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.

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.

Intrathecal Morphine Versus Extended-Release Epidural Morphine for Postoperative Pain Control in Pediatric Patients Undergoing Posterior Spinal Fusion.

BACKGROUND: Posterior spinal fusion for scoliosis is one of the most painful elective pediatric surgeries. Good postoperative pain control allows early ambulation and return of ability to tolerate oral intake. Options for analgesia in this patient population are suboptimal. We hypothesized that extended-release epidural morphine (EREM) would provide better pain control and less adverse effects compared to intrathecal (IT) morphine. METHODS: The primary outcome was total IV morphine consumption during 0-48 hours postoperatively. Secondary outcomes included time until first patient-controlled analgesia (PCA) demand, pain scores, and adverse opioid effects. After institutional review board approval, 71 subjects undergoing posterior spinal fusion for idiopathic scoliosis completed the study. The subjects were randomly allocated to 7.5 µg/kg IT morphine or 150 µg/kg EREM. The final IT morphine and EREM groups contained 37 and 34 subjects, respectively. Postoperative pain was treated with morphine PCA, ketorolac, oral oxycodone, and acetaminophen. Morphine consumption, pain scores, nausea and vomiting, pruritus, and respiratory depression were measured every 4 hours. Parents completed a caregiver questionnaire about their child's pain control regimen after the first postoperative day. RESULTS: There was no difference in total morphine consumption over the first 48 hours between subjects in the EREM and IT morphine groups: median (range) 42.2 (5.5-123.0) and 34.0 (4.5-128.8) mg, respectively (P = .27). EREM and IT morphine groups had no difference in time until first PCA demand. Pain scores were no different between the groups from 8 to 24 hours after surgery. Compared to IT morphine, EREM subjects had lower pain scores from 28 to 36 hours after surgery. The reported incidence of pruritus was lower in the EREM subjects. CONCLUSIONS: There was no difference in total morphine consumption or time until first PCA demand between the EREM and IT morphine groups. EREM provides a longer duration of analgesia after posterior spinal fusion for scoliosis and may be associated with less opioid-induced pruritus.

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.

Pharmacogenetics in perioperative medicine.

PURPOSE OF REVIEW: This review will discuss the most recent developments in pharmacogenetics of commonly used perioperative medications, new collaboration networks in the field of personalized medicine, and future clinical implications of pharmacogenetics. RECENT FINDINGS: Evidence now suggests that pharmacogenetics has a role in the effects of analgesic, sedative, beta-blocker, local anesthetic, antiemetic, and obstetric medications. Variants in the µ opioid receptor gene change the analgesic effects of morphine. Additional opioids recently studied include remifentanil, methadone, tramadol, and codeine. Ibuprofen's clearance varies with CYP2C9*3 genotype. Midazolam is primarily metabolized by the CYP3A4/CYP3A5 enzymes. Enzyme induction was found to be about 50% greater with CYP3A5*3 homozygous genotype. Variations in minimum alveolar concentrations of volatile anesthetics and subcutaneous lidocaine efficacy have been attributed in part to melanocortin-1 receptor variants. Metoprolol achieved different effects in patients with CYP2D6 and beta1-receptor polymorphisms. Genetic background of the beta2-receptor contributes to susceptibility for experiencing preterm labor. The Pharmacogenomics Research Network and the Clinical Pharmacogenetics Implementation Consortium are partnerships of researchers who are dedicated to elucidating how the genome contributes to an individual patient's medication responses. SUMMARY: In the near future, pharmacogenetic approaches may facilitate personalized perioperative intervention trials.

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.

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.

The Association Between Adjuvant Pain Medication Use and Outcomes Following Pediatric Spinal Fusion.

STUDY DESIGN: A comparative effectiveness database study. OBJECTIVE: The aim of this study was to describe variation in use of adjuvant therapies for managing postoperative pain in in patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and determine association between use of these therapies and patient outcomes. SUMMARY OF BACKGROUND DATA: Variation in postoperative pain management for children undergoing PSF for AIS likely impacts outcomes. Minimal evidence exists to support strategies that most effectively minimize prolonged intravenous (IV) opioids and hospitalizations. METHODS: We included patients aged 10 to 18 years discharged from one of 38 freestanding children's hospitals participating in a national database from December 1, 2012, to January 5, 2015, with ICD9 codes indicating scoliosis and PSF procedure. Use of ketorolac, gamma aminobutyric acid (GABA) analogues (GABAa), and benzodiazepines was compared across hospitals. Hierarchical logistic regression adjusting for confounders and accounting for clustering of patients within hospitals was used to estimate association between these therapies and odds of prolonged duration of IV opioids, prolonged length of stay (LOS), and early readmissions. RESULTS: Across hospitals, use of ketorolac and GABAa was highly variable and increased over time among 7349 subjects. Use of ketorolac was independently associated with significantly lower odds of prolonged LOS [odds ratio (OR) 0.75, 95% confidence interval (95% CI) 0.64-0.89] and prolonged duration of IV opioid (OR 0.84, 95% CI 0.73-0.98). GABAa use was significantly associated with decreased odds of prolonged IV opioid use (OR 0.63, 95% CI 0.53-0.75). Readmission rate at 30 days was 1.6% and most strongly associated with prolonged LOS. CONCLUSION: In this national cohort of children with AIS undergoing PSF, patients who received postoperative ketorolac or GABAa were less likely to have prolonged IV opioid exposure. Given the rapid increase in use of adjuvant therapies without strong evidence, resources should be devoted to multicenter trials in order to optimize effectiveness and outcomes. LEVEL OF EVIDENCE: 3.

Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from defects in the multienzyme complex NADPH-oxidase (phagozyte oxidase, phox), which normally produces microbicidal reactive oxygen metabolites (ROM). The reason for our patient's CGD was unusual, as revealed by the following in vitro findings in neutrophils and EBV-transformed B-cells: lack of flavocytochrome b(558) expression, restoration of significant ROM production after transduction with gp91-phox cDNA by a retrovirus vector, an 879G-->A, Trp289-->Stop mutation in one X chromosomal gp91-phox allele, a one-sided paternal X chromosome inactivation, as shown by a lyonization assay at the HUMARA locus, and the result of a dihydrorhodamine 123 flow cytometry assay revealing consistently that 1 in 2500 neutrophils produced ROM at normal levels. Our conclusion: A presumed autosomal form of CGD has been excluded. Instead, a spontaneous mutation in gp91-phox coinciding with an extreme X chromosome inactivation ratio resulted in X-linked CGD in this young woman.

Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay.

BACKGROUND: Chronic granulomatous disease (CGD) is a phagocyte disorder caused by mutations in nicotinamide dinucleotide phosphate (NADPH) oxidase subunits. The dihydrorhodamine 123 (DHR) assay is an effective test for CGD that for most patients also might help to differentiate between the 2 most common forms, X-linked (X) gp91(phox) defect CGD and autosomal recessive (AR) p47(phox) defect CGD. However, some male patients with X-CGD have DHR patterns that overlap the AR-CGD pattern. OBJECTIVE: The purpose of this investigation was to develop a diagnostic paradigm to delineate male patients with X-CGD expressing a DHR pattern suggestive of p47(phox) deficiency. METHODS: The DHR assay measured change in fluorescence of DHR-loaded granulocytes after phorbol myristate acetate (PMA) stimulation. Western blot analysis measured the presence of NADPH oxidase subunits gp91(phox), p47(phox), p67(phox), and p22(phox). CYBB exonic sequencing was performed on PCR-amplified genomic DNA through use of intronic flanking primers. Ferricytochrome-c assay evaluated specific superoxide production by PMA-stimulated granulocytes. RESULTS: Although 83% of patients with X-CGD have virtually no neutrophil DHR activity, we found that 17% of patients, proven to have X-CGD by other criteria, have modest DHR activity that is most consistent with p47(phox) deficiency. We describe a diagnostic paradigm to deal with such patients, and we present 2 cases, along with results of additional studies, including carrier evaluation, protein assessment, and mutation analysis, that are useful in establishing the genotype under these circumstances. DHR assays from the 2 patients described showed a fluorescence shift most characteristic of p47(phox)-AR-CGD; however, each of the patients' mothers showed mosaicism with a bimodal DHR pattern. Patient 1 had some gp91(phox) protein with a Y41D mutation and modest superoxide activity. Patient 2 had a normal level of gp91(phox) protein with a C537R mutation without detectable superoxide activity, as determined by ferricytochrome-c assay, despite the modest DHR activity. CONCLUSIONS: Evaluation of male patients with CGD with modest DHR activity should initially include evaluation of potential female carriers for mosaicism with the use of the DHR assay. In circumstances in which this is uninformative, patients should be referred to centers capable of additional testing, including Western blot analysis and CYBB mutation analysis, to clarify the disease genotype.

Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/beta -microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells.

In previous studies amphotropic MFGS-gp91phox (murine onco-retrovirus vector) was used in a clinical trial of X-linked chronic granulomatous disease (X-CGD) gene therapy to achieve transient correction of oxidase activity in 0.1% of neutrophils. We later showed that transduced CD34+ peripheral blood stem cells (CD34+ PBSCs) from this trial transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in correction of only 2.5% of human neutrophils. However, higher rates of transduction into stem cells are required. In the current study we demonstrate that the same vector (MFGS-gp91phox) pseudo-typed with RD114 envelope in a 4-day culture/transduction regimen results in a 7-fold increase in correction of NOD/SCID mouse repopulating X-CGD CD34+ PBSCs (14%-22% corrected human neutrophils; human cell engraftment 13%-67%). This increase may result from high expression of receptor for RD114 that we demonstrate on CD34+CD38- stem cells. Using RD114-MFGS encoding cyan fluorescent protein to allow similar studies of normal CD34+ PBSCs, we show that progressively higher levels of gene marking of human neutrophils (67%-77%) can be achieved by prolongation of culture/transduction to 6 days, but with lower rates of human cell engraftment. Our data demonstrate the highest reported level of functional correction of any inherited metabolic disorder in human cells in vivo with the NOD/SCID mouse system using onco-retrovirus vector.