http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–4 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1029912
ORIGINAL ARTICLE
Ductal closure with intravenous paracetamol: a new approach to patent ductus arteriosus treatment
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Kainan University on 04/02/15 For personal use only.
Asli Memisoglu1, Zeynep Alp U¨nkar1, Nilufer Cetiner2, Figen Akalın2, Hulya Ozdemir1, Hu¨lya Selva Bilgen1, and Eren Ozek1 1
Division of Neonatology and 2Division of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Marmara University, Istanbul, Turkey
Abstract
Keywords
Objectives: Indomethacin and ibuprofen are commonly used in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA). These drugs are associated with serious adverse events, including gastrointestinal perforation, renal failure and bleeding. The role of paracetamol has been proposed for the treatment of PDA. Methods: We report a series of 11 neonates (birth weight: 415–1580 g; gestational age: 23–30.3 weeks) who were treated with paracetamol for a hsPDA. Neonates with hsPDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin. The condition of significant PDA was defined by the presence of at least one of the following criteria: internal ductal diameter # 1.4 mm/kg body weight, left atrium (LA)-to-aortic (Ao) root ratio 41.4, unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta along with clinical findings. Intravenous (IV) paracetamol was given at doses 15 mg/kg every 6 h for three days. Results: Successful ductal closure was achieved in 10 out of 11 babies (90.9%). No adverse or side effects were observed during the treatment. Conclusions: On the basis of these results, paracetamol could be considered as a promising and safe therapy for the treatment of PDA in preterm infants.
Paracetamol, patent ductus arteriosus, premature
Introduction Optimal management of patent ductus arteriosus (PDA) in the premature infant is a controversial issue [1]. The ductus arteriosus in normal term infants constricts rapidly after birth, resulting in ductal intimal hypoxia, remodelling and permanent closure [2]. In extremely premature infants, failure of ductus arteriosus constriction is common, affecting 70% at 528 weeks and 80% at 24–25 weeks [3,4]. Problems associated with failure of early PDA constriction include heart failure, ventilator dependence, hypotension, pulmonary haemorrhage, periventricular haemorrhage, necrotizing enterocolitis (NEC) and abnormalities of brain perfusion [2,5]. When therapeutic intervention to facilitate ductal closure is indicated, indomethacin and ibuprofen are the generally accepted drugs for hemodynamically significant PDA (hsPDA) in preterm neonates [1]. However, these drugs might have some serious adverse effects, including renal failure, gastrointestinal perforation and bleeding [5–7]. In vulnerable infants with renal failure or thrombocytopenia, choosing these drugs for medical closure of PDA is Address for correspondence: Dr. Asli Memisoglu, Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Marmara University, Istanbul, Turkey. E-mail: [email protected]
History Received 28 January 2015 Revised 10 March 2015 Accepted 12 March 2015 Published online 2 April 2015
challenging. Very recently paracetamol, an inhibitor of the peroxidase component of prostaglandin-H2 synthetase, has been proposed for the treatment of these cases [8–10]. Paracetamol has not been extensively studied, but appears to have similar efficacy to ibuprofen and indomethacin. In fact, paracetamol has many side effects, most of them are dose related, and are not fully studied in neonates. In this report, we present a series of 11 tiny preterm babies with hsPDA, treated with paracetamol in the presence of contraindication to ibuprofen or indomethacin.
Materials and methods Eleven neonates (birth weight: 415–1580 g; gestational age: 23–30.3 weeks), who were admitted to the Neonatal Intensive Care Unit at Marmara University Hospital Istanbul between November 2012 to June 2014, treated with intravenous (IV) paracetamol for clinically and hsPDA. Neonates with significant PDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin, including feeding intolerance, necrotizing enterocolitis (NEC), significant impairment of renal function, active bleeding, thrombocytopenia and/or coagulation defects. Paracetamol (Perfalgan; Bristol-Myers Squibb, Laboratories RENAUDIN, Itxassou, France) was given at doses 15 mg/kg every 6 h for
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A. Memisoglu et al.
