1), (ii) 14 −7 −7 mg/kg between H70 and H108 (dose level 2), (iii) 18 −9 −9 mg/kg after H108 (dose level 3). The ibuprofen-induced DA closure was compared between ibuprofen schedules, and the Cox proportional-hazard regression was performed to identify factors associated with the ibuprofen efficacy. Tolerance was assessed through renal function, acidosis, and platelet count. One hundred forty-three infants met the inclusion criteria. The ibuprofen-induced DA closure was observed in 67 infants (46.8%). One course of ibuprofen at dose level 1 was more efficient in closing the DA than other schedules (dose level 1, one course (n = 70): 71%, dose level 2 or 3, one course (n = 20): 45%, two-course schedules (n = 53): 15%, p < 0.0001). Independent factors associated with ibuprofen-induced DA closure were a complete antenatal schedule of steroids (p = 0.001), a lower CRIB II score (p = 0.009), and a lower and earlier exposure to ibuprofen (p < 0.0001 and p = 0.002). No severe side effects were observed. Neonatal mortality and morbidities were similar regardless of the infant’s response to ibuprofen.

  Conclusion: Increasing ibuprofen doses with postnatal age failed to reach an efficacy similar to earlier treatment. Although the infant response to ibuprofen was likely to depend on multiple factors, the optimal use of ibuprofen included its early initiation.

What is Known:

• Ibuprofen is the current first-line treatment for patent ductus arteriosus during the early neonatal period in very preterm infants.

• However, the ibuprofen efficacy rapidly declined with postnatal age during the first week of life. A dose escalation of ibuprofen according to postnatal age has been suggested to improve the ibuprofen-induced ductus arteriosus closure.

What is New:

• The rapid drop of ibuprofen’s ability to close hemodynamically significant patent ductus arteriosus persisted beyond the postnatal day 2 despite the dose adjustment arguing for an early initiation to optimize its efficacy.

• The early selection of patients who will suffer from patent ductus arteriosus-related morbidities and who will positively respond to ibuprofen is an issue that could determine the future place of ibuprofen in the patent ductus arteriosus management.

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Abbreviations

CI:

Confidence interval

CRIB II score:

Clinical risk index for babies II score

DA:

Ductus arteriosus

hsPDA:

Hemodynamically significant patent ductus arteriosus

Ibuprofen-THAM:

Ibuprofen-tris-hydroxymethyl-aminomethane

PDA:

Patent ductus arteriosus

SD:

Standard deviation

References

  1. Hundscheid T, van den Broek M, van der Lee R, de Boode WP (2019) Understanding the pathobiology in patent ductus arteriosus in prematurity—beyond prostaglandins and oxygen. Pediatr Res 86:28–38. https://doi.org/10.1038/s41390-019-0387-7

    Article  CAS  PubMed  Google Scholar 

  2. Hamrick SEG, Hansmann G (2010) Patent ductus arteriosus of the preterm infant. Pediatrics 125:1020–1030. https://doi.org/10.1542/peds.2009-3506

    Article  PubMed  Google Scholar 

  3. Garland J, Buck R, Weinberg M (1994) Pulmonary hemorrhage risk in infants with a clinically diagnosed patent ductus arteriosus: a retrospective cohort study. Pediatrics 94:719–723

    Article  CAS  PubMed  Google Scholar 

  4. Khanafer-Larocque I, Soraisham A, Stritzke A et al (2019) Intraventricular hemorrhage: risk factors and association with patent ductus arteriosus treatment in extremely preterm neonates. Front Pediatr 7:408. https://doi.org/10.3389/fped.2019.00408

    Article  PubMed  PubMed Central  Google Scholar 

  5. Deng Y, Zhang H, Zhao Z et al (2022) Impact of patent ductus arteriosus shunt size and duration on risk of death or severe respiratory morbidity in preterm infants born in China. Eur J Pediatr 181:3131–3140. https://doi.org/10.1007/s00431-022-04549-x

    Article  PubMed  PubMed Central  Google Scholar 

  6. Van Overmeire B, Smets K, Lecoutere D et al (2000) A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 343:674–681. https://doi.org/10.1056/NEJM200009073431001

    Article  PubMed  Google Scholar 

  7. Hundscheid T, El-Khuffash A, McNamara PJ, de Boode WP (2022) Survey highlighting the lack of consensus on diagnosis and treatment of patent ductus arteriosus in prematurity. Eur J Pediatr 181:2459–2468. https://doi.org/10.1007/s00431-022-04441-8

    Article  PubMed  PubMed Central  Google Scholar 

  8. Engbers AGJ, Völler S, Flint RB et al (2022) The effect of ibuprofen exposure and patient characteristics on the closure of the patent ductus arteriosus in preterm infants. Clin Pharmacol Ther 112:307–315. https://doi.org/10.1002/cpt.2616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hirt D, Van Overmeire B, Treluyer J-M et al (2008) An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol 65:629–636. https://doi.org/10.1111/j.1365-2125.2008.03118.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ohlsson A, Walia R, Shah SS (2020) Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD003481.pub8

