Pharmacokinetic studies on cladribine

The aims of the present study were to delineate the pharmacokinetics, in plasma and leukaemia cells, of cladribine (M), and to describe factors influencing the outcome of administration of CdA in order to individualize and optimize treatment. CdA is a nucleoside analogue with a cytotoxic activity in low-grade lymphoproliferative disorders and childhood acute myelogenous leukaemia. In addition, it has an immunomodulating effect used in multiple sclerosis. CdA is unstable at low pH and is deglycosylated by bacterial nucleoside phosphorylases. CdA can also be cleaved, in an enzymatic reaction in the presence of the hepatic enzyme methylthioadenosine phosphorylase, to the main metabolite 2chloroadenine (CAde). A more stable fluorinated analogue of CdA has been developed, 2-chloro-2'-arabio-fluoro-2'- deoxyadenosine (CAFdA). A reversed-phase high-performance liquid chromatographic method was developed for analyses of CdA, CAde and CAFdA. To minimize degradation before analysis, samples should be kept cold and not stored for more than 10 weeks. In a study Of 17 patients with leukaemia, we found large interpatient variability in both pharmacokinetic variables and a four-fold difference in activating enzyme activity. No clear correlations were seen between the plasma levels of CdA and the intracellular concentration of the active triphosphate, or to the response of treatment. The half-life was to some degree shorter for intracellular CdA-phosphates compared to CdA in plasma. In another study including 53 patients, we found no correlation between the the activity of the activating enzymes and the antiproliferative activity of CdA or the intracellular nucleotide levels of CdA in vitro. However, there was a large interindividual variability in enzyme activity and cytotoxicity. In a retrospective study consisting of 163 patients with different diagnoses, receiving different doses of CdA, administered by four different routes, using different treatment schedules, leaving different numbers of blood samples at different times, we used non- linear mixed effect modelling for the pharmaco-kinetic evaluation. For patients in the population with a mean weight of 73 kg, the clearance was 35 L/h with interindividual variability of 49% and half-life was estimated to be 17 hours. The oral bioavailability was 33% but the vari-ability after oral treatment was not increased compared with the variability after intravenous infusion. Individualized dosing on bases of BSA or weight is in this study not superior to administer all patients a fixed dose. The metabolite CAde has a lower cytotoxic effect than CdA, but may contribute to the cytotoxicity after oral administration, since 5 times more CAde was formed after oral treatment than after iv infusion (n=31 patients) and protein-binding of CAde is twice that of CdA. In conclusion, CdA can, by preference, be orally administered if the dose is adjusted for bioavailability and cytotoxicity of the metabolite, CAde

Cross-sectional study identifying high-alert substances in medication error reporting among Swedish paediatric inpatients

Aim: The aims were to characterise paediatric medication errors and to identify the prevalence of known high-alert substances in these errors. Methods: All paediatric drug-related incident reports and complaints nationally reported to the Health and Social Care Inspectorate in Sweden 2011-2017 regarding inpatients were characterised by context and modal details. In addition, drug use at a university hospital was matched to local incident reports. Drug substances were classified using three high-alert lists. Results: On a national level, there were 160 reports (2.5 per 10 000 patients) in which the three high-alert lists were found in different degrees (17/35/47%). Morphine (n = 12), vancomycin (n = 11) and potassium (n = 7) were most frequently involved. Eighty per cent of the reports concerned patients aged 0-6 years. Intravenous was the most common route of administration (66%). On a university hospital level, the prevalence of all types of drug incidents reports was 1.7% among all inpatients. The prevalence of local incident reports involving high-alert substances was almost double that of non-alert substances. Conclusion: Existing high-alert drug lists are relevant for paediatric inpatients. A higher awareness and usage of such lists among hospital staff prescribing, dispensing and administering drugs to children may have the potential to reduce medication errors

Pediatricians’ Understanding and Experiences of an Electronic Clinical-Decision-Support-System

Objectives: Subsequent dosing errors after implementing an Electronic Medical Record (EMR) at a pediatric hospital in Sweden led to the development, in close collaboration with the clinical profession, of a Clinical Decision Support System (CDSS) with Dose Range Check and Weight Based Dose Calculation integrated directly in the EMR. The aim of this study was to explore the understanding and experiences of the CDSS among Swedish pediatricians after one year of practice.Methods: Semi-structured interviews with physicians at different levels of the health care system were performed with seventeen pediatricians working at three different pediatrics wards in Stockholm County Council. The interviews were analysed with a thematic analysis without pre-determined categories.Results: Six categories and fourteen subcategories emerged from the analysis. The categories included the use, the benefit, the confidence, the situations of disregards, the misgivings/risks and finally the development potential of the implemented CDSS with Weight Based Dose Calculation and Dose Range Check.  Conclusions:  A need for CDSS in the prescribing for children is evident but also the need for further development based on the practical knowledge of the clinical profession

