Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents.

BACKGROUND: Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient. OBJECTIVE: The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11-18 years. METHODS: All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration-time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters. RESULTS: Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations. CONCLUSIONS: The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity. TRIAL REGISTRATION: EudraCT: 2014-004554-34.

Subjective evaluation of psychosocial well-being in children and youths with overweight or obesity: the impact of multidisciplinary obesity treatment.

PURPOSE: To investigate the effects of a multidisciplinary childhood obesity treatment programme on subjective evaluations of psychosocial well-being and quality of life. METHODS: This longitudinal observational study included 1291 children, adolescents and young adults, 6-22 years of age, with overweight or obesity. At entry and after 2-82 months of obesity treatment, the patients evaluated the following domains of psychosocial well-being on a visual analogue scale: quality of life, mood, appetite, bullying, motivation for weight loss and body image satisfaction. The degree of overweight was calculated using a body mass index (BMI) standard deviation score (SDS) at each visit. RESULTS: At entry, the mean BMI SDS was 2.81 (range: 1.35-6.65, 95% confidence interval (95% CI): 2.44-3.18). After a median of 14 months of treatment, the median reduction in BMI SDS was 0.29 (95% CI: 0.26-0.31, p < 0.0001). Improvements were observed in the domains of quality of life, mood, appetite, bullying and body image satisfaction (p < 0.0001). Larger reductions in BMI SDS were associated with greater improvements in the domains of quality of life (p = 0.001), mood (p = 0.04) and body image satisfaction (p < 0.0001), independent of BMI SDS at entry. However, improvements in psychosocial well-being were also observed in those increasing their BMI SDS (n = 315). CONCLUSIONS: In a large group of children and youths, psychosocial well-being improved during a multidisciplinary childhood obesity treatment programme, irrespective of the degree of obesity at treatment entry. Greater reductions in BMI SDS were associated with greater improvements in psychosocial well-being, but even in the group increasing their BMI SDS improvements were observed.

A large frontal QRS-T angle is a strong predictor of the long-term risk of myocardial infarction and all-cause mortality in the diabetic population.

BACKGROUND: A large angle between the QRS vector and the T-wave vector (QRS-T angle) in electrocardiograms (ECGs) has recently been introduced as a marker of poor prognosis. The prognostic value in diabetes is unknown. We assessed the long-term predictive power of the frontal plane QRS-T angle in the diabetic population. METHODS: In 1992-93, the diabetic population of the municipality of Horsens, Denmark, was delineated by the prescription method, and an age- and gender-stratified sample of 240 diabetic persons was randomly selected. In 2015, 12-lead ECGs taken in 1993-94 were analyzed. Vital statistics were obtained from the Danish Civil Registration System and data regarding hospitalizations taken from The National Patient Registry in July 2015. RESULTS: In total, 178 people agreed to participate (74%) in the study, with the mean (sd) age being 58.9 (10.2) years and 56% being male. The total observation time was 21.5 (0.18) years, during which time 122 (69%) persons died, 32 (18%) suffered a myocardial infarction (MI) and 126 (71%) reached the composite endpoint of non-fatal MI or all-cause death. In Cox regression multivariate analysis a QRS-T angle above 90° was found to be an independent predictor of all-cause death (HR=2.2 (95% CI: 1.3-3.8)), MI (HR=2.95 (95% CI: 1.1-7.7)) and MI or all-cause death (HR=2.0 (95% CI: 1.2-3.5)) (all p<0.05), when adjusting for the effects of co-variates (gender, age, length of diabetes, BMI, total cholesterol, diabetes type, hemoglobin A1c, smoking, hypertension and previous MI). CONCLUSION: A large QRS-T angle is a strong, independent long-term predictor of all-cause mortality, MI and MI or all-cause death in the diabetic population.