Pharmacokinetics of intravenous paracetamol (acetaminophen) and ductus arteriosus closure after premature birth

2021 ◽  
Author(s):  
Naïm Bouazza ◽  
Jean‐Marc Treluyer ◽  
Frantz Foissac ◽  
Saïk Urien ◽  
Outi Aikio ◽  
...  
Keyword(s):  
Premature Birth ◽  
Ductus Arteriosus ◽  
Intravenous Paracetamol

scholarly journals Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-Resistant or Contraindicated Preterm Infants: Three Cases Reports

2017 ◽  
Vol 07 (04) ◽  
pp. e230-e233 ◽  
Author(s):  
Shun Matsumura ◽  
Ayumi Oshima ◽  
Sumie Fujinuma ◽  
Kosuke Tanaka ◽  
Nobuhiko Nagano ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Premature Infants ◽  
Ductus Arteriosus ◽  
Limited Data ◽  
Gastrointestinal Complications ◽  
Surgical Closure ◽  
Institutional Ethics ◽  
Intravenous Paracetamol ◽  
Administration Protocol ◽  
Patent Ductus

Background Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed.

scholarly journals IV Paracetamol for closure of patent ductus arteriosus in preterm neonates admitted to a tertiary care centre

2018 ◽  
Vol 5 (2) ◽  
pp. 294 ◽  
Author(s):  
Sunil B. ◽  
Shruthi Patel ◽  
Girish N.
Keyword(s):  
Side Effects ◽  
Preterm Infants ◽  
Ductus Arteriosus ◽  
Treatment Options ◽  
Tertiary Care ◽  
Current Treatment ◽  
Preterm Neonates ◽  
Tertiary Care Centre ◽  
Vascular Connection ◽  
Intravenous Paracetamol

Background: Ductus arteriosus is a vascular connection between the pulmonary artery and descending aorta. The incidence is inversely related to birth weight and gestational age (GA). In preterm infants it varies between 40% and 60% on the third day of life. At present, the choice of treatment of clinically significant PDA is with either ibuprofen or indomethacin, but they carry many contraindications and potential side effects. Hence it is important to consider that paracetamol may be used as an alternative to other non steroidal anti-inflammatory drugs and is effective in ductal closure with minimal side effects.Methods:Thirty six preterm infants with hemodynamically significant PDA(hs-PDA) were treated with intravenous paracetamol and subsequent closure was evaluated clinically and by follow-up 2D-Echo.Results: PDA closure following intravenous paracetamol was evident in 27 babies (75%). There were no significant side effects noted with paracetamol therapy.Conclusions: This study shows that paracetamol could offer favourable safety profile in comparison to current treatment options. Therefore, paracetamol may be accepted as a first-line drug treatment for PDA in preterm infants. 

scholarly journals Comparison of the effect of two drugs paracetamol with intravenous ibuprofen in patent ductus arteriosus treatment

2020 ◽  
Vol 9 (5) ◽  
pp. 690
Author(s):  
Mehrdad Mirzarahimi ◽  
Ramin Emamzadeghan ◽  
Afsaneh Enteshari Moghaddam ◽  
Narges Falsafi
Keyword(s):  
Patent Ductus Arteriosus ◽  
Ductus Arteriosus ◽  
Alternative Therapy ◽  
Cyclooxygenase Inhibitors ◽  
Arterial Duct ◽  
Intravenous Paracetamol ◽  
Liver Parameters ◽  
Intravenous Ibuprofen ◽  
Patent Ductus

