Effectiveness of Dual Medication Therapy (Oral Acetaminophen and Oral Ibuprofen) for the Management of Patent Ductus Arteriosus in Extremely Premature Infants: A Feasibility TrialFunding None.
Objective The study aimed to evaluate the efficacy of dual medication therapy (DMT) with oral acetaminophen and oral ibuprofen for the closure of a hemodynamically significant patent ductus arteriosus (hsPDA).
Study Design In a prospective case–control cohort study (July 2017–May 2019), infants <29 weeks' gestational age and birth weight <1,000 g at ≤14 postnatal days with hsPDA and ratio of the smallest ductal diameter to the ostium of the left pulmonary artery diameter >0.5 were eligible. Infants received 10 mg/kg oral ibuprofen followed by two additional doses of 5 mg/kg at 24 and 48 hours after the initial ibuprofen dose and concomitant treatment with 15 mg/kg oral acetaminophen every 6 hours for 3 days (12 doses). Success of PDA treatment was defined as a small or absent PDA as ascertained by echocardiographic measurements. The p-values of comparisons were adjusted for multiple comparisons to preserve an error rate of 5%.
Results Overall, 20 infants received oral DMT and 11 infants received intravenous single medication therapy (SMT) with ibuprofen. The rates of successful PDA treatment following the first treatment in DMT and SMT groups were not statistically different (11/20 [55%] vs. 4/11 [36%], p = 0.46). However, DMT significantly decreased PDA size (mean difference = 0.54 mm, 95% confidence interval [CI]: 0.21–0.96, adjusted p-value = 0.0002) and PDA/LPA ratio (mean difference = 0.27, 95% CI: 0.10–0.47, adjusted p-value = 0.0004). We observed no evidence of hematologic, hepatic, or renal impairment.
Conclusion DMT achieved a greater degree of PDA closure than SMT and did not result in abnormalities in hepatic and renal profile.
No consensus on optimal medication for PDA treatment is available.
Dual oral medication therapy (ibuprofen and acetaminophen) could be an effective alternative treatment for PDA.
Dual oral medication therapy (ibuprofen and acetaminophen) may have a better safety profile than currently approved medications such as intravenous indomethacin and intravenous ibuprofen.
The portion of the study was presented at the Pediatric Academic Societies meeting from April 24 to May 1, 2019 at Baltimore, MD.
Eingereicht: 11. Juni 2020
Angenommen: 20. November 2020
17. Januar 2021 (online)
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- 1 Dice JE, Bhatia J. Patent ductus arteriosus: an overview. J Pediatr Pharmacol Ther 2007; 12 (03) 138-146
- 2 Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation 2006; 114 (17) 1873-1882
- 3 Prescott S, Keim-Malpass J. Patent ductus arteriosus in the preterm infant: diagnostic and treatment options. Adv Neonatal Care 2017; 17 (01) 10-18
- 4 Coceani F, Baragatti B. Mechanisms for ductus arteriosus closure. Semin Perinatol 2012; 36 (02) 92-97
- 5 Smith GC. The pharmacology of the ductus arteriosus. Pharmacol Rev 1998; 50 (01) 35-58
- 6 Benitz WE. Committee on Fetus and Newborn, American Academy of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics 2016;137(01):
- 7 Clyman RI, Campbell D, Heymann MA, Mauray F. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin-induced closure. Circulation 1985; 71 (01) 141-145
- 8 Silver MM, Freedom RM, Silver MD, Olley PM. The morphology of the human newborn ductus arteriosus: a reappraisal of its structure and closure with special reference to prostaglandin E1 therapy. Hum Pathol 1981; 12 (12) 1123-1136
- 9 Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006; 117 (04) 1113-1121
- 10 Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA, Lorenz JM. The ductus arteriosus rarely requires treatment in infants > 1000 grams. Am J Perinatol 2008; 25 (10) 661-666
- 11 Mehta S, Younoszai A, Pietz J, Achanti B. Pharmacological closure of the patent ductus arteriosus. Images Paediatr Cardiol 2003; 5 (01) 1-15
