http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–3 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.871630
SHORT REPORT
Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Imperial College London on 06/06/14 For personal use only.
Irena Kessel1,3*, Dan Waisman1,3*, Karen Lavie-Nevo1,3, Marcelo Golzman2,3, Avraham Lorber3,4*, and Avi Rotschild1,3* 1
Department of Neonatology and 2Department of Pharmacy, Carmel Medical Center, Haifa, Israel, 3Rappaport School of Medicine, Technion – Israel Institute of Technology, Haifa, Israel, and 4Pediatric Cardiology Institute, Meyer Children’s Hospital, Rambam Health Care Campus, Haifa, Israel
Abstract
Keywords
Paracetamol was reported to be effective for patent ductus arteriosus (PDA) closure. We present a case series of PDA closure by paracetamol in seven premature infants. During the treatment, paracetamol blood levels did not exceed the recommended levels for analgesia and hyperthermia in six tested infants. None of the patients demonstrated significant disturbances of liver function.
Blood level, closure, paracetamol, patent ductus arteriosus
Introduction Patent ductus arteriosus (PDA) may lead to the significant elevation of pulmonary blood flow and consequent lifethreatening events in premature infants [1]. If it does not close spontaneously and non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated or not effective, surgical ligation is indicated. Both treatment modalities have adverse effects [1,2]. Paracetamol is a part of pain management in premature infants, and it was reported to be effective for PDA closure [3–5]. No adverse effects were noted when the drug was used in the recommended doses [4].
Case-series presentation We present a case series of PDA closure by paracetamol (Novimol Drops, C.T.S., Israel) 15 mg/kg naso-gastric (NG) tube administration every 6 h in seven premature infants. All of them were mechanically ventilated for respiratory distress syndrome, had hemodynamically significant PDA diagnosed clinically and confirmed by means of echo-Doppler cardiography. Each of them had absolute contraindications for NSAIDs or failed to response to NSAIDs administration. A ductus-dependent cardiac anomaly was excluded by means of echo-Doppler cardiography. During the treatment, liver function tests were performed for all seven infants, and six of *These authors have equally contributed to the present work. Address for correspondence: Irena Kessel, MD, Department of Neonatology, Carmel Medical Center, Rappaport School of Medicine, Technion – Israel Institute of Technology, 7 Michal Street, Haifa 34362, Israel. Tel: 972 4 8250257. Fax: 972 4 8250774. E-mail:
[email protected] History Received 23 August 2013 Revised 16 November 2013 Accepted 30 November 2013 Published online 6 February 2014
them were monitored for paracetamol blood levels. Multidisciplinary clinical and ethical discussions were held, and Ministry of Health permission for off-label drug use and parental consent following an appropriate explanation were obtained. Presented infants were born from 26 till 30 weeks of gestational age and had birth weight from 789 up to 1322 g. Clinical follow-up was performed daily and echo-Doppler cardiography was accomplished every 3 d. In five infants, NSAIDs were contraindicated, and in another two infants there was PDA re-canalization after NSAIDs treatment. In five patients, clinical signs of PDA disappeared within 48 h, the duct closure was confirmed by echocardiography and the treatment was discontinued after 3 d. One infant was treated for 7 d, retained the duct patency for 2 weeks following the treatment, with subsequent closure. Another infant with extremely severe respiratory disease received paracetamol treatment twice. The first course that was started on the sixth day of life due to contraindications for NSAIDs lasted for 7 d and failed. The second course was given from the 21st till 24th d of life as a last attempt of treatment before surgical ligation and proved to be successful. Liver function tests and paracetamol blood levels of the treated patients are presented in Table 1. None of the patients demonstrated significant disturbances of liver function, but in three infants a mild transient gamma glutamine transferase (GGT) elevation was observed. Paracetamol blood levels did not exceed the recommended levels for analgesia and hyperthermia in six tested infants. None of the patients suffered from bleeding, thrombocytopenia or renal failure.
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Table 1. Liver function and paracetamol blood levels. GOT* (normal range 1–50 units/l) Before During After
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A. B. C. D. E. E. F. G.