J Matern Fetal Neonatal Med, Early Online: 1–4
three days. To monitor the safety of paracetamol treatment, we collected data regarding serum concentration of liver enzymes, total and direct bilirubin, creatinine and urea nitrogen. However, we did not analyze plasma levels of paracetamol. This is an observational study in a group of selected patients where ibuprofen was contraindicated due to the high risk of side effects; thus, we had no control group. The first echocardiographic examination was performed in the first 24 h of life in all babies. The ductal closure was confirmed with repeated echocardiography after 72 h of administration of IV paracetamol. Since common international consensus has not been reached on the definition of hsDA yet, the hsPDA was defined as the presence of a left atrium (LA)-to-aortic (Ao) root diameter ratio of 1.4 or greater in the parasternal long-axis view, an internal ductal diameter of 1.4 mm/kg body weight or greater, left ventricular enlargement and unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta [11,12]. Patient’s symptomatology (status of metabolic acidosis, diminished urine output, lung overload signs, heart failure findings, etc.) was considered in making the decision of PDA’s pharmacologic treatment. Echocardiography was performed using a Philips HD 11 XE, 8S transducer (Philips Medical Systems, Bothell, WA). Each infant in this series received IV paracetamol after written parental consent was obtained for off-label usage of this well-known drug.
Statistical analyses Data are reported as means ± standard deviations and ranges. The Statistical Package for the Social Sciences version 16.0 (SPSS Inc., Chicago, IL) was performed for statistical analyses.
Results A total of 12 preterm infants received IV paracetamol for closure of PDA in this study. One of them (400 g, 22 weeks, boy) was excluded since he died because of renal failure on 3rd day-of-life (DOL) before control echocardiography could be performed. Out of the remaining patients (n ¼ 11), eight were boys (72.7%) and three were girls (27.3%) with a median gestational age of 26.6 weeks (range: 23–30.3 weeks) and a
median birth weight of 790 g (range: 415–1580 g). The mean gestational age of the 11 patients was 26.5 ± 3.0 weeks, and their mean birth weight was of 897.1 ± 356.3 g. Paracetamol treatment was started at 4.6 ± 3 days (median: 3, range: 1–15). The mean internal ductal diameter was 1.5 ± 0.3 mm (median: 1.5, range: 1.1–1.9), and the LA-to-aorta ratio was 1.4 ± 0.2 (median: 1.4, range: 1–1.7). The mean internal ductal diameter per kg (as means of body weight) was 1.9 ± 0.4 mm (median: 1.9, range: 1.2–2.6). The PDA was successfully closed with paracetamol in 10 (90.9%) of the 11 patients. Only one of the infants had undergone surgical ligation. Two out of the 11 patients died. One of them died because of late-onset sepsis on DOL 15 and the other one died because of renal failure resulting from extreme immaturity on DOL 4. The patients’ characteristics are summarized in Table 1. During the study period, no adverse or side effect were observed including elevated liver enzymes or significant temperature difference due to paracetamol treatment.
Discussion There is still controversy about whether the PDA is a pathology requiring treatment or if it is just a reflection of delayed transitional adaptation in very low birth weight (VLBW) infants [6]. Since its persistence in preterm babies is associated with an increased risk of morbidity, including NEC, bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment, medical treatment might be indicated if hsPDA develops [12]. The size and direction of L-R shunt, duration of ductal patency, extent of the steal phenomenon and adequacy of the compensatory mechanism of premature myocardium and other organs are consistent with the clinical consequences [2]. The decision of treatment is usually made according to the presence of a clinical and hsPDA. Indomethacin and ibuprofen called cyclooxygenase (COX) inhibitors are currently used for the treatment of hsPDA [13]. These drugs, however, might cause renal, gastrointestinal adverse effects and bleeding problems and any benefits of this therapy should be carefully balanced against this potential hazards. In 2011, Hammerman et al. reported for the first time five cases of preterm infants with PDA who had been treated successfully with oral paracetamol, which inhibits the peroxidase components of prostaglandin synthetase [8]. Additionally, some more reports, published within the past
Table 1. The characteristics of patients’ paracetamol used.
