|Year : 2018 | Volume
| Issue : 3 | Page : 121-124
Oral paracetamol versus intravenous paracetamol in the closure of patent ductus arteriosus: A proportion meta-analysis
Jesmin Hossain1, Mohammad Kamrul Hassan Shabuj2
1 Department of Pediatric Cardiology, National Heart Foundation Hospital, Dhaka, Bangladesh
2 Department of Neonatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
|Date of Web Publication||2-Aug-2018|
Dr. Mohammad Kamrul Hassan Shabuj
Department of Neonatology, Bangabandhu Sheikh Mujib Medical University, Dhaka
Source of Support: None, Conflict of Interest: None
Background: Patent ductus arteriosus (PDA) is a common cause of neonatal morbidity. We aimed to do this meta-analysis to compare the efficacy of oral paracetamol/acetaminophen and intravenous (IV) paracetamol for the closure of hemodynamically significant PDA (hsPDA) in preterm infants. Methodology: Medline, Embase, and Google Scholar databases were searched for citations. We included 14 studies with significant PDA and used either oral or IV paracetamol for PDA treatment. Pooled proportion of PDA closured was analyzed. Results: We included 14 studies with 454 premature infants having PDA. Pooled proportion of PDA closure with oral paracetamol was 77.79% (95% confidential interval [CI] 72.92—82.15) in fixed effect and 75.77% (95% 65.48—84.74) in random effect model. In case of IV paracetamol group, pooled portion of PDA closure was 81.52% (95% 74.00—87.64) and 81.52 (95% CI 74.62—87.55) in fixed and random model, respectively. The difference of proportion in the fixed effect model was 3.75% (95% CI, −5.08—11.64) (P = 0.37), and in the random effect model, it was 5.75 (95% CI, 3.14—13.74) (P = 0.181). Conclusion: Our study concluded that pooled proportion of PDA closure is comparable with oral versus IV route of paracetamol use.
Keywords: Paracetamol, patent ductus arteriosus, proportion meta-analysis
|How to cite this article:|
Hossain J, Shabuj MK. Oral paracetamol versus intravenous paracetamol in the closure of patent ductus arteriosus: A proportion meta-analysis. J Clin Neonatol 2018;7:121-4
|How to cite this URL:|
Hossain J, Shabuj MK. Oral paracetamol versus intravenous paracetamol in the closure of patent ductus arteriosus: A proportion meta-analysis. J Clin Neonatol [serial online] 2018 [cited 2019 Dec 15];7:121-4. Available from: http://www.jcnonweb.com/text.asp?2018/7/3/121/238392
| Introduction|| |
Ductus arteriosus (DA) is the shunt that makes communication between pulmonary artery to aorta and it is one of the basic shunts necessary in the prenatal life to maintain fetal circulation., After birth due to transition of circulation, it will be closed. At 24—72 h, it is functionally closes in the term and healthy newborns., Ductus closure happens after birth due to increased postnatal levels of PaO2, increased in pulmonary flow, and decline of prostaglandin E2 (PGE2), and due to reduction PGE2 vasodilation effect on DA.,, It may be remained open for some unwanted effect of transition. It is reported that patent DA (PDA) is common among preterm infants, 30% in very low birth weight infants (<1500 g) and 50% in extremely low birth weight ones (<1000 g). Failure to closure ductus in the preterm infants for long period of time leads to severe respiratory distress, requires prolonged ventilatory support, and increases change of pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, renal functional impairment, intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, and death. These aforementioned complications indicated the urgency of PDA treatment. There are several modalities of treatment of PDA. Paracetamol is one of the treatment options. Several case series and meta-analysis,, showed that paracetamol has similar effect as ibuprofen. However, our main concern is different route of administration of paracetamol. We did this meta-analysis to see the efficacy of oral use of paracetamol versus intravenous (IV) paracetamol.
