Off-label drug use, medication errors and adverse drug events : among Swedish pediatric inpatients

Background: In pediatrics, treatment with drugs is an important and fully integrated part of everyday medical practice. However, authorized drugs specified to be used in children are often lacking which leads to off-label use, i.e. outside of approved product monographs. Another challenge is medication errors (ME) which is an important cause of adverse drug events (ADE) in hospitalized children. The consequences and effects of these conditions are largely unknown. Studies within the field of pediatric, and especially neonatal, drug safety are lacking. Unsafe drug use may be an important and unrecognized contributor to suboptimal health in this vulnerable group with limited capacity for drug metabolism and excretion. Aim: The general aim of the thesis was to explore the magnitude of drug safety issues within Swedish pediatric inpatients. More specifically we aimed to investigate; I. National extent of off-label drug-use, II. Contents in national ME incident reports, III. Type of ADEs in a pediatric inpatient setting and IV. The views of pediatricians on a clinical decision support system (CDSS) to aid in prescribing drugs. Methods: In the four papers we used different study approaches. In paper I we performed a descriptive cross-sectional study based on collection of drug charts during two time-points. In paper II we used an analytic cross-sectional register-based study on Lex Maria incident reports and complaints from the Health and Social Care Inspectorate. In paper III we carried out a cohort study using a chart review with a pediatric trigger tool covering 600 admissions stratified in four different units, and in paper IV we used qualitative semi-structured interviews with pediatricians. Results: Paper I showed that half of all drug orders received by pediatric inpatients was outside approved product monographs, extemporaneously prepared or unlicensed. In paper II the ME reports indicated frequent occurrence of substances from three previously known high-alert lists with specified error characteristics among the different drug handling processes. In paper III we showed that skin/tissue/vascular harm, omission of analgesic drug therapy and hospital acquired infections are the most abundant ADEs as identified by an extended set of medical record triggers. In paper IV the CDSS-experiences of pediatricians emerged into six categories being: use, benefit, confidence, situations of disregards, misgivings/risks and development potential. Conclusions: Paper I found a similar situation in Sweden regarding off-label and unlicensed drug use as in many other countries. Paper II found that the existing high-alert lists are relevant for pediatric inpatients and suggested the use of process dependent high-alert lists. Paper III found that ADEs are common in pediatric inpatients and that the incidence varied with ADE-type, depending on ward and time after admission. In paper IV the experiences of pediatricians after the implementation of a CDSS gave insights on usability and the need for future developments

Association of Adherence to Surfactant Best Practice Uses with Clinical Outcomes among Neonates in Sweden

Importance: While surfactant therapy for respiratory distress syndrome (RDS) in preterm infants has been evaluated in clinical trials, less is known about how surfactant is used outside such a framework. Objective: To evaluate registered use, off-label use, and omissions of surfactant treatment by gestational age (GA) and associations with outcomes, mainly among very preterm infants (GA <32 weeks). Design, Setting, and Participants: This population-based cohort study used registry data for 97377 infants born in Sweden between 2009 and 2018. Infants did not have malformations and were admitted for neonatal care. Data analysis was conducted from June 2019 to June 2020. Exposures: Timing and number of surfactant administrations, off-label use, and omission of use. Registered use was defined by drug label (1-3 administrations for RDS). Omissions were defined as surfactant not administered despite mechanical ventilation for RDS. Main Outcome and Measures: In-hospital survival, pneumothorax, intraventricular hemorrhage grade 3 to 4, duration of mechanical ventilation, use of postnatal systemic corticosteroids for lung disease, treatment with supplemental oxygen at 28 days' postnatal age and at 36 weeks' postmenstrual age. Odds ratios (ORs) were calculated and adjusted for any prenatal corticosteroid treatment, cesarean delivery, GA, infant sex, Apgar score at 10 minutes, and birth weight z score of less than -2. Results: In total, 7980 surfactant administrations were given to 5209 infants (2233 [42.9%] girls; 2976 [57.1%] boys): 629 (12.1%) born at full term, 691 (13.3%) at 32 to 36 weeks' GA, 1544 (29.6%) at 28 to 31 weeks' GA, and 2345 (45.0%) at less than 28 weeks' GA. Overall, 977 infants (18.8%) received off-label use. In 1364 of 3508 infants (38.9%) with GA of 22 to 31 weeks, the first administration of surfactant was given more than 2 hours after birth, and this was associated with higher odds of pneumothorax (adjusted OR [aOR], 2.59; 95% CI, 1.76-3.83), intraventricular hemorrhage grades 3 to 4 (aOR, 1.71; 95% CI, 1.23-2.39), receipt of postnatal corticosteroids (aOR, 1.57; 95% CI, 1.22-2.03), and longer duration of assisted ventilation (aOR, 1.34; 95% CI, 1.04-1.72) but also higher survival (aOR, 1.45; 95% CI, 1.10-1.91) than among infants treated within 2 hours of birth. In 146 infants (2.8%), the recommended maximum of 3 surfactant administrations was exceeded but without associated improvements in outcome. Omission of surfactant treatment occurred in 203 of 3551 infants (5.7%) who were receiving mechanical ventilation and was associated with lower survival (aOR, 0.49; 95% CI, 0.30-0.82). In full-term infants, 336 (53.4%) of those receiving surfactant had a diagnosis of meconium aspiration syndrome. Surfactant for meconium aspiration was not associated with improved neonatal outcomes. Conclusions and Relevance: In this study, adherence to best practices and labels for surfactant use in newborn infants varied, with important clinical implications for neonatal outcomes

