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Background: Fluoroquinolones, one of the most commonly prescribed antibiotic classes, have been implicated in cases of central nervous system (CNS) and peripheral nervous system (PNS) adverse events, which highlights the need for epidemiologic studies of the neurological safety of fluoroquinolones., Purpose: To evaluate the safety of fluoroquinolones with regard to risk of diagnosed neurological dysfunction., Methods: We conducted a propensity score-matched inception cohort study using claims data from a commercially insured population. Our study included adults prescribed an oral fluoroquinolone or comparator antibiotic between January 2000 and September 2015 for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, uncomplicated urinary tract infection, or acute bronchitis. Our outcomes were CNS dysfunction, and four separate but complementary PNS dysfunction outcomes. Cox proportional hazards models were estimated after matching on propensity scores fitted using the variables age, sex, epilepsy, hereditary peripheral neuropathy, renal dysfunction, diabetes, gabapentinoid use, statin use, isoniazid use, and chemotherapy use., Results: Our cohort contained 976 568 individuals exposed to a fluoroquinolone antibiotic matched 1:1 with a comparator. Matching produced balance (standardized mean difference <0.1) on all variables included in the propensity score. The hazard ratio associated with fluoroquinolone exposure was 1.08 (95% confidence interval 1.05-1.11) for CNS dysfunction, and 1.09 (95% CI 1.07-1.11) for the most commonly occurring PNS dysfunction outcome., Conclusions: Fluoroquinolone antibiotic use was associated with the development of neurological dysfunction versus comparator antibiotic use in the adult population., (© 2021 John Wiley & Sons Ltd.)

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus , Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis / pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis., Competing Interests: Conflict of interest: P.M. Mourani reports grants from NIH NHLBI and NIH NICHD, during the conduct of the study. Conflict of interest: M.K. Sontag reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: K.M. Williamson has nothing to disclose. Conflict of interest: J.K. Harris has nothing to disclose. Conflict of interest: R. Reeder has nothing to disclose. Conflict of interest: C. Locandro has nothing to disclose. Conflict of interest: T.C. Carpenter reports grants from NIH NHLBI and NIH NICHD, during the conduct of the study. Conflict of interest: A.B. Maddux reports a grant from Parker B. Francis Foundation (Fellowship Award) and NIH/NICHD K23HD096018, outside the submitted work. Conflict of interest: K. Ziegler reports grants from NIH NHLBI during the conduct of the study. Conflict of interest: E.A.F. Simões reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: C.M. Osborne has nothing to disclose. Conflict of interest: L. Ambroggio has nothing to disclose. Conflict of interest: M.K. Leroue has nothing to disclose. Conflict of interest: C.E. Robertson has nothing to disclose. Conflict of interest: C. Langelier has nothing to disclose. Conflict of interest: J.L. DeRisi reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: J. Kamm has nothing to disclose. Conflict of interest: M.W. Hall reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: A.F. Zuppa has nothing to disclose. Conflict of interest: J. Carcillo has nothing to disclose. Conflict of interest: K. Meert reports grants from NIH, during the conduct of the study. Conflict of interest: A. Sapru reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: M.M. Pollack reports grants from NIH, during the conduct of the study. Conflict of interest: P. McQuillen reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: D.A. Notterman has nothing to disclose. Conflict of interest: J.M. Dean reports grants from NIH, during the conduct of the study. Conflict of interest: B.D. Wagner reports grants from NIH NHLBI, during the conduct of the study., (Copyright ©ERS 2021.)

