Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Oral Versus Intravenous Paracetamol: Which Is Better In Closure Of Patent Ductus Arterious In Very Low Birth Weight Infants? Selim Sancak, MD, Tulin Gokmen Yildirim, MD, Sevilay Topcuoglu MD, Taner Yavuz, MD, Guner Karatekin, MD, Fahri Ovali, MD doi: 10.3109/14767058.2014.989829 Abstract
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Objectives: Compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants. Methods: Eighteen VLBW infants with HSPDA treated with either intravenous (n=10) or oral (n=8) paracetamol at 60 mg/kg/day for 3 consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes. Results: After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% vs. 70%), but it was not statistically significant (p=0.588). Liver function tests were normal after the treatment. Conclusion: Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data.
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Title: Oral Versus Intravenous Paracetamol: Which Is Better In Closure Of Patent Ductus Arterious In Very Low Birth Weight Infants? Running Head: Oral Versus Intravenous Paracetamol For Ductal Closure Authors: Selim Sancak, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Laurentian University on 12/05/14 For personal use only.
Neonatal Intensive Care Unit, Istanbul, TR Tulin Gokmen Yildirim, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Sevilay Topcuoglu MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Taner Yavuz, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Pediatric Cardiology, Istanbul, TR Guner Karatekin, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Fahri Ovali, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Correspondence:
Address: Zeynep Kamil Kadın ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi Opr. Dr. Burhanettin Üstünel Cad. No:10, Üsküdar İstanbul – Asya- TURKEY Tel : +905354282224 Fax: +90216 391 06 90 E-mail: [email protected]
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ABSTRACT Objectives: Compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants. Methods: Eighteen VLBW infants with HSPDA treated with either intravenous (n=10) or oral (n=8) paracetamol at 60 mg/kg/day for 3 consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes. Results: After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% vs. 70%), but it was not statistically significant (p=0.588). Liver function tests were normal after the treatment. Conclusion: Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data. INTRODUCTION Hemodynamically significant patent ductus arteriosus (HSPDA) affects 40% of very low birth weight (VLBW) infants [1]. A HSPDA leads to detrimental clinical outcomes during the first few days of life [2]. Left to right shunt through the duct causes pulmonary congestion and decreased systemic blood flow. Therefore it is an important risk factor for chronic lung disease, necrotising enterocolitis and neurological damage [3]. Early symptomathic therapy (1-3 days of age), as compared with late symptomathic therapy (7-10 days of age), has been found to reduce pulmonary morbidity, to decrease the need
for subsequent surgical ductal ligation and to be associated with less necrotizing enterocolitis (NEC) [4]. Particularly, in infants with birth weight below 1000 g, HSPDA may be associated with greater bronchopulmoary displasia [5], intraventricular hemorrhage (IVH) [6], NEC [7] and mortality [8].
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Sadeck et al conducted a study with preterm infants who had PDA and weighing less than 1000 g at birth. The protection of conservative and pharmacological treatments for the combined outcome death/BPD was demonstrated, although the conservative treatment was related to higher mortality. They also showed that infants treated with prostaglandin inhibitors (indomethacin or ibuprofen) demonstrated less bronchopulmonary displasia (BPD), retinopathy of prematurity (ROP) and NEC compared to those who underwent surgical ligation [9]. Ductal patency maintained by circulating prostaglandins in intrauterine life. These prostaglandins are synthesised by prostaglandin-H2 synthetase (PGHS) which has two components; cyclo-oxygenase (COX) and peroxidase [10]. The most widely used COX enzyme inhibitors for ductal closure are indomethacin and ibuprofen. The success rate of these drugs in HSPDA closure is about 75-93% [11]. However, they may cause serious side effects such as peripheral vasoconstriction, gastrointestinal bleeding and perforation, decreased platelet aggregation, hyperbilirubinemia, and renal failure. There are also frequent contraindications for indomethacin and ibuprofen such as IVH, thrombocytopenia,and acute renal injury [12]. Paracetamol, has been recently proposed for the treatment of HSPDA [12]. It prevents prostaglandin synthesis by inhibiting peroxidase component of the PGHS which is different from COX inhibitors [13-14]. Lucas et al has shown that paracetamol inhibition was prominent at decreased local peroxidase concentration [15]. Although there are few case series and only one study evaluating the efficacy of paracetamol treatment [12,13,16-22], there is not any study that compares intravenous and oral paracetamol in the treatment of HSPDA. We performed a retrospective observational study to compare the efficacy and safety of oral and intravenous paracetamol for the pharmacological closure of HSPDA in VLBW infants. METHODS
The study was conducted in neonatal intensive care unit of the Zeynep Kamil Maternity and Children’s Training and Research Hospital, in Istanbul, Turkey, between January 2013 and June 2014. This unit has 58 incubators and serves as a referral Level III NICU with approximately 2300 newborn admissions per year. This retrospective study was approved by the local ethics committee.