- 12 Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?. J Perinatol 2010; 30 (04) 241-252
- 13 Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth 2008; 18 (10) 915-921
- 14 Grèen K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol). Prostaglandins 1989; 37 (03) 311-315
- 15 Terrin G, Conte F, Scipione A. et al. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital J Pediatr 2014; 40 (01) 21
- 16 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2018; 9: CD003481
- 17 Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Neonatology 2012; 102 (01) 9-15
- 18 Mitra S, Florez ID, Tamayo ME. et al. 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 2018; 319 (12) 1221-1238
- 19 Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011; 128 (06) e1618-e1621
- 20 Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013; 8 (11) e77888
- 21 Oncel MY, Yurttutan S, Erdeve O. et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014; 164 (03) 510-4.e1
- 22 El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017; 176 (02) 233-240
- 23 Rostas SE, McPherson CC. Pharmacotherapy for patent ductus arteriosus: current options and outstanding questions. Curr Pediatr Rev 2016; 12 (02) 110-119
- 24 Watterberg KL, Gerdes JS, Cole CH. et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004; 114 (06) 1649-1657
- 25 Baud O, Watterberg KL. Prophylactic postnatal corticosteroids: early hydrocortisone. Semin Fetal Neonatal Med 2019; 24 (03) 202-206
- 26 Morris IP, Goel N, Chakraborty M. Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis. Eur J Pediatr 2019; 178 (08) 1171-1184
- 27 Ramos FG, Rosenfeld CR, Roy L, Koch J, Ramaciotti C. Echocardiographic predictors of symptomatic patent ductus arteriosus in extremely-low-birth-weight preterm neonates. J Perinatol 2010; 30 (08) 535-539
- 28 Le J, Gales MA, Gales BJ. Acetaminophen for patent ductus arteriosus. Ann Pharmacother 2015; 49 (02) 241-246
- 29 NeoProfen (ibuprofen lysine) injection [product information]. Lebanon, NJ: Recordati Rare Diseases Inc; Accessed 2013 at: https://www.recordatirarediseases.com/sites/www.recordatirarediseases.com/files/inline-files/neoprofen-pi_0.pdf
- 30 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33 (01) 179-201
- 31 Boghossian NS, Page GP, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr 2013; 162 (06) 1120-1124 , 1124.e1
- 32 Stevenson DK, Wright LL, Lemons JA. et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994. Am J Obstet Gynecol 1998; 179 (6 Pt 1): 1632-1639
- 33 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92 (04) 529-534
- 34 Akaike H. A new look at the statistical model identification. 1974; 19 (06) 716-723
- 35 Shelton EL, Waleh N, Plosa EJ. et al. Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. Pediatr Res 2018; 84 (03) 458-465
- 36 Kimani S, Surak A, Bhattacharya S. Use of combination therapy with Acetaminophen and Ibuprofen for the treatment of patent ductus arteriosus in premature neonates. In. PAS meeting, Baltimore: Poster session. Accessed 2019 at: https://www.sciencegate.app/doi/abs/10.1093/pch/pxaa057
- 37 Hochwald O, Mainzer G, Borenstein-Levin L. et al. Adding paracetamol to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a double-blind, randomized, placebo-controlled pilot study. Am J Perinatol 2018; 35 (13) 1319-1325
- 38 Tekgunduz KS, Ceviz N, Demirelli Y. et al. Intravenous paracetamol for patent ductus arteriosus in premature infants - a lower dose is also effective. Concerning the article by M.Y. Oncel et al: intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants [Neonatology 2013;103:166-169]. Neonatology 2013; 104 (01) 6-7
- 39 McPherson C, Luecke CM, Liviskie CJ, Zeller BN, Vesoulis ZA. Acetaminophen serum concentrations in infants treated intravenously for patent ductus arteriosus. J Pediatr Pharmacol Ther 2019; 24 (02) 134-137