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mitra S, Florez ID, Tamayo ME et al (2018) Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 319:1221. https://doi.org/10.1001/jama.2018.1896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rozé J-C, Cambonie G, Le Thuaut A et al (2021) Effect of early targeted treatment of ductus arteriosus with ibuprofen on survival without cerebral palsy at 2 years in infants with extreme prematurity: a randomized clinical trial. J Pediatr 233:33-42.e2. https://doi.org/10.1016/j.jpeds.2020.12.008

    Article  CAS  PubMed  Google Scholar 

  13. Mertens L, Seri I, Marek J et al (2011) Targeted neonatal echocardiography in the neonatal intensive care unit: practice guidelines and recommendations for training. J Am Soc Echocardiogr 24:1057–1078. https://doi.org/10.1016/j.echo.2011.07.014

    Article  PubMed  Google Scholar 

  14. Singh Y, Tissot C, Fraga MV et al (2020) International evidence-based guidelines on point of care ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:65. https://doi.org/10.1186/s13054-020-2787-9

    Article  PubMed  PubMed Central  Google Scholar 

  15. El Hajjar M (2005) Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 90:F419–F422. https://doi.org/10.1136/adc.2003.027698

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fenton T, Kim J (2013) A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. In: BMC Pediatr. https://pubmed.ncbi.nlm.nih.gov/23601190/?from_term=Fenton+TR+2003&from_pos=1. Accessed 14 Mar 2020

  17. Jobe AH, Bancalari E (2001) Bronchopulmonary dysplasia. Am J Respir Crit Care Med 163:1723–1729. https://doi.org/10.1164/ajrccm.163.7.2011060

    Article  CAS  PubMed  Google Scholar 

  18. Papile L-A, Burstein J, Burstein R, Koffler H (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92:529–534. https://doi.org/10.1016/S0022-3476(78)80282-0

    Article  CAS  PubMed  Google Scholar 

  19. de Klerk JCA, van Paassen N, van Beynum IM et al (2021) Ibuprofen treatment after the first days of life in preterm neonates with patent ductus arteriosus. J Matern Fetal Neonatal Med 34:2411–2417. https://doi.org/10.1080/14767058.2019.1667323

    Article  CAS  PubMed  Google Scholar 

  20. Dani C, Vangi V, Bertini G et al (2012) High-dose ibuprofen for patent ductus arteriosus in extremely preterm infants: a randomized controlled study. Clin Pharmacol Ther 91:590–596. https://doi.org/10.1038/clpt.2011.284

    Article  CAS  PubMed  Google Scholar 

  21. Clyman RI, Liebowitz M, Kaempf J et al (2019) PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. J Pediatr 205:41-48.e6. https://doi.org/10.1016/j.jpeds.2018.09.012

    Article  PubMed  Google Scholar 

  22. Olsson KW, Jonzon A, Sindelar R (2019) Early haemodynamically significant patent ductus arteriosus does not predict future persistence in extremely preterm infants. Acta Paediatr 108:1590–1596. https://doi.org/10.1111/apa.14752

    Article  PubMed  Google Scholar 

  23. de Klerk JCA, Engbers AGJ, van Beek F et al (2020) Spontaneous closure of the ductus arteriosus in preterm infants: a systematic review. Front Pediatr 8:541. https://doi.org/10.3389/fped.2020.00541

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sung SI, Lee MH, Ahn SY et al (2020) Effect of nonintervention vs oral ibuprofen in patent ductus arteriosus in preterm infants: a randomized clinical trial. JAMA Pediatr 174:755. https://doi.org/10.1001/jamapediatrics.2020.1447

    Article  PubMed  Google Scholar 

  25. de Waal K, Phad N, Stubbs M et al (2021) A randomized placebo-controlled pilot trial of early targeted nonsteroidal anti-inflammatory drugs in preterm infants with a patent ductus arteriosus. J Pediatr 228:82-86.e2. https://doi.org/10.1016/j.jpeds.2020.08.062

    Article  CAS  PubMed  Google Scholar 

  26. Mitra S, Scrivens A, von Kursell AM, Disher T (2020) Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD013278.pub2

  27. Hundscheid T, Onland W, Kooi EMW et al (2022) Expectant management or early ibuprofen for patent ductus arteriosus. N Engl J Med NEJMoa2207418. https://doi.org/10.1056/NEJMoa2207418

  28. Benitz WE, Committee on Fetus and Newborn, Watterberg KL et al (2016) Patent ductus arteriosus in preterm infants. Pediatrics 137:e20153730. https://doi.org/10.1542/peds.2015-3730

