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Al-Shaibi S, Abushanab D, Abounahia F, Awaisu A, Al-Badriyeh D. Cost-Effectiveness Analysis of Ibuprofen Versus Indomethacin or Paracetamol for the Treatment of Patent Ductus Arteriosus in Preterm Neonates. Curr Probl Cardiol 2023; 48:101751. [PMID: 37088173 DOI: 10.1016/j.cpcardiol.2023.101751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 04/25/2023]
Abstract
This was a first-time evaluation that sought to analyze the cost-effectiveness of oral paracetamol and intravenous (IV) indomethacin as alternatives to ibuprofen for PDA in neonates. Decision-analytic, literature-based, economic simulation models were constructed, to follow up the use and consequences of oral/IV ibuprofen versus IV indomethacin, and oral/IV ibuprofen versus oral paracetamol, as first-line therapies for PDA closure. Model outcomes of interest were "success", defined as PDA closure with/without adverse events, or "failure" due to no response to the first course of treatment, death or premature discontinuation of therapy due to adverse events. Oral ibuprofen is dominant/cost-effective over IV indomethacin in 97.9% of simulated cases, but oral paracetamol was 75.2% dominant/cost-effective over oral ibuprofen. Against IV ibuprofen, IV indomethacin was 55.3% dominant/cost-effective, whereas oral paracetamol was dominant/cost-effective in 98.5% of the cases. Sensitivity analyses confirmed the robustness of the study results. For PDA closure, while IV indomethacin was cost-effective against IV ibuprofen, oral paracetamol was cost-effective against both oral and IV ibuprofen.
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Affiliation(s)
- Samaher Al-Shaibi
- Department of Pharmacy, Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Dina Abushanab
- Neonatal Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Fouad Abounahia
- Drug Information Department, Hamad Medical Corporation, Doha, Qatar
| | - Ahmed Awaisu
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
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Yurttutan S. A perspective on the potential side effects of paracetamol use in the treatment of PDA. Pediatr Res 2022; 92:1505-1506. [PMID: 35352002 DOI: 10.1038/s41390-022-02025-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/06/2022] [Indexed: 12/30/2022]
Affiliation(s)
- Sadık Yurttutan
- Department of Pediatrics, Division of Neonatology, Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey.
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The Association of Patent Ductus Arteriosus with Inflammation: A Narrative Review of the Role of Inflammatory Biomarkers and Treatment Strategy in Premature Infants. Int J Mol Sci 2022; 23:ijms232213877. [PMID: 36430355 PMCID: PMC9699120 DOI: 10.3390/ijms232213877] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/27/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Patent ductus arteriosus (PDA) is a common cardiovascular complication that complicates clinical care in the intensive care of premature infants. Prenatal and postnatal infections and the inflammation process can contribute to PDA, and intrauterine inflammation is a known risk factor of PDA. A variety of inflammatory biomarkers have been reported to be associated with PDA. Chorioamnionitis induces the fetal inflammatory process via several cytokines that have been reported to be associated with the presence of PDA and may have a role in the vascular remodeling process or vessel dilation of the ductus. On the other hand, anti-inflammatory agents, such as antenatal steroids, decrease PDA incidence and severity in patients born to those with chorioamnionitis. Proinflammatory cytokines, which are expressed more significantly in preterm neonates and chorioamnionitis, are associated with the presence of PDA. In this review, we focus on the pathogenesis of PDA in preterm infants and the role of biomarkers associated with the perinatal inflammatory process.
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Wright CJ. Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences? J Pediatr 2021; 235:264-276.e1. [PMID: 33617854 PMCID: PMC9810455 DOI: 10.1016/j.jpeds.2021.02.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 01/05/2023]
Affiliation(s)
- Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.
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Shahmirzadi G, Nooripour S, Ziari A, Danaei N. Comparison of Gastrointestinal Complications of Paracetamol and Ibuprofen in the Management of Infants with Patent Ductus Arteriosus: A Randomized Clinical Trial Study. Int J Prev Med 2021; 12:48. [PMID: 34211679 PMCID: PMC8223912 DOI: 10.4103/ijpvm.ijpvm_387_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 12/09/2019] [Indexed: 11/28/2022] Open
Abstract
Background: Patent ductus arteriosus (PDA) is one of the more common congenital heart defects in preterm neonates. The closure of PDA can be done with ibuprofen; however, this drug is associated with many contraindications and potential side-effects. In the past years, paracetamol has been proposed for the treatment of PDA. This study was designed to evaluate the efficacy and gastrointestinal complications of paracetamol and ibuprofen for the pharmacological closure of PDA in preterm infants. Methods: In a clinical trial study, 40 preterm infants with echocardiographically confirmed PDA were randomly assigned to receive either paracetamol (n = 23; 15 mg/kg every 6 h for 2 days) or ibuprofen (n = 17; initial dose of 10 mg/kg, followed by 5 mg/kg every 12 h for 2 days). The neonates matched for gestational age and weight. We used t-test for parametric, Chi-square for categorial, and Wilcoxson for nonparametric variables. Significant level was considered less than 0.05. Results: Platelet count, BUN and creatinine levels, and closure of PDA had not significant difference between two groups (P > 0.05). Incidence and severity of GI bleeding, feeding intolerance, and NEC were significantly more in infants who received paracetamol than ibuprofen (P < 0.05). Conclusions: There were no differences in the rate of PDA closure between the two drugs, but with respect to complications, rate and severity of GI bleeding, feeding intolerance, and NEC were significantly more in infants who received paracetamol than ibuprofen. Therefore, paracetamol could not be used as a proper alternative agent for ibuprofen in the treatment of PDA in preterm infants.
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Affiliation(s)
- Gohar Shahmirzadi
- Department of Pediatric, Semnan University of Medical Science, Semnan, Iran.,Students Research Committee, Semnan University of Medical Science, Semnan, Iran
| | | | - Abbas Ziari
- Social Determinants of Health Research Center, Semnan University of Medical Science, Semnan, Iran
| | - Navid Danaei
- Department of Pediatric, Semnan University of Medical Science, Semnan, Iran
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Manalastas M, Zaheer F, Nicoski P, Weiss MG, Amin S. Acetaminophen Therapy for Persistent Patent Ductus Arteriosus. Neoreviews 2021; 22:e320-e331. [PMID: 33931477 DOI: 10.1542/neo.22-5-e320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Persistence of a left-to-right shunt caused by a patent ductus arteriosus (PDA) leads to significant sequelae in extremely premature infants as a result of pulmonary overcirculation and systemic steal. Although timing and duration of treatment for a persistent clinically significant PDA differ among institutions, standard pharmacologic interventions are the nonsteroidal anti-inflammatory drugs indomethacin and ibuprofen. Acetaminophen has emerged as an alternative to indomethacin and ibuprofen with less significant adverse effects, but there is no consensus regarding its use. This review summarizes the most recent evidence for the use of acetaminophen in PDA treatment.
