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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Case Report
 :: Discussion
 :: Acknowledgment
 ::  References
 ::  Article Tables

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CASE SERIES
Year : 2013  |  Volume : 59  |  Issue : 4  |  Page : 312-314

Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates


Department of Neonatology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India

Date of Submission15-Apr-2013
Date of Decision17-Jun-2013
Date of Acceptance01-Aug-2013
Date of Web Publication17-Dec-2013

Correspondence Address:
B Jasani
Department of Neonatology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.123164

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 :: Abstract 

We herewith report a case series of six premature neonates with hemodynamically significant paten ductus successfully treated with oral paracetamol. This is a first case series describing the use of oral paracetamol treatment patent ductus in preterm neonates from India. Further prospective randomized-controlled trials are needed to evaluate the efficacy and safety of oral paracetamol in the treatment of patent ductus in preterm neonates.


Keywords: Paracetamol, preterm neonates, patent ductus arteriosus


How to cite this article:
Jasani B, Kabra N, Nanavati R N. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013;59:312-4

How to cite this URL:
Jasani B, Kabra N, Nanavati R N. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med [serial online] 2013 [cited 2019 Jun 27];59:312-4. Available from: http://www.jpgmonline.com/text.asp?2013/59/4/312/123164



 :: Introduction Top


Persistent patent ductus arteriosus (PDA) renders the preterm neonates vulnerable to pulmonary over-circulation with diminished systemic blood flow. The increase in pulmonary blood flow in the setting of prematurity can lead to pulmonary edema, loss of lung compliance, and deterioration of respiratory status, which ultimately leads to the development of chronic lung disease. Therapeutic medical interventions that are most commonly used for closure of a hemodynamically significant patent ductus arteriosus (hsPDA) are cyclooxygenase inhibitors, mainly indomethacin and intravenous/oral ibuprofen. Overall the efficacy of both these drugs in the treatment of PDA is similar and is about 60 to 70%. [1],[2] . However, these drugs can cause undesired side effects such as peripheral vasoconstriction, gastrointestinal perforations, weakened platelet aggregation, and hyperbilirubinemia [3],[4] . Intravenous indomethacin and intravenous ibuprofen are expensive and not readily available. A drug like oral paracetamol, if successful, would not only eliminate these adverse effects but can also offer a cheaper and better alternative. Recently serendipitously it was found that oral paracetamol therapy may be effective in the closure of PDA in preterm neonates, who do not respond to traditional drugs [5] . We herewith report a case series, which provides further evidence of efficacy of oral paracetamol in the closure of hsPDA in preterm neonates.


 :: Case Report Top


[Table 1] summarizes the characteristics of neonates who had hsPDA and were treated with oral paracetamol. The baseline characteristics (birth weight, gestational age); age at presentation, echocardiographic findings and response to therapy is also narrated.
Table 1: Case summary of neonates with hsPDA who were treated with oral paracetamol


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All of the six neonates had hsPDA that was confirmed by echocardiography. Three neonates did not respond to Indomethacin and one to ibuprofen treatment. In two others treatment with indomethacin/ibuprofen was contraindicated. In general contraindications for indomethacin or ibuprofen treatment includes: Renal failure, hyperbilirubinemia and severe thrombocytopenia.

Treatment with oral paracetamol (Crocin drops 100 mg/ml, Glaxo Smithkline Consumer Healthcare, India) was started in these cases at a dose of 15 mg/kg every 6 h after echocardiographic confirmation of hsPDA. Repeat echocardiographic evaluation was performed on Day 3 of treatment. In the event of evidence of a persistent hsPDA, duration of therapy was extended up to 7 days. Further follow-up echocardiography was performed on completion of 7 days of therapy.

A total of six preterm neonates birth weight (range: 1040 to 1235 g), gestational age (range: 28.56 to 31.14 weeks) who admitted in neonatal intensive care unit of a level III tertiary unit are reported in this case series. Out of the six babies four babies had respiratory distress syndrome and all of them received natural surfactant. The age at administration of surfactant was 5.87 ± 1.25h. Two neonates with hsPDA in addition also had sepsis. Median age at paracetamol administration was 128 hours (range 62-214 h). The median duration of therapy was 82.5 h. (range 56-102 h) and median age at closure of ductus was 209.5h (range 130-210 h). Complete closure was observed in 6/6 (100%) of babies. None of the babies had any adverse effect. Pre and post-treatment levels of liver enzymes were normal in all neonates.