Case 1 2 3 4 5 6 7 8 9 10 11
Gestation age (weeks)
Birth weight (g)
23.6 30.3 29.3 29.3 23 26.6 24 23 24 30 26.6
545 1580 970 1255 710 845 415 710 790 1380 700
Ductal diameter as mm (mm/kg body weight) 1.4 1.9 1.9 1.8 1.2 1.7 1.1 1.5 1.5 1.3 1.3
(2.6) (1.3) (2.0) (1.4) (1.7) (2.0) (2.6) (2.1) (1.9) (1.2) (1.9)
LA/Ao
Timing of paracetamol treatment (Postnatal day)
Treatment success
Survival
1.5 1.2 1.6 1.2 1.1 1.4 1 1.4 1.7 1.6 1.4
15 12 2 2 3 2 2 5 1 3 4
Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes
Yes Yes Yes No Yes Yes No Yes Yes Yes Yes
Ductal closure with intravenous paracetamol
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DOI: 10.3109/14767058.2015.1029912
few years, suggested that oral or IV paracetamol was as successful as ibuprofen and indomethacin in closing the ductus [14–17]. Yurttutan et al. used oral paracetamol as the first line drug in a small case series of preterm babies with PDA and demonstrated that the treatment was successful [10]. Two articles along with three letters reported on the IV paracetamol treatment for PDA [9,18]. Terrin et al. reported eight preterm babies with hsPDA, who were treated with paracetamol because of contraindication to ibuprofen or indomethacin [18]. Successful closure was obtained in six out of the eight neonates without any adverse effect. Oncel et al. studied the effect of IV paracetamol as the first line drug in 10 preterm infants with gestational age 24–29 weeks, who had feeding intolerance and PDA [9]. IV paracetamol resulted in successful closure of hsPDA in all patients without any adverse effects. Three letters to editors concerning the article by Oncel et al. reported their own experiences with IV paracetamol, and according to their experience, the paracetamol treatment was not successful or caused adverse effect [19–21]. In one of these letters, paracetamol was started after a median postnatal 22 days and the treatment failure might be reasonable. The letter of Alan et al. demonstrated that closure of PDA of three preterm infants had failed with subsequent paracetamol treatment after the first ibuprofen course [20]. An animal study showed that the clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration [22]. One retrospective study evaluated 102 preterm infants with gestational age 432 weeks, who were introduced to IV paracetamol before the age of 72 h [23]. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 h. After the early introduction of paracetamol, it was found that the annual incidence of PDA decreased from 30.7% to 14.7% without any undesirable effect. We think that the timing of paracetamol therapy might determine the success of this treatment. There are two studies comparing the efficacy and safety of oral paracetamol with those of oral ibuprofen in preterm infants with PDA [24,25]. These comparisons in preterm infants with PDA revealed similar efficacies in view of the rate of ductal closure and one of them even showed a decreased risk of hyperbilirubinemia or gastrointestinal bleeding with oral paracetamol treatment [24]. The IV paracetamol treatment was successful in all of our patients except Case number 8. The reopening of ductus in this baby was detected on DOL 27 and he had undergone PDA ligation. In this baby it was not the failure of PDA closure by paracetamol, but long-term ventilator dependency and infection might have caused reopening of PDA. Tekgunduz et al very recently published a letter concerning 15 mg/kg/dose of paracetamol would be harmful [21]. The authors reported that these dosing regimens had caused elevated liver enzymes in extremely preterm infants and suggested that 10 mg/kg/dose (three doses in a day) would be more safe. Although, we used higher doses than the dose in this study, we have not observed any adverse effect in our very preterm patients including the one with a birth weight of 400 g. We recognize several limitations of our study. Most importantly, we did not analyze plasma levels of paracetamol and it is not a controlled study. More studies concerning