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Affiliation(s)
| | | | - Pamela Nicoski
- Division of Neonatology, and.,Department of Pharmacy, Loyola University Medical Center, Maywood, IL
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Bahrami R, Ezzatabadi A, Mehdizadegan N, Mohammadi H, Amoozgar H, Edraki M. Does high dose intravenous acetaminophen affect liver function for PDA closure in premature neonate? Ital J Pediatr 2021; 47:37. [PMID: 33596978 PMCID: PMC7890839 DOI: 10.1186/s13052-020-00940-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 11/21/2020] [Indexed: 01/10/2023] Open
Abstract
Objectives The aim of this study was to collect consistent data on the efficacy and safety and evaluation hepatotoxicity of intravenous acetaminophen for the treatment of PDA in preterm infants. Methods This is an observational longitudinal prospective study on 46 preterm infants with PDA who treated with high dose of acetaminophen and evaluated with echocardiography and serum liver enzymes at Hafez and Zeinabiyeh hospitals from January 2016 to December 2019. Result Forty-six preterm infants with PDA treated with intravenous acetaminophen. Rate of closure of PDA was 82.6. There was no significant difference after treatment regarding AST, ALT, Albumin, total and direct bilirubin (P value > 0.05) and no adverse side effects were observed in association with intravenous acetaminophen. Conclusion High dose of acetaminophen is not more effective than that with standard doses although without hepatotoxic side effect for PDA closure.
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Affiliation(s)
- Reza Bahrami
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pediatrics, Division of Pediatric Cardiology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, 7193711351, Iran
| | - Aida Ezzatabadi
- Medical School, Shiraz University of Medical Sciences, Medical School, Shiraz, Iran
| | - Nima Mehdizadegan
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. .,Department of Pediatrics, Division of Pediatric Cardiology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, 7193711351, Iran.
| | - Hamid Mohammadi
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pediatrics, Division of Pediatric Cardiology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, 7193711351, Iran
| | - Hamid Amoozgar
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pediatrics, Division of Pediatric Cardiology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, 7193711351, Iran
| | - Mohammadreza Edraki
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pediatrics, Division of Pediatric Cardiology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, 7193711351, Iran
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Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr 2021; 180:807-816. [PMID: 32888085 PMCID: PMC7886841 DOI: 10.1007/s00431-020-03780-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/06/2020] [Accepted: 08/10/2020] [Indexed: 11/04/2022]
Abstract
Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25+0-31+6 weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar.Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.Trial registration: Clinicaltrials.gov : NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30. What is Known: • The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol. What is New: • Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect. • These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.
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Meena V, Meena DS, Rathore PS, Chaudhary S, Soni JP. Comparison of the efficacy and safety of indomethacin, ibuprofen, and paracetamol in the closure of patent ductus arteriosus in preterm neonates - A randomized controlled trial. Ann Pediatr Cardiol 2020; 13:130-135. [PMID: 32641884 PMCID: PMC7331836 DOI: 10.4103/apc.apc_115_19] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/15/2019] [Accepted: 12/09/2019] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION In this prospective study, we compared the efficacy and safety of ibuprofen, indomethacin, and paracetamol in the closure of patent ductus arteriosus (PDA) in preterm neonates. MATERIALS AND METHODS This randomized prospective study was conducted in the Division of Pediatric Cardiology, M. D. M and Umaid Hospital, Jodhpur. A total of 105 preterm neonates with gestational age <37 weeks and hemodynamically significant PDA (hs-PDA) diagnosed clinically and confirmed by echocardiography were enrolled. All neonates were randomly assigned in a ratio of 1:1:1 to oral indomethacin (Group A, 3 doses at an interval of 12 h with a starting dose of 0.2 mg/kg), oral ibuprofen (Group B, 10 mg/kg ibuprofen followed by 5 mg/kg/day for 2 days), or IV paracetamol (Group C, 15 mg/kg every 6 hourly for 3 consecutive days). After the completion of the first course, neonates were assessed clinically as well as by echocardiography to confirm PDA closure. If PDA remained open, the second course of the same drug was given and repeat assessment was done within 24 h of the last dose. In addition to an echocardiographic examination, complete blood counts, renal and liver function tests were performed. RESULTS Our study shows that there was no significant difference observed in PDA closure among all the three treatment groups after the completion of two courses of treatment. The cumulative rate of PDA closure was 68% in the indomethacin group, 77.14% in the ibuprofen group, and 71.43% in the paracetamol group (P = 0.716). There were no significant changes found in Hb, platelet, blood urea nitrogen (BUN), creatinine, and liver enzymes after treatment in the paracetamol group (P > 0.05). BUN and serum creatinine levels were significantly increased after treatment in indomethacin and ibuprofen groups (P < 0.0001 and P < 0.05, respectively). CONCLUSION Our study shows that IV paracetamol is as effective as indomethacin and ibuprofen in promoting the closure of hs-PDA in premature infants with a better safety profile.
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Affiliation(s)
- Vasudha Meena
- Department of Paediatric Medicine, Division of Paediatric Cardiology, Dr. S. N. Medical College, MDM Hospital for Mother and Child, Jodhpur, Rajasthan, India
| | | | - Pradeep Singh Rathore
- Department of Paediatric Medicine, Division of Paediatric Cardiology, Dr. S. N. Medical College, MDM Hospital for Mother and Child, Jodhpur, Rajasthan, India
| | - Sandeep Chaudhary
- Department of Paediatric Medicine, Division of Paediatric Cardiology, Dr. S. N. Medical College, MDM Hospital for Mother and Child, Jodhpur, Rajasthan, India
| | - Jai Prakash Soni
- Department of Paediatric Medicine, Division of Paediatric Cardiology, Dr. S. N. Medical College, MDM Hospital for Mother and Child, Jodhpur, Rajasthan, India
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Höck M, Brunner B, Rier V, Thöni S, Trawöger R, Geiger R, Schermer E, Karall T, Kiechl-Kohlendorfer U. Prophylactic low-dose paracetamol administration associated with lowered rate of patent ductus arteriosus in preterm infants - Impact on outcome and pain perception. Pediatr Neonatol 2020; 61:84-91. [PMID: 31345732 DOI: 10.1016/j.pedneo.2019.06.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 06/07/2019] [Accepted: 06/28/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND To determine the rate of patent ductus arteriosus after prophylactic low-dose paracetamol administration, the impact on outcome parameters, possible treatment side-effects and the influence on pain perception. METHODS We report retrospective single-centre outcome data of premature infants ≤ 32 weeks of gestation (n = 476). The intervention group received intravenous paracetamol, the control group obtained no preventive therapy. Ductal closure rate and outcome parameters were compared between the two groups. Adverse effects were determined by laboratory parameters. For the assessment of pain the Bernese Pain Scale for Neonates was used. RESULTS The rate of patent ductus arteriosus was significantly lower in the paracetamol-treated group compared to the control group (13.6% vs. 38.2%, p < 0.001). With regard to secondary outcome parameters, severe and moderate bronchopulmonary dysplasia (2.7% vs. 7.4%, p = 0.023), severe retinopathy of prematurity (0% vs. 4.4%, p = 0.002) and late onset sepsis (2.7% vs. 8.3%, p = 0.009) were significantly less frequent in the paracetamol group. Except for a 1.5-fold increased risk for hyperbilirubinemia (86.0% vs. 77.6%, p = 0.035) in the paracetamol group following treatment, no significant differences in laboratory parameters were found. Relating to pain, the administration of Glucose 33% was significantly more often necessary in the control group compared to the paracetamol-treated group (mean 13.48 vs. 8.71, p < 0.001), just as the need for additional treatment with systemic analgesics, which was more frequent in the control group (mean 0.72 vs. 0.57, p = 0.361). CONCLUSION In our study we were able to show a significantly lower rate of patent ductus arteriosus after prophylactic paracetamol administration without serious adverse effect, but a beneficial influence of this regime on the patient's pain perception.