The objective of this study was to describe the pharmacokinetics (PK) of intravenous phenobarbital in neonates and infants on extracorporeal membrane oxygenation (ECMO) and to provide dosing recommendations in this population. We performed a retrospective single-center PK study of phenobarbital in neonates and infants on ECMO between January 1, 2014, and December 31, 2018. We developed a population PK model using nonlinear mixed-effects modeling, performed simulations using the final PK parameters, and determined optimal dosing based on attainment of peak and trough concentrations between 20 and 40 mg/L. We included 35 subjects with a median (range) age and weight of 14 days (1-154 days) and 3.4 kg (1.6-8.1 kg), respectively. A total of 194 samples were included in the analysis. Five children (14%) contributing 30 samples (16%) were supported by continuous venovenous hemodiafiltration (CVVHDF). A 1-compartment model best described the data. Typical clearance and volume of distribution for a 3.4-kg infant were 0.038 L/h and 3.83 L, respectively. Clearance increased with age and CVVHDF. Although on ECMO, phenobarbital clearance in children on CVVHDF was 6-fold higher than clearance in children without CVVHDF. In typical subjects, a loading dose of 30 mg/kg/dose followed by maintenance doses of 6-7 mg/kg/day administered as divided doses every 12 hours reached goal concentrations. Age did not impact dosing recommendations. However, higher doses were needed in children on CVVHDF. We strongly recommend therapeutic drug monitoring in children on renal replacement therapy (excluding slow continuous ultrafiltration) while on ECMO., (© 2020, The American College of Clinical Pharmacology.)

Background: Vancomycin is eliminated by glomerular filtration, but current approaches to estimate kidney function in children are unreliable. The authors sought to compare the suitability of cystatin C (CysC)-based glomerular filtration rate equations with the most commonly used creatinine-based equation, bedside Schwartz, to estimate vancomycin clearance (CL)., Methods: This prospective observational study enrolled critically ill patients (2-18 years) receiving intravenous vancomycin at the Children's Hospital of Philadelphia during December 2015-November 2017. Vancomycin levels were collected during clinical care and at 3 times during a single dosing interval. Plasma CysC was measured within 24 hours before intravenous vancomycin (baseline) initiation or immediately after enrollment and along with the third pharmacokinetic sample. Nonlinear mixed effects modeling was performed using NONMEM software. Covariate selection was used to test model fit with inclusion of the estimated glomerular filtration rate (eGFR) on CL using bedside Schwartz versus various published CysC-based equations., Results: In total, 83 vancomycin levels were obtained from 20 children. The median age was 12.7 years; 6 patients were women. A 1-compartment model best described the data; CL was allometrically scaled to 0.75. During covariate selection, inclusion of the eGFR calculated using a CysC-based equation significantly improved model fit [reduction in objective function value (OFV) range: -17.191 to -18.704] than bedside Schwartz ([INCREMENT]OFV -12.820). Including the full age spectrum equation, an eGFR equation based on both creatinine and CysC, led to the largest OFV reduction (-22.913); female sex was also a significant covariate of CL in the model. Final model pharmacokinetic indices were CL = 0.29 L/h/kg and volume of distribution = 0.48 L/kg., Conclusions: CysC-based equations help better estimate vancomycin CL than bedside Schwartz in critically ill children.