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pharmacokinetics, pharmacodynamics and toxicity profile of paracetamol in preterm neonates are needed. Our experience indicates that the paracetamol treatment of PDA seems to be considerably effective in the preterm infants including the tiniest ones. Randomized controlled trials are required on optimal time, dosage regimes, safety and efficacy of paracetamol. Although, it is currently not licensed for PDA closure, paracetamol is a promising therapy and should be evaluated in future clinical studies.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Hammerman C, Bin-Nun A, Kaplan M. Managing the patent ductus arteriosus in the premature neonate: a new look at what we thought we knew. Semin Perinatol 2012;36:130–8. 2. Clyman R, Noori S. The very low birth weight neonate with hemodynamically significant ductus arteriosus during the first postnatal week. In: Polin RA, Kleinmann CS, Seri I, eds. Hemodynamics and cardiology. 2nd ed. Philadelphia: Elsevier Saunders; 2012:269–91. 3. Madan JC, Kendrick D, Hagadorn JI, et al. National Institute of Child Health and Human Development Neonatal Research Network. Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome. Pediatrics 2009;123:674–81. 4. Koch J, Hensley G, Roy L, et al. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006;117:1113–21. 5. Hamrick S, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010;125:1020–30. 6. Allegaert K, Anderson B, Simons S, van Overmeire B. Paracetamol to induce ductus arteriosus closure: is it valid? Arch Dis Child. 2013;98:462–6. 7. Brunner B, Hoeck M, Schermer E, et al. Patent ductus arteriosus low platelets. Cyclooxygenase inhibitors and intraventricular hemorrhage in very low birth weight preterm infants. J Pediatr 2013; 163:23–8. 8. Hammerman C, Bin-Nun A, Markovitch E, et al. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011;128:e1618–21. 9. Oncel MY, Yurttutan S, Degirmencioglu H, et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013;103:166–9. 10. Yurttutan S, Oncel MY, Arayıcı S, et al. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 2013;26:825–7. 11. El Hajjar M, Vaksmann G, Rakza T, et al. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005;90:F419–22. 12. Hamrick S, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010;125:1020–30. 13. Clyman RI. Patent ductus arteriosus in the preterm infant. In: Gleason CA, Devaskar SU, eds. Avery’s diseases of the newborn. 9th ed. Philadelphia: Elsevier Saunders; 2012:751–61. 14. Oncel MY, Yurttutan S, Uras N, et al. An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013;98:F94. 15. Sinha R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol 2013;2:30–2. 16. Ozdemir OM, Dogan M, Kucuktas K, et al. Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol 2014;35:276–9.
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17. Nadir E, Kassem E, Foldi S, et al. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol 2014;34: 748–9. 18. Terrin G, Conte F, Scipione A, et al. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Italian J Pediatrics 2014;40:21–4. 19. Roofthooft DW, van Beynum IM, Helbing WA, et al. Paracetamol for ductus arteriosus closure: not always a success story. 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;104:170. 20. Alan S, Kahvecioglu D, Erdeve O, et al. Is paracetamol a useful treatment for ibuprofen-resistant patent ductus arteriosus? 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;104:168–9.
J Matern Fetal Neonatal Med, Early Online: 1–4
21. Tekgunduz KS, Ceviz N, Demirelli Y, et al. Intravenous paracetamol for patent ductus arteriosus in premature infants – a lower dose is also effective. Neonatology 2013;104:6–7. 22. El-Khuffash A, Jain A, Corcoran D, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res 2014;76: 238–44. 23. Aikio O, Ha¨rkin P, Saarela T, Hallman M. Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants. J Matern Fetal Neonatal Med 2014;27:1252–6. 24. Dang D, Wang D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013;8:e77888–92. 25. 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: 510–14.
ORIGINAL ARTICLE
Ductal closure with intravenous paracetamol: a new approach to patent ductus arteriosus treatment
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Kainan University on 04/02/15 For personal use only.
