Synnöve Lindemalm

Validation of triggers and development of a pediatric trigger tool to identify adverse events

BackgroundLittle is known about adverse events (AEs) in pediatric patients. Record review is a common methodology for identifying AEs, but in pediatrics the record review tools generally have limited focus. The aim of the present study was to develop a broadly applicable record review tool to identify AEs in pediatric inpatients.MethodsUsing a broad literature review and expert opinion with a modified Delphi process, a pediatric trigger tool with 88 triggers, definitions, and descriptions including AE preventability decision support was developed and tested in a random sample of 600 hospitalized pediatric patients admitted in 2010 to a single university children’s hospital. Four registered nurse-physician teams performed complete two-stage retrospective reviews of 150 records each from either neonatal, surgical/orthopedic, medicine, or emergency medicine units.ResultsRegistered nurse review identified 296 of 600 records with triggers indicating potential AEs. Records (n = 121) with only false positive triggers not indicating any potential AEs were not forwarded to the next review stage. On subsequent physician review, 204 (34.0%) of patients were found to have had 563 AEs, range 1–27 AEs/patient. A total of 442 preventable AEs were found in 161 patients (26.8%), range 1–22. Overall, triggers were found 3,598 times in 417 (69.5%) records, with a mean of 6 (median 1, range 0–176) triggers per patient. The overall positive predictive value of the triggers was 22.9%, (range 0.0-100.0%). The final pediatric trigger tool, developed with a second Delphi round, required 29 triggers.ConclusionsAEs are common in pediatric patients and most are preventable. The main contributions of this study are to further develop and adapt trigger definitions, including AE preventability decision support, to introduce new triggers in pediatric care, as well as to apply pediatric triggers in different clinical specialties. Our findings resulted in a national pediatric trigger tool, and might also be adapted internationally. The pediatric trigger tool can help healthcare organizations to measure and analyze the AEs occurring in hospitalized children in order to improve patient safety.

Application of population pharmacokinetics to cladribine

BackgroundThe nucleoside analog cladribine is used for the treatment of a variety of indolent B- and T-cell lymphoid malignancies. The primary aim of the study was to evaluate the population distribution of pharmacokinetic parameters in patients undergoing treatment with cladribine and to detect the influence of different covariates on the pharmacokinetic parameters.MethodsThis pharmacokinetic study presents the results of a retrospective population pharmacokinetic analysis based on pooled data from 161 patients, who were given cladribine in different administration routes in various dosing regimens. The plasma concentrations of cladribine were determined by reversed-phase high-performance liquid chromatography using a solid phase extraction with a limit of quantitation of 1 nM using 1 mL of plasma.ResultsA three compartment structural model best described the disposition of cladribine. Clearance was found to be 39.3 L/hour, with a large interindividual variability. The half-life for the terminal phase was 16 hours. Bioavailability was 100% and 35% for subcutaneous and oral administration, respectively, with low interindividual variability. None of the investigated covariates were found to be correlated with the pharmacokinetic parameters.ConclusionAs interindividual variability in apparent clearance after oral administration was not significantly higher compared to that following infusion, cladribine could be administered orally instead of intravenously if compensated for its lower bioavailability. Individualized dosing on basis of body surface area or weight does not represent an improvement in this study as compared to administering a fixed dose to all patients.

Distribution of 2-chloro-2′-deoxyadenosine, 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine, Fludarabine and Cytarabine in mice: a whole-body autoradiography study

The distribution characteristics of tritiated nucleoside analogs, 2-chloro-2′-deoxyadeonosine (CdA), 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA), 2-fluoroarabinosyladenine (F-ara-A) and cytosine arabinoside (ara-C) were compared in mice using whole-body autoradiography. CdA, CAFdA and F-ara-A have quite similar molecular structures, but they differ substantially in clinical activity as well as the side effects. Eight mice were injected intravenously in couples. One mouse from each pair was killed 20 min postinjection and the other mouse from each pair 4 h after the injection. The distribution, of the label was then analyzed by whole-body autoradiography.The distribution of the nucleoside analogs was rapid and uniform. High concentrations were found in highly perfused organs. After 4 h the overall concentration had decreased but relatively high activities were found in the skin for CdA and CAFdA, in the thymus for ara-C and the bone marrow for CdA.Both CdA and CAFdA were found in the brain, but the concentration, was surprisingly lower after 4 h for CAFdA, a lipophilic and more stable analog as compared to CdA. There was an uptake of CdA, F-ara-A and CAFdA in the skin. There were signs of retention of ara-C in parts of the thymus.The present investigations indicate that the nucleoside analog transport to the brain in mice is not primarily dependent upon passive diffusion over a lipophilic barrier, but suggestive of a specific transport mechanism.