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Preterm infants with a gestational age ≤30 weeks, birth weight ≤1250 g and had echocardiographic evidence of HSPDA who were unresponsive to ibuprofen (two courses of iv or oral ibuprofen at an initial dose of 10 mg/kg followed by 5 mg/kg at 24 hours intervals) or contraindications to ibuprofen (i.e. intraventricular hemorrhage ≥grade 3, platelet count 1,5 and diastolic aortic retrograde flow [7]. Two dimensional color doppler echocardiography was performed with Philips En Visor C HD ultrasound (Royal Philips Electronics, Amsterdam, Netherlands). A multifrequency 12 MHz sector probe was used. Exclusion criteria were major congenital abnormalities, right to left shunt through duct, and persistent pulmonary hypertension. Each preterm infant received either intravenous paracetamol (Perfalgan; Bristol Myers Squibb, Munich, Germany) or oral paracetamol (Calpol; GlaxoSmithKline, Istanbul, Turkey), at a dose of 60 mg/kg/day divided into four doses for three days of a course. Before and 24 hours after the end of paracetamol treatment, total bilirubin levels Alanine transaminase (ALT), and Aspartate
transaminase(AST)
were
determined
and
cranial
ultrasonography
and
echocardiography were performed in all patients. If PDA did not close, a second course of paracetamol was administered in the same way. If the ductus arteriosus was still hemodynamically significant after two courses of paracetamol, surgical ligation was performed. A second echocardiographic control was performed 3 days after ductal closure to check for reopening. Ductal closure rate and liver function tests were the major outcome measures. Secondary outcomes were surgical ligation rate, duration of mechanical ventilation, BPD rate, duration of hospitalisation and death.
Statistical analyses were performed using the statistical Package for the Social Sciences (SPSS) version 17.0 (Inc, Chicago, IL, USA). Descripted analyses were presented using medians and minimum-maximum range for the non-normally distributed and ordinal variables. Since all of the measurements were not normally distributed, nonparametric tests were conducted to compare these parameters, as well as to compare the ordinal variables. Man Whitney U test and Wilcoxon test were used for continuous variables and Chi square and Fisher’s exact test was
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used for categorical variables. A p-value of less than 0,05 was considered to show a statistically significant result. RESULTS During the study period, there were 18 preterm VLBW infants with HSPDA who failed or could not be given ibuprofen because of a contraindication. Ten preterm infants were treated with
intravenous paracetamol while 8 were treated with oral paracetamol. Clinical
characteristics, except postnatal treatment age, were similar between the two groups. Paracetamol therapy was started significantly later in the oral paracetamol group (p=0.003). Comparison of the clinical chararacteristics and outcomes of the patients are shown in Table 1. There was not any increase in liver function tests following paracetamol treatment (Table 2). There were no treatment-related side effects of paracetamol either. After the first course of treatment, the HSPDA closed in 2/8 (25%) of the patients in the oral paracetamol group versus 4/10 (40%) of those in the intravenous paracetamol group (P=0.502). Six out of 8 patients (75%) in the oral paracetamol group and 6 out of 10 patients (60%) in the iv paracetamol group required a second course of drug therapy. Cumulative closure rates were 7/8 (88%) and 7/10 (70%) in oral and iv paracetamol groups, respectively. One patient in each group underwent surgical ligation. Re-opening was not observed in both groups. Clinical characteristics and echocardiographic findings of the patients are depicted in table 3. Without concerning of administration way, succesful ductal closure rate was 33% (6/18) and 66% (8/12) with 1 and 2 cure of paracetamol, respectively. Total cumulative closure rate was 78% (14/18) in all patients.
DISCUSSION Cyclooxigenase inhibitors used for the treatment of HSPDA have many adverse effects such as gastrointestinal bleeding, spontaneous intestinal perforation, NEC, acute renal impairment, as well as contraindications such as hyperbilirubinemia and trombocytopenia [12,14-16,18]. Therefore paracetamol has been used in these circumstances as a safer alternative.
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The first paracetamol use for HSPDA treatment was reported by Hammerman et al. [20]. Five preterm infants (26-32 weeks of gestation; postnatal age, minimum-maximum:3-35 days) with ibuprofen resistant HSPDA or with contraindications for ibuprofen were successfully treated with oral paracetamol and no adverse effect was observed. Oncel et al [16] also reported that paracetamol is an alternative drug for the treatment of HSPDA in whose ibuprofen therapy either has failed or been contraindicated, and they found that it was effective in 87,5 % of the cases. Yurttutan et al [17] reported that five out of six preterm infants were treated successfully with oral paracetamol as a first line theraphy (83%). We administered oral paracetamol to 8 patients with HSPDA, and seven of them successfully treated (88%). Oncel et al reported a preliminary case report that 10 preterm infants treated with intravenous paracetamol with HSPDA because of feeding contraindicated or had feeding intolerance. They demonstrated 100% success in ductal closure [22]. In our study, we showed that seven out of ten preterm infants were treated successfully with intravenous paracetamol (70%). Need for second cure was 75% and 60% in oral and iv group, respectively. It was obvious that oral group got paracetamol after one week of age which was probably the reason for repeated therapy. A recent study reported that elevated transaminase levels were seen due to intravenous paracetamol treatment for PDA closure and they stated that a lower dose of paracetamol is also effective without causing any side effects [23]. We did not observe any adverse effects related to paracetamol treatment either in the oral or intravenous group with 60 mg/kg/day dose qid up to six days. Pretreatment AST levels were higher in iv paracetamol group regarding to the age at start of paracetamol which was in the first few days because they were in a more unstabile condition (on ventilatory treatment, more O2 and cardiotonic requirement). But there were not
statistically significant difference for pre- and posttreatment AST levels between groups (p=0.1 and p=0.5, respectively). Recently, it has been reported that in a prospective randomised trial 90 preterm infants with HSPDA were assigned to oral paracetamol or oral ibuprofen, and oral paracetamol was found as effective as oral ibuprofen [24].