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Affiliation(s)
- Michaela Höck
- Medical University of Innsbruck, Department of Paediatrics II, Division of Neonatology, Austria
| | - Barbara Brunner
- Medical University of Innsbruck, Department of Paediatrics II, Division of Neonatology, Austria
| | - Vera Rier
- Medical University of Innsbruck, Department of Paediatrics II, Division of Neonatology, Austria
| | - Stefanie Thöni
- Medical University of Innsbruck, Department of Paediatrics II, Division of Neonatology, Austria
| | - Rudolf Trawöger
- Medical University of Innsbruck, Department of Paediatrics II, Division of Neonatology, Austria
| | - Ralf Geiger
- Medical University of Innsbruck, Department of Paediatrics III, Division of Cardiology, Pulmonology, Allergology and Cystic Fibrosis, Austria
| | - Elisabeth Schermer
- Medical University of Innsbruck, Department of Paediatrics III, Division of Cardiology, Pulmonology, Allergology and Cystic Fibrosis, Austria
| | - Thomas Karall
- Medical University of Innsbruck, Department of Paediatrics III, Division of Cardiology, Pulmonology, Allergology and Cystic Fibrosis, Austria
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García-Robles A, Gimeno Navarro A, Serrano Martín MDM, Párraga Quiles MJ, Parra Llorca A, Poveda-Andrés JL, Vento Torres M, Aguar Carrascosa M. Paracetamol vs. Ibuprofen in Preterm Infants With Hemodynamically Significant Patent Ductus Arteriosus: A Non-inferiority Randomized Clinical Trial Protocol. Front Pediatr 2020; 8:372. [PMID: 32766181 PMCID: PMC7380081 DOI: 10.3389/fped.2020.00372] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 06/02/2020] [Indexed: 11/13/2022] Open
Abstract
Background: Currently, the first line treatment of persistent ductus arteriosus (PDA) is either indomethacin or ibuprofen. However, the potentially life-threatening side effects associated to their use have prompted physicians to look for alternative options. The incorporation of paracetamol as an alternative to ibuprofen in the management of PDA is still based on insufficient clinical evidence. Hence, more clinical trials are needed to establish a therapeutic role for paracetamol in the management of PDA that take into consideration short- and long-term safety and efficacy outcomes. Study Design: This is a non-inferiority, randomized, multicenter, double-blinded study to evaluate the efficacy, and safety of intravenous (IV) paracetamol vs. IV ibuprofen (standard treatment) for PDA in preterm patients with a gestational age ≤ 30 weeks. At baseline, patients will be randomized (1:1) to treatment with paracetamol or ibuprofen. The primary endpoint is closure of the ductus after the first treatment course. Secondary endpoints are related to effectiveness (need for a second treatment course, rescue treatment, reopening rate, time to definitive closure, need for surgical ligation), safety (early and long-term complications), pharmacokinetics, and pharmacodynamics, pharmacogenetics, pharmacoeconomics, and genotoxicity. Long-term follow-up to 24 months of corrected postnatal age will be performed using Bayley III neurodevelopmental scale. Trial Registration: ClinicalTrials.gov Identifier: NCT04037514. EudraCT: 2015-003177-14.
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Affiliation(s)
- Ana García-Robles
- Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Pharmacy, University and Polytechnic Hospital La Fe, Valencia, Spain
| | - Ana Gimeno Navarro
- Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain
| | | | | | - Anna Parra Llorca
- Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain
| | | | - Máximo Vento Torres
- Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain
| | - Marta Aguar Carrascosa
- Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.,Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain
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12
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Schindler T, Smyth J, Bolisetty S, Michalowski J, Lui K. 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; 9:e031428. [PMID: 31666270 PMCID: PMC6830666 DOI: 10.1136/bmjopen-2019-031428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION The 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 ANALYSIS This 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 DISSEMINATION A 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 NUMBER ACTRN12616001517460.
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Affiliation(s)
- Tim Schindler
- Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - John Smyth
- Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Srinivas Bolisetty
- Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Joanna Michalowski
- Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
| | - Kei Lui
- Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
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13
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Karabulut B, Paytoncu S. Efficacy and Safety of Oral Paracetamol vs. Oral Ibuprofen in the Treatment of Symptomatic Patent Ductus Arteriosus in Premature Infants. Paediatr Drugs 2019; 21:113-121. [PMID: 31025304 DOI: 10.1007/s40272-019-00331-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The ductus arteriosus (DA) is situated between the aortic arch and the pulmonary artery in fetal circulation, and its closure is one of the most important changes required for the transition to extrauterine life. Prolonged duration of patent DA (PDA) impairs hemodynamics and contributes both to morbidity associated with prematurity and to mortality. Therefore, when best to initiate treatment and what drug to use as first-line treatment to close the ductus is important. OBJECTIVE The aim of this study was to compare the efficacy and side effects of the oral forms of ibuprofen and paracetamol and to contribute to the literature investigating the first drug to be selected in the medical treatment of PDA. METHODS This observational, retrospective cohort study was conducted in infants born at ≤ 28 weeks' gestation and admitted to our Neonatal Intensive Care Unit (Manisa Merkezefendi State Hospital, Manisa, Turkey) between February 2015 and April 2018. Included infants were born at ≤ 28 weeks' gestation, had PDA-related clinical findings and hemodynamically significant PDA on echocardiography, and received oral ibuprofen or oral paracetamol therapy as the closure treatment. RESULTS The most common clinical findings for the diagnosis of PDA were hyperdynamic circulation, tachycardia, and increased oxygen requirement. In total, 43 of the 51 (84.3%) premature infants in the ibuprofen group and 32 of the 36 (88.8%) in the paracetamol group achieved PDA closure after the first treatment cycle. There was no statistically significant difference between the two groups in terms of respiratory morbidity, renal and liver function, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, length of hospital stay, and mortality. CONCLUSIONS Our results indicate that oral paracetamol was as effective as oral ibuprofen in the medical treatment of PDA. In addition, both drugs were considered well-tolerated in terms of effects on kidney, liver, and intestinal functions. Our results demonstrate that oral paracetamol can be used effectively and safely as the first-line treatment of PDA.
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Affiliation(s)
- Birol Karabulut
- Pediatrics, Division of Neonatology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey.
| | - Sebnem Paytoncu
- Pediatrics, Division of Pediatric Cardiology, Manisa Merkezefendi State Hospital, Manisa, Turkey
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Vaidya R, Wilson D, Paris Y, Madore L, Singh R. Use of acetaminophen for patent ductus arteriosus treatment: a single center experience. J Matern Fetal Neonatal Med 2019; 33:2723-2729. [PMID: 30563380 DOI: 10.1080/14767058.2018.1559810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Purpose: Patent ductus arteriosus (PDA) continues to be one of the most common complications associated with preterm birth. Up to 70% of infants born before 28 weeks gestational age may require some form of medical or surgical treatment for PDA closure. Recent studies have suggested acetaminophen to be a promising new alternative to indomethacin and ibuprofen for closure of PDA with potentially fewer adverse effects. Our aim for the study was to report our experience regarding the efficacy of acetaminophen compared to indomethacin for treatment of hemodynamically significant PDA (hs-PDA) in infants born in our institution.Material and methods: Retrospective cohort study of all preterm infants born <34-week gestation with hs-PDA, treated with acetaminophen or indomethacin as the first line medication for hs-PDA. Primary outcome of successful PDA closure rate (small or no PDA) and secondary outcomes of short-term morbidities and immediate adverse events were compared between the two cohorts.Results: Of the 43 infants, 25 were treated with acetaminophen and 18 with indomethacin, as first line for hs-PDA. Successful PDA closure rate was slightly lower for acetaminophen compared to indomethacin, although statistically not significant (acetaminophen: 40% versus indomethacin: 55.5%, p = .31). No significant differences in short-term morbidities including necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), late onset sepsis (LOS), retinopathy of prematurity (ROP) and intraventricular hemorrhage (IVH), or immediate side effects including oliguria, hyponatremia, elevated BUN/creatinine, thrombocytopenia were found between the two cohorts.Conclusions: Acetaminophen treatment of hs-PDA resulted in similar successful PDA closure rate compared to indomethacin in our small cohort of patients.
