Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

BACKGROUND: Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. METHODS: We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. RESULTS: Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. CONCLUSIONS: Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Preoperative Vancomycin Administration for Surgical Site Prophylaxis: Plasma and Soft-Tissue Concentrations in Pediatric Neurosurgical and Orthopedic Patients.

BACKGROUND: Vancomycin is used for antibiotic prophylaxis in pediatric surgical patients without a complete understanding of plasma and soft-tissue pharmacokinetics. Guidelines recommend incision within 60 minutes after administration; however, tissue vancomycin concentrations at that early time may not be therapeutic. We conducted a study of plasma and skin concentrations in pediatric neurosurgical and orthopedic patients to characterize intraoperative vancomycin pharmacokinetics. METHODS: Patients (0.1-18.8 years of age) undergoing posterior spinal fusion (n = 30) or ventriculoperitoneal shunt placement (n = 30) received intravenous vancomycin 15 mg/kg (maximum 1000 mg) over 1 hour. Skin was biopsied at incision and skin closure. Blood samples were collected at incision, at 2 and 4 hours intraoperatively, and at closure. Population pharmacokinetic analysis was performed to characterize pharmacokinetic parameter estimates and to develop a model of intraoperative plasma and skin vancomycin concentrations versus time. RESULTS: Pharmacokinetic analysis included data from 59 subjects, 130 plasma samples, and 107 skin samples. A 2-compartment model, volume of the central (Vc) and volume of the peripheral compartment (V2), proved to have the best fit. Stepwise covariate selection yielded a significant relationship for body surface area on elimination clearance and body weight on V2. Skin vancomycin concentrations rose continuously during surgery. Modeling predicted that equilibration of skin and plasma vancomycin concentrations took ≥5 hours. CONCLUSIONS: Skin vancomycin concentrations immediately after a preoperative dose are relatively low compared with concentrations at the end of surgery. It may be advisable to extend the time between dose and incision if higher skin concentrations are desired at the start of surgery.

Opioids in the Management of Acute Pediatric Pain: An Update in a Time of Crisis.

Management of acute pain in children is fundamental to our practice. Its myriad benefits include reduced suffering, improved patient satisfaction, more rapid recovery, and a reduced risk of developing postsurgical chronic pain. Although a multimodal analgesic approach is now routinely used, informed and judicious use of opioid receptor agonists remains crucial in this treatment paradigm, as long as the benefits and risks are fully understood. Further, an ongoing public health response to the current opioid crisis is required to help prevent new cases of opioid addiction, identify opioid-addicted individuals, and ensure access to effective opioid addiction treatment, while at the same time continuing to safely meet the needs of patients experiencing pain.

Utility of gabapentin in meeting physical therapy goals following posterior spinal fusion in adolescent patients with idiopathic scoliosis.

OF BACKGROUND DATA: Posterior spinal fusion surgery for scoliosis requires extensive postoperative analgesic care. In 2014, we initiated the use of gabapentin as an adjunct for multimodal pain management in spine fusion patients. The effect of gabapentin on postoperative recovery in scoliosis patients was evaluated using the time to meet postoperative physical therapy goals. This measure was chosen because the actions required to achieve the goals are specific and reproducible. Secondary outcomes included morphine equivalents and maximum pain scores. AIMS: The purpose of this study was to evaluate the effects of gabapentin on time to achieve physical therapy goals following posterior spinal fusion in adolescents with scoliosis. METHODS: A retrospective chart review was performed and patients treated perioperatively with gabapentin were compared with those who did not receive gabapentin. Outcome measures included the postoperative day that physical therapy goals were met, days to discharge, morphine equivalents, and maximum pain scores. The 4 physical therapy goals included logroll, transition from lying to sitting, ambulate 250 feet, and ascend/descend at least 3 stairs. RESULTS: There were 50 patients in the gabapentin group and 51 patients in the control group. In the gabapentin group, there was a statistically significant decrease in the time required to meet physical therapy goals. Notably, gabapentin was independently associated with a 5.34 times higher odds of completion of the most challenging physical therapy goal (stairs) within 1 day (P = .04; 95% CI=1.24-37.44). There was not a statistically significant difference in length of hospital stay between the groups (P = .116; 95% CI=0-1). CONCLUSION: In this retrospective analysis, the use of perioperative gabapentin is associated with a statistically significant decrease in time to completing physical therapy goals after spinal fusion for adolescent idiopathic scoliosis.

The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis.

BACKGROUND: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg. L-1 is described in adults. AIMS: The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. METHODS: Pooled intravenous ketorolac (0.5 mg. kg-1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. RESULTS: There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L. h-1. 70 kg-1 and intercompartment clearance was 4.43 (CV 95.6%) L. h-1. 70 kg-1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L. 70 kg-1 and V2 5.53 (CV 47.6%) L. 70 kg-1 . CONCLUSION: Clearance, expressed as L. h-1. kg-1 , decreased with age from infancy. A dosing regimen of 0.5 mg. kg-1 every 6 hours maintains a trough concentration larger than 0.37 mg. L-1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations.

Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients.

Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.

Pharmacokinetics of single-dose intravenous ketorolac in infants aged 2-11 months.

BACKGROUND: Ketorolac is a parenterally available nonsteroidal antiinflammatory drug that nonselectively inhibits cyclooxygenase. Ketorolac is an attractive alternative to opioids in the pediatric population because of its favorable side effect profile; it provides postoperative analgesia similar to morphine, but is associated with significantly less respiratory depression, pruritus, and emesis. Despite the efficacy of ketorolac in young patients, there are minimal data to characterize the pharmacokinetic variables of ketorolac in infants younger than 6 months. METHODS: In this study, 17 infants younger than 1 year old, without renal or liver disease, undergoing elective surgery received a single-dose of IV ketorolac 0.5 mg/kg. Blood was sampled at 0, 5, 10, 15, 30, 60, and 120 minutes, and at 4, 6, 12, and 24 hours. Ketorolac levels were analyzed using a specific and validated high-performance liquid chromatography method with mass spectrometry (LC-LC/MS/MS). Pharmacokinetic analysis of individual subjects and population pharmacokinetic modeling was performed using SAAM II and PopKinetics, respectively (SAAM Institute, University of Washington). RESULTS: Characterization of pharmacokinetic parameters was possible in 14 subjects. The data were best described by a 2-compartment model. Estimated individual parameters were clearance 1.49 ± 1.12 mL/min/kg, Vss (volume of distribution at steady state) 0.31 ± 0.11 L/kg, and half-life of 236 ± 169 minutes. Estimated population pharmacokinetic parameters were clearance 1.52 mL/min/kg and Vss 0.29 L/kg. There was a trend toward lower clearances in younger patients. CONCLUSION: This is the first report of individualized pharmacokinetic parameters of ketorolac in children in which the majority of subjects were younger than 6 months old.