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

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

Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients : a model to describe early post-transplantation apparent clearance

  In this study 1) the predictive capacity of two previously derived population pharmacokinetic models of tacrolimus in paediatric liver transplant recipients were tested during Bayesian forecasting 2) a new population pharmacokinetic model was developed focusing on the immediate post-transplant period and 3) this new model was applied in a simulation exercise to devise a new dosing scheme for initial oral dosing of tacrolimus.  Pharmacokinetic, demographic and covariate data were collected retrospectively from patient records.  The Abbottbase PKS program was used for Bayesian forecasting.  Actual tacrolimus concentrations were compared to those predicted by the program and bias and precision determined.  The NONMEM program was used for building of a new population pharmacokinetic model.  Factors screened for influence on the pharmacokinetic parameters were weight, age, sex, post-operative day, whole/cut-down donor liver, haematocrit, serum albumin, bilirubin, serum creatinine, creatinine clearance, liver function tests and country of origin.  Data were collected from 20 patients for Bayesian forecasting and from 73 patients for population pharmacokinetic modelling.  Predictive performance of the two previous population models was poor in the immediate post-transplant period (range of precision, bias).  Tacrolimus pharmacokinetics appeared to change rapidly over this period.  During the first and third month after transplantation use of only one previous sample during Bayesian forecasting providing the best predictive performance.  The final population model estimated a typical apparent clearance of tacrolimus of 0.148 L/h/kg0.75 immediately following the transplantation, increasing to a maximum of 1.37 L/h/ kg0.75 and typical apparent distribution volume of 27.2 L/kg.  An alternative initial dosing schedule was developed based on an initial loading dose followed by a maintenance dose that increased with time, with drug dosing based on allometric scaling.

Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients : a model to describe early post-transplantation apparent clearance

  In this study 1) the predictive capacity of two previously derived population pharmacokinetic models of tacrolimus in paediatric liver transplant recipients were tested during Bayesian forecasting 2) a new population pharmacokinetic model was developed focusing on the immediate post-transplant period and 3) this new model was applied in a simulation exercise to devise a new dosing scheme for initial oral dosing of tacrolimus.  Pharmacokinetic, demographic and covariate data were collected retrospectively from patient records.  The Abbottbase PKS program was used for Bayesian forecasting.  Actual tacrolimus concentrations were compared to those predicted by the program and bias and precision determined.  The NONMEM program was used for building of a new population pharmacokinetic model.  Factors screened for influence on the pharmacokinetic parameters were weight, age, sex, post-operative day, whole/cut-down donor liver, haematocrit, serum albumin, bilirubin, serum creatinine, creatinine clearance, liver function tests and country of origin.  Data were collected from 20 patients for Bayesian forecasting and from 73 patients for population pharmacokinetic modelling.  Predictive performance of the two previous population models was poor in the immediate post-transplant period (range of precision, bias).  Tacrolimus pharmacokinetics appeared to change rapidly over this period.  During the first and third month after transplantation use of only one previous sample during Bayesian forecasting providing the best predictive performance.  The final population model estimated a typical apparent clearance of tacrolimus of 0.148 L/h/kg0.75 immediately following the transplantation, increasing to a maximum of 1.37 L/h/ kg0.75 and typical apparent distribution volume of 27.2 L/kg.  An alternative initial dosing schedule was developed based on an initial loading dose followed by a maintenance dose that increased with time, with drug dosing based on allometric scaling.

Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients : a model to describe early post-transplantation apparent clearance

  In this study 1) the predictive capacity of two previously derived population pharmacokinetic models of tacrolimus in paediatric liver transplant recipients were tested during Bayesian forecasting 2) a new population pharmacokinetic model was developed focusing on the immediate post-transplant period and 3) this new model was applied in a simulation exercise to devise a new dosing scheme for initial oral dosing of tacrolimus.  Pharmacokinetic, demographic and covariate data were collected retrospectively from patient records.  The Abbottbase PKS program was used for Bayesian forecasting.  Actual tacrolimus concentrations were compared to those predicted by the program and bias and precision determined.  The NONMEM program was used for building of a new population pharmacokinetic model.  Factors screened for influence on the pharmacokinetic parameters were weight, age, sex, post-operative day, whole/cut-down donor liver, haematocrit, serum albumin, bilirubin, serum creatinine, creatinine clearance, liver function tests and country of origin.  Data were collected from 20 patients for Bayesian forecasting and from 73 patients for population pharmacokinetic modelling.  Predictive performance of the two previous population models was poor in the immediate post-transplant period (range of precision, bias).  Tacrolimus pharmacokinetics appeared to change rapidly over this period.  During the first and third month after transplantation use of only one previous sample during Bayesian forecasting providing the best predictive performance.  The final population model estimated a typical apparent clearance of tacrolimus of 0.148 L/h/kg0.75 immediately following the transplantation, increasing to a maximum of 1.37 L/h/ kg0.75 and typical apparent distribution volume of 27.2 L/kg.  An alternative initial dosing schedule was developed based on an initial loading dose followed by a maintenance dose that increased with time, with drug dosing based on allometric scaling.

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