[Interhospital transport of sick newborns in Denmark].

Interhospital transport of sick newborn infants is dangerous, but the risk of adverse events can be reduced, when transport is being performed by trained neonatal retrieval teams. In this review, we describe the current organisation of neonatal retrieval service in Denmark. The services are based at the neonatal intensive care units of the four university hospitals. Improved cooperation and harmonisation of operations between the teams is needed, as this is a prerequisite for the development of a national clinical consensus guideline and national quality metrics enabling benchmarking both within Denmark and abroad.

Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study.

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.

The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants.

Polymedicated neonates and young infants may be at risk of harmful cumulative exposure to toxic excipients like ethanol, propylene glycol and benzyl alcohol during routine clinical care. The aim of this study was to calculate the cumulative daily alcohol exposure (mg/kg/day) in polymedicated neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥2 medicinal products/day and infants ≥3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products. In total, 45% (n = 288) of patients were exposed to an alcohol of interest; 2% (n = 14) were exposed to benzyl alcohol (BA), 38% (n = 237) to ethanol and 23% (n = 146) to propylene glycol (PG). Of the total number of prescriptions involving ethanol-containing medicinal products (n = 334), 51% would alone exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits recommended by EMA 260.5 and 19.1 times, respectively. Tolerance limits for ethanol and PG as proposed by the EMA are frequently exceeded in polymedicated neonates and infants due to the cumulative effect of these alcohols. Alternative formulations may minimize excipient exposure.

New treatment of early fetal chylothorax.

OBJECTIVE: To evaluate OK-432, a preparation of Streptococcus pyogenes, in the treatment of early fetal chylothorax. METHODS: A prospective study of all fetuses (n=7) with persistent early chylothorax (gestational ages 16-21 weeks) referred to the tertiary center of fetal medicine in Denmark in 2003-2005. Fetuses were injected with 0.2-1.0 mg of OK-432 into the pleural cavity. The treatment was repeated if there were persistent or increasing pleural effusions after 1-3 weeks. The main outcome measures included remission of pleural effusions and fetal and infant morbidity and mortality. RESULTS: Total remission of pleural effusions was obtained in all fetuses after one or two intrapleural injections of OK-432. No adverse effects of the treatment were observed. No fetus developed hydrops, and all experienced an uncomplicated third trimester. All children were born healthy without pleural effusions, lung hypoplasia, or hydrops. CONCLUSION: Persistent early chylothorax is a condition with a high mortality rate and no established treatment option. Use of OK-432 is a promising therapy for selected fetuses with persistent chylothorax early in the second trimester.

Safe excipient exposure in neonates and small children - protocol for the SEEN project.

INTRODUCTION: The pharmacokinetics of excipients in neonates differs from that of older children. In a recent pan--European survey, two thirds of neonates received at least one potentially harmful excipient, such as ethanol and benzoates. The content of sweeteners varied by route of administration (more common by enteral than parenteral route), and regional differences were revealed. The survey did not identify if the content of excipients was more pronounced in medications prescribed for specific medical diseases, e.g. more common in cardiovascular conditions than lung diseases. Furthermore, the quantitative amount of e.g. ethanol in the multi-medicated neonate has not been investigated. The aim of the present study was to quantify the total amount of excipients administered to poly-medicated neonatal and paediatric patients during hospitalisation; and to investigate if any particular medical diseases are treated with potentially harmful excipients. METHODS: This is a retrospective cohort study based on chart-audit on multi-medicated patients ≤ 5 years of age treated at the Rigshospitalet, Denmark. Preparations with ethanol, propylene glycol, benzyl alcohol, parabens, acesulfame p, aspartame, glycerol, sorbitol and polysorbate-80 will be recorded and cumulative amounts will be calculated. CONCLUSION: By quantifying the amount of harmful excipients to which paediatric patients are exposed, the study will contribute to a risk/benefit assessment of the medication standards of neonatal and paediatric patients. FUNDING: The Danish Council for Independent Research, grant-id: DFF - 6110-00266. TRIAL REGISTRATION: This study was registered at clinicaltrials.gov (reg. no. NCT02545712).

Copeptin and MR-proADM in umbilical cord plasma reflect perinatal stress in neonates born to mothers with diabetes and MR-proANP reflects maternal diabetes.

AIM: To examine concentrations of three cardiovascular propeptides in umbilical cord plasma of neonates born to mothers with Type 1, Type 2 and gestational diabetes. Measurement of cardiovascular markers in umbilical cord plasma may potentially help identify neonates at risk of postnatal complications. Neonates born to mothers with diabetes have an increased risk of neonatal morbidity and mortality, and measurement of these new biomarkers may potentially help identify neonates at risk of these complications. SUBJECTS & METHODS: Copeptin, midregional proadrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) were measured in cord plasma of neonates (n = 63) born to mothers with the three types of diabetes. Associations with maternal glycemic control, mode of delivery and neonatal metabolic acidosis were examined. RESULTS: Umbilical cord plasma copeptin concentrations were lowest in neonates after elective cesarean sections (6.1 pmol/l; interquartile range [IQR]: 4.5-9.1) compared with emergency cesarean sections (156 pmol/l; IQR: 9.6-311; p = 0.019) and vaginal delivery (831 pmol/l; IQR: 107-2407; p < 0.0001). MR-proADM was also affected by mode of delivery; however, this seemed more likely to be caused by an inverse association with the acid-base balance. In this population, only MR-proANP plasma concentrations were related to type of diabetes. Neonates born to mothers with Type 1 diabetes had higher concentrations (median 260 pmol/l; IQR: 222-318) compared with Type 2 diabetes (175 pmol/l; IQR: 169-200; p = 0.003) and gestational diabetes (200 pmol/l; IQR: 149-276; p = 0.009). CONCLUSION: Umbilical cord plasma copeptin and MR-proADM concentrations primarily reflect perinatal stress associated with mode of delivery and the degree of fetal acidosis, whereas MR-proANP concentrations are higher in neonates born to mothers with Type 1 diabetes.

[Extracorporeal membrane oxygenation of a child with severe chemical pneumonia]. / Ekstrakorporal membranoxygenering af et barn med svær kemisk pneumoni.

This case presents a thirteen months old child with severe acute respiratory distress syndrome after ingestion of lamp oil (hydrocarbon). Mechanical ventilation including high-frequency oscillation could not stabilise the course, and the child developed pneumothorax and emphysema. Treatment was changed to veno-arterial extracorporeal membrane oxygenation (ECMO) on the third day. After nine days of ECMO and further two days of conventional ventilatory treatment he was extubated, and four months later the child presented with normal X-ray of the lungs and without any signs of disease.