BackgroundThe majority of young children with wheezing have transient symptoms typically associated with viral upper respiratory tract infections and do not have increased risks of asthma later in life. Episodes with severe respiratory symptoms are reported in these chil-dren too. How to diagnose these patients makes clear ev-idence based treatment guidelines unfeasible. Children aged 0–5 years with wheezing may be symptomatically treated with inhaled short-acting beta-2-adrenergic-ago-nist therapy. If no relief of symptoms or severe symptoms, treatment guidelines recommend oral or systemic gluco-corticoids. Since no exact therapeutic interval exists for oral glucocorticoids, there is inconsistency on the dosing recommendations. Moreover, currently the only licensed glucocorticoid preparations in Denmark are tablets or i.v. formulations. These formulations are not suitable, since young children are unable to swallow tablets, and i.v. ad-ministration is associated with unnecessary discomfort. In consequence, children younger than 5 years are treated with extemporaneous preparations, off-label, or unli-censed medications. Use of extemporaneous formula-tions prelude several drawbacks e.g. formulation diversity, differences in bioavailability, limited shelf-live, safety-pro-file, taste etc. Despite the wide therapeutic index of glu-cocorticoids, it is important that they are administrated at the lowest effective dose as a considerable number of dose dependent adverse events exist for these drugs.ObjectiveTo describe the use of extemporaneous glu-cocorticoids in children≤5 years of age diagnosed with acute symptoms of asthmatic bronchitis, compared to existing guidelines across three regional paediatric depart-ments. Second, to examine if high or low dose glucocor-ticoid influences the length of hospitalisation.MethodsA descriptive, chart-based study including three paediatric departments in the Capital Region of Denmark. All patients 0–5 years of age diagnosed with acute symptoms of asthmatic bronchitis in 2013–2015 were eligible for inclusion at the day they received at least one extemporaneously prepared administration of pred-nisolone.ResultsDuring the three-year period almost 560 ad-missions were included, of which 70% were boys. The average age was 22,3 months±13,3, and the average weight 12,2 kg ±2,9. A priori, the paediatric wards used dif-ferent dosing regimens, which were reflected in the data, primarily varying from 1 mg/kg to 2 mg/kg for the first dose administrated. The patients received eight different kinds of extemporaneous formulations, with no obvious pattern of choice. For statistical analyses COX-regression were used. No coherence between dosing and length of hospitalisation were found.ConclusionThis survey shows that the paediatric depart-ments used a variety of extemporaneous liquid prednis-olone formulations interchangeably. The degree of in-consistency raises issues concerning optimal dosing and potential toxicity. Since no association between higher doses and shorter length of hospitalisation w...
IntroductionA chart-review of 200 neonates randomly selected from the Neonatal Intensive Care Unit (NICU) of the university hospital in Copenhagen revealed that ap-proximately 10% received intravenous (i.v.) paracetamol≥4 days (unpublished data). Paracetamol (acetaminophen) is commonly used to control mild-to-moderate pain or to reduce opioid exposure either by oral, rectal or intrave-nous route. The newborn population includes a hetero-geneous group with substantial differences in their drug disposition characteristics. Hence, reflecting their degree of immaturity, organ dysfunction, as well as genetic vari-ation in drug metabolising enzymes and potential drug interactions. Different types of pain and pain assessment tools are used in neonatology. The pharmacokinetics and metabolism of i.v. paracetamol have been extensively published but there is very limited data on the pharma-codynamics (PD) and safety of this drug. The PARASHUTE trial will explore intravenous paracetamol in neonates in relation to: Primary objective: Safety of prolonged use (>72 hours); Secondary key objectives: Analgesic effect (PD) in neonates with chest tubes. Drug-excipient interaction with ethanol containing drugs (CYP2E1)EndpointsPrimary endpoints: To described the concentration-time data of plasma paracetamol (APAP), APAP-sulphate, APAP-glucuronide, oxidative metabolites and liver bio-markers (ALAT, PP, bilirubin) in neonates treated with i.v. paracetamol every sixth hour.Secondary endpoints: Pain scores (COMFORTneo pain scale) combined with paracetamol concentrations and cumulative rescue dosages of morphine.Levels of oxida-tive metabolites of paracetamol and levels of p-ethanol in patients receiving one or more ethanol containing drugs.DesignA multicenter phase IV safety trial on prolonged i.v paracetamol administration in neonates combined with a randomised placebo controlled trial assessing ef-fect on pain.ParticipantsNeonates at any gestational age at birth for the safety and excipient study. However, for the for the PD study patients with chest tube due to pneumothorax or pleural effusion without prior operation are eligible for inclusion. For the PD and drug-excipient study the patient must weigh >1 kg.Sample sizeSafety and excipient trial: 60; PD trial: 48:29 (unequal allocation)InterventionThe safety trial will follow clinical practice and i.v. paracetamol (10 mg/kg) will be administered. Plasma samples will be collected through an arterial line if present for clinical reasons. In neonates without arteri-al access, two heel pricks are necessary (start and end of trial) to collect blood. Additional plasma samples will only be collected when venipuncture is performed for clinical indications i.e. opportunistically.Patients with chest tubes are, after bolus morphine and insertion of tube, unequally allocated to i.v. paracetamol + rescue morphine or i.v. saline + res-cue morphine. In addition to COMFORTneo pain scores and p-paracetamol, safety parameters will be gathered.Study durationSeptember 2017 – January 2019 (PD tri-al will e...
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