1
|
Dawes JM, Howard RF. Neonatal Pain: Significance, Assessment, and Management. NEONATAL ANESTHESIA 2023:505-527. [DOI: 10.1007/978-3-031-25358-4_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
2
|
McCulley DJ, Jensen EA, Sucre JMS, McKenna S, Sherlock LG, Dobrinskikh E, Wright CJ. Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures. Am J Physiol Lung Cell Mol Physiol 2022; 323:L1-L13. [PMID: 35503238 PMCID: PMC9208439 DOI: 10.1152/ajplung.00080.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/20/2022] [Accepted: 04/25/2022] [Indexed: 11/22/2022] Open
Abstract
Over the past decade, clinicians have increasingly prescribed acetaminophen (APAP) for patients in the neonatal intensive care unit (NICU). Acetaminophen has been shown to reduce postoperative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data.
Collapse
Affiliation(s)
- David J McCulley
- Division of Neonatology, Department of Pediatrics, University of California, San Diego, California
| | - Erik A Jensen
- Division of Neonatology, Department of Pediatrics, The Children's Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | | | - Sarah McKenna
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
| | - Laura G Sherlock
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
| | - Evgenia Dobrinskikh
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
| |
Collapse
|
3
|
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: 12] [Impact Index Per Article: 3.0] [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.
| |
Collapse
|
4
|
Hallman M, Treluyer JM, Aikio O, Rozé J. Early closure mechanisms of the ductus arteriosus in immature infants. Acta Paediatr 2021; 110:1995-2007. [PMID: 33655615 DOI: 10.1111/apa.15826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/22/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
AIM According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. METHODS Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. RESULTS Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose-dependently constrict the ductus. Ibuprofen and indomethacin cause non-specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low-dose corticosteroid supplementation. CONCLUSION The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.
Collapse
Affiliation(s)
- Mikko Hallman
- Department of Pediatrics Oulu University Hospital Oulu Finland
- PEDEGO Research Unit Medical Research Center University of Oulu Oulu Finland
| | - Jean Marc Treluyer
- Faculté de Médecine Université de Paris Paris France
- CIC‐1419 InsermCochin‐Necker Paris France
| | - Outi Aikio
- Department of Pediatrics Oulu University Hospital Oulu Finland
- PEDEGO Research Unit Medical Research Center University of Oulu Oulu Finland
| | - Jean‐Christophe Rozé
- Department of Neonatology Nantes University Hospital Nantes France
- Centre d'Investigation ClinIque CIC1413INSERMNantes University Hospital Nantes France
| |
Collapse
|
5
|
Locci C, Cuzzolin L, Capobianco G, Antonucci R. Paracetamol overdose in the newborn and infant: a life-threatening event. Eur J Clin Pharmacol 2021; 77:809-815. [PMID: 33388821 DOI: 10.1007/s00228-020-03077-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/23/2020] [Indexed: 11/25/2022]
Abstract
PURPOSE Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.
Collapse
Affiliation(s)
- Cristian Locci
- Pediatric Clinic, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Laura Cuzzolin
- Department of Diagnostics & Public Health-Section of Pharmacology, University of Verona, Verona, Italy
| | - Giampiero Capobianco
- Gynecologic and Obstetric Clinic, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Roberto Antonucci
- Pediatric Clinic, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.
| |
Collapse
|
6
|
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.