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There are a few studies searching for ductal closure using oral versus intravenous formulation of the same agent. Gokmen et al. found that PDA closure rate was significantly higher with oral ibuprofen compared to intravenous ibuprofen [25]. They did not measure plasma levels of ibuprofen. However, absorbtion is slower with oral ibuprofen than with intravenous ibuprofen, and the longer half-life probably prolongs the time of contact with the ductus, leading to a higher response. In a pilot study, Raju et al reported that ibuprofen was absorbed rapidly after oral administration, with peak plasma concentrations after 1 to 2 hours [26]. Sharma et al reported wide interindividual variability in the plasma concentration, elimination- half-life, and area under the plasma concentration-time curve [27]. In our study, although the age of oral paracetamol group was significantly higher (p=0,003) than iv paracetamol group, ductal closure rate was higher in oral paracetamol group (88% vs 70%). Since our study was retrospective, we could not measure serum paracetamol levels. However, we speculate that ductal closure was better with the prolonged drug exposure as a result of longer half life with oral treatment. In order to demonstrate this effect, further randomized controlled trials with measurement of drug levels are required. Gestational age and birth weight were lower in iv paracetamol group than oral group, but there were no statistically difference between groups. Yang et al reported that PDA closure is age-related, and early administration of indomethacin could increase PDA closure [28]. In our study,
although age at start of
paracetamol theraphy was significantly higher in oral paracetamol group compared to iv group (median (range):11,5 (4-24) vs 3 (2-11) days), total ductal closure rate was higher in oral paracetamol group. We supposed that oral paracetamol theraphy was more efficacious than iv paracetamol theraphy.
Although our study is retrospective and includes a small number of patients, it is important that it is the first report comparing the effects of oral versus intravenous paracetamol for PDA treatment in VLBW preterm infants. We showed that oral treatment was as effective and safe as intravenous treatment. Since oral paracetamol is cheaper, more available and noninvasive, it may be preferable to intravenous paracetamol. Although it was not statistically significant, ductal closure rate was higher in oral J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Laurentian University on 12/05/14 For personal use only.
paracetamol group than in the intravenous group a larger, randomised controlled clinical trial is needed to establish the true benefit. Acknowledgments: none. Declaration of Interest Statement The authors report no declarations of interest. No financial interest in any product discussed. References 1. Fanos V, Benini D, Verlato G, Errico G, Cuzzolin L. Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus. Fundam Clin Pharmacol 2005;19:187-193. 2. Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010;125(5):1020-1030. 3. Thomas RL, Parker GC, Van OvermeireB, Aranda JV. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. Eur J Pediatr 2005;164:135-140. 4. Clyman RI. Recommendations for the postnatal use of indomethacin: An analysis of four separate treatment strategies. J Pediatr 1996;128:601-607. 5. Redline RW, Wilson-Costello D, Hack M. Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants. Pediatr Res 2002;52:713-9.
6. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183-6. 7. Noerr B. Current controversies in the understanding of necrotizing enterocolitis Part 1. Adv Neonatal Care 2003;3:107-20. 8. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept
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the null hypothesis? J Perinatol 2010;30:241-52. 9. Sadeck LS, Leone CR, Procianoy RS, Guinsburg R, Marba ST, Martinez FE, et al. Effects of therapeutic approach on the neonatal evolution of very low birth weight infants with patent ductus arteriosus. J Pediatr (Rio J). 2014 Jul 19. 10. Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate 2006;89(4):330-335. 11. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of a patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2007;3:CD003481. 12. Van Overmeire B, Smets K, Lecoutere D, Van De Broek H, Weiler J. De Groote K, Langhendnes JP. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343(10):674-681. 13. 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. 14. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants. A randomized controlled trial. J Pediatr 2014 Mar;164(3):510-4. 15. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: role of cyclo-oxigenase. FASEB J 2005;19:635-7. 16. Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, Erdeve O, Dilmen U. An alternative drug (paracetamol) in ibuprofen resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013 Jan;98:F94.
17. Yurttutan S, Oncel MY, Arayıcı S, Uras N, Altug N, Erdeve O, Dilmen U. A different firstchoice drug in the management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 2013 May;26(8):825-827. 18. Ozmert MA, Ozdemir, Dogan M, Kucuktascı K, Ergin H, Sahin O. Paracetamol theraphy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol
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2014;35:276-279. 19. Jasani B, Kabra N, Nanavati R. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013 Oct-Dec;59(4):312-4. 20. Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Pediatrics 2011;128(6):e1618-21. 21. Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R, Ventriglia F, De Curtis M. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neaonates. Ital J Pediatr 2014 Feb 20;40(1):21. 22. Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O, Dilmen U. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013;103:166-169. 23. Tekgunduz KS, Ceviz N, Demirelli Y, Olgun H, Caner I, Sahin IO, Yolcu C. Intravenous paracetamol for patent ductus arteriosus in premature infants: a lover dose is also effective. Neonatology 2013;104(1):6-7. 24. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014 Mar;164(3):510-4.e1. 25. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. J Pediatr 2011;158:549-554. 26. Raju NV, Bharadwaj RA, Thomas R, Konduri GG. Ibuprofen use to reduce the incidence and severity of bronchopulmonary dysplasia: a pilot study. J perinatol 2000;20:13-6.