  29. El-Khuffash A, Rios DR, McNamara PJ (2021) Toward a rational approach to patent ductus arteriosus trials: selecting the population of interest. J Pediatr 233:11–13. https://doi.org/10.1016/j.jpeds.2021.01.012

    Article  PubMed  Google Scholar 

  30. Cambonie G, Clyman RI, Rozé J-C (2021) Management of persistent ductus arteriosus in very premature neonates. Results of the French TRIOCAPI trial, perspectives for clinicians, and subsequent studies on this topic. Arch Pédiatrie 28:501–503. https://doi.org/10.1016/j.arcped.2021.07.002

    Article  CAS  Google Scholar 

  31. EL-Khuffash A, James AT, Corcoran JD et al (2015) A patent ductus arteriosus severity score predicts chronic lung disease or death before discharge. J Pediatr 167:1354-1361.e2. https://doi.org/10.1016/j.jpeds.2015.09.028

    Article  PubMed  Google Scholar 

  32. Gokulakrishnan G, Kulkarni M, He S et al (2022) Brain natriuretic peptide and N-terminal brain natriuretic peptide for the diagnosis of haemodynamically significant patent ductus arteriosus in preterm neonates. Cochrane Database Syst Rev 2022:. https://doi.org/10.1002/14651858.CD013129.pub2

  33. Gonen I, Babayigit A, Bornaun H et al (2021) SIMPLE: A novel scoring system for predicting hemodynamically significant patent ductus arteriosus without echocardiographic evaluation in extremely low birth weight infants. Front Pediatr 9:649515. https://doi.org/10.3389/fped.2021.649515

  34. Clyman RI, Ballard PL, Sniderman S et al (1981) Prenatal administration of betamethasone for prevention of patent ductus arteriosus. J Pediatr 98:123–126. https://doi.org/10.1016/S0022-3476(81)80557-4

    Article  CAS  PubMed  Google Scholar 

  35. Chorne N, Jegatheesan P, Lin E et al (2007) Risk factors for persistent ductus arteriosus patency during indomethacin treatment. J Pediatr 151:629–634. https://doi.org/10.1016/j.jpeds.2007.05.007

    Article  CAS  PubMed  Google Scholar 

  36. Xodo S, Trombetta G, Celante L et al (2022) Partial vs. complete course of antenatal corticosteroid prophylaxis: an Italian single center retrospective study. Front Pediatr 10:894526. https://doi.org/10.3389/fped.2022.894526

  37. Park H, Park KH, Kim YM et al (2018) Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: a retrospective study. BMC Pregnancy Childbirth 18:146. https://doi.org/10.1186/s12884-018-1780-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim ES, Kim E-K, Choi CW et al (2010) Intrauterine inflammation as a risk factor for persistent ductus arteriosus patency after cyclooxygenase inhibition in extremely low birth weight infants. J Pediatr 157:745-750.e1. https://doi.org/10.1016/j.jpeds.2010.05.020

    Article  CAS  PubMed  Google Scholar 

  39. Desfrere L, Zohar S, Morville P et al (2005) Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 30(2):121–132. https://doi.org/10.1111/j.1365-2710.2005.00630.x

    Article  CAS  PubMed  Google Scholar 

  40. Isayama T, Kusuda S, Reichman B et al (2020) Neonatal intensive care unit-level patent ductus arteriosus treatment rates and outcomes in infants born extremely preterm. J Pediatr 220:34-39.e5. https://doi.org/10.1016/j.jpeds.2020.01.069

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Neonatology Unit, CHRU de Tours, Tours, France

    Laure Carneiro & Antoine Bouissou

  2. Neonatology Department, CHU de Caen Normandie, 14000, Caen, France

    Geraldine Favrais

  3. INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron Institut Blood and Brain @ Caen-Normandie (BB@C), Normandie University, UNICAEN, 14000, Caen, France

    Geraldine Favrais

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Contributions

GF designed the study protocol, obtained ethics approval, performed the preliminary and final data analysis, and contributed to the writing and critical reading of the manuscript. LC actively participated in the patient screening and enrollment, the data collection, and the preliminary and final data analysis. LC wrote the first draft of the manuscript. AB contributed to the writing and critical reading of the manuscript.

Corresponding author

Correspondence to Geraldine Favrais.

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Ethics approval

The study was performed in accordance with the Declaration of Helsinki. The local ethics committee (2020−047) and local data protection authority (2020−063) approved the study protocol.

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Oral and written information were provided to parents or authorized guardians. They could refuse the exploitation of their child’s data.

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The authors declare no competing interests.

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Communicated by Daniele De Luca.

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Carneiro, L., Bouissou, A. & Favrais, G. Increasing the dose of ibuprofen with postnatal age to close a hemodynamically significant patent ductus arteriosus in very preterm infants. Eur J Pediatr 182, 3527–3535 (2023). https://doi.org/10.1007/s00431-023-04986-2

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