Collapse
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
| |
Collapse
|
7
|
Juujärvi S, Saarela T, Pokka T, Hallman M, Aikio O. Intravenous paracetamol for neonates: long-term diseases not escalated during 5 years of follow-up. Arch Dis Child Fetal Neonatal Ed 2021; 106:178-183. [PMID: 32943529 DOI: 10.1136/archdischild-2020-319069] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/03/2020] [Accepted: 08/13/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To evaluate the long-term adverse reactions of paracetamol in children who required intensive care shortly after birth. Paracetamol is a widely used analgesic in neonates, but the long-term studies are lacking. Previous epidemiological studies have reported associations between early paracetamol intake and diseases in childhood. DESIGN Five-year follow-up cohort of children who required intensive care shortly after birth. SETTING Single tertiary care hospital; neonatal and paediatric intensive care units. INTERVENTIONS Intravenous paracetamol was administered for pain and discomfort to the neonates during their intensive care, while for the control infants, it was not available. MAIN OUTCOME MEASURES The primary outcome was the incidence of asthma; secondary outcomes were neonatal diseases and long-term morbidities (atopic dermatitis, inflammatory bowel disease, autism, speech disorders, cerebral palsy). Long-term morbidities were adjusted based on antenatal and neonatal risk factors. RESULTS We screened all neonates admitted to the intensive care units soon after birth in Oulu University Hospital, Oulu, Finland, during 1 October 2007 to 31 December 2013. Altogether, 1552 infants needed intensive care. Of them, 735 (47%) were treated with intravenous paracetamol. We obtained their long-term data from the Finnish National Institute for Health and Welfare, including all physician-made diagnoses from all primary healthcare units and hospitals in Finland. We found no difference in the asthma incidence or in other long-term morbidities between paracetamol-treated and non-exposed infants. CONCLUSIONS Intravenous paracetamol given to neonates did not associate with childhood disorders compared with the non-exposed infants during the 5-year follow-up. The previous hypothesis that early paracetamol use causes childhood morbidities was not confirmed.
Collapse
Affiliation(s)
- Sanna Juujärvi
- PEDEGO Research Unit and MRC Oulu, University of Oulu, Oulu, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Timo Saarela
- PEDEGO Research Unit and MRC Oulu, University of Oulu, Oulu, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Tytti Pokka
- PEDEGO Research Unit and MRC Oulu, University of Oulu, Oulu, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Mikko Hallman
- PEDEGO Research Unit and MRC Oulu, University of Oulu, Oulu, Finland.,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Outi Aikio
- PEDEGO Research Unit and MRC Oulu, University of Oulu, Oulu, Finland .,Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| |
Collapse
|
8
|
Haslund-Krog SS, Hertel S, Dalhoff K, Poulsen S, Christensen U, Wilkins D, van den Anker J, Brink Henriksen T, Holst H. Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study. BMJ Paediatr Open 2019; 3:e000427. [PMID: 31206077 PMCID: PMC6542439 DOI: 10.1136/bmjpo-2018-000427] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 02/25/2019] [Accepted: 02/26/2019] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION Anticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates have been of short duration (1-3 days) and hepatic biomarkers and paracetamol metabolism are rarely reported in the same studies.We aim to investigate the safety (hepatic tolerance) and effectiveness of prolonged paracetamol exposure in neonates by measuring hepatic biomarkers, plasma concentrations of paracetamol and its metabolites and pain scores. In addition, we study a possible interaction between ethanol and paracetamol. METHODS AND ANALYSIS A multicentre interventional cohort study.Neonates of any gestational age and up to 44 weeks postmenstrual age, treated with oral or intravenous paracetamol can be included.Alanine aminotransferase (ALT) and bilirubin are measured at baseline or within 24 hours after treatment initiation. P-paracetamol and metabolites are measured at steady state and every 2 days (opportunistically) together with ALT and bilirubin and lastly after discontinuation of treatment. COMFORT neo pain scores are collected longitudinally. COMFORT neo pain scores and population pharmacokinetic analysis of paracetamol samples will be analysed simultaneously using non-linear mixed effects models. One and two compartment models with first-order elimination will be tested for disposition. In addition, plasma ethanol is measured if the patient receives concomitant treatment with intravenous or oral phenobarbital containing ethanol as an excipient. ETHICS AND DISSEMINATION Inclusion of patients can be postponed 24 hours after the first paracetamol dose. This is intended to make the inclusion process less stressful for parents. This study uses standard dosing strategies. The potential risks are additional blood samples, which are collected opportunistically to reduce additional heel pricks. TRIAL REGISTRATIONNUMBER Ethics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017-106, 05952.