27. Sharma PK, Garg SK, Narang A. Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol 2003;43:968-73. 28. Yang CZ, Lee J. Factors affecting successful closure of hemodynamically significant patent ductus arteriosus with indomethacin in extremely low birth weight infants. World J Pediatr 2008
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May;4(2):91-6.
Table 1. Comparison of the clinical chararacteristics and outcomes of cases Oral paracetamol
Intravenous
P value
(n=8)
paracetamol (n=10)
Birth weight,g*
1160 (660-1285)
785 (730-1100)
0,068
Gestational age, weeks *
28,1 (24,1-30)
26,7 (25,3-28,7)
0,062
Male/Female
4/4
3/10
0,63
Antenatal steroid
4/8
5/10
1
Prolonged premature rupture of mebrane,
2/8 (25%)
5/10 (50%)
0,28
Delivery by cesarean section,
6/8 (%75)
7/10 (70%)
0,814
Resuscitation in delivery room,
6/8 (75%)
7/10 (70%)
0,81
Respiratory distress syndrome,
8/8 (100%)
9/10 (90%)
1
Caffeine,
8/8 (%100)
10/10 (%100)
1
Ductal diameter,mm *
1,8 (1,7-2,4)
2,1 (1,7-2,5)
0,137
La/Ao *
1,65 (1,3-1,9)
1,75 (1,5-1,9)
0,258
Age at start of paracetamol,days *
11,5 (4-24)
3 (2-11)
0,003
Ductal closure with one course,
2/8 (25%)
4/10 (40%)
0,502
Ductal closure with two courses,
7/8 (88%)
7/10 (70%)
0,588
Surgical ligation
1/8 (13%)
1/10 (10%)
1
Duration of mechanical ventilation, days
26,5 (4-36)
29 (17-66)
0,213
BPD,
8/8 (100%)
8/10 (80%)
0,477
ROP required anti-VEGF treatment
3/8 (38%)
3/10 (30%)
0,737
Duration of hospitalisation, days *
61,5 (38-81)
62,5 (17-113)
0,965
Death, n (%)
1/8 (13%)
3/10 (30)
0,588
La: Left atrium, Ao: Aortic root diameter, BPD: Bronchopulmonary dysplasia, ROP: Retinopathy of prematurity *The values are given as median (minimum-maximum)
Table 2. Evaluation of liver function tests before and after paracetamol treatment
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Oral paracetamol
Intravenous paracetamol
Pre-treatment
Post-treatment P value
Pre-treatment
Post-treatment P value
AST (U/L)
25,5 (17-38)
25,5 (17-86)
0,574
60,5 (4-162)
24,5 (12-109)
0,017
ALT (U/L)
18,5 (6-56)
15 (6-56)
0,35
9,5 (4-25)
9,1 (6-19)
0,281
Total bilirubin (mg/dL)
3,7 (0,8-5,4)
2,1 (0,7-4,1)
0,017
5,5 (0,7-9,7)
4,5 (0,6-11)
0,224
*The values are given as median (minimum-maximum)
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Tablo 3. Clinical characteristics and echocardiographic findings of the patients. Case Gestation Birth Internal Age weeks ductal (weeks) (g) diameter (mm) 1 27,1 730 2,3 2 25,3 755 2,1 3 28,7 1100 1,7 4 26,6 1050 2,2 5 26,7 740 1,8 6 26,7 1020 2,3 7 26,0 780 1,9 8 28,0 900 2,1 9 25,9 735 2,1 10 28,0 790 2,5 11 29,0 1250 2,4 12 28,1 1120 1,7 13 30,0 1285 2,1 14 24,1 765 1,8 15 27,0 660 1,7 16 27,4 900 1,9 17 28,6 1200 1,8 18 27,7 1215 1,7
La:Ao Current Previous contraindication ibuprofen for ibuprofen treatment 1,5 1,8 1,6 1,9 1,5 1,9 1,6 1,8 1,8 1,9 1,8 1,3 1,4 1,5 1,8 1,7 1,9 1,4
IVH grade 3 Trombocytopenia IVH grade 3 IVH grade 3 Trombocytopenia IVH grade 3 IVH grade 3 IVH grade 4 IVH grade 3 IVH grade 4 IVH grade 4 none none none none none none none
none none none none none none none none none none none 2 courses 2 courses 2 courses 2 courses 2 courses 2 courses 2 courses
Administration Age at start of Duration of route of paracetamol paracetamol paracetamol (days) treatment (days) IV 5 3 IV 7 3 IV 3 6 IV 3 6 IV 2 3 IV 3 6 IV 2 6 PO 5 6 IV 2 3 IV 3 6 PO 4 6 PO 24 6 PO 14 6 PO 12 6 PO 11 3 IV 11 6 PO 11 6 PO 14 3
La: Left atrium, Ao: Aortic root diameter, IVH: intraventricular hemorrhage, IV: intravenous, PO: Peroral,
Result
Surgical ligation
closed closed not closed not closed closed closed not closed closed closed closed closed closed closed closed closed closed not closed closed
No No No No No No Yes No No No No No No No No No Yes No
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Objectives: Compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants. Methods: Eighteen VLBW infants with HSPDA treated with either intravenous (n=10) or oral (n=8) paracetamol at 60 mg/kg/day for 3 consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes. Results: After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% vs. 70%), but it was not statistically significant (p=0.588). Liver function tests were normal after the treatment. Conclusion: Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data.