Background: Patent ductus arteriosus (PDA) is a common cause of morbidity and mortality among premature infants that affects more than 40% of them. PDA treatment includes medical and surgical treatment. Most drugs used to block PDA are cyclooxygenase inhibitors (ibuprofen and indomethacin). The role of paracetamol as an alternative therapy in PDA ligation has been considered in recent years due to the potential side effects of cyclooxygenase inhibitors.Methods: Patients in the first group were treated with intravenous paracetamol at a dose of 15 mg/kg every 6 hours for three days and the second group was treated with intravenous ibuprofen at a daily dose of 10 mg/kg daily and 5 mg/kg for the second and third days. At the end of the treatment period (day 3), they underwent echocardiography again. If the echocardiographic findings indicated no closure of the arterial duct, patients were treated with the aforementioned drug for another period and rechecked at the end of the third day, and at each stage required information was collected.Results: Arterial duct closure in paracetamol group was 96.7% and in ibuprofen group was 100%. The effects of both paracetamol and ibuprofen were similar in terms of renal parameters but in terms of effects on liver parameters. The effect of paracetamol on all liver parameters except aspartate transaminase (AST) was significant, but ibuprofen was able to affect only bilirubin among liver parameters and had no significant effect on both AST and alanine aminotransferase, parameters.Conclusions: Results showed that both paracetamol and ibuprofen are effective in treating of PDA and had similar impact.

Late medical therapy of patent ductus arteriosus using intravenous paracetamol

2015 ◽  
Vol 100 (3) ◽  
pp. F253-F256 ◽  
Author(s):  
Afif EL-Khuffash ◽  
Adam T James ◽  
Aoife Cleary ◽  
Jana Semberova ◽  
Orla Franklin ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Medical Therapy ◽  
Ductus Arteriosus ◽  
Intravenous Paracetamol ◽  
Patent Ductus

Prophylactic intravenous paracetamol use in extremely premature infants for patent ductus arteriosus

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Musa Silahli ◽  
Zeynel Gokmen ◽  
Mehmet Tekin
Keyword(s):  
Patent Ductus Arteriosus ◽  
Retinopathy Of Prematurity ◽  
Ductus Arteriosus ◽  
Hemodynamic Instability ◽  
Extremely Low Birth Weight ◽  
Control Group ◽  
Low Birth Weight Infants ◽  
Intravenous Paracetamol ◽  
Prophylactic Use ◽  
Patent Ductus

AbstractObjectivesPatency of ductus arteriosus (PDA) is a very common problem among extremely low birth weight infants (ELBW). Hemodynamic instability caused by PDA is associated with important morbidities. This study aims to evaluate the effects of prophylactic intravenous paracetamol on the hemodynamically significant patent ductus arteriosus (hsPDA).MethodsA total of 75 infants of <28 week-gestational age were enrolled into the study which was retrospective. Prophylactic paracetamol as the experimental group and none-prophylaxis group as the control group were compared in the study.ResultsThere were 35 subjects in the prophylactic paracetamol group (PPG), and 40 in the control group. Primary outcome measures were ductal closure, ductal diameter, grade 3–4 IVH, and repeated ibuprofen need for the treatment of hsPDA. At the time of the evaluation by echo, hsPDA, and the diameter of the ductus higher than 1 mm were found significantly lower in the PPG (p=0.004 and p=0.013). Additionally, the repeated course of ibuprofen was significantly lower in the PPG (p=0.025). Secondary outcomes were the other perinatal morbidities. According to the results of the study, the male gender is 6.6, and the paracetamol use is 5.5 times more likely to suffer from ROP.ConclusionsThe results of the study indicated that prophylactic paracetamol use in ELBW infants decreases the likelihood of hsPDA. The repeated course of ibuprofen for the treatment of hsPDA can be reduced. Furthermore, it can be understood that while prophylactic use of paracetamol is preventive for intraventricular hemorrhage, it does not function in the same way for retinopathy of prematurity or bronchopulmonary dysplasia. It might even worse the retinopathy of prematurity. Further prospective randomized controlled and larger sample-sized studies are needed.