Collapse
Affiliation(s)
| | - Steen Hertel
- Neonatal Intensive Care Unit, Rigshospitalet, Copenhagen, Denmark
| | - Kim Dalhoff
- Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
| | - Susanne Poulsen
- Neonatal Intensive Care Unit, Rigshospitalet, Copenhagen, Denmark
| | - Ulla Christensen
- Department of Pediatrics, Neonatal Intensive Care Unit, Aarhus Universitetshospital, Aarhus, Denmark
| | - Diana Wilkins
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - John van den Anker
- Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA
- Division of Pediatric Pharmacology and Pharmacometrics, Universitat Basel, Basel, BS, Switzerland
| | - Tine Brink Henriksen
- Department of Pediatrics, Neonatal Intensive Care Unit, Aarhus Universitetshospital, Aarhus, Denmark
| | - Helle Holst
- Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
| |
Collapse
|
9
|
Cuzzolin L, Bardanzellu F, Fanos V. The dark side of ibuprofen in the treatment of patent ductus arteriosus: could paracetamol be the solution? Expert Opin Drug Metab Toxicol 2018; 14:855-868. [PMID: 29938546 DOI: 10.1080/17425255.2018.1492550] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Patent ductus arteriosus (PDA) persistence is associated, in prematures, to several complications. The optimal PDA management is still under debate, especially regarding the best therapeutic approach and the time to treat. The available drugs are not exempt from contraindications and side effects; ibuprofen itself, although representing the first-choice therapy, can show nephrotoxicity and other complications. Paracetamol seems a valid alternative to classic nonsteroidal anti-inflammatory Drugs, with a lower toxicity. Areas covered: Through an analysis of the published literature on ibuprofen and paracetamol effects in preterm neonates, this review compares the available treatments for PDA, analyzing the mechanisms underlining ibuprofen-associated nephrotoxicity and the eventual paracetamol-induced hepatic damage, also providing an update of what has been yet demonstrated and a clear description of the still open issues. Expert Opinion: Paracetamol is an acceptable alternative in case of contraindication to ibuprofen; its toxicity, in this setting, is very low. Lower doses may be effective, with even fewer risks. In the future, paracetamol could represent an efficacious first-line therapy, although its safety, optimal dosage, and global impact have to be fully clarified through long-term trials, also in the perspective of an individualized and person-based therapy taking into account the extraordinary individual variability.
Collapse
Affiliation(s)
- Laura Cuzzolin
- a Department of Diagnostics & Public Health-Section of Pharmacology , University of Verona , Verona , Italy
| | - Flamina Bardanzellu
- b Neonatal Intensive Care Unit, Neonatal Pathology and Neonatal Section , AOU and University of Cagliari , Cagliari , Italy
| | - Vassilios Fanos
- b Neonatal Intensive Care Unit, Neonatal Pathology and Neonatal Section , AOU and University of Cagliari , Cagliari , Italy
| |
Collapse
|
10
|
Ginsberg G, Vulimiri SV, Lin YS, Kancherla J, Foos B, Sonawane B. A framework and case studies for evaluation of enzyme ontogeny in children's health risk evaluation. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2017; 80:569-593. [PMID: 28891786 PMCID: PMC8018602 DOI: 10.1080/15287394.2017.1369915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals.
Collapse
Affiliation(s)
- Gary Ginsberg
- Partnership in Pediatric and Environmental Health, Hartford, CT 06134, USA
| | - Suryanarayana V. Vulimiri
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
| | - Yu-Sheng Lin
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
| | - Jayaram Kancherla
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20740, USA
| | - Brenda Foos
- Office of Children’s Health Protection, U.S. Environmental Protection Agency, Washington, DC, USA
| | - Babasaheb Sonawane
- National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA
- Current Address: 13204 Moran Drive, North Potomac, MD 20878
| |
Collapse
|
11
|
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: 33] [Impact Index Per Article: 4.1] [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.