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Affiliation(s)
- Ruben Vaidya
- Department of Pediatrics, Division of Newborn Medicine, University of Massachusetts Medical School- Baystate, Springfield, MA, USA
| | - Donna Wilson
- Epidemiology & Biostatistics, Office of Research University of Massachusetts Medical School- Baystate, Springfield, MA, USA
| | - Yvonne Paris
- Department of Pediatrics, Division of Pediatric Cardiology, University of Massachusetts Medical School- Baystate, Springfield, MA, USA
| | - Laura Madore
- Department of Pediatrics, Division of Newborn Medicine, University of Massachusetts Medical School- Baystate, Springfield, MA, USA
| | - Rachana Singh
- Department of Pediatrics, Division of Newborn Medicine, University of Massachusetts Medical School- Baystate, Springfield, MA, USA
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Guimarães AFM, Araújo FDR, Meira ZMA, Tonelli HAF, Duarte GG, Ribeiro LC, Rezende GQM, Castilho SRT. Acetaminophen in low doses for closure of the ductus arteriosus of the premature. Ann Pediatr Cardiol 2019; 12:97-102. [PMID: 31143033 PMCID: PMC6521660 DOI: 10.4103/apc.apc_42_18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Objective The objective of the study is to report the experience with acetaminophen in low doses as an alternative to the treatment of the ductus arteriosus of the preterm newborn. Materials and Methods Retrospective study including preterm newborns with patent ductus arteriosus who received oral acetaminophen because treatment with indomethacin had failed or is contraindicated. A dosage consisted of a first dose of 25 mg/kg and maintenance doses of 30 mg/kg/day, for 3 to 7 days. A second cycle was administered in cases of reopening of the ductus arteriosus. The rates of ductal closure and surgery were calculated. Patients were categorized into responder and nonresponder groups for acetaminophen, and the average values of ductal diameter, weight, gestational age, and postnatal age were compared. Results Eighty-seven preterm newborns, with a postnatal age from 3 to 27 days, with average values of ductus arteriosus equal to 2.5 ± 0.8 mm/kg, gestational age 27.2 ± 1.9 weeks, and birth weight 888.9 ± 241 g, received acetaminophen for 3 to 7 days. A second cycle was administered in 15 preterm newborns. The ductus closure rate, after one or two cycles, was 74.7%, and the recommendations for surgical closure were progressively reduced from 50% in the 1st year to 6.2% in the past year. Lower ductal closure rate occurred in the group of newborns with the lowest average weight (P = 0.018), the highest average ductal diameter (P = 0.002), and the lowest average gestational age (P = 0.09). Postnatal age at the start of acetaminophen use was shown to be irrelevant regarding the treatment (P = 0.591). Conclusions Acetaminophen in low doses showed to be an effective alternative for the closure of the ductus arteriosus for preterm newborns in whom treatment with indomethacin or ibuprofen failed or was contraindicated.
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Affiliation(s)
- Adriana Furletti Machado Guimarães
- Department of Pediatrics, Division of Neonatology, Hospital Foundation of Minas Gerais State, Minas Gerais, Brazil.,Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Fátima Derlene Rocha Araújo
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Zilda Maria Alves Meira
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil.,Department of Pediatrics, Division of Pediatric Cardiology, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Henrique Assis Fonseca Tonelli
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Guilherme Gomes Duarte
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Lívia Castro Ribeiro
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Gabriele Queiroz Monteiro Rezende
- Department of Pediatrics, Division of Neonatology, Hospital Foundation of Minas Gerais State, Minas Gerais, Brazil.,Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Sandra Regina Tolentino Castilho
- Department of Pediatrics, Division of Pediatric Cardiology, Clinics Hospital of the Federal University of Minas Gerais, Minas Gerais, Brazil
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El-Farrash RA, El Shimy MS, El-Sakka AS, Ahmed MG, Abdel-Moez DG. Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Matern Fetal Neonatal Med 2018; 32:3647-3654. [PMID: 29695206 DOI: 10.1080/14767058.2018.1470235] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Objective: The objective of this study is to evaluate the efficacy and safety of oral paracetamol versus oral ibuprofen in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. Study design: An interventional randomized case-control study, registered in ClinicalTrials.gov (NCT03265782), was conducted on 60 preterm infants with gestational age ≤34 weeks, postnatal age of 2-7 d and color Doppler echocardiographic evidence of hsPDA. Neonates were randomly assigned to two groups: 30 received oral ibuprofen and 30 received oral paracetamol. With failure of ductal closure, a second course of ibuprofen or paracetamol was given. The included newborns were subjected to detailed history, clinical examination, laboratory investigations that included complete blood count, renal, and liver function tests and echocardiographic evaluation. Results: Oral paracetamol was as effective as ibuprofen for the closure of patent ductus arteriosus (PDA) with one course of treatment (p > .05). Moreover, oral paracetamol was superior to ibuprofen among neonates who needed second course of treatment with significant decrease in end diastolic flow velocity in the left pulmonary artery (0.35 ± 0.09 versus 0.19 ± 0.06, p = .014), right ventricular systolic pressure (40.50 ± 12.91 versus 20.50 ± 0.58, p = .016) and left atrium to aortic root ratio (1.23 ± 0.14 versus 1.07 ± 0.04, p = .046) when compared to ibuprofen group. Furthermore, the mean difference between pre- and post-treatment PDA size was significantly higher in the paracetamol group compared with ibuprofen group after the second course of treatment (1.07 ± 0.32 versus 0.73 ± 0.38, p = .024). Oral paracetamol was comparable with ibuprofen in terms of the rate of non-surgical ductal closure [28 (93.3%) versus 24 (80%), p = .591]. In addition, oral paracetamol was as safe as oral ibuprofen in terms of gastrointestinal perforation or bleeding, necrotizing enterocolitis, bronchopulmonary dysplasia, intraventricular hemorrhage, thrombocytopenia, hepatic or renal dysfunction. Conclusions: Oral paracetamol is an effective and well-tolerated first-line drug treatment for PDA in premature infants.