Asli Memisoglu1, Zeynep Alp U¨nkar1, Nilufer Cetiner2, Figen Akalın2, Hulya Ozdemir1, Hu¨lya Selva Bilgen1, and Eren Ozek1 1
Division of Neonatology and 2Division of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Marmara University, Istanbul, Turkey
Abstract
Keywords
Objectives: Indomethacin and ibuprofen are commonly used in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA). These drugs are associated with serious adverse events, including gastrointestinal perforation, renal failure and bleeding. The role of paracetamol has been proposed for the treatment of PDA. Methods: We report a series of 11 neonates (birth weight: 415–1580 g; gestational age: 23–30.3 weeks) who were treated with paracetamol for a hsPDA. Neonates with hsPDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin. The condition of significant PDA was defined by the presence of at least one of the following criteria: internal ductal diameter # 1.4 mm/kg body weight, left atrium (LA)-to-aortic (Ao) root ratio 41.4, unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta along with clinical findings. Intravenous (IV) paracetamol was given at doses 15 mg/kg every 6 h for three days. Results: Successful ductal closure was achieved in 10 out of 11 babies (90.9%). No adverse or side effects were observed during the treatment. Conclusions: On the basis of these results, paracetamol could be considered as a promising and safe therapy for the treatment of PDA in preterm infants.
Paracetamol, patent ductus arteriosus, premature
Introduction Optimal management of patent ductus arteriosus (PDA) in the premature infant is a controversial issue [1]. The ductus arteriosus in normal term infants constricts rapidly after birth, resulting in ductal intimal hypoxia, remodelling and permanent closure [2]. In extremely premature infants, failure of ductus arteriosus constriction is common, affecting 70% at 528 weeks and 80% at 24–25 weeks [3,4]. Problems associated with failure of early PDA constriction include heart failure, ventilator dependence, hypotension, pulmonary haemorrhage, periventricular haemorrhage, necrotizing enterocolitis (NEC) and abnormalities of brain perfusion [2,5]. When therapeutic intervention to facilitate ductal closure is indicated, indomethacin and ibuprofen are the generally accepted drugs for hemodynamically significant PDA (hsPDA) in preterm neonates [1]. However, these drugs might have some serious adverse effects, including renal failure, gastrointestinal perforation and bleeding [5–7]. In vulnerable infants with renal failure or thrombocytopenia, choosing these drugs for medical closure of PDA is Address for correspondence: Dr. Asli Memisoglu, Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Marmara University, Istanbul, Turkey. E-mail: [email protected]
History Received 28 January 2015 Revised 10 March 2015 Accepted 12 March 2015 Published online 2 April 2015
challenging. Very recently paracetamol, an inhibitor of the peroxidase component of prostaglandin-H2 synthetase, has been proposed for the treatment of these cases [8–10]. Paracetamol has not been extensively studied, but appears to have similar efficacy to ibuprofen and indomethacin. In fact, paracetamol has many side effects, most of them are dose related, and are not fully studied in neonates. In this report, we present a series of 11 tiny preterm babies with hsPDA, treated with paracetamol in the presence of contraindication to ibuprofen or indomethacin.
Materials and methods Eleven neonates (birth weight: 415–1580 g; gestational age: 23–30.3 weeks), who were admitted to the Neonatal Intensive Care Unit at Marmara University Hospital Istanbul between November 2012 to June 2014, treated with intravenous (IV) paracetamol for clinically and hsPDA. Neonates with significant PDA were treated with paracetamol in the presence of contraindications to ibuprofen or indomethacin, including feeding intolerance, necrotizing enterocolitis (NEC), significant impairment of renal function, active bleeding, thrombocytopenia and/or coagulation defects. Paracetamol (Perfalgan; Bristol-Myers Squibb, Laboratories RENAUDIN, Itxassou, France) was given at doses 15 mg/kg every 6 h for
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A. Memisoglu et al.