Pediatricians’ Understanding and Experiences of an Electronic Clinical-Decision-Support-System

Objectives: Subsequent dosing errors after implementing an Electronic Medical Record (EMR) at a pediatric hospital in Sweden led to the development, in close collaboration with the clinical profession, of a Clinical Decision Support System (CDSS) with Dose Range Check and Weight Based Dose Calculation integrated directly in the EMR. The aim of this study was to explore the understanding and experiences of the CDSS among Swedish pediatricians after one year of practice.Methods: Semi-structured interviews with physicians at different levels of the health care system were performed with seventeen pediatricians working at three different pediatrics wards in Stockholm County Council. The interviews were analysed with a thematic analysis without pre-determined categories.Results: Six categories and fourteen subcategories emerged from the analysis. The categories included the use, the benefit, the confidence, the situations of disregards, the misgivings/risks and finally the development potential of the implemented CDSS with Weight Based Dose Calculation and Dose Range Check.  Conclusions:  A need for CDSS in the prescribing for children is evident but also the need for further development based on the practical knowledge of the clinical profession

Manipulated Oral and Rectal Drugs in a Paediatric Swedish University Hospital, a Registry-Based Study Comparing Two Study-Years, Ten Years Apart

This is a registry-based study with the aim of describing and comparing the frequency of manipulations of solid oral and rectal medicines in 2009 and 2019 at inpatient units and an emergency department in a paediatric hospital within a Swedish university hospital. All patients aged 1 month–18 years with oral or rectal administrations were included. In total, 140,791 oral and rectal administrations were included in 2009, and 167,945 oral and rectal administrations were included in 2019. The frequency of patients receiving at least one manipulated oral medicine decreased between the study years, both in inpatient units and in the emergency department (from 19% to 17%, p = 0.0029 and from 11% to 5%, p p p < 0.0001, respectively). The results show a decrease in the manipulation of both oral and rectal medicines to paediatric patients in 2019 compared to 2009. Even though this implies a safer practice, there is still a pronounced lack of child-friendly dosage forms and suitable strengths enabling the safe administration of medicines to sick children

'Working outside the box'-an interview study regarding manipulation of medicines with registered nurses and pharmacists at a Swedish paediatric hospital

AIM: Studies on frequencies of manipulated medicines in paediatric care are common, but there is little knowledge of experiences of pharmacists and registered nurses in this area. The aim of this study was to explore registered nurses' and pharmacists' reasoning in the manipulation of medicines to paediatric inpatients. METHODS: Semistructured interviews with twelve registered nurses and seven pharmacists were performed at a Swedish paediatric university hospital. The interviews were transcribed verbatim and analysed using content analysis. RESULTS: Four major categories emerged from the analysis of the interviews: medicines management, knowledge, consulting others and organisation. Medicines management involved the process of drug handling, which is prescribing, reconstitution or manipulation and administration. Knowledge concerned both the knowledge base and how healthcare personnel seek information. Consulting others involved colleagues, registered nurses and pharmacists, between registered nurses, pharmacists and physicians and between registered nurses, pharmacists and caregivers. Organisation covered documentation, time and working environment. CONCLUSION: Both pharmacists and registered nurses stated that manipulation of medicines to paediatric patients was often necessary but felt unsafe due to lack of supporting guidelines. Pharmacists were natural members of the ward team, contributing with specific knowledge about medicines and formulations

Identifying neonatal adverse events in preterm and term infants using a Paediatric Trigger Tool

AIM: To explore the incidence and characteristics of inpatient neonatal adverse events in a Swedish setting. METHODS: A retrospective record review, using a trigger tool, performed by registered nurses and a neonatologist, at a University Hospital. The identified adverse events were categorised by, for example, preventability, severity and time of occurrence. RESULTS: A random selection of 150 admissions representing 3531 patient days were reviewed (mean [SD] birthweight 2620 [1120]g). Three hundred sixty adverse events were identified in 78(52.0%) infants and 305(84.7%) of these were assessed as being preventable. The overall adverse event rate was 240 per 100 admissions and 102.0 per 1000 patient days. Preterm infants had a higher rate than term infants (353 versus 79 per 100 admissions, p=0.001), however with regard to the length of stay, the rates were similar. Most adverse events were temporary and less severe (n=338/360, 93.9%) and the most common type involved harm to skin, tissue or blood vessels (n=163/360, 45.3%). Forty percent (n=145) of adverse events occurred within the first week of admission. CONCLUSION: Adverse events were common in neonatal care and many occurred during the first days of treatment. Characterisation of adverse events may provide focus areas for improvements in patient safety