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Title: Oral Versus Intravenous Paracetamol: Which Is Better In Closure Of Patent Ductus Arterious In Very Low Birth Weight Infants? Running Head: Oral Versus Intravenous Paracetamol For Ductal Closure Authors: Selim Sancak, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Laurentian University on 12/05/14 For personal use only.
Neonatal Intensive Care Unit, Istanbul, TR Tulin Gokmen Yildirim, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Sevilay Topcuoglu MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Taner Yavuz, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Pediatric Cardiology, Istanbul, TR Guner Karatekin, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Fahri Ovali, MD, Zeynep Kamil Maternity and Children's Training and Research Hospital, Neonatal Intensive Care Unit, Istanbul, TR Correspondence:
Address: Zeynep Kamil Kadın ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi Opr. Dr. Burhanettin Üstünel Cad. No:10, Üsküdar İstanbul – Asya- TURKEY Tel : +905354282224 Fax: +90216 391 06 90 E-mail: [email protected]
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ABSTRACT Objectives: Compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants. Methods: Eighteen VLBW infants with HSPDA treated with either intravenous (n=10) or oral (n=8) paracetamol at 60 mg/kg/day for 3 consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes. Results: After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% vs. 70%), but it was not statistically significant (p=0.588). Liver function tests were normal after the treatment. Conclusion: Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data. INTRODUCTION Hemodynamically significant patent ductus arteriosus (HSPDA) affects 40% of very low birth weight (VLBW) infants [1]. A HSPDA leads to detrimental clinical outcomes during the first few days of life [2]. Left to right shunt through the duct causes pulmonary congestion and decreased systemic blood flow. Therefore it is an important risk factor for chronic lung disease, necrotising enterocolitis and neurological damage [3]. Early symptomathic therapy (1-3 days of age), as compared with late symptomathic therapy (7-10 days of age), has been found to reduce pulmonary morbidity, to decrease the need
for subsequent surgical ductal ligation and to be associated with less necrotizing enterocolitis (NEC) [4]. Particularly, in infants with birth weight below 1000 g, HSPDA may be associated with greater bronchopulmoary displasia [5], intraventricular hemorrhage (IVH) [6], NEC [7] and mortality [8].
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Sadeck et al conducted a study with preterm infants who had PDA and weighing less than 1000 g at birth. The protection of conservative and pharmacological treatments for the combined outcome death/BPD was demonstrated, although the conservative treatment was related to higher mortality. They also showed that infants treated with prostaglandin inhibitors (indomethacin or ibuprofen) demonstrated less bronchopulmonary displasia (BPD), retinopathy of prematurity (ROP) and NEC compared to those who underwent surgical ligation [9]. Ductal patency maintained by circulating prostaglandins in intrauterine life. These prostaglandins are synthesised by prostaglandin-H2 synthetase (PGHS) which has two components; cyclo-oxygenase (COX) and peroxidase [10]. The most widely used COX enzyme inhibitors for ductal closure are indomethacin and ibuprofen. The success rate of these drugs in HSPDA closure is about 75-93% [11]. However, they may cause serious side effects such as peripheral vasoconstriction, gastrointestinal bleeding and perforation, decreased platelet aggregation, hyperbilirubinemia, and renal failure. There are also frequent contraindications for indomethacin and ibuprofen such as IVH, thrombocytopenia,and acute renal injury [12]. Paracetamol, has been recently proposed for the treatment of HSPDA [12]. It prevents prostaglandin synthesis by inhibiting peroxidase component of the PGHS which is different from COX inhibitors [13-14]. Lucas et al has shown that paracetamol inhibition was prominent at decreased local peroxidase concentration [15]. Although there are few case series and only one study evaluating the efficacy of paracetamol treatment [12,13,16-22], there is not any study that compares intravenous and oral paracetamol in the treatment of HSPDA. We performed a retrospective observational study to compare the efficacy and safety of oral and intravenous paracetamol for the pharmacological closure of HSPDA in VLBW infants. METHODS
The study was conducted in neonatal intensive care unit of the Zeynep Kamil Maternity and Children’s Training and Research Hospital, in Istanbul, Turkey, between January 2013 and June 2014. This unit has 58 incubators and serves as a referral Level III NICU with approximately 2300 newborn admissions per year. This retrospective study was approved by the local ethics committee.
