Journal Information
Vol. 82. Issue 5.
Pages 362-363 (01 May 2015)
Vol. 82. Issue 5.
Pages 362-363 (01 May 2015)
Scientific Letter
DOI: 10.1016/j.anpede.2015.05.006
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Paracetamol could be useful in the treatment of patent ductus arteriosus in the very-low-birth-weight infant
El paracetamol podría ser útil en el tratamiento del ductus arterioso persistente en el recién nacido de muy bajo peso
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M.E. Pérez Domínguez, S. Rivero Rodríguez, F. García-Muñoz Rodrigo
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fgarciamu@gmail.com

Corresponding author.
Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
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Table 1. Characteristics of patent ductus arteriosus at initiation of treatment, and outcomes.
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Dear Editor,

Patent ductus arteriosus (PDA) is frequently found in preterm newborns and its incidence increases with lower gestational age (GA), rising up to 60% in neonates of gestational ages 26 weeks and less.1 Clinically, it is associated with an increase in morbidity and mortality, including pulmonary oedema and haemorrhage, intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity. The treatment of PDA includes fluid restriction, diuretics, nonselective cyclooxygenase (COX) inhibitors (indomethacin or ibuprofen) and, if all these fail, surgical closure. Recently, several authors have proposed the use of paracetamol for pharmacological closure of PDA if traditional medications fail or are contraindicated. As far as we know, there is no evidence on the use of paracetamol for this purpose in extremely preterm newborns in Spain. We present the cases of two patients with haemodynamically significant ductus (hsPDA) with contraindications for the administration of ibuprofen in which we tried alternative treatment with paracetamol before surgical closure.

Cases (Table 1)

  • 1.

    Twin, female, second-born at 26+0/7 weeks of GA with a birth weight of 720g. Prenatal corticosteroids administered. Delivery by urgent caesarean section due to placenta praevia. Apgar score: 6/8. Noninvasive ventilation until 14h of life, when intubation and surfactant administration were required, with good response. Reintubation 12h later due to clinical deterioration and NEC. Two days later a hsPDA, anaemia and thrombocytopaenia were detected. Consent was obtained from parents and treatment with intravenous (IV) paracetamol initiated. A control echocardiogram showed a closed ductus and normal haemodynamic parameters. Normal liver function. The patient evolved favourably and she was discharged at a postnatal age of 72 days.

  • 2.

    Neonate, female, born at 23+5/7 weeks of GA with a birth weight of 690g. Chorioamnionitis. Prenatal corticosteroids (partial course). Vaginal delivery with cephalic presentation. Apgar score: 3/5. Intubated and given a dose of surfactant at birth. Mechanical ventilation and vasoactive medication since admission. On day 6, a hsPDA was diagnosed. Intravenous ibuprofen was initiated (one dose) and, with the verbal consent of parents, switched to IV paracetamol due to thrombocytopaenia and grade III IVH. The follow-up echocardiogram (9th day) showed a small and haemodynamically non-significant ductus arteriosus. The PDA reopened at 11 days. Surgical closure was performed the next day with poor outcome: abdominal distension, septic appearance. The infant died 2 days post surgery.

Table 1.

Characteristics of patent ductus arteriosus at initiation of treatment, and outcomes.

  Age at initiation of paracetamol  Inner diameter of PDA (mm)  Left atrium/aorta ratio  Reverse diastolic flow  Previous ibuprofen  Contraindication for ibuprofen  Dose and duration of paracetamol  Outcome 
Patient 1  3rd day  3.5  Yes  No  Severe thrombocytopaeniaNEC  15mg/kg/6h×48Closure in 48hSurvival 
Patient 2  7th day  2.3  1.9  Yes  1 dose  Severe thrombocytopaeniaIVH grade III  15mg/kg/6h×72h+7.5mg/kg/6h×48Initial improvementReopeningSurgical closureDeath 

Approximately three years ago, Hammerman et al2 published their initial experience with pharmacological closure of PDA with oral paracetamol in 5 patients. In the index patient, a newborn with 26 weeks of GA, paracetamol was administered for a different indication at 21/2 weeks of life and it was observed that a hsPDA that had not responded to two courses of ibuprofen had suddenly closed two days later. Following this, another four neonates of 26–29 weeks of GA in whom treatment with ibuprofen was contraindicated or had failed were treated with paracetamol. All patients showed either closure or a significant reduction in the size of the ductus 48h after administration of paracetamol, and full closure in one week. On the basis of this first experience, other authors have used oral or intravenous paracetamol to treat PDA in small series of patients. A review of these studies has been recently published by Allegaert et al.3

The main concern raised by these studies has to do with the lack of data on the pharmacokinetics and pharmacodynamics of paracetamol in extremely preterm newborns and the safety of its use in this population. There is also considerable controversy regarding the dosage used, which is double the dose used for analgesia in term newborns. The mechanism of action of paracetamol is not fully understood either, and in many of the published cases its use followed the administration and failure of ibuprofen, so it is not possible to know whether there was a synergistic effect between the two medications.

In the only randomised study conducted to date,4 80 patients completed the course of treatment. The efficacy in the pharmacological closure of PDA was similar for ibuprofen (77.5%) and paracetamol (72.5%) administered by the oral route, and both drugs proved to be safe.4 These are relevant findings, since COX inhibitors, despite having a success rate of 70–85%, are not free from side effects, such as, oliguria, gastrointestinal perforations, impaired platelet aggregation, hyperbilirubinaemia, etc. Ibuprofen has also been associated with an increased risk of BPD.5

In summary, although further prospective, controlled and appropriately designed studies are needed to establish the safety, efficacy and optimal dosage of paracetamol for the treatment of PDA in extremely preterm infants, these last experiences appear promising, at least in cases where traditional drugs fail or are contraindicated, and when avoiding surgery is deemed reasonable.

References
[1]
F. García-Muñoz Rodrigo, A. García-Alix Pérez, J.A. García Hernández, J. Figueras Aloy, Grupo SEN1500.
Morbimortalidad en recién nacidos al límite de la viabilidad en España: estudio de base poblacional.
An Pediatr, 80 (2014), pp. 348-356
[2]
C. Hammerman, A. Bin-Nun, E. Markovitch, M.S. Schimmel, M. Kaplan, D. Fink.
Ductal closure with paracetamol: a surprising new approach to patent ductusarteriosus treatment.
Pediatrics, 128 (2011), pp. e1618-e1621
[3]
K. Allegaert, B. Anderson, S. Simons, B. van Overmeire.
Paracetamol to induce ductusarteriosus closure: is it valid?.
Arch Dis Child, 98 (2013), pp. 462-466
[4]
M.Y. Oncel, S. Yurttutan, O. Erdeve, N. Uras, N. Altug, S.S. Oguz, et al.
Oral paracetamol versus oral ibuprofen in the management of patent ductusarteriosus in preterm infants: a randomized controlled trial.
J Pediatr, 164 (2014), pp. 510-514.e1
[5]
L.J. Jones, P.D. Craven, J. Attia, A. Thakkinstian, I. Wright.
Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants.
Arch Dis Child Fetal Neonatal Ed, 96 (2011), pp. F45-F52

Please cite this article as: Pérez Domínguez ME, Rivero Rodríguez S, García-Muñoz Rodrigo F. El paracetamol podría ser útil en el tratamiento del ductus arterioso persistente en el recién nacido de muy bajo peso. An Pediatr (Barc). 2015;82:362–363.

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