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Affiliation(s)
- Rania A El-Farrash
- a Department of Pediatrics, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Mohammed S El Shimy
- a Department of Pediatrics, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Abeer S El-Sakka
- a Department of Pediatrics, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Manal G Ahmed
- b Neonatal Intensive Care Unit at the Maternity Hospital , Ain Shams University , Cairo , Egypt
| | - Dina G Abdel-Moez
- b Neonatal Intensive Care Unit at the Maternity Hospital , Ain Shams University , Cairo , Egypt
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Juujärvi S, Saarela T, Hallman M, Aikio O. Intravenous paracetamol was associated with closure of the ductus arteriosus in extremely premature infants. Acta Paediatr 2018; 107:605-610. [PMID: 29105147 DOI: 10.1111/apa.14137] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/02/2017] [Accepted: 10/30/2017] [Indexed: 11/30/2022]
Abstract
AIM Symptomatic patent ductus arteriosus may lead to serious complications in extremely preterm and extremely low birthweight infants and is often resistant to medication. We evaluated early intravenous paracetamol for pain prevention during respiratory therapy, in an attempt to understand the ductal treatment of such infants. METHODS Our cohort were 295 extremely preterm or extremely low birthweight infants, born at less than 28 weeks or 1000 g, respectively, who were treated in the neonatal intensive care unit of Oulu University Hospital from 2002 to 2015, before and after intravenous paracetamol was introduced in June 2009. Ductal closure dates, paracetamol medication details, morbidities and mortality data were evaluated. RESULTS Intravenous paracetamol was given to 128 infants, starting at a median of 4.4 hours age (range: 0-169 hours), with a mean total dosage of 212 mg/kg (range: 7.5-1175 mg/kg). We also included 167 controls who were mainly treated before we used intravenous paracetamol. Ibuprofen (p < 0.001) and ligation (p = 0.002) were lower in the paracetamol group than controls. No adverse effects were detected. Paracetamol was not associated with other morbidities. CONCLUSION We found that early use of intravenous paracetamol decreased the incidence of ductal therapies in extremely premature or extremely low birthweight infants.
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Affiliation(s)
- S Juujärvi
- PEDEGO Research Unit and Medical Research Centre Oulu; University of Oulu; Oulu Finland
- Department of Children and Adolescents; Oulu University Hospital; Oulu Finland
| | - T Saarela
- PEDEGO Research Unit and Medical Research Centre Oulu; University of Oulu; Oulu Finland
- Department of Children and Adolescents; Oulu University Hospital; Oulu Finland
| | - M Hallman
- PEDEGO Research Unit and Medical Research Centre Oulu; University of Oulu; Oulu Finland
- Department of Children and Adolescents; Oulu University Hospital; Oulu Finland
| | - O Aikio
- PEDEGO Research Unit and Medical Research Centre Oulu; University of Oulu; Oulu Finland
- Department of Children and Adolescents; Oulu University Hospital; Oulu Finland
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18
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Pharande P, Watson H, Tan K, Sehgal A. Oral Paracetamol for Patent Ductus Arteriosus Rescue Closure. Pediatr Cardiol 2018; 39:183-190. [PMID: 29043398 DOI: 10.1007/s00246-017-1745-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 09/30/2017] [Indexed: 11/24/2022]
Abstract
The objective of this study was to ascertain the efficacy of oral paracetamol in closing a symptomatic patent ductus arteriosus (PDA) when used as 'rescue' option. After obtaining ethics approval, a retrospective appraisal of the data from April 2014 to July 2015 was performed. Infants who were administered oral paracetamol either after unsuccessful therapy with ibuprofen or where it was considered contraindicated were included. A previously published echocardiographic scoring schema to stratify for ductal disease severity was used. Using univariate analysis, characteristics of infants with successful closure were compared with partial (a priori reduction in composite score by ≥ 50% of pretreatment) or no closure. Twenty infants with gestation age and birthweight of 25.7 ± 1.5 weeks and 724.1 ± 143 g, respectively, were studied. Complete closure was noted in 10 (50%) infants with additional four infants showing a significant reduction in haemodynamic shunting. Gestational age at birth and at therapy, chronological age at therapy, birthweight and total fluid intake were comparable between the two groups. The pre-therapy composite score had a significant association with successful closure (the higher the echocardiographic score, the lesser the closure). Concomitant furosemide therapy and late-onset sepsis had a high likelihood ratio of unsuccessful closure (11.01 [2-tailed, p = 0.005] and 5.3 [2-tailed, p = 0.07]), respectively. Oral paracetamol may be a possible therapeutic option in premature infants where therapy with first-line agents is unsuccessful or contraindicated. Concomitant sepsis and furosemide administration may affect successful therapy.
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Affiliation(s)
- Pramod Pharande
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.
| | - Hadley Watson
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia
| | - Kenneth Tan
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.,Department of Paediatrics, Monash University, Melbourne, Australia
| | - Arvind Sehgal
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.,Department of Paediatrics, Monash University, Melbourne, Australia
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de Albuquerque Botura C, da Rocha BA, Balensiefer T, Ames FQ, Bersani-Amado CA, Nakamura Cuman RK. Oral pharmacological treatment for patent ductus arteriosus in premature neonates with hemodynamic repercussions. ASIAN PAC J TROP MED 2017; 10:1080-1083. [PMID: 29203106 DOI: 10.1016/j.apjtm.2017.10.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 08/29/2017] [Accepted: 09/16/2017] [Indexed: 10/18/2022] Open
Abstract
OBJECTIVE To evaluate the efficacy of oral indomethacin, ibuprofen, and paracetamol in oral dosage form on patent ductus arteriosus (PDA) in premature neonates with significant clinical and hemodynamic repercussions (CHRs) and to determine the effect of these respective treatments on renal function. METHODS A retrospective study of cases of PDA in premature neonates in the Neonatal Intensive Care Unit was conducted. The treatments consisted of indomethacin [0.2 mg/(kg·d), 3-day cycle], ibuprofen [10 mg/(kg·d) followed by 5 mg/(kg·d), 3-day cycle], and paracetamol (15 mg/kg every 6 h, 5-day cycle). The drugs were administered as an oral solution. The following variables were considered: gestational age, newborn weight at birth, Apgar score, diuresis, serum creatinine and urea levels, and serum electrolyte levels (sodium and potassium). RESULTS Treatment with indomethacin presented efficacy of 87.5% in closure of the ductus with a mean outcome period of 3.5 d. In premature neonates with CHRs and contraindications for indomethacin, the initial treatment with either ibuprofen or paracetamol failed to close the ductus. However, when this treatment was followed by indomethacin, closure occurred in 66.7% of the neonates, with an outcome period of 9.66 d. The initial treatment with one cycle of ibuprofen followed by one or two cycles of paracetamol failed to close the ductus. CONCLUSIONS Oral indomethacin was effective for closure of the PDA in premature neonates with severe CHRs. Oral paracetamol or ibuprofen for PDA closure in premature neonates with severe CHRs and contraindications for indomethacin was ineffective. However, results in clinical improvements of neonates allowed the subsequent use of indomethacin and successful closure of the ductus. A significant reduction of diuresis occurred in neonates who were treated with indomethacin, either as a first-line treatment or after the failure of ibuprofen or paracetamol.