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Preterm infants with a gestational age ≤30 weeks, birth weight ≤1250 g and had echocardiographic evidence of HSPDA who were unresponsive to ibuprofen (two courses of iv or oral ibuprofen at an initial dose of 10 mg/kg followed by 5 mg/kg at 24 hours intervals) or contraindications to ibuprofen (i.e. intraventricular hemorrhage ≥grade 3, platelet count 1,5 and diastolic aortic retrograde flow [7]. Two dimensional color doppler echocardiography was performed with Philips En Visor C HD ultrasound (Royal Philips Electronics, Amsterdam, Netherlands). A multifrequency 12 MHz sector probe was used. Exclusion criteria were major congenital abnormalities, right to left shunt through duct, and persistent pulmonary hypertension. Each preterm infant received either intravenous paracetamol (Perfalgan; Bristol Myers Squibb, Munich, Germany) or oral paracetamol (Calpol; GlaxoSmithKline, Istanbul, Turkey), at a dose of 60 mg/kg/day divided into four doses for three days of a course. Before and 24 hours after the end of paracetamol treatment, total bilirubin levels Alanine transaminase (ALT), and Aspartate
transaminase(AST)
were
determined
and
cranial
ultrasonography
and
echocardiography were performed in all patients. If PDA did not close, a second course of paracetamol was administered in the same way. If the ductus arteriosus was still hemodynamically significant after two courses of paracetamol, surgical ligation was performed. A second echocardiographic control was performed 3 days after ductal closure to check for reopening. Ductal closure rate and liver function tests were the major outcome measures. Secondary outcomes were surgical ligation rate, duration of mechanical ventilation, BPD rate, duration of hospitalisation and death.
Statistical analyses were performed using the statistical Package for the Social Sciences (SPSS) version 17.0 (Inc, Chicago, IL, USA). Descripted analyses were presented using medians and minimum-maximum range for the non-normally distributed and ordinal variables. Since all of the measurements were not normally distributed, nonparametric tests were conducted to compare these parameters, as well as to compare the ordinal variables. Man Whitney U test and Wilcoxon test were used for continuous variables and Chi square and Fisher’s exact test was
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used for categorical variables. A p-value of less than 0,05 was considered to show a statistically significant result. RESULTS During the study period, there were 18 preterm VLBW infants with HSPDA who failed or could not be given ibuprofen because of a contraindication. Ten preterm infants were treated with
intravenous paracetamol while 8 were treated with oral paracetamol. Clinical
characteristics, except postnatal treatment age, were similar between the two groups. Paracetamol therapy was started significantly later in the oral paracetamol group (p=0.003). Comparison of the clinical chararacteristics and outcomes of the patients are shown in Table 1. There was not any increase in liver function tests following paracetamol treatment (Table 2). There were no treatment-related side effects of paracetamol either. After the first course of treatment, the HSPDA closed in 2/8 (25%) of the patients in the oral paracetamol group versus 4/10 (40%) of those in the intravenous paracetamol group (P=0.502). Six out of 8 patients (75%) in the oral paracetamol group and 6 out of 10 patients (60%) in the iv paracetamol group required a second course of drug therapy. Cumulative closure rates were 7/8 (88%) and 7/10 (70%) in oral and iv paracetamol groups, respectively. One patient in each group underwent surgical ligation. Re-opening was not observed in both groups. Clinical characteristics and echocardiographic findings of the patients are depicted in table 3. Without concerning of administration way, succesful ductal closure rate was 33% (6/18) and 66% (8/12) with 1 and 2 cure of paracetamol, respectively. Total cumulative closure rate was 78% (14/18) in all patients.
DISCUSSION Cyclooxigenase inhibitors used for the treatment of HSPDA have many adverse effects such as gastrointestinal bleeding, spontaneous intestinal perforation, NEC, acute renal impairment, as well as contraindications such as hyperbilirubinemia and trombocytopenia [12,14-16,18]. Therefore paracetamol has been used in these circumstances as a safer alternative.
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The first paracetamol use for HSPDA treatment was reported by Hammerman et al. [20]. Five preterm infants (26-32 weeks of gestation; postnatal age, minimum-maximum:3-35 days) with ibuprofen resistant HSPDA or with contraindications for ibuprofen were successfully treated with oral paracetamol and no adverse effect was observed. Oncel et al [16] also reported that paracetamol is an alternative drug for the treatment of HSPDA in whose ibuprofen therapy either has failed or been contraindicated, and they found that it was effective in 87,5 % of the cases. Yurttutan et al [17] reported that five out of six preterm infants were treated successfully with oral paracetamol as a first line theraphy (83%). We administered oral paracetamol to 8 patients with HSPDA, and seven of them successfully treated (88%). Oncel et al reported a preliminary case report that 10 preterm infants treated with intravenous paracetamol with HSPDA because of feeding contraindicated or had feeding intolerance. They demonstrated 100% success in ductal closure [22]. In our study, we showed that seven out of ten preterm infants were treated successfully with intravenous paracetamol (70%). Need for second cure was 75% and 60% in oral and iv group, respectively. It was obvious that oral group got paracetamol after one week of age which was probably the reason for repeated therapy. A recent study reported that elevated transaminase levels were seen due to intravenous paracetamol treatment for PDA closure and they stated that a lower dose of paracetamol is also effective without causing any side effects [23]. We did not observe any adverse effects related to paracetamol treatment either in the oral or intravenous group with 60 mg/kg/day dose qid up to six days. Pretreatment AST levels were higher in iv paracetamol group regarding to the age at start of paracetamol which was in the first few days because they were in a more unstabile condition (on ventilatory treatment, more O2 and cardiotonic requirement). But there were not
statistically significant difference for pre- and posttreatment AST levels between groups (p=0.1 and p=0.5, respectively). Recently, it has been reported that in a prospective randomised trial 90 preterm infants with HSPDA were assigned to oral paracetamol or oral ibuprofen, and oral paracetamol was found as effective as oral ibuprofen [24].