Intravenous Paracetamol Treatment in the Management of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants

Neonatology ◽  
2013 ◽  
Vol 103 (3) ◽  
pp. 166-169 ◽  
Author(s):  
Mehmet Yekta Oncel ◽  
Sadik Yurttutan ◽  
Halil Degirmencioglu ◽  
Nurdan Uras ◽  
Nahide Altug ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Patent Ductus Arteriosus ◽  
Ductus Arteriosus ◽  
Extremely Low Birth Weight ◽  
Low Birth Weight Infants ◽  
Intravenous Paracetamol ◽  
Patent Ductus

SP10 Paracetamol levels following intravenous therapy in neonates less than 28 weeks gestation

2018 ◽  
Vol 103 (2) ◽  
pp. e1.2-e1
Author(s):  
Mulholland Peter ◽  
Heuchan AnneMarie
Keyword(s):  
Patent Ductus Arteriosus ◽  
Gestational Age ◽  
Liver Toxicity ◽  
Ductus Arteriosus ◽  
List Type ◽  
Term Infants ◽  
Intravenous Paracetamol ◽  
Before And After ◽  
Gastrointestinal Side Effects ◽  
Patent Ductus

IntroductionParacetamol is a mainstay analgesic for neonatal pain and is increasingly used for management of patent ductus arteriosus (PDA) in very premature infants. The BNF for Children (BNFC) gives no dose recommendations for babies <28 weeks gestational age (GA) for analgesia and no recommendations for management of PDA. A recent review1 of current literature only covered babies of ≥32 weeks gestation. We report on the paracetamol levels and safety profiles obtained in thirteen babies of <28 weeks GA, using an extended dosage regimen2 over five days with maximum daily dose of 60 mg/kg/day; twice that recommended by the BNFC for analgesia in infants <32 weeks gestation.MethodBabies <28 weeks GA, received regular paracetamol for five days intravenously for PDA3 based on the following regimen initially introduced to the unit as part of a clinical trial (PDA TOLERATE)4 babies did not have to participate in the trial to receive paracetamol for PDA.Regimen: 20 mg/kg loading dose followed by 10 or 12.5 mg/kg QID depending on corrected gestational age (CGA) lower dose for those 23+0 to 25+6 and =7 days at time of treatment, incrementing to a maximum of 15 mg/kg QID. Target paracetamol levels were 1520 mg/l with dose reduction if >25 mg/l and discontinuation if >40 mg/l. Since the major concern about paracetamol is liver toxicity plasma transaminases and bilirubin were obtained before and after (within 96 hours) treatment.ResultsThirteen babies were treated with paracetamol for PDA. Median gestation at birth was 24+3 weeks (range 23+2–26+2) with a median CGA at treatment of 26+4 weeks (range 25+3–28+0). Median weight was 735 g (range 520 g – 990 g). All babies had paracetamol levels <25 mg/L with a median level of 12.7 mg/L (range 7–24). No dose reductions were required. Serum transaminases and bilirubin were normal before and after treatment. There were no clinical gastrointestinal side effects.ConclusionThese data suggests these higher doses of paracetamol may be safe for babies of <28 weeks gestation requiring regular dosing, for up to five days, regardless of indication. Paracetamol levels obtained were lower than the target levels set for PDA TOLERATE but consistent with weight based pharmacokinetic models in moderate preterm and term infants in previous studies.4 Given the variation in levels obtained it may be beneficial to monitor paracetamol levels in babies receiving regular dosing.ReferencesMian P, Knibbe CA, Tibboel D, et al. What is the dose of intravenous paracetamol for pain relief in neonates?Arch Dis Child2017;102:653–654.El-Khuffash A, Jain A, Corcoran D, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res2014;76(3):238–244.Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus (PDA:TOLERATE). ClinicalTrials.gov Identifier USA NCT0195832, NHS HRA UK Clinicaltrials.gov identifier NCT01958320.Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: Size matters most. Arch Dis Child2011;96:575–5802.

scholarly journals Safety and Feasibility of Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-/Ibuprofen-Resistant or -Contraindicated Preterm Infants: A Case Series

