Oral drug dosing following bariatric surgery: General concepts and specific dosing advice.

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended-release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advice for oral drug therapy after bariatric surgery, implying that a risk assessment on a case-by-case basis is required for each drug.

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.

Child and Adolescent Bariatric Surgery in an Urban Tertiary Center: Special Anesthetic Considerations for Obesity.

Children and adolescents with obesity who present for weight loss surgery are a unique subset of patients. A thorough understanding of the perioperative needs of these individuals is essential to avoid deleterious complications. This review illustrates the necessity for specialized care, including the continued need of specified drug dosing and a systematic approach in the management of the pediatric bariatric patient.

Implications of Perioperative Polypharmacy in Adolescents Undergoing Bariatric Surgery: a Single-Center Experience.

Adolescents seeking bariatric surgery may present with pre-existing psychiatric diagnoses for which they use chronic medications. To heighten awareness concerning perioperative polypharmacy in adolescents with extreme obesity, we conducted a retrospective review of patients undergoing laparoscopic sleeve gastrectomy between February 2010 and May 2017 at Children's National Health System (CNHS). A total of 167 adolescent patients had pre-existing psychiatric diagnoses which included depression (50%), anxiety (23%), ADHD (23%), and binge eating disorder (11%). Medications prescribed to treat these diagnoses included selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Additionally, all patients were given fentanyl, ondansetron, morphine, and acetaminophen perioperatively. Although no life threatening symptoms of drug-drug interactions (DDIs) were appreciated, the combined use of many different potent drugs in these patients warrants attention.

Prophylactic Use of Enoxaparin in Adolescents During Bariatric Surgery-a Prospective Clinical Study.

INTRODUCTION: Severe obesity predisposes youth to a higher risk of venous thromboembolism (VTE). This study evaluates a BMI-stratified prophylactic dosing regimen of enoxaparin in adolescents with severe obesity undergoing surgery. METHODS: Adolescents aged 12-20 years received prophylactic enoxaparin at 40 mg SC (for a BMI < 50 kg/m2) and 60 mg SC (for a BMI ≥ 50 kg/m2) every 12 h until discharge. Blood samples were drawn at pre-dose, 1, 2, 4, 6, and 12 h. Plasma Anti-Factor Xa (Anti-FXa) activity was used as a surrogate marker for enoxaparin pharmacokinetics. RESULTS: Ten female and two male obese adolescents (age range 14-19 years) had a mean BMI of 49.9 kg/m2 (38.4-58 kg/m2). Four patients had a BMI of less than 50 kg/m2 and received 40 mg enoxaparin, resulting in a mean dosage of 0.352 ± 0.070 mg/kg body weight. Eight patients were dosed with 60 mg enoxaparin every 12 h, resulting in a mean dosage of 0.395 ± 0.028 mg/kg. Peak plasma anti-FXa activity (Cmax) ranged from 0.14 to 0.30 IU/mL, median Cmax was 0.205 IU/mL. Median Tmax was 5.67 h (range 3.78-7.52 h). Median AUCi was 1.00 h IU/mL (range 0.42-1.67 h IU/mL). Ten out of 12 patients (83%) reached the primary endpoint with anti-FXa activity in the range for VTE prevention (0.1-0.3 IU/mL). CONCLUSIONS: Our dosing scheme of 40 mg vs. 60 mg enoxaparin stratified according to BMI proved to be effective in reaching prophylactic anti-FXa activity in 83% of adolescent patients.

Analgesic Requirements in Adolescents Undergoing Bariatric Surgery-an Observational Study.

AIM: To examine the impact of preexisting psychiatric/psychological diagnoses on perioperative analgesic requirements in adolescents with morbid obesity undergoing bariatric surgery. METHODS: A retrospective cohort study of adolescents with morbid obesity undergoing bariatric surgery. Primary and secondary outcomes included perioperative analgesic intake and pain scores (Numerical Rating Scale (0-10) NRS) throughout the hospital stay. RESULTS: From our Bariatric Surgery Research Registry, we identified 17 adolescents with psychiatric/psychological diagnoses prior to undergoing bariatric surgery. Fifteen patients from the same registry and without such diagnosis undergoing bariatric surgery during the same time interval served as controls. In both groups, there was a predominance of female patients. During the perioperative period, in both groups, oral morphine equivalent and ketorolac and acetaminophen intake were similar. Notably, the perioperative median pain scores at the times examined were below 5 for all patients. The median pain scores in the PACU, day of surgery, and first postoperative day were similar. Conversely, on postoperative day 2, pain scores were higher in patients with diagnoses of psychiatric/psychological disorders (p = 0.004) compared to those without. CONCLUSION: In this cohort of morbidly obese adolescents undergoing bariatric surgery, patients with and without preexisting psychiatric/psychological diagnoses had similar analgesic requirements during the perioperative period. This finding appears contrary to those suggesting that preexisting depression and/or anxiety might be associated with increased analgesic requirements during the perioperative period.