J Matern Fetal Neonatal Med, Early Online: 1–4
three days. To monitor the safety of paracetamol treatment, we collected data regarding serum concentration of liver enzymes, total and direct bilirubin, creatinine and urea nitrogen. However, we did not analyze plasma levels of paracetamol. This is an observational study in a group of selected patients where ibuprofen was contraindicated due to the high risk of side effects; thus, we had no control group. The first echocardiographic examination was performed in the first 24 h of life in all babies. The ductal closure was confirmed with repeated echocardiography after 72 h of administration of IV paracetamol. Since common international consensus has not been reached on the definition of hsDA yet, the hsPDA was defined as the presence of a left atrium (LA)-to-aortic (Ao) root diameter ratio of 1.4 or greater in the parasternal long-axis view, an internal ductal diameter of 1.4 mm/kg body weight or greater, left ventricular enlargement and unrestrictive pulsatile transductal flow, reverse or absent diastolic flow in the descending aorta [11,12]. Patient’s symptomatology (status of metabolic acidosis, diminished urine output, lung overload signs, heart failure findings, etc.) was considered in making the decision of PDA’s pharmacologic treatment. Echocardiography was performed using a Philips HD 11 XE, 8S transducer (Philips Medical Systems, Bothell, WA). Each infant in this series received IV paracetamol after written parental consent was obtained for off-label usage of this well-known drug.
Statistical analyses Data are reported as means ± standard deviations and ranges. The Statistical Package for the Social Sciences version 16.0 (SPSS Inc., Chicago, IL) was performed for statistical analyses.
Results A total of 12 preterm infants received IV paracetamol for closure of PDA in this study. One of them (400 g, 22 weeks, boy) was excluded since he died because of renal failure on 3rd day-of-life (DOL) before control echocardiography could be performed. Out of the remaining patients (n ¼ 11), eight were boys (72.7%) and three were girls (27.3%) with a median gestational age of 26.6 weeks (range: 23–30.3 weeks) and a
median birth weight of 790 g (range: 415–1580 g). The mean gestational age of the 11 patients was 26.5 ± 3.0 weeks, and their mean birth weight was of 897.1 ± 356.3 g. Paracetamol treatment was started at 4.6 ± 3 days (median: 3, range: 1–15). The mean internal ductal diameter was 1.5 ± 0.3 mm (median: 1.5, range: 1.1–1.9), and the LA-to-aorta ratio was 1.4 ± 0.2 (median: 1.4, range: 1–1.7). The mean internal ductal diameter per kg (as means of body weight) was 1.9 ± 0.4 mm (median: 1.9, range: 1.2–2.6). The PDA was successfully closed with paracetamol in 10 (90.9%) of the 11 patients. Only one of the infants had undergone surgical ligation. Two out of the 11 patients died. One of them died because of late-onset sepsis on DOL 15 and the other one died because of renal failure resulting from extreme immaturity on DOL 4. The patients’ characteristics are summarized in Table 1. During the study period, no adverse or side effect were observed including elevated liver enzymes or significant temperature difference due to paracetamol treatment.
Discussion There is still controversy about whether the PDA is a pathology requiring treatment or if it is just a reflection of delayed transitional adaptation in very low birth weight (VLBW) infants [6]. Since its persistence in preterm babies is associated with an increased risk of morbidity, including NEC, bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment, medical treatment might be indicated if hsPDA develops [12]. The size and direction of L-R shunt, duration of ductal patency, extent of the steal phenomenon and adequacy of the compensatory mechanism of premature myocardium and other organs are consistent with the clinical consequences [2]. The decision of treatment is usually made according to the presence of a clinical and hsPDA. Indomethacin and ibuprofen called cyclooxygenase (COX) inhibitors are currently used for the treatment of hsPDA [13]. These drugs, however, might cause renal, gastrointestinal adverse effects and bleeding problems and any benefits of this therapy should be carefully balanced against this potential hazards. In 2011, Hammerman et al. reported for the first time five cases of preterm infants with PDA who had been treated successfully with oral paracetamol, which inhibits the peroxidase components of prostaglandin synthetase [8]. Additionally, some more reports, published within the past
Table 1. The characteristics of patients’ paracetamol used.