37 14 75 14 11 25 34 21
18 44 17 22 33 21
38 22 17 20 19 32 34 13
GPTy (normal range 35–140 units/l) Before 11 55 9 55 5 6 11 5
During 55 11 5 6 11 7
After 12 12 8 6 5 5 11 55
GGTz (normal range 12–132 units/l) Before During
102 70 48 91 146 97
99 114 75 53 150 79
Paracetamol levels (10–20 mg/ml recommended for pain and fever control)
2 d after/ 7 d after
Before 5th dose (mg/ml)
Before 9th dose (mg/ml)
24 h after the last dose (mg/ml)
160/123 92 67 94 44 208/94 244/98 67
– 10.9
– 19.5 27.1 11.8 24.3 4.8 18.7 12.7
– 51 13.5 13.2 13.9 5.9 15.6 10.2
7.0 10.1 4.9 14.5 10.6
*GOT – glutamate oxaloacetate transaminase. yGPT – glutamate pyruvate tranaminase. zGGT – gamma glutamyl transpeptidase
Discussion We report the series of seven premature infants with hemodynamically significant PDAs that were successfully closed by NG paracetamol. Each infant had one or more absolute contraindications for NSAIDs such as intraventricular hemorrhage, thrombocytopenia, disturbed renal function, rapid bilirubin blood level elevation or they failed to respond to NSAIDs administration. During the treatment, all infants were monitored for liver function, and paracetamol blood levels were followed-up in six of them. Hemodynamically significant PDA closure by off-label oral paracetamol was reported to be achieved within 48 h and confirmed by echocardiography in most of the treated infants [4,5]. Paracetamol seems to inhibit peroxidase segment of the enzyme prostaglandin synthetase, unlike NSAIDs that inhibit cyclooxygenase pathway of this enzyme [4,5]. NSAIDs are associated with significant adverse effects, including peripheral vasoconstriction, gastrointestinal bleeding and perforation, renal failure, oliguria and impaired platelet aggregation [1,4,5]. In premature infants, ibuprofen has been associated with inhibition of bilirubin glucuronidation in the liver and hyperbilirubinemia [4]. These adverse effects emphasize the possible benefits of alternative treatment with paracetamol for PDA management. Hammerman et al. did not report paracetamol-associated adverse effects [4] and Oncel et al. demonstrated normal pre- and post-treatment liver enzymes levels [5]. However, the potential paracetamol hepatotoxycty is attributed to the production of N-acetyl-p-benzoquinone-imine by the hepatic cytochrome P-450 [6]. Paracetamol concentration for such hepatotoxicity is unknown. In our series, none of the patients presented high paracetamol blood levels or significant liver function disturbances except for mild temporary elevation of GGT in 3 infants (Table 1). The precise paracetamol dose and the route of its administration for PDA closure are not established yet. When administrated intravenously (IV) for pain control in neonates of 27–45 weeks’ GA, paracetamol mean serum concentration was influenced by infants’ weight [7]. Oncel et al. used IV paracetamol 15 mg/kg every 6 h for 3 d to close PDA in preterm infants [8]. As far as we know, there are two ongoing trials investigating the effectiveness and safety of
paracetamol for the indication of PDA closure [9,10]. In one of them paracetamol is administrated IV, while in the other the route of administration is oral. In both trials, the treatment is started with a loading dose that is followed by maintenance doses with intervals depending on GA [9,10]. To the best of our knowledge, there is no published data concerning the target paracetamol concentration for an effective and safe PDA closure in premature infants. Paracetamol is approved for analgesia and hyperthermia for premature infants, and it is recognized as safe when used in the recommended doses [3]. The recommended plasma paracetamol concentrations for antipyretic and analgesic effects in infants are 10–20 mg/ml [11]. Most measured paracetamol blood concentrations in our series were comparable with those recommended for pain and fever control (Table 1) [11]. In two infants, paracetamol transient level elevation of 24.3 mg/ml and 27.1 mg/ml was demonstrated before dose 9. In both cases after the end of treatment, blood levels returned to the range recommended for pain and fever. Both infants showed normal liver functions test results during the treatment. Our case series adds to the existing knowledge the data of paracetamol blood levels during its administration for PDA closure in premature infants. The dosage in our case series was based on the recommendations for pain control in preterm infants and on previous reports of paracetamol use for PDA closure [3–5]. The second course of paracetamol for PDA closure might be considered in cases of failed treatment.
Conclusions Our data suggest that paracetamol is an effective and safe therapeutic option for PDA closure, provided the recommended doses for pain control are used, as well as paracetamol blood levels and liver function are monitored. Our results support previous reports that proposed the use of paracetamol as an alternative treatment for PDA before surgical ligation in patients who failed or had contraindications for NSAIDs administration. Prospective trials may provide further insight of paracetamol effectiveness and safety as an additional or even as a first-line agent for PDA closure in neonates.
DOI: 10.3109/14767058.2013.871630
Acknowledgements The authors gratefully acknowledge their staff member Tali Ben-Ari, RN, MA, IBCLC.
Declaration of interest The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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