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There are a few studies searching for ductal closure using oral versus intravenous formulation of the same agent. Gokmen et al. found that PDA closure rate was significantly higher with oral ibuprofen compared to intravenous ibuprofen [25]. They did not measure plasma levels of ibuprofen. However, absorbtion is slower with oral ibuprofen than with intravenous ibuprofen, and the longer half-life probably prolongs the time of contact with the ductus, leading to a higher response. In a pilot study, Raju et al reported that ibuprofen was absorbed rapidly after oral administration, with peak plasma concentrations after 1 to 2 hours [26]. Sharma et al reported wide interindividual variability in the plasma concentration, elimination- half-life, and area under the plasma concentration-time curve [27]. In our study, although the age of oral paracetamol group was significantly higher (p=0,003) than iv paracetamol group, ductal closure rate was higher in oral paracetamol group (88% vs 70%). Since our study was retrospective, we could not measure serum paracetamol levels. However, we speculate that ductal closure was better with the prolonged drug exposure as a result of longer half life with oral treatment. In order to demonstrate this effect, further randomized controlled trials with measurement of drug levels are required. Gestational age and birth weight were lower in iv paracetamol group than oral group, but there were no statistically difference between groups. Yang et al reported that PDA closure is age-related, and early administration of indomethacin could increase PDA closure [28]. In our study,
although age at start of
paracetamol theraphy was significantly higher in oral paracetamol group compared to iv group (median (range):11,5 (4-24) vs 3 (2-11) days), total ductal closure rate was higher in oral paracetamol group. We supposed that oral paracetamol theraphy was more efficacious than iv paracetamol theraphy.
Although our study is retrospective and includes a small number of patients, it is important that it is the first report comparing the effects of oral versus intravenous paracetamol for PDA treatment in VLBW preterm infants. We showed that oral treatment was as effective and safe as intravenous treatment. Since oral paracetamol is cheaper, more available and noninvasive, it may be preferable to intravenous paracetamol. Although it was not statistically significant, ductal closure rate was higher in oral J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Laurentian University on 12/05/14 For personal use only.
paracetamol group than in the intravenous group a larger, randomised controlled clinical trial is needed to establish the true benefit. Acknowledgments: none. Declaration of Interest Statement The authors report no declarations of interest. No financial interest in any product discussed. References 1. Fanos V, Benini D, Verlato G, Errico G, Cuzzolin L. Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus. Fundam Clin Pharmacol 2005;19:187-193. 2. Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010;125(5):1020-1030. 3. Thomas RL, Parker GC, Van OvermeireB, Aranda JV. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. Eur J Pediatr 2005;164:135-140. 4. Clyman RI. Recommendations for the postnatal use of indomethacin: An analysis of four separate treatment strategies. J Pediatr 1996;128:601-607. 5. Redline RW, Wilson-Costello D, Hack M. Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants. Pediatr Res 2002;52:713-9.
6. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183-6. 7. Noerr B. Current controversies in the understanding of necrotizing enterocolitis Part 1. Adv Neonatal Care 2003;3:107-20. 8. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept
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the null hypothesis? J Perinatol 2010;30:241-52. 9. Sadeck LS, Leone CR, Procianoy RS, Guinsburg R, Marba ST, Martinez FE, et al. Effects of therapeutic approach on the neonatal evolution of very low birth weight infants with patent ductus arteriosus. J Pediatr (Rio J). 2014 Jul 19. 10. Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate 2006;89(4):330-335. 11. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of a patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2007;3:CD003481. 12. Van Overmeire B, Smets K, Lecoutere D, Van De Broek H, Weiler J. De Groote K, Langhendnes JP. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343(10):674-681. 13. 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. 14. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants. A randomized controlled trial. J Pediatr 2014 Mar;164(3):510-4. 15. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: role of cyclo-oxigenase. FASEB J 2005;19:635-7. 16. Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, Erdeve O, Dilmen U. An alternative drug (paracetamol) in ibuprofen resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013 Jan;98:F94.
17. Yurttutan S, Oncel MY, Arayıcı S, Uras N, Altug N, Erdeve O, Dilmen U. A different firstchoice drug in the management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 2013 May;26(8):825-827. 18. Ozmert MA, Ozdemir, Dogan M, Kucuktascı K, Ergin H, Sahin O. Paracetamol theraphy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol
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2014;35:276-279. 19. Jasani B, Kabra N, Nanavati R. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013 Oct-Dec;59(4):312-4. 20. Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Pediatrics 2011;128(6):e1618-21. 21. Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R, Ventriglia F, De Curtis M. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neaonates. Ital J Pediatr 2014 Feb 20;40(1):21. 22. Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O, Dilmen U. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013;103:166-169. 23. Tekgunduz KS, Ceviz N, Demirelli Y, Olgun H, Caner I, Sahin IO, Yolcu C. Intravenous paracetamol for patent ductus arteriosus in premature infants: a lover dose is also effective. Neonatology 2013;104(1):6-7. 24. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014 Mar;164(3):510-4.e1. 25. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. J Pediatr 2011;158:549-554. 26. Raju NV, Bharadwaj RA, Thomas R, Konduri GG. Ibuprofen use to reduce the incidence and severity of bronchopulmonary dysplasia: a pilot study. J perinatol 2000;20:13-6.
