The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p

A modified Delphi to define drug dosing errors in pediatric critical care

Abstract Background There is no globally accepted definition for dosing error in adult or pediatric practice. The definition of pediatric dosing error varies greatly in the literature. The objective of this study was to develop a framework, informed by a set of principles, for a clinician-based definition of drug dosing errors in critically ill children, and to identify the range that practitioners agree is a dosing error for different drug classes and clinical scenarios. Methods We conducted a nationwide three staged modified Delphi from May to December 2019. Expert clinicians included Canadian pediatric intensive care unit (PICU) physicians, pharmacists and nurses, with a least 5 years’ experience. Outcomes were underlying principles of drug dosing, and error thresholds, as defined by proportion above and below reference range, for common PICU medications and clinical scenarios. Results Forty-four participants met eligibility, and response rates were 95, 86 and 84% for all three rounds respectively. Consensus was achieved for 13 of 15 principles, and 23 of 30 error thresholds. An over-dosed drug that is intercepted, an under-dose of a possibly life-saving medication, dosing 50% above or below target range and not adjusting for a drug interaction were agreed principles of dosing error. Altough there remained much uncertainty in defining dosing error, expert clinicians agreed that, for most medication categories and clinical scenarios, dosing over or below 10% of reference range was considered an error threshold. Conclusion Dosing principles and threshold are complex in pediatric critical care, and expert clinicians were uncertain about whether many scenarios were considered in error. For most intermittent medications, dosing over 10% below or above reference range was considered a dosing error, although this was largely influenced by clinical context and drug properties. This consensus driven error threshold will help guide routine clinical dosing practice, standardized reporting and drug quality improvement in pediatric critical care

Prospective observational study on the incidence of medication errors during simulated resuscitation in a paediatric emergency department

Objectives To characterise the incidence and nature of medication errors during paediatric resuscitations. Design A prospective observational study of simulated emergencies. Setting Emergency department of a tertiary paediatric hospital. Participants Teams that included a clinician who commonly leads “real” resuscitations, at least two assisting physicians, and two or three paediatric nurses. Interventions The teams conducted eight mock resuscitations, including ordering medications. Exercises were videotaped and drugs ordered and administered during the resuscitation were recorded. Syringes and drugs prepared during the resuscitation were collected and analysed for concentrations and actual amounts. Main outcome measures Number and type of drug errors. Results Participants gave 125 orders for medications. In 21 (17%) of the orders the exact dose was not specified. Nine dosing errors occurred during the ordering phase. Of these errors, five were intercepted before the drug reached the patient. Four 10-fold errors were identified. In nine (16%) out of 58 syringes analysed, measured drug concentrations showed a deviation of at least 20% from the ordered dose. A large deviation (at least 50%) from the expected dose was found in four (7%) cases. Conclusions Medication errors commonly occur during all stages of paediatric resuscitation. Many errors could be detected only by analysing syringe content, suggesting that such errors may be a major source of morbidity and mortality in resuscitated children