Collapse
|
12
|
Cerebellar level of neurotransmitters in rats exposed to paracetamol during development. Pharmacol Rep 2016; 68:1159-1164. [DOI: 10.1016/j.pharep.2016.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 06/06/2016] [Accepted: 06/07/2016] [Indexed: 01/24/2023]
|
13
|
Härkin P, Härmä A, Aikio O, Valkama M, Leskinen M, Saarela T, Hallman M. Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr 2016; 177:72-77.e2. [PMID: 27215779 DOI: 10.1016/j.jpeds.2016.04.066] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 03/16/2016] [Accepted: 04/20/2016] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To study the biologic effect of paracetamol, an inhibitor of prostaglandin synthase, on early closure of ductus arteriosus, and to evaluate possible adverse effects associated with the drug. STUDY DESIGN In a controlled, double-blind, phase I-II trial, very low gestational age (<32 weeks) infants requiring intensive care were randomly assigned to intravenous paracetamol or placebo (0.45% NaCl). A loading dose of 20 mg/kg was given within 24 hours of birth, followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound examinations of ductal calibers were performed before the first dose, and until 1 day after the last dose. The main outcome was a decrease in the ductal caliber without side effects. RESULTS Of 63 screened infants, 48 were randomized: 23 were assigned to paracetamol and 25 to placebo. Before the intervention, their ductal calibers were similar. During the intervention, the ductus closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours (31.1-324) for the paracetamol-treated vs 338 hours (118-557) for controls (P = .045). Paracetamol serum levels were within the therapeutic range, and no adverse effects were evident. CONCLUSIONS Prophylactic paracetamol induced early closure of the ductus arteriosus without detectable side effects. Further trials are required to determine whether intravenous paracetamol may safely prevent symptomatic patent ductus arteriosus. TRIAL REGISTRATION ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.
Collapse
Affiliation(s)
- Pia Härkin
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Antti Härmä
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Outi Aikio
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
| | - Marita Valkama
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Markku Leskinen
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Timo Saarela
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Mikko Hallman
- PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| |
Collapse
|
14
|
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.
Collapse
|
15
|
Härmä A, Aikio O, Hallman M, Saarela T. Intravenous Paracetamol Decreases Requirements of Morphine in Very Preterm Infants. J Pediatr 2016; 168:36-40. [PMID: 26323200 DOI: 10.1016/j.jpeds.2015.08.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/29/2015] [Accepted: 08/03/2015] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To determine whether intravenous paracetamol therapy is effective in pain therapy in premature infants. STUDY DESIGN From June 2009 to December 2011, 108 infants born very low gestational age (<32 weeks) (VLGA) were given intravenous paracetamol before the age of 72 hours. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 hours. One hundred ten VLGA infants admitted from October 2007 to May 2009 formed the comparison group who received no paracetamol. Intravenous morphine was exclusively used as the opiate. Morphine dosage was calculated as the cumulative dose administered during the neonatal intensive care unit period. Pain symptoms were screened using pain scale scoring Neonatal Infant Acute Pain Assessment Scale. The number of apneas during the neonatal intensive care unit stay, and ventilation days per patient, were calculated. RESULTS The mean (SD) total number of paracetamol doses per patient was 16.9 (11.7), and the postnatal age for the first dose was 13.3 (13.8) hours. Infants in the paracetamol group needed significantly fewer morphine doses per patient than the comparisons, 1.78 (4.56) doses vs 4.35 (11.53), P = .044. The exposed had lower cumulative morphine dosage 0.17 (0.45) mg/kg vs 0.37 (0.96) mg/kg, P = .047. There were no differences in the Neonatal Infant Acute Pain Assessment Scale scores, or the numbers of apneas, or ventilation days. There was no evidence of adverse events including hepatic toxicity. CONCLUSION The need for morphine decreased significantly after the introduction of paracetamol for the VLGA infants.
