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Vol. 88. Núm. 6.Junio 2018
Páginas 299-356
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Vol. 88. Núm. 6.Junio 2018
Páginas 299-356
Scientific Letter
DOI: 10.1016/j.anpede.2017.07.004
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Paracetamol: Useful treatment of choice for persistent arterial duct in very low weight premature newborns
Paracetamol: tratamiento útil de elección para el ductus arterioso persistente en prematuros de muy bajo peso
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Raquel Gálvez Criado, Silvia Rodríguez Blanco, Ignacio Oulego Erroz, Aquilina Jiménez González, Paula Alonso Quintela
Servicio de Pediatría, Complejo Asistencial Universitario, León, Spain
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Table 1. Patient characteristics.
Table 2. Sonographic features of patent ductus arteriosus and treatment characteristics.
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The presence of a haemodynamically significant patent ductus arteriosus (hsPDA) in preterm newborns (PTNBs) is associated with prolonged need of mechanical ventilation, bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), metabolic acidosis, intraventricular haemorrhage (IVH), pulmonary haemorrhage and periventricular leukomalacia.1 For this reason, pharmacological closure of the ductus is common practice, usually through administration of non-selective cyclooxygenase (COX) inhibitors, indomethacin or ibuprofen. Since these drugs may cause adverse events, other agents, such as paracetamol, are being investigated that may be safer while still effective. In this article, we describe our experience with paracetamol in these patients.

In our unit, active measures for closure of PAD are implemented in PTNBs that develop symptoms or with sonographic signs of moderate to severe haemodynamic compromise in whom spontaneous closure is unlikely. The first line of treatment is ibuprofen, which is delivered intravenously. In the last 4 years, we have used paracetamol by the oral or intravenous route in 15 PTNBs with satisfactory results. In all these newborns, paracetamol was administered because treatment with ibuprofen had failed or the patient had contraindications for it. Parents gave consent to the use of paracetamol after being informed that it was an off-label use of the drug. Table 1 summarises the basic characteristics of the patients. The mean gestational age at birth was 26+4 weeks (median, 26+6 weeks; range 24+6–29+1 weeks) and the mean birth weight was 928g (median, 980g; range, 480–1480g). The most frequent indication for treatment with paracetamol (7/15 patients) was a recent history of IVH, which had been severe in 6/15 patients. Three patients developed NEC and 2 died. Table 2 summarises the findings of the sonographic assessment of PDA and the main treatment-related variables. Half of the patients had been previously treated with ibuprofen. Paracetamol was given at a dose of 15mg per kilogram of body weight every 6h. We considered that closure of the PDA was successful if complete closure was achieved, or if the hsPDA improved to a minor PDA with no haemodynamic effects and requiring no further treatment. In our case series, successful closure was achieved in 10/15 patients, with the remaining 5 requiring surgical closure. None of the patients had side effects that could be attributed to paracetamol in the short term.

Table 1.

Patient characteristics.

Patient  Birth weight (g)  Gestational age
(weeks) 
Sex  Prenatal steroids  CRIB II  IVH (grade)  NEC  Discharged alive 
990  28+5  Male  Full course  Yes (II)  No  Yes 
480  27+4  Female  Full course  Yes (IV)  Yes  Yes 
1080  27  Male  No  Yes (III)  No  Yes 
800  25+5  Male  Full course  Yes (I)  No  Yes 
1000  26+2  Female  Full course  No  Yes  No 
980  26+6  Male  Partial course  Yes (III)  No  Yes 
700  24+6  Female  Full course  Yes (III)  No  Yes 
1250  27+5  Male  Partial course  No  No  Yes 
1480  29+1  Male  Full course  No  No  Yes 
10  820  25  Male  Full course  Yes (III)  Yes  Yes 
11  980  26+6  Male  Partial course  Yes (III)  No  No 
12  840  25+5  Male  Full course  No  No  Yes 
13  690  27+5  Female  Full course  No  No  Yes 
14  660  27+3  Female  Full course  No  No  Yes 
15  1170  26+6  Male  Partial course  Yes (II)  No  Yes 
Table 2.

Sonographic features of patent ductus arteriosus and treatment characteristics.

