Janelle D. Vaughns

Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents

AIM In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents. METHODS Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2. RESULTS Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8-55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ). CONCLUSIONS The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.

Clinical Pharmacology of Frequently Used Intravenous Drugs During Bariatric Surgery in Adolescents

Obesity represents one of the most important public health issues according to the World Health Organization. Additionally, in a recent National Health and Nutrition Survey of 2011-2012, approximately 17 % of children and adolescents in the United States were considered obese. The obesity rate is higher within the adolescent age group as compared to preschool children. Childhood obesity is particularly problematic, because the co-morbid disease states which accompany obesity may require frequent pharmacotherapy and/ or surgical intervention. Despite the potential for increased pharmacotherapy among obese patients, there is a paucity of dosing guidelines for this special population. Optimal drug dosing in obese pediatric patients has not been sufficiently explored as the present data available are mostly specific for obese adults. In this review, we present an overview concerning what is currently known about the pharmacokinetics and pharmacogenetics of frequently used drugs including midazolam, fentanyl and its newer derivatives, morphine, ketamine, acetaminophen, dexmedetomidine and enoxaparin in obese adolescents undergoing bariatric surgery. We will also summarize the current dosing recommendations of anesthetic drugs in bariatric anesthesia.

Dexmedetomidine as an adjuvant for perioperative pain management in adolescents undergoing bariatric surgery: An observational cohort study

BACKGROUND The anesthetic management of adolescents undergoing bariatric surgery presents a number of challenges, including increased risk of postoperative opioid-related respiratory depression. These patients could benefit from adjunctive analgesics with opioid-sparring effects to optimize perioperative pain control. Dexmedetomidine, a selective α2-adrenoreceptor agonist, has sedative and analgesic properties with no respiratory depressant effects. OBJECTIVE To determine the effect of intraoperative dexmedetomidine on opioid requirement and perioperative pain management in obese adolescents undergoing bariatric surgery. METHODS An observational study of 26 consecutive patients treated with and without dexmedetomidine during the intraoperative period was conducted. The dexmedetomidine treated patients received a loading dose over 30min and a continuous infusion thereafter. The standard group represented patients who received an institutional standard anesthetic without dexmedetomidine. The primary outcome was total perioperative intravenous morphine equivalent (MEq). We also examined reported pain scores during the perioperative period. RESULTS While there were no significant differences in age, height and weight category, there were imbalances on race distribution between the two groups. Both groups received similar doses of ketorolac and acetaminophen perioperatively. Overall, during 48h postoperatively, the dexmedetomidine group received significantly less total MEq administration compared with the standard group. Three patients in the dexmedetomidine group required ephedrine to treat an episode of hypotension. DISCUSSION These results suggest that the use of dexmedetomidine during bariatric surgery in the morbidly obese adolescent population is associated with decreased opioid utilization during the perioperative period. Future randomized studies will determine the role of dexmedetomidine in the pain management of obese adolescents undergoing bariatric surgery. STUDY TYPE Therapeutic, Level III.

Accuracy of rapid sequence intubation medication dosing in obese patients intubated in the ED.

OBJECTIVE There are limited data regarding appropriateness of sedative and paralytic dosing of obese patients undergoing rapid sequence intubation (RSI) in the emergency department. The goal of this study was to compare rates of appropriate succinylcholine and etomidate doses in obese and nonobese patients. METHODS Retrospective review using a database of endotracheally intubated patients using RSI in an urban, tertiary care academic emergency department, from November 2009 to June 2011. Dosing for succinylcholine and etomidate was calculated as milligrams per kilogram of total body weight (TBW) for each patient, defining appropriate dosing as succinylcholine 1-1.5 mg/kg TBW and etomidate 0.2-0.4 mg/kg TBW. Logistic regression analysis was used to estimate the association between appropriate dosing and World Health Organization body mass index classification. RESULTS A total of 440 patients were included in the study, 311 (70.7%) classified as nonobese and 129 (29.3%) as obese. two hundred thirty-three (56%) received an inappropriate succinylcholine dose and 107 (24%) received an inappropriate etomidate dose. Obese patients were more likely to be underdosed with succinylcholine (odds ratio [OR], 63.7; 95% confidence interval [CI], 17.8-228.1) and etomidate (OR, 178.3; 95% CI, 37.6-844.7). Nonobese patients were more likely to be overdosed with succinylcholine (OR, 62.5; 95% CI, 17.9-250) and etomidate (OR, 166.7; 95% CI, 37.0-1000). CONCLUSION Obese patients were more likely to be underdosed during RSI compared with nonobese patients, whereas nonobese patients were more likely to be overdosed with RSI medications. Most obese and nonobese patients were inappropriately dosed with RSI medications, suggesting that physicians are not dosing these medications based on weight.

Obesity and Pediatric Drug Development.

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty‐five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty‐four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population.