2020 ◽  
Vol 10 (01) ◽  
pp. e49-e53
Author(s):  
Ayumi Oshima ◽  
Shun Matsumura ◽  
Ayaka Iwatani ◽  
Machiko Morita ◽  
Sumie Fujinuma ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Preterm Infants ◽  
Premature Infants ◽  
Ductus Arteriosus ◽  
Case Series ◽  
High Plasma ◽  
Gastrointestinal Complications ◽  
Surgical Closure ◽  
Intravenous Paracetamol ◽  
Patent Ductus

Abstract Background Although indomethacin and ibuprofen are the standard treatments for hemodynamically significant patent ductus arteriosus (hsPDA), they are associated with renal impairment and gastrointestinal complications. Paracetamol for hsPDA closure does not provoke a peripheral vasoconstrictive effect and seems to have effects similar to those of indomethacin and ibuprofen. We have previously reported the safety of low-dose (7.5 mg/kg) intravenous paracetamol for preterm infants with hsPDA, who were indomethacin-resistant or -contraindicated but did not affect the need for surgical PDA ligation. However, reports considering the use of higher-dose (15 mg/kg) paracetamol for hsPDA have not been published in Japan. Cases In 16 premature infants in whom indomethacin or ibuprofen was contraindicated or ineffective, 15 mg/kg of paracetamol was intravenously administered every 6 hours for 3 days after obtaining parental consent. hsPDA closure or narrowing was observed in 14 infants (88%), with the need for surgical closure totally avoided in nine cases (56%). High plasma paracetamol levels were observed in three cases. No paracetamol-related side effects or adverse events were reported. Conclusion The intravenous administration of higher dose paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials to explore the optimized dose and timing of administration are needed.

scholarly journals Early PARacetamol (EPAR) trial: a study protocol for a randomised controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants

BMJ Open ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. e031428 ◽  
Author(s):  
Tim Schindler ◽  
John Smyth ◽  
Srinivas Bolisetty ◽  
Joanna Michalowski ◽  
Kei Lui
Keyword(s):  
Preterm Infants ◽  
Controlled Trial ◽  
Ductus Arteriosus ◽  
Primary Analysis ◽  
Double Blind ◽  
Safe Alternative ◽  
Target Sample Size ◽  
Intravenous Paracetamol ◽  
Registration Number ◽  
Randomised Controlled

IntroductionThe optimal management of patent ductus arteriosus (PDA) remains contentious. The medications used to treat PDA are often non-steroidal anti-inflammatory drugs, which are associated with a number of unwanted adverse effects. Paracetamol is a medication with an excellent safety profile in infants and has been suggested as a safe alternative medication in situations where other medications have failed or are contraindicated. There are limited data on the use of early, intravenous paracetamol in preterm infants.Methods and analysisThis trial aims to address whether early treatment with paracetamol will reduce the number of infants requiring intervention for PDA. This is a randomised, double-blind, placebo-controlled trial in preterm infants <29 weeks’ gestation. At 6 hours of life, infants with a ductus arteriosus >0.9 mm will be randomised to receive either (1) intravenous paracetamol at a dose of 15 mg/kg initially, followed by every 6 hours at a dose of 7.5 mg/kg for 5 days; or (2) intravenous 5% dextrose every 6 hours for 5 days. The primary outcome is the need for any intervention for management of PDA up to 5 days. Secondary outcomes include closure of the ductus arteriosus at 5 days, size of the ductus arteriosus, ductal reopening, systemic blood flow, mortality and significant morbidities. The target sample size of 100 infants yields >80% power, at the two-sided 5% level significance, to detect a 50% reduction in the need for intervention assuming that approximately 60% of infants in this study would otherwise have required intervention for PDA.Ethics and disseminationA report on the results of the planned analyses will be prepared. The results of the primary analysis of all end points will be presented at medical conferences and submitted for publication in peer-reviewed journals. Separate manuscripts pertaining to the second aim of the study may be written, and these will also be submitted for publication in peer-reviewed journals.Trial registration numberACTRN12616001517460.

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