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review.

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.

Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review.

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.

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.

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults.

BACKGROUND: The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. METHODS: Data from 19 obese adolescents [102.7 kg (62-149.5 kg)] and 20 morbidly obese adults [144 kg (112-186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW - WTfor age and length) was evaluated. RESULTS: The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called 'excess weight' model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. DISCUSSION: We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.

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.

Use of Fentanyl in Adolescents with Clinically Severe Obesity Undergoing Bariatric Surgery: A Pilot Study.

BACKGROUND: The number of obese pediatric patients requiring anesthesia is rapidly increasing. Although fentanyl is a commonly used narcotic during surgery, there are no pharmacokinetic (PK) data available for optimal dosing of fentanyl in adolescents with clinically severe obesity. MATERIALS AND METHODS: An institutional review board-approved exploratory pilot study was conducted in six adolescents aged 14-19 years undergoing bariatric surgery. Mean total body weight (TBW) and mean BMI were 137.4 ± 14.3 kg and 49.6 ± 6.4 kg/m2 (99.5th BMI percentile), respectively. Fentanyl was administered intravenously for intraoperative analgesia based on ideal body weight per standard of care. PK blood samples were drawn over a 24-h post-dose period. Fentanyl PK parameters were calculated by non-compartmental analysis. RESULTS: Mean fentanyl AUC0-∞ was 1.5 ± 0.5 h·ng/mL. Systemic clearance of fentanyl was 1522 ± 310 mL/min and 11.2 ± 2.6 mL/min·kg TBW. Volume of distribution was 635 ± 282 L and 4.7 ± 2.1 L/kg TBW. While absolute clearance was increased, absolute volume of distribution was comparable to previously established adult values. CONCLUSIONS: These results suggest that fentanyl clearance is enhanced in adolescents with clinically severe obesity while volume of distribution is comparable to previously published studies. STUDY REGISTRATION: NCT01955993 (clinicaltrials.gov).

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.

Use of Enoxaparin in Obese Adolescents During Bariatric Surgery--a Pilot Study.

BACKGROUND: Obese patients have a higher risk of venous thromboembolism when immobilized due to surgery. The objective of this study was to assess anti-factor Xa activity in adolescent bariatric surgical patients receiving prophylactic enoxaparin. METHODS: Four morbidly obese adolescents undergoing laparoscopic sleeve gastrectomy were enrolled. Enoxaparin was administered (40 mg subcutaneous (SC) if BMI ≤50 kg/m(2) or 60 mg SC if BMI >50 kg/m(2)) for prevention of venous thromboembolism every 12 h starting after induction of anesthesia until discharge. Plasma anti-factor Xa activity was assessed over 12 h after the first dose and used as a surrogate marker for enoxaparin levels. Non-compartmental analysis of anti-factor Xa activity levels was performed and compared with previously published studies. RESULTS: Patients recruited were 16 to 18 years of age with a mean BMI of 52.6 ± 5.8 kg/m(2) (>99th BMI percentile). Peak anti-factor Xa activity ranged from 0.20 to 0.23 IU/mL in our study population, compared to 0.38 to 0.53 IU/mL in the cited lean comparator groups. CONCLUSIONS: Our current dosing practice of 40 mg SC for individuals with a BMI ≤50 kg/m(2) and 60 mg for individuals with a BMI ≥50 kg/m(2) resulted in anti-factor Xa activity that was sufficient for adequate thromboprophylaxis in adolescent bariatric surgical patients. Our data also demonstrates lower drug exposures in the obese when compared to lean patients. Therefore, randomized controlled efficacy and safety studies are urgently needed to guide the use of low-molecular-weight heparins in the pediatric and adolescent obese population.