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Affiliation(s)
| | - Bruno Ambrósio da Rocha
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil
| | | | - Franciele Queiroz Ames
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil
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Paracetamol in Patent Ductus Arteriosus Treatment: Efficacious and Safe? BIOMED RESEARCH INTERNATIONAL 2017; 2017:1438038. [PMID: 28828381 PMCID: PMC5554551 DOI: 10.1155/2017/1438038] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 05/22/2017] [Accepted: 06/11/2017] [Indexed: 12/19/2022]
Abstract
In preterm infants, failure or delay in spontaneous closure of Ductus Arteriosus (DA), resulting in the condition of Patent Ductus Arteriosus (PDA), represents a significant issue. A prolonged situation of PDA can be associated with several short- and long-term complications. Despite years of researches and clinical experience on PDA management, unresolved questions about the treatment and heterogeneity of clinical practices in different centers still remain, in particular regarding timing and modality of intervention. Nowadays, the most reasonable strategy seems to be reserving the treatment only to hemodynamically significant PDA. The first-line therapy is medical, and ibuprofen, related to several side effects especially in terms of nephrotoxicity, is the drug of choice. Administration of oral or intravenous paracetamol (acetaminophen) recently gained attention, appearing effective as traditional nonsteroidal anti-inflammatory drugs (NSAIDs) in PDA closure, with lower toxicity. The results of the studies analyzed in this review mostly support paracetamol efficacy in ductal closure, with inconstant low and transient elevation of liver enzymes as reported side effect. However, more studies are needed to confirm if this therapy shows a real safety profile and to evaluate its long-term outcomes, before considering paracetamol as first-choice drug in PDA treatment.
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El-Mashad AER, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017; 176:233-240. [PMID: 28004188 DOI: 10.1007/s00431-016-2830-7] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 12/07/2016] [Accepted: 12/12/2016] [Indexed: 02/08/2023]
Abstract
UNLABELLED In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure (P = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups (P < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups (P < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group (P = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups (P > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure (P < 0.001). CONCLUSION Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding. What is Known: • Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen. What is New: • It is the first large study that compares the efficacy and side effects of the three drugs in one study.
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MESH Headings
- Acetaminophen/administration & dosage
- Acetaminophen/adverse effects
- Acetaminophen/therapeutic use
- Analgesics, Non-Narcotic/administration & dosage
- Analgesics, Non-Narcotic/adverse effects
- Analgesics, Non-Narcotic/therapeutic use
- Analysis of Variance
- Cyclooxygenase Inhibitors/administration & dosage
- Cyclooxygenase Inhibitors/adverse effects
- Cyclooxygenase Inhibitors/therapeutic use
- Ductus Arteriosus, Patent/diagnostic imaging
- Ductus Arteriosus, Patent/drug therapy
- Female
- Gestational Age
- Humans
- Ibuprofen/administration & dosage
- Ibuprofen/adverse effects
- Ibuprofen/therapeutic use
- Indomethacin/administration & dosage
- Indomethacin/adverse effects
- Indomethacin/therapeutic use
- Infant, Extremely Premature
- Infant, Newborn
- Infant, Very Low Birth Weight
- Infusions, Intravenous
- Intensive Care Units, Neonatal
- Male
- Prospective Studies
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Affiliation(s)
| | - Heba El-Mahdy
- Pediatric Department, Tanta University Hospital, Elgeish street, Tanta, Egypt
| | - Doaa El Amrousy
- Pediatric Department, Tanta University Hospital, Elgeish street, Tanta, Egypt.
| | - Marwa Elgendy
- Pediatric Department, Tanta University Hospital, Elgeish street, Tanta, Egypt
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El-Khuffash A, Weisz DE, McNamara PJ. Reflections of the changes in patent ductus arteriosus management during the last 10 years. Arch Dis Child Fetal Neonatal Ed 2016; 101:F474-8. [PMID: 27118761 DOI: 10.1136/archdischild-2014-306214] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/06/2016] [Indexed: 11/04/2022]
Abstract
Despite a large body of scientific evidence on the management of premature infants with a patent ductus arteriosus controversy remains and neonatologists remain challenged for knowing which patient to treat, what is the most optimal timing of treatment and which treatments have a positive impact on both short-term and long-term outcomes. In this review article we discuss the increased body of evidence over the past 10 years, much of which questions the role of treatment and suggests the need to reconsider how haemodynamic significance is adjudicated. In addition, we discuss novel approaches to assessment and diagnosis, and highlight areas for future investigation.
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Affiliation(s)
- Afif El-Khuffash
- Department of Neonatology, Rotunda Hospital, Dublin, Ireland Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Dany E Weisz
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Patrick J McNamara
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
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23
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Valerio E, Valente MR, Salvadori S, Frigo AC, Baraldi E, Lago P. Intravenous paracetamol for PDA closure in the preterm: a single-center experience. Eur J Pediatr 2016; 175:953-66. [PMID: 27146832 DOI: 10.1007/s00431-016-2731-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 04/23/2016] [Accepted: 04/28/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED Increasing recent evidence favors paracetamol use for patent ductus arteriosus (PDA) closure in preterms. Our study aims were (1) to assess efficacy and safety of intravenous (i.v.) paracetamol for PDA closure in a 23-32-week preterm population, as "first-line" (when traditional ibuprofen treatment was contraindicated) or "rescue" treatment (after ibuprofen failed), and (2) to identify predictors of PDA closure. The cumulative efficacy of consecutive cycles of i.v. paracetamol on PDA closure was confirmed after both "first-line" and "rescue" treatment, the overall PDA closure rates being, respectively, 56.7 and 61.1 % (p = 0.7624) after two cycles and 63.3 and 77.8 % (p = 0.2959) after three cycles. No toxicity was apparent after either "first-line" or "rescue" i.v. paracetamol treatment. On multivariate analysis, gestational age (GA) emerged as an independent predictor of PDA closure in the "first-line" i.v. paracetamol treatment group, while clinical risk index for babies (CRIB) score (a patient risk index based on birth weight, GA at birth, sex, patient's temperature on admission, and maximum base excess in first 12 h of life) was an independent predictor of PDA closure failure in the "rescue" group. CONCLUSION I.V. paracetamol proved effective in our study population. Randomized control trials (RCTs) are warranted to further investigate the efficacy and safety of i.v. paracetamol for PDA closure in preterms. WHAT IS KNOWN • Oral paracetamol has been judged as effective as oral ibuprofen for PDA closure in the preterm. • To date, only a handful of non-randomized studies exist to support the effectiveness of i.v. paracetamol in PDA closure. What is New: • Our observations confirm the clinical efficacy of i.v. paracetamol for PDA closure in a very low birth weight (VLBW)/extremely low birth weight (ELBW) preterm population. • Gestational age and CRIB score emerge as independent predictors of PDA closure.
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Affiliation(s)
- Enrico Valerio
- Neonatal Intensive Care Unit, Department of Woman and Child's Health, University of Padua, Medical School, Via Giustiniani, 3, 35128, Padova, Italy.