Estimation of body surface area in various childhood ages – validation of the Mosteller formula

Aim:  The aim of the present study was to validate the Mosteller formula for the estimation of body surface area (BSA) in various childhood ages. Many physiological processes including drug metabolism correlate with values for BSA. In addition, dosing of many drugs, especially drugs with low therapeutic index, for example, anti‐neoplastics, are based on estimated values of BSA.

In vitro topo II-DNA complex accumulation and cytotoxicity of etoposide in leukaemic cells from patients with acute myelogenous and chronic lymphocytic leukaemia

Topoisomerase II (topo II) is the target enzyme of etoposide, and DNA--topo II complex accumulation is considered crucial for the cytotoxic effect. We used a SDS--KCl precipitation assay to determine the complex accumulation induced by etoposide in leukaemic cells isolated from 58 patients, 31 with acute myelogenous leukaemia (AML), and 27 with chronic lymphocytic leukaemia (CLL). To investigate whether the sensitivity towards etoposide was dependent on the complex accumulation in the cells, we investigated the drug-induced DNA damage using a DNA unwinding assay and the in vitro cytotoxicity of etoposide using the MTT assay. AML cells had higher complex accumulation (P=0.006) and more DNA damage (P=0.029) compared with CLL cells. The data support a relationship between etoposide-induced complex accumulation and DNA damage in leukaemic cells from AML and CLL patients. However, the induced DNA damage did not translate to in vitro cytotoxicity, suggesting that other factors, such as DNA repair and apoptosis functions, also play important roles to determine the etoposide sensitivity.

In situ coating makes it easier for children to swallow and tolerate tablets and capsules

Getting children to swallow tablets and capsules is a challenge, and factors that influence their ability to swallow include taste, smell and texture. The aim of this study was to explore how well paediatric patients tolerated and accepted the MedCoat® in situ coating for tablets and capsules.

Off-label drug use evaluation in paediatrics—applied to ciprofloxacin when used as treatment of cholangitis

To evaluate drug and indication specific off‐label use in paediatrics, applied to ciprofloxacin (CPFX) in cholangitis.

5PSQ-114 Frequency of manipulated medicines administered to paediatric in-patients: a register study

Background The use of off-label drug and manipulation are very common in paediatrics, since there is a lack of drugs in suitable strengths and child-friendly dosage forms. A manipulation is the physical alteration of a drug dosage form with the purpose to extract and administer the prescribed proportion of a drug dose. In an earlier study, we concluded that tablets should not be split to receive a smaller dose due to the irregularity of the resulting halves, but we still lack information on how common this procedure is. Purpose To study the frequency of manipulated medicines administered to paediatric inpatients at a large children’s hospital during 1 year. Material and methods To answer this question, we collected data for all administered doses during 12 months at the paediatric wards at our children’s hospital, from a hospital-based register. All administered doses where the number of tablets or suppositories were decimal were added and calculated as a percentage of all administered doses. Data were anonymous but information regarding sex, age, hospital ward and number of drugs per patient were available and were analysed. Results During 1 year, approximately 4 50 000 doses of medicine are administered to paediatric patients in our children’s hospital. Preliminary results show that 7% of all administered doses are for a decimal number of tablets or suppositories in all age groups. The medicines that most frequently were prescribed and administered as decimal numbers were clobazam tablets and ibuprofen suppositories. Conclusion Our results clearly illustrate the need for more child-appropriate medicines/strengths. Most often there is a lack of knowledge of how manipulation of medicines influences the dosing accuracy and often we do this to our most vulnerable patients. Further studies are needed to investigate the relation between manipulation of medicines and dosing accuracy, and to establish best practice when manipulation is necessary. No conflict of interest

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 to support the prevention of medication errors. After implementing a CDSS, organized efforts are crucial to understand the need for further development based on the practical knowledge of the clinical profession. Different contextual settings of health care organisations do affect the way how physicians think and act in work. When implementing a CDSS in practice we need to describe and analyse the context where the CDSS should be used as well as the prescribers’ needs in work.