Collapse
Affiliation(s)
- Antti Härmä
- PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Outi Aikio
- PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
| | - Mikko Hallman
- PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Timo Saarela
- PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| |
Collapse
|
16
|
Pacifici GM, Allegaert K. Clinical pharmacology of paracetamol in neonates: a review. CURRENT THERAPEUTIC RESEARCH 2015; 77:24-30. [PMID: 25709719 PMCID: PMC4329422 DOI: 10.1016/j.curtheres.2014.12.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 12/03/2014] [Indexed: 11/22/2022]
Abstract
Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks' gestation, 45 mg/kg/d in preterm infants of 34 weeks' gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted.
Collapse
Affiliation(s)
- Gian Maria Pacifici
- Translational Department and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Karel Allegaert
- Neonatal Intensive Care Unit, Division of Woman and Child, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
17
|
Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats—Focus on the spinal cord. Int J Dev Neurosci 2015; 47:133-9. [DOI: 10.1016/j.ijdevneu.2015.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 08/25/2015] [Accepted: 09/09/2015] [Indexed: 12/21/2022] Open
|
18
|
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.
Collapse
|
19
|
Abstract
Drug metabolism importantly determines drug concentrations. The efficacy and safety of many drugs prescribed for children are, therefore, dependent on intraindividual and interindividual variation in drug-metabolising enzyme activity. During growth and development, changes in drug-metabolising enzyme activity result in age-related differences in drug disposition, most pronounced in preterm infants and young infants. The shape of the developmental trajectory is unique to the drug-metabolising enzyme involved in the metabolism of individual drugs. Other factors impacting drug metabolism are underlying disease, drug-drug interactions and genetic variation. The interplay of age with these other factors may result in unexpected variation in drug metabolism in children of different ages. Extrapolation of adult data to guide drug dosing in children should be done with caution. The younger the child, the less reliable is the extrapolation. This review aims to identify the primary sources of variability of drug metabolism in children, the knowledge of which can ultimately guide the practitioner towards effective and safe drug therapy.
Collapse
Affiliation(s)
- Saskia N de Wildt
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - D Tibboel
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - J S Leeder
- Department of Pediatrics, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri, USA
| |
Collapse
|
20
|
Abstract
Effective management of procedural and postoperative pain in neonates is required to minimize acute physiological and behavioral distress and may also improve acute and long-term outcomes. Painful stimuli activate nociceptive pathways, from the periphery to the cortex, in neonates and behavioral responses form the basis for validated pain assessment tools. However, there is an increasing awareness of the need to not only reduce acute behavioral responses to pain in neonates, but also to protect the developing nervous system from persistent sensitization of pain pathways and potential damaging effects of altered neural activity on central nervous system development. Analgesic requirements are influenced by age-related changes in both pharmacokinetic and pharmacodynamic response, and increasing data are available to guide safe and effective dosing with opioids and paracetamol. Regional analgesic techniques provide effective perioperative analgesia, but higher complication rates in neonates emphasize the importance of monitoring and choice of the most appropriate drug and dose. There have been significant improvements in the understanding and management of neonatal pain, but additional research evidence will further reduce the need to extrapolate data from older age groups. Translation into improved clinical care will continue to depend on an integrated approach to implementation that encompasses assessment and titration against individual response, education and training, and audit and feedback.
Collapse
Affiliation(s)
- Suellen M Walker
- Correspondence Suellen Walker, Portex Unit: Pain Research; 6th Floor Cardiac Wing, UCL Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK,
| |
Collapse
|
21
|
Aikio O, Härkin P, Saarela T, Hallman M. Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants. J Matern Fetal Neonatal Med 2013; 27:1252-6. [DOI: 10.3109/14767058.2013.854327] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|