| | - Marta Rossella Valente
- Neonatal Intensive Care Unit, Department of Woman and Child's Health, University of Padua, Medical School, Via Giustiniani, 3, 35128, Padova, Italy
| | - Sabrina Salvadori
- Neonatal Intensive Care Unit, Department of Woman and Child's Health, University of Padua, Medical School, Via Giustiniani, 3, 35128, Padova, Italy
| | - Anna Chiara Frigo
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Medical School, Padova, Italy
| | - Eugenio Baraldi
- Neonatal Intensive Care Unit, Department of Woman and Child's Health, University of Padua, Medical School, Via Giustiniani, 3, 35128, Padova, Italy
| | - Paola Lago
- Neonatal Intensive Care Unit, Department of Woman and Child's Health, University of Padua, Medical School, Via Giustiniani, 3, 35128, Padova, Italy
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Sivanandan S, Agarwal R. Pharmacological Closure of Patent Ductus Arteriosus: Selecting the Agent and Route of Administration. Paediatr Drugs 2016; 18:123-38. [PMID: 26951240 DOI: 10.1007/s40272-016-0165-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Opinions are divided regarding the management of a persistently patent ductus arteriosus (PDA). Some of the adverse effects associated with a large hemodynamically significant duct, including prolonged ventilation, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and mortality, indicate that active management of infants with large ductal shunts may sometimes be necessary. Indomethacin and ibuprofen are the two US FDA-approved cyclooxygenase (COX) inhibitors used for the closure of a ductus in preterm babies. Both these drugs are effective in 70-80% of extremely low birthweight infants. Treatment with COX inhibitors may be associated with renal impairment, gastrointestinal hemorrhage, NEC, and spontaneous intestinal perforation when given concurrently with steroids, as well as changes in cerebrovascular auto-regulation. Ibuprofen appears to be a better choice for PDA closure, with a better side effect profile and efficacy that equals that of indomethacin. However, long-term outcome studies of ibuprofen are lacking, and prophylactic ibuprofen is ineffective in decreasing severe IVH. The choice of one drug over the other also depends on local availability of both drugs and the intravenous or enteral preparation. The oral preparation of ibuprofen appears as effective as the intravenous preparation. The use of paracetamol to close a hemodynamically significant PDA has increased in recent years. Paracetamol also decreases prostacyclin synthesis; however, unlike COX inhibitors, it does not have a peripheral vaso-constrictive effect and can be given to infants with contraindications to non-steroidal anti-inflammatory drugs. It appears to have similar efficacy based on limited data available from randomized trials. Until more data are available on efficacy, safety, and long-term outcomes, it cannot be recommended as the first choice.
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Affiliation(s)
- Sindhu Sivanandan
- Division of Neonatology, Department of Pediatrics (Newborn Health Knowledge Center (NHKC), ICMR Center for Advanced Research in Newborn Health and WHO Collaborating Centre for Newborn Training and Research, New Private Ward-1st Floor, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Ramesh Agarwal
- Division of Neonatology, Department of Pediatrics (Newborn Health Knowledge Center (NHKC), ICMR Center for Advanced Research in Newborn Health and WHO Collaborating Centre for Newborn Training and Research, New Private Ward-1st Floor, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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Terrin G, Conte F, Oncel MY, Scipione A, McNamara PJ, Simons S, Sinha R, Erdeve O, Tekgunduz KS, Dogan M, Kessel I, Hammerman C, Nadir E, Yurttutan S, Jasani B, Alan S, Manguso F, De Curtis M. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016; 101:F127-F136. [PMID: 26283668 DOI: 10.1136/archdischild-2014-307312] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 07/24/2015] [Indexed: 01/27/2023]
Abstract
OBJECTIVES We performed a systematic review and meta-analysis of all the available evidence to assess the efficacy and safety of paracetamol for the treatment of patent ductus arteriosus (PDA) in neonates, and to explore the effects of clinical variables on the risk of closure. DATA SOURCE MEDLINE, Scopus and ISI Web of Knowledge databases, using the following medical subject headings and terms: paracetamol, acetaminophen and patent ductus arteriosus. Electronic and manual screening of conference abstracts from international meetings of relevant organisations. Manual search of the reference lists of all eligible articles. STUDY SELECTION Studies comparing paracetamol versus ibuprofen, indomethacin, placebo or no intervention for the treatment of PDA. DATA EXTRACTION Data regarding efficacy and safety were collected and analysed. RESULTS Sixteen studies were included: 2 randomised controlled trials (RCTs) and 14 uncontrolled studies. Quality of selected studies is poor. A meta-analysis of RCTs does not demonstrate any difference in the risk of ductal closure (Mantel-Haenszel model, RR 1.07, 95% CI 0.87 to 1.33 and RR 1.03, 95% CI 0.92 to 1.16, after 3 and 6 days of treatment, respectively). Proportion meta-analysis of uncontrolled studies demonstrates a pooled ductal closure rate of 49% (95% CI 29% to 69%) and 76% (95% CI 61% to 88%) after 3 and 6 days of treatment with paracetamol, respectively. Safety profiles of paracetamol and ibuprofen are similar. CONCLUSIONS Efficacy and safety of paracetamol appear to be comparable with those of ibuprofen. These results should be interpreted with caution, taking into account the non-optimal quality of the studies analysed and the limited number of neonates treated with paracetamol so far.
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Affiliation(s)
- Gianluca Terrin
- Department of Gynecology-Obstetrics and Perinatal Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Conte
- Department of Pediatrics and Pediatric Neuropsychiatry, Sapienza University of Rome, Rome, Italy
| | - Mehmet Yekta Oncel
- Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey
| | - Antonella Scipione
- Department of Pediatrics and Pediatric Neuropsychiatry, Sapienza University of Rome, Rome, Italy
| | - Patrick J McNamara
- Department of Neonatology, The Hospital for Sick Children, Toronto, Canada
| | - Sinno Simons
- Division of Neonatology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Rahul Sinha
- Department of Pediatrics and Neonatology, 167 Military Hospital, Pathankot, Punjab, India
| | - Omer Erdeve
- Division of Neonatology, Department of Pediatrics, Ankara University School of Medicine Children's Hospital, Ankara, Turkey
| | - Kadir S Tekgunduz
- Department of Neonatology, Ataturk University Medical Faculty, Erzurum, Turkey
| | - Mustafa Dogan
- Division of Cardiology, Department of Pediatrics, Pamukkale University, Denizli, Turkey
| | - Irena Kessel
- Department of Neonatology, Carmel Medical Center, Haifa, Israel
| | - Cathy Hammerman
- Department of Neonatology, Shaare Zedek Medical Center, Hebrew University, Jerusalem, Israel
| | - E Nadir
- Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Sadik Yurttutan
- Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey
| | - Bonny Jasani
- Department of Neonatology, KEM Hospital, Mumbai, India
| | - Serdar Alan
- Division of Neonatology, Hitit University, Corum, Turkey
| | | | - Mario De Curtis
- Department of Pediatrics and Pediatric Neuropsychiatry, Sapienza University of Rome, Rome, Italy
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Sallmon H, Koehne P, Hansmann G. Recent Advances in the Treatment of Preterm Newborn Infants with Patent Ductus Arteriosus. Clin Perinatol 2016; 43:113-29. [PMID: 26876125 DOI: 10.1016/j.clp.2015.11.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
A patent ductus arteriosus (PDA) is associated with several adverse clinical conditions. Several strategies for PDA treatment exist, although data regarding the benefits of PDA treatment on outcomes are sparse. Moreover, the optimal treatment strategy for preterm neonates with PDA remains subject to debate. It is still unknown whether and when PDA treatment should be initiated and which approach (conservative, pharmacologic, or surgical) is best for individual patients (tailored therapies). This article reviews the current strategies for PDA treatment with a special focus on recent developments such as oral ibuprofen, high-dose regimens, and the use of paracetamol (oral, intravenous).