| Methodology|| |
Data search and data extraction
Medline, Embase, and Google Scholar databases were searched for citation. Data forms were used to collect required information. Two reviewers extracted the articles that included hemodynamically significant PDA (hsPDA) in preterm infants and used paracetamol as an intervention. hsPDA was defined as the presence of at least one of the following criteria: internal ductal diameter 1.4 mm/kg body weight, left atrium -to-aortic root ratio >1.4, and unrestrictive pulsatile transductal flow. For proportional meta-analysis, we included those articles that included only paracetamol or paracetamol with placebo and paracetamol versus ibuprofen. We used the medical subject heading term and title as a searching procedure of the articles. Two reviewers independently extracted data, if there was any disagreement solved by consensus.
Quality assessment of the studies
The quality of the trials, assessed by the Cochrane-Recommended Grading Recommendation Assessment and Evaluation, was low-grade quality as majority of the articles were case series.
The extracted data were analyzed by the weighted proportion ratio by Mantel-Haenszel fixed and random effect model. Revman, version 5.3, Copenhagen, Denmark and Medcal software, were used for data analysis. The pooled data were presented by the forest plot and heterogeneity was analyzed by Q and I2 statistics, and publication bias was assessed by funnel plot.
| Results|| |
We included 14 studies with 454 premature infants having PDA. Of those studies, five studies were controlled trails [Figure 1]. The study characteristics were described in terms of gestational age, route of administration, duration of treatment, and events of closure of PDA [Table 1]. Pooled proportion of PDA closure with oral paracetamol was 77.79% (95% confidential interval [CI] 72.92—82.15) in fixed effect and 75.77% (95% 65.48—84.74) in random effect model [Figure 2] and publication bias was shown by funnel plot and there was good symmetry of the plot [Figure 3]. In case of IV paracetamol group, pooled portion of PDA closure was 81.52% (95% 74.00—87.64) and 81.52 (95% CI 74.62—87.55) in fixed and random model, respectively [Figure 4], and publication bias also assessed by the funnel plot [Figure 5]. The difference of proportion was in the fixed effect model was 3.75% (95% CI, −5.08—11.64) (P = 0.37), and in the random effect model, it was 5.75 (95% CI, 3.14—13.74) (P = 0.181). Hence, both in the fixed and random effect model, oral and IV paracetamol was comparable.
|Figure 4: Funnel plot for publication bias analysis in oral Paracetamol group|
Click here to view
|Figure 5: Funnel plot for publication bias analysis in IV Paracetamol group|
Click here to view
| Discussion|| |
In this meta-analysis, we compared the efficacy of oral paracetamol with the efficacy of IV paracetamol in terms of closure of hsPDA in premature infants in 14 studies. We had analyzed the proportion of PDA closure in ten case series and four controlled trials. Our study finding was comparable with the several studies in terms of proportion of PDA closure, but all those studies also did the invention comparison meta-analysis with ibuprofen versus paracetamol with 2 RCTs., Das et al. The meta-analysis of the five randomized controlled trials (RCTs) done by Huang et al. showed that proportion PDA closure was comparable with our study. However, this study also compared paracetamol with ibuprofen. No study was found that compared oral paracetamol versus IV paracetamol. The strength of our study was (i) More studies were included (ii) Publication bias was analyzed and showed funnel plot symmetry. Our study had several limitations: (i) no subgroup analysis was done for different dose schedule, for duration of treatment, (ii) not all the included studies were RCT, and (iii) we did not show the adverse effect comparison.
| Conclusion|| |
Events of closure of hsPDA in premature infants with oral and IV paracetamol were comparable in pooled proportion, and any route of administration can be used.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Fanos V, Pusceddu M, Dessì A, Marcialis MA. Should we definitively abandon prophylaxis for patent ductus arteriosus in preterm new-borns? Clinics (Sao Paulo) 2011;66:2141-9.
Mitra S, Florez ID, Tamayo ME, Aune D, Mbuagbaw L, Veroniki AA, et al.
Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: A protocol for a systematic review and network meta-analysis. BMJ Open 2016;6:e011271.
Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Patent ductus arteriosus in preterm infants: Do we have the right answers? Biomed Res Int 2013;2013:676192.
Benitz WE; Committee on Fetus and Newborn, American Academy of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics 2016;137:e20153730.
Bhattacharya M, Asselin P, Hardy P, Guerguerian AM, Shichi H, Hou X, et al.
Developmental changes in prostaglandin E(2) receptor subtypes in porcine ductus arteriosus. Possible contribution in altered responsiveness to prostaglandin E(2). Circulation 1999;100:1751-6.
Bouayad A, Kajino H, Waleh N, Fouron JC, Andelfinger G, Varma DR, et al.
Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus. Am J Physiol Heart Circ Physiol 2001;280:H2342-9.
Antonucci R, Bassareo P, Zaffanello M, Pusceddu M, Fanos V. Patent ductus arteriosus in the preterm infant: New insights into pathogenesis and clinical management. J Matern Fetal Neonatal Med 2010;23 Suppl 3:34-7.
Clyman RI, Mauray F, Roman C, Heymann MA, Payne B. Factors determining the loss of ductus arteriosus responsiveness to prostaglandin E. Circulation 1983;68:433-6.
Abrams SE, Walsh KP, Coker SJ, Clarkson MJ. Responses of the post-term arterial duct to oxygen, prostaglandin E2, and the nitric oxide donor, 3-morpholinosydnonimine, in lambs and their clinical implications. Br Heart J 1995;73:177-81.
Reller MD, Rice MJ, McDonald RW. Review of studies evaluating ductal patency in the premature infant. J Pediatr 1993;122:S59-62.
Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani HM, Nwaesei C, et al.
Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: Further analyses from the trial of indomethacin prophylaxis in preterms (TIPP). J Pediatr 2006;148:730-4.
Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: Time to accept the null hypothesis? J Perinatol 2010;30:241-52.
Das RR, Arora K, Naik SS. Efficacy and safety of paracetamol versus ibuprofen for treating patent ductus arteriosus in preterm infants: A meta-analysis. J Clin Neonatol 2014;3:183-90. [Full text]
Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev 2015;3:CD010061.
Huang X, Wang F, Wang K. Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: A meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med 2018;31:2216-22.
Bagheri MM, Niknafs P, Sabsevari F, Torabi MH, Bahman Bijari B, Noroozi E, et al.
Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus. Iran J Pediatr 2016;26:e3975.
Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med 2016;12:2531-6.
Yurttutan S, Oncel MY, Arayicı S, Uras N, Altug N, Erdeve O, 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.
Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H, et al.
Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: A randomized controlled trial. PLoS One 2013;8:e77888.
Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol 2014;34:748-9.
Härkin P, Härmä A, Aikio O, Valkama M, Leskinen M, Saarela T, et al.
Paracetamol accelerates closure of the ductus arteriosus after premature birth: A randomized trial. J Pediatr 2016;177:72-700.
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;176:233-40.
Dasai D, Kluckow M. The efficacy of paracetamol for PDA closure in preterm infants. J Paediatr Child Health 2012;48:126-7.
Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D, et al.
Ductal closure with paracetamol: A surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011;128:e1618-21.
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al.
Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: A randomized controlled trial. J Pediatr 2014;164:510-40.
Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R, et al.
Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital J Pediatr 2014;40:21.
Dash SK, Kabra NS, Avasthi BS, Sharma SR, Padhi P, Ahmed J, et al.
Enteral paracetamol or intravenous indomethacin for closure of patent ductus arteriosus in preterm neonates: A randomized controlled trial. Indian Pediatr 2015;52:573-8.
Memisoglu A, Alp Ünkar Z, Cetiner N, Akalın F, Ozdemir H, Bilgen HS, et al.
Ductal closure with intravenous paracetamol: A new approach to patent ductus arteriosus treatment. J Matern Fetal Neonatal Med 2016;29:987-90.
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.
] [Full text]
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]