Patient  PDA size (mm/kg)  LA:Ao ratio  Previous ibuprofen treatment  Initiation paracetamol (days of life+weight)  Paracetamol (days)  Indication  Success  Surgery 
1.8  –  Yes (1 dose)  7,
900
IVH+thrombocytopaenia  Yes  No 
–  No  8,
550
IVH  Yes  No 
2.59  1.6  No  7,
1140
IVH  Yes  No 
2.5  1.7  Yes (1 cycle)  27,
960
IVH+treatment failure  No  Yes 
1.6  1.6  Yes (1 cycle)  14,
1100
Treatment failure  Yes  No 
2.75  2.7  No  3,
880
IVH  Yes  No 
3.57  2.5  No  10,
710
IVH  No  Yes 
1.44  1.8  No  15,
1280
Risk of NEC  Yes  No 
1.55  2.3  Yes (2 cycles)  21,
1760
Treatment failure  Yes  No 
10  3.9  1.56  No  4,
820 
Pulmonary haemorrhage+thrombocytopaenia  No  Yes 
11  2.93  1.3  Yes (2 cycles)  13,
1680
Thrombocytopaenia+sepsis  Yes  No 
12  2.3  Yes (1 cycle)  19,
1000
Sepsis  No  Yes 
13  2.33  –  Yes (2 cycles)  15,
770
Sepsis  No  Yes 
14  2.6  1.46  No  9,
760
Thrombocytopaenia  Yes  No 
15  2.56  1.8  No  3,
1770
IVH  Yes  No 

Since Hammerman et al.2 discovered by chance that paracetamol can achieve closure of PDA in PTNBs, several studies have been published that propose its use as an alternative treatment in cases where first-line drugs have failed or are contraindicated. Recently, several clinical trials3,4 have shown that paracetamol may be as efficacious as ibuprofen, reporting proportions of PDA closure nearing 75%, somewhat higher than the proportion achieved in our small sample (10/15 patients; 66.7%); however, this approach is used infrequently, almost incidentally, in Spain. Paracetamol is currently proposed as an efficacious and possibly safer alternative to traditional COX inhibitors, whose use is limited due to their contraindications and potential adverse effects (kidney failure, NEC, severe hyperbilirubinaemia, sepsis, coagulopathy, haemorrhage, etc.). The short-term side effects of paracetamol observed to date have been minimal, and paracetamol may have the additional advantage of being more effective in hypoxic states (which are frequent in PTNBs), as it is believed to act on the peroxidase function of COX.5 However, further evidence from clinical trials is required to establish its non-inferiority in comparison to treatment indomethacin or ibuprofen as well as its safety, especially in the long term. On the other hand, PTNBs are at higher risk of liver toxicity due to their immaturity, and the dose of paracetamol used for PDA closure is higher than the dose used for analgesia or reduction of fever (45–60mg/kg/day compared to 30–40mg/kg/day). Furthermore, some case series have found a long-term association of paracetamol use with autism spectrum disorders and neurodevelopmental disorders, and it is recommended that patients treated with this approach are followed up closely with thorough neuropsychiatric evaluations.6 In our small series, all survivors have had adequate psychomotor development, including the two patients that have already reached 2 years of corrected age.

References
[1]
W.E. Benitz,Committee on Fetus and Newborn
Patent ductus arteriosus in preterm infants
Pediatrics, 137 (2016), pp. e20153730
[2]
C. Hammerman,A. Bin-Nun,E. Markovitch,M.S. Schimmel,M. Kaplanl,D. Fink
Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment
Pediatrics, 128 (2011), pp. e1618-e1621 http://dx.doi.org/10.1542/peds.2011-0359
[3]
K. Allegaert,B. Anderson,S. Simons,B. van Overmeire
Paracetamol to induce ductus arteriosus closure: is it valid?
Arch Dis Child, 98 (2013), pp. 462-466 http://dx.doi.org/10.1136/archdischild-2013-303688
[4]
M.Y. Oncel,S. Yurttutan,O. Erdeve,N. Uras,N. Altug,S.S. <et al=""></et> Oguz
Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial
[5]
A. Ohlsson,P.S. Shah
Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants
Cochrane Database Syst Rev, 3 (2015), pp. CD010061
[6]
M.E. Pérez Domínguez,S. Rivero Rodríguez,F. García-Muñoz Rodrigo
El paracetamol podría ser útil en el tratamiento del ductus arterioso persistente en el recién nacido de muy bajo peso
An Pediatr, 82 (2014), pp. 362-363

Please cite this article as: Gálvez Criado R, Rodríguez Blanco S, Oulego Erroz I, Jiménez González A, Alonso Quintela P. Paracetamol: tratamiento útil de elección para el ductus arterioso persistente en prematuros de muy bajo peso. An Pediatr (Barc). 2018;88:353–355.

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