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Affiliation(s)
- Hannes Sallmon
- Department of Neonatology, Charité University Medical Center, Augustenburger Platz 1, Berlin 13353, Germany
| | - Petra Koehne
- Department of Neonatology, Charité University Medical Center, Augustenburger Platz 1, Berlin 13353, Germany
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
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Oncel MY, Erdeve O. Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus. World J Clin Pediatr 2016; 5:75-81. [PMID: 26862505 PMCID: PMC4737696 DOI: 10.5409/wjcp.v5.i1.75] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/22/2015] [Accepted: 01/07/2016] [Indexed: 02/05/2023] Open
Abstract
Patent ductus arteriosus (PDA) is a common clinical condition in preterm infants which is inversely related to birth weight and gestational age. Cyclooxygenase inhibitors such as indomethacin and ibuprofen which block the prostaglandin conversion from arachidonic acid are the most commonly used drugs for ductal closure. This review focuses on the safety and efficacy oral medications in the management of PDA in preterm infants. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects when compared to indomethacin. PDA closure rates are better with oral than with intravenous ibuprofen probably due to the pharmacokinetic of the drug. However, these medications were reported to be associated with several adverse including transient renal failure, gastrointestinal bleeding and perforation, hyperbilirubinemia and platelet dysfunction. Paracetamol seems be an alternative to PDA therapy with lower adverse events and side effects.
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Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants. Cardiol Young 2015; 25:1060-4. [PMID: 25160728 DOI: 10.1017/s1047951114001577] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. MATERIALS AND METHODS A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. RESULTS A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). CONCLUSION Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.
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Abstract
Objective: To evaluate the literature describing acetaminophen use in treatment of patent ductus arteriosus (PDA). Data Sources: Searches were conducted in MEDLINE with full text (EBSCOhost; 1946 to September 2014) using the search terms acetaminophen, paracetamol, and patent ductus arteriosus. The references of identified articles were reviewed to identify other relevant articles. Study Selection and Data Extraction: Human clinical trials and case reports limited to the English language were reviewed. In all, 12 case reports and 2 randomized, controlled clinical trials explored the use of acetaminophen in treating PDA. Data Synthesis: The case reports described the use of oral or intravenous acetaminophen in patients with contraindications to or who had previously failed nonsteroidal anti-inflammatory drug therapy for PDA. More than 76% of patients achieved successful PDA closure in reported cases. The clinical trials compared the efficacy of oral acetaminophen versus oral ibuprofen in preterm infants. Acetaminophen was noninferior to ibuprofen, with closure rates from 72.5% to 81.2%. The acetaminophen dose used in most case series and trials was 15 mg/kg dose every 6 hours for 3 days. Acetaminophen therapy was well tolerated, with only a few incidents of elevated liver enzymes being reported. Conclusion: Oral acetaminophen is an alternative to PDA therapy in preterm infants when indomethacin/ibuprofen is not effective or is contraindicated, and it may be considered before surgical ligation.
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Affiliation(s)
- Jennifer Le
- Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA
| | - Mark A. Gales
- Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA
- Integris Baptist Medical Center, Oklahoma City, OK, USA
| | - Barry J. Gales
- Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA
- Integris Baptist Medical Center, Oklahoma City, OK, USA
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30
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Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol 2014; 34:748-749. [PMID: 24854626 DOI: 10.1038/jp.2014.96] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Revised: 04/13/2014] [Accepted: 04/15/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To determine the effectiveness of paracetamol in closing patent ductus arteriosus (PDA) in preterm infants of our population. STUDY DESIGN Infants with symptomatic PDA who failed or could not get ibuprofen treatment, and who were candidates for surgical ligation, were administered oral paracetamol 15 mg kg⁻¹ every 6h, for up to 7 days and were monitored for clinical, echocardiographic and laboratorial courses. RESULT Seven infants, between 24-27 weeks' gestation, were included. In four the DA was closed while treated by paracetamol-in one of them the DA reopened, treated with paracetamol again, and closed. In one infant, the DA almost closed, symptoms disappeared, and the DA subsequently closed spontaneously later. Two needed surgical ligation. There were no hematologic or biochemical abnormalities. CONCLUSION Although there is the possibility that PDA may have closed spontaneously, it is proposed that paracetamol could contribute to the closure of PDA in preterm infants.
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Affiliation(s)
- E Nadir
- Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - E Kassem
- Unit of Pediatric Cardiology, Hillel Yaffe Medical Center, Hadera, Israel
| | - S Foldi
- Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - A Hochberg
- Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - M Feldman
- Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
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31
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El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, Poole SD, Shelton EL, Milne GL, Reese J, McNamara PJ. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res 2014; 76:238-44. [PMID: 24941212 PMCID: PMC4321957 DOI: 10.1038/pr.2014.82] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 02/19/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). METHODS Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. RESULTS Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). CONCLUSION The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.
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Affiliation(s)
| | - Amish Jain
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - David Corcoran
- Department of Pediatrics, The Rotunda Hospital, Dublin, Ireland
| | - Prakesh S. Shah
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Christopher W. Hooper
- Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Naoko Brown
- Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Stanley D. Poole
- Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Elaine L. Shelton
- Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ginger L. Milne
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jeff Reese
- Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Patrick J. McNamara
- Department of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada,Department of Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
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Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014; 164:510-4.e1. [PMID: 24359938 DOI: 10.1016/j.jpeds.2013.11.008] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 10/11/2013] [Accepted: 11/05/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To compare the efficacy and safety of oral paracetamol and oral ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in preterm infants. STUDY DESIGN This prospective, randomized, controlled study enrolled 90 preterm infants with gestational age ≤ 30 weeks, birthweight ≤ 1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA. Each enrolled patient received either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral ibuprofen (initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours). RESULTS Spontaneous closure rate for the entire study group was 54%. After the first course of treatment, the PDA closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the oral paracetamol group (P = .6). The reopening rate was higher in the paracetamol group than in the ibuprofen group, but the reopening rates were not statistically different (24.1% [7 of 29] vs 16.1% [5 of 31]; P = .43). The cumulative closure rates after the second course of drugs were high in both groups. Only 2 patient (2.5%) in the paracetamol group and 3 patients (5%) in the ibuprofen group required surgical ligation. CONCLUSION This randomized, controlled clinical study compared oral paracetamol with ibuprofen in preterm infants and demonstrated that paracetamol may be a medical alternative in the management of PDA.
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Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R, Ventriglia F, De Curtis M. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital J Pediatr 2014; 40:21. [PMID: 24555510 PMCID: PMC3940001 DOI: 10.1186/1824-7288-40-21] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 02/16/2014] [Indexed: 02/06/2023] Open
Abstract
Inhibitors of the cyclo-oxygenase component of prostaglandin-H2 synthetase, namely indomethacin and ibuprofen, are commonly used in the treatment of hemodynamically significant patent ductus arteriosus. These drugs are associated with serious adverse events, including gastrointestinal perforation, renal failure and bleeding. The role of paracetamol, an inhibitor of the peroxidase component of prostaglandin-H2 synthetase, has been proposed for the treatment of patent ductus arteriosus. We report a series of 8 neonates (birth weight: 724 ± 173 g; gestational age: 26 ± 2 weeks) treated with paracetamol for a hemodynamically significant patent ductus arteriosus, because of contraindications to ibuprofen or indomethacin. Successful closure was achieved in 6 out of 8 babies (75%). Median ductal diameter was significantly reduced after treatment (from 1.2 mm, range 1.0-2.5 mm to 0.6 mm, range 0.0-2.5 mm, p = 0.038). No adverse or side effects were observed during treatment. On the basis of these results, paracetamol could be considered a promising and safe therapy for the treatment of patent ductus arteriosus in neonates.
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Affiliation(s)
- Gianluca Terrin
- Department of Gynecology-Obstetrics and Perinatal Medicine, University "La Sapienza", Viale del Policlinico 155, 00161 Rome, Italy.
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