Case 1 2 3 4 5 6 7 8 9 10 11
Gestation age (weeks)
Birth weight (g)
23.6 30.3 29.3 29.3 23 26.6 24 23 24 30 26.6
545 1580 970 1255 710 845 415 710 790 1380 700
Ductal diameter as mm (mm/kg body weight) 1.4 1.9 1.9 1.8 1.2 1.7 1.1 1.5 1.5 1.3 1.3
(2.6) (1.3) (2.0) (1.4) (1.7) (2.0) (2.6) (2.1) (1.9) (1.2) (1.9)
LA/Ao
Timing of paracetamol treatment (Postnatal day)
Treatment success
Survival
1.5 1.2 1.6 1.2 1.1 1.4 1 1.4 1.7 1.6 1.4
15 12 2 2 3 2 2 5 1 3 4
Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes
Yes Yes Yes No Yes Yes No Yes Yes Yes Yes
Ductal closure with intravenous paracetamol
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DOI: 10.3109/14767058.2015.1029912
few years, suggested that oral or IV paracetamol was as successful as ibuprofen and indomethacin in closing the ductus [14–17]. Yurttutan et al. used oral paracetamol as the first line drug in a small case series of preterm babies with PDA and demonstrated that the treatment was successful [10]. Two articles along with three letters reported on the IV paracetamol treatment for PDA [9,18]. Terrin et al. reported eight preterm babies with hsPDA, who were treated with paracetamol because of contraindication to ibuprofen or indomethacin [18]. Successful closure was obtained in six out of the eight neonates without any adverse effect. Oncel et al. studied the effect of IV paracetamol as the first line drug in 10 preterm infants with gestational age 24–29 weeks, who had feeding intolerance and PDA [9]. IV paracetamol resulted in successful closure of hsPDA in all patients without any adverse effects. Three letters to editors concerning the article by Oncel et al. reported their own experiences with IV paracetamol, and according to their experience, the paracetamol treatment was not successful or caused adverse effect [19–21]. In one of these letters, paracetamol was started after a median postnatal 22 days and the treatment failure might be reasonable. The letter of Alan et al. demonstrated that closure of PDA of three preterm infants had failed with subsequent paracetamol treatment after the first ibuprofen course [20]. An animal study showed that the clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration [22]. One retrospective study evaluated 102 preterm infants with gestational age 432 weeks, who were introduced to IV paracetamol before the age of 72 h [23]. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 h. After the early introduction of paracetamol, it was found that the annual incidence of PDA decreased from 30.7% to 14.7% without any undesirable effect. We think that the timing of paracetamol therapy might determine the success of this treatment. There are two studies comparing the efficacy and safety of oral paracetamol with those of oral ibuprofen in preterm infants with PDA [24,25]. These comparisons in preterm infants with PDA revealed similar efficacies in view of the rate of ductal closure and one of them even showed a decreased risk of hyperbilirubinemia or gastrointestinal bleeding with oral paracetamol treatment [24]. The IV paracetamol treatment was successful in all of our patients except Case number 8. The reopening of ductus in this baby was detected on DOL 27 and he had undergone PDA ligation. In this baby it was not the failure of PDA closure by paracetamol, but long-term ventilator dependency and infection might have caused reopening of PDA. Tekgunduz et al very recently published a letter concerning 15 mg/kg/dose of paracetamol would be harmful [21]. The authors reported that these dosing regimens had caused elevated liver enzymes in extremely preterm infants and suggested that 10 mg/kg/dose (three doses in a day) would be more safe. Although, we used higher doses than the dose in this study, we have not observed any adverse effect in our very preterm patients including the one with a birth weight of 400 g. We recognize several limitations of our study. Most importantly, we did not analyze plasma levels of paracetamol and it is not a controlled study. More studies concerning
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pharmacokinetics, pharmacodynamics and toxicity profile of paracetamol in preterm neonates are needed. Our experience indicates that the paracetamol treatment of PDA seems to be considerably effective in the preterm infants including the tiniest ones. Randomized controlled trials are required on optimal time, dosage regimes, safety and efficacy of paracetamol. Although, it is currently not licensed for PDA closure, paracetamol is a promising therapy and should be evaluated in future clinical studies.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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