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GUEST EDITORIAL
Year : 2013  |  Volume : 59  |  Issue : 4  |  Page : 251-252

Paracetamol to close the patent ductus arteriosus: From serendipity toward evidence based medicine


Department of Development and Regeneration, KU Leuven; Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

Date of Web Publication17-Dec-2013

Correspondence Address:
K Allegaert
Department of Development and Regeneration, KU Leuven; Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven
Belgium
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.123141

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How to cite this article:
Allegaert K. Paracetamol to close the patent ductus arteriosus: From serendipity toward evidence based medicine. J Postgrad Med 2013;59:251-2

How to cite this URL:
Allegaert K. Paracetamol to close the patent ductus arteriosus: From serendipity toward evidence based medicine. J Postgrad Med [serial online] 2013 [cited 2019 Nov 13];59:251-2. Available from: http://www.jpgmonline.com/text.asp?2013/59/4/251/123141


Persistent patent ductus arteriosus (PDA) is associated with increased neonatal morbidity, including necrotizing enterocolitis, bronchopulmonary dysplasia and neurodevelopmental impairment. [1] Ibuprofen or indomethacin administered to preterm infants promote ductal closure, but these drugs are neither without side-effect, including renal, pulmonary, cerebral impairment while surgical closure itself is also associated with poorer neurologic outcome. [2] Moreover, there are also contra-indications for ibuprofen or indomethacin administration. Consequently, there is a need for alternative treatments that result in better closure rates or fewer adverse effects. A "serendipity" observation of Hammerman et al. recently linked paracetamol exposure with PDA closure. [3]

However, it should not be taken for granted yet that paracetamol induces PDA closure. If closure is driven by prostaglandin (PG) reduction, we should be aware that paracetamol has only very weak peripheral PG related effects and exerts its main effects (analgesia, fever reduction) through the central nervous system. [4],[5] Related to PG synthesis, paracetamol inhibits peroxidase (POX) (PGG2 to PGH2 conversion, POX) as one of its mechanisms of action. It hereby functions as a reducing co-substrate so that less PGG2 can be converted to PGH2 [Figure 1]. However, this inhibition is competitive with the PGG2 concentration itself and peroxides (sources are white blood cells, thrombocytes = Not present in the central nervous system). Consequently, the peripheral PGH2 inhibition of PGH2 production is very limited and the pharmacological link between paracetamol exposure and systemic PG reduction related PDA closure is very weak. [4],[5]
Figure 1: The arachidonic acid pathway, with specific emphasis on the interaction of paracetamol (inhibiting) or endogenous compounds (hydroperoxide, PGG2, stimulating) at the peroxidase enzyme

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However, we believe in the relevance of serendipity, with sildenafil for pulmonary hypertension and propranolol to treat hemangiomata of infancy as two recent illustrations of the clinical benefit of such observations. Despite the available data on their clinical benefit, the administration of these compounds for these indications is still offlabel and unlicensed. Related to paracetamol for PDA closure however, we urgently need a shift from a serendipity driven practice toward evidence based medicine. This includes pharmacokinetics, effectiveness and safety. At present, we know that an association between paracetamol exposure (60 mg/kg/24 h, 2-7 days, either oral or intravenous) and closure of the PDA has been reported. Including the six cases currently reported, observations in a still limited number (n<50) of (extreme) preterm neonates are available, but none were included in prospective or comparative studies. [5],[6] Moreover, there are data on paracetamol pharmacokinetics and safety, but these data were based on lower dosing regimens (20-40 mg/kg/24 h, 1-2 days) and were collected in more mature neonates. [7],[8] Consequently, we do not have subpopulation specific pharmacokinetics, nor safety data. Finally, we are unaware of any median paracetamol concentration to aim for to induce closure of the ductus. Consequently, dose seeking studies and in vitro studies are needed to guide dosing.

Serendipity is an important driver to further improve pharmacotherapy in neonates. However, the next steps to further document the potential benefits of paracetamol or reject its claimed effects necessitates a more robust study design, that will include issues related to pharmacokinetics, effectiveness and safety.


 :: Acknowledgments Top


Karel Allegaert is supported by the fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800209N). There are no conflicts of interest to report.

 
 :: References Top

1.Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: Are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 2012;36:123-9.  Back to cited text no. 1
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2.Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I. Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Arch Dis Child Fetal Neonatal Ed 2011;96:F45-52.  Back to cited text no. 2
[PUBMED]    
3.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. 3
[PUBMED]    
4.Anderson BJ. Paracetamol (Acetaminophen): Mechanisms of action. Paediatr Anaesth 2008;18:915-21.  Back to cited text no. 4
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5.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.  Back to cited text no. 5
[PUBMED]    
6.Jasani B, Kabra N, Nanavati RN. Oral paracetamol in treatment of closure of patent ductusarteriosus in preterm neonates: A case series. J Postgrad Med 2013;59:315-17.  Back to cited text no. 6
    
7.Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: Size matters most. Arch Dis Child 2011;96:575-80.  Back to cited text no. 7
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8.Allegaert K, Rayyan M, De Rijdt T, Van Beek F, Naulaers G. Hepatic tolerance of repeated intravenous paracetamol administration in neonates. Paediatr Anaesth 2008;18:388-92.  Back to cited text no. 8
[PUBMED]    


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