 :: Discussion Top


Traditional nonsteroidal anti-inflammatory drugs promote ductal constriction by inhibiting prostaglandin synthesis. Prostaglandin synthetase has two components, a cyclooxygenase and a peroxidase, that operate at distinct, active sites on the same protein with different catalytic activities. At the active cyclooxygenase site, arachidonic acid undergoes oxygenation and forms PGG2, which is then acted on by the peroxidase component of the enzyme, forming PGH2. Indomethacin and ibuprofen compete with the arachidonic acid substrate for the active cyclooxygenase site. Thus, the potency of these drugs is influenced by endogenous arachidonic acid levels. Paracetamol also inhibits prostaglandin synthetase activity. [6] . Although the precise mechanism of action of paracetamol in the closure of PDA in preterm remains uncertain, paracetamol seems to act at the peroxidase segment of the enzyme which indicates that paracetamol-mediated inhibition is facilitated by a reduction in the concentration of local peroxide. [7] There have been reports of paracetamol promoting ductal constriction, albeit mostly in pregnant animal models, [8],[9] and there has been one case report of human in utero ductal closure after maternal self-medication with a combination of nimesulide and acetaminophen. [10] In a recent case series by Hammerman et al., [5] paracetamol was given to two patients who did not respond to ibuprofen and to three patients with contraindications to treatment (hyperbilirubinemia, thrombocytopenia). Successful hsPDA closure was observed in all five preterm infants without any side effect. More recently two case reports of use of intravenous paracetamol have appeared in the literature. [11],[12] Extensive clinical experience with the use of paracetamol in neonates has been accumulated due to its widespread use in pain relief with minimal side effects. [13]

Further prospective randomized-controlled trials are needed to evaluate the efficacy and safety of oral paracetamol in the treatment of hsPDA in preterm neonates. Until results of such studies are available, it should be used with caution where established therapies fail or are contraindicated. Oral paracetamol therapy could have potentially several advantages: Inexpensive, easy availability no peripheral vasoconstrictive effect and it can be given orally to infants with clinical contraindications for nonsteroidal anti-inflammatory drugs (indomethacin/ibuprofen).


 :: Acknowledgment Top


Authors thank the Dean Dr. Sandhya Kamath, Seth GS Medical College and KEM Hospital, Mumbai for permitting them to publish the manuscript.

 
 :: References Top

1.Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2010;4:CD003481.  Back to cited text no. 1
[PUBMED]    
2.Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: A systematic review and meta-analysis. Neonatology. 2012;102:9-15.  Back to cited text no. 2
    
3.Zecca E, Romagnoli C, De Carolis M, Costa S, Marra R, De Luca D. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics. 2009;124:480-4.  Back to cited text no. 3
    
4.Rheinlaender C, Helfenstein D, Walch E, Berns M, Obladen M, Koehne P. Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr. 2009;98:36-42.  Back to cited text no. 4
    
5.Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: A surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011; 128:e1618-21.  Back to cited text no. 5
[PUBMED]    
6.Green K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by paracetamol. Prostaglandins. 1989;37:311-5.  Back to cited text no. 6
    
7.Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: Role of cyclo-oxygenase. FASEB J. 2005;19:635-7.  Back to cited text no. 7
    
8.Momma K, Takao A. Transplacental cardiovascular effects of four popular analgesics in rats. Am J Obstet Gynecol. 1990;162:1304-10.  Back to cited text no. 8
[PUBMED]    
9.Peterson RG. Consequences associated with nonnarcotic analgesics in the fetus and newborn. Fed Proc. 1985;44:2309-13.  Back to cited text no. 9
[PUBMED]    
10.Simbi KA, Secchieri S, Rinaldo M, Demi M, Zanardo V. In utero ductal closure following near-term maternal self-medication with nimesulide and acetaminophen. J Obstet Gynaecol. 2002;22:440-5.  Back to cited text no. 10
    
11.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. 2012 Dec 19;103:166-9.  Back to cited text no. 11
    
12.Yurttutan S, Oncel MY, Arayýcý S, Uras N, Altug N, Erdeve O, Dilmen U. A different first-choice drug in the medical management of patent ductus arteriosus: Oral paracetamol. J Matern Fetal Neonatal Med. 2013 Jan 15. [Epub ahead of print].  Back to cited text no. 12
    
13.Wilson-Smith EM, Morton NS. Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists. Paediatr Anaesth. 2009;19:329-37.  Back to cited text no. 13
    



 
 
    Tables

  [Table 1]

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