27. Sharma PK, Garg SK, Narang A. Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol 2003;43:968-73. 28. Yang CZ, Lee J. Factors affecting successful closure of hemodynamically significant patent ductus arteriosus with indomethacin in extremely low birth weight infants. World J Pediatr 2008
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May;4(2):91-6.
Table 1. Comparison of the clinical chararacteristics and outcomes of cases Oral paracetamol
Intravenous
P value
(n=8)
paracetamol (n=10)
Birth weight,g*
1160 (660-1285)
785 (730-1100)
0,068
Gestational age, weeks *
28,1 (24,1-30)
26,7 (25,3-28,7)
0,062
Male/Female
4/4
3/10
0,63
Antenatal steroid
4/8
5/10
1
Prolonged premature rupture of mebrane,
2/8 (25%)
5/10 (50%)
0,28
Delivery by cesarean section,
6/8 (%75)
7/10 (70%)
0,814
Resuscitation in delivery room,
6/8 (75%)
7/10 (70%)
0,81
Respiratory distress syndrome,
8/8 (100%)
9/10 (90%)
1
Caffeine,
8/8 (%100)
10/10 (%100)
1
Ductal diameter,mm *
1,8 (1,7-2,4)
2,1 (1,7-2,5)
0,137
La/Ao *
1,65 (1,3-1,9)
1,75 (1,5-1,9)
0,258
Age at start of paracetamol,days *
11,5 (4-24)
3 (2-11)
0,003
Ductal closure with one course,
2/8 (25%)
4/10 (40%)
0,502
Ductal closure with two courses,
7/8 (88%)
7/10 (70%)
0,588
Surgical ligation
1/8 (13%)
1/10 (10%)
1
Duration of mechanical ventilation, days
26,5 (4-36)
29 (17-66)
0,213
BPD,
8/8 (100%)
8/10 (80%)
0,477
ROP required anti-VEGF treatment
3/8 (38%)
3/10 (30%)
0,737
Duration of hospitalisation, days *
61,5 (38-81)
62,5 (17-113)
0,965
Death, n (%)
1/8 (13%)
3/10 (30)
0,588
La: Left atrium, Ao: Aortic root diameter, BPD: Bronchopulmonary dysplasia, ROP: Retinopathy of prematurity *The values are given as median (minimum-maximum)
Table 2. Evaluation of liver function tests before and after paracetamol treatment
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Oral paracetamol
Intravenous paracetamol
Pre-treatment
Post-treatment P value
Pre-treatment
Post-treatment P value
AST (U/L)
25,5 (17-38)
25,5 (17-86)
0,574
60,5 (4-162)
24,5 (12-109)
0,017
ALT (U/L)
18,5 (6-56)
15 (6-56)
0,35
9,5 (4-25)
9,1 (6-19)
0,281
Total bilirubin (mg/dL)
3,7 (0,8-5,4)
2,1 (0,7-4,1)
0,017
5,5 (0,7-9,7)
4,5 (0,6-11)
0,224
*The values are given as median (minimum-maximum)
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Tablo 3. Clinical characteristics and echocardiographic findings of the patients. Case Gestation Birth Internal Age weeks ductal (weeks) (g) diameter (mm) 1 27,1 730 2,3 2 25,3 755 2,1 3 28,7 1100 1,7 4 26,6 1050 2,2 5 26,7 740 1,8 6 26,7 1020 2,3 7 26,0 780 1,9 8 28,0 900 2,1 9 25,9 735 2,1 10 28,0 790 2,5 11 29,0 1250 2,4 12 28,1 1120 1,7 13 30,0 1285 2,1 14 24,1 765 1,8 15 27,0 660 1,7 16 27,4 900 1,9 17 28,6 1200 1,8 18 27,7 1215 1,7
La:Ao Current Previous contraindication ibuprofen for ibuprofen treatment 1,5 1,8 1,6 1,9 1,5 1,9 1,6 1,8 1,8 1,9 1,8 1,3 1,4 1,5 1,8 1,7 1,9 1,4
IVH grade 3 Trombocytopenia IVH grade 3 IVH grade 3 Trombocytopenia IVH grade 3 IVH grade 3 IVH grade 4 IVH grade 3 IVH grade 4 IVH grade 4 none none none none none none none
none none none none none none none none none none none 2 courses 2 courses 2 courses 2 courses 2 courses 2 courses 2 courses
Administration Age at start of Duration of route of paracetamol paracetamol paracetamol (days) treatment (days) IV 5 3 IV 7 3 IV 3 6 IV 3 6 IV 2 3 IV 3 6 IV 2 6 PO 5 6 IV 2 3 IV 3 6 PO 4 6 PO 24 6 PO 14 6 PO 12 6 PO 11 3 IV 11 6 PO 11 6 PO 14 3
La: Left atrium, Ao: Aortic root diameter, IVH: intraventricular hemorrhage, IV: intravenous, PO: Peroral,
Result
Surgical ligation
closed closed not closed not closed closed closed not closed closed closed closed closed closed closed closed closed closed not closed closed
No No No No No No Yes No No No No No No No No No Yes No