Objectives: Refractory status epilepticus (RSE) is often treated with midazolam boluses and continuous infusions, but there is considerable variability in dosing and efficacy. We aimed to evaluate the performance of a clinical midazolam dose escalation pathway for the treatment of pediatric RSE that was designed based on a novel midazolam pharmacokinetic model., Design: Prospective pharmacokinetic study of midazolam bolus and escalation of continuous midazolam infusion., Setting: Pediatric Intensive Care Unit in quaternary-care academic hospital., Subjects: Children between two months to seventeen years of age who received clinically-indicated midazolam infusion for treatment of RSE., Intervention: Blood sampled at regular intervals during treatment. Main study outcome measure was the accuracy of a pharmacokinetic model to predict serum midazolam concentrations., Measurements and Main Results: We analysed data from six subjects. Three subjects had serum midazolam concentrations close to those predicted by our initial model (accuracy 88.9-170.2 %) which incorporates body weight, hepatic function, and renal function. For the other three subjects, all of whom were receiving pre-existing chronic benzodiazepine therapy prior to the RSE episode, the model grossly overestimated serum concentrations (predictive error 420.3-722.5 %). Once the model was corrected for the impact of pre-existing chronic benzodiazepine use on clearance, predicted concentrations more closely reflected those measured in subjects., Conclusion: We evaluated a clinical midazolam RSE treatment pathway but discovered that the model on which the pathway was based was not accurate for all patients. We therefore developed a novel pharmacokinetic midazolam model in children with RSE treated with continuous midazolam infusion. This model incorporates body weight, hepatic and renal function, and importantly, a correction factor for pre-existing chronic benzodiazepine use. Once validated, this model may guide dosing and drive the development of more effective treatment pathways for continuous midazolam in RSE., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Vancomycin is a commonly used antibiotic, which requires therapeutic drug monitoring to ensure optimal treatment. Microsampling assays are attractive tools for pediatric clinical research and therapeutic drug monitoring. Results: A LC-MS/MS method for the quantification of vancomycin in human whole blood employing volumetric absorptive microsampling (VAMS ® ) devices (20 μl) was developed and validated. Vancomycin was stable in human whole blood VAMS under assay conditions. Stability for vancomycin was established for at least 160 days as dried microsamples at -78°C. Conclusion: This method is currently being utilized for the quantitation of vancomycin in whole blood VAMS for an ongoing pediatric clinical study and representative clinical data are reported.

Objectives: To develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens., Design: Retrospective single-center pharmacokinetic study., Setting: Cardiac ICU at Children's Hospital of Philadelphia., Patients: Consecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018., Interventions: None., Measurements and Main Results: A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3-3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0-26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4-5 mg/kg/d reached goal concentration in all neonates., Conclusions: In neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20-30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

Background: Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases., Objectives: To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies., Methods: (i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®., Results: Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin., Conclusions: All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 μL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 μg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To describe factors associated with platelet transfusion during pediatric extracorporeal membrane oxygenation and the relationships among platelet transfusion, complications, and mortality., Design: Secondary analysis of data collected prospectively by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014., Setting: Eight Collaborative Pediatric Critical Care Research Network-affiliated hospitals., Patients: Age less than 19 years old and treated with extracorporeal membrane oxygenation., Interventions: None., Measurements and Main Results: Of 511 children, 496 (97.1%) received at least one platelet transfusion during extracorporeal membrane oxygenation. Neonatal age, venoarterial extracorporeal membrane oxygenation, and various acute and chronic diagnoses were associated with increased average daily platelet transfusion volume (milliliters per kilogram body weight). On multivariable analysis, average daily platelet transfusion volume was independently associated with mortality (per 1 mL/kg; odds ratio, 1.05; CI, 1.03-1.08; p < 0.001), whereas average daily platelet count was not (per 1 × 10/L up to 115 × 10/L; odds ratio, 1.00; CI, 0.98-1.01; p = 0.49). Variables independently associated with increased daily bleeding risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day, a primary cardiac indication for extracorporeal membrane oxygenation, adolescent age, and an acute diagnosis of congenital cardiovascular disease. Variables independently associated with increased daily thrombotic risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day and venoarterial extracorporeal membrane oxygenation. Variables independently associated with decreased daily thrombotic risk included full-term neonatal age and an acute diagnosis of airway abnormality., Conclusions: Platelet transfusion was common in this multisite pediatric extracorporeal membrane oxygenation cohort. Platelet transfusion volume was associated with increased risk of mortality, bleeding, and thrombosis.

Background and Objectives: Chart reviews are frequently used for research, care assessments, and quality improvement activities despite an absence of data on reliability and validity. We aim to describe a structured chart review methodology and to establish its validity and reliability., Methods: A generalizable structured chart review methodology was designed to evaluate causes of morbidity or mortality and to identify potential therapeutic advances. The review process consisted of a 2-tiered approach with a primary review completed by a site physician and a short secondary review completed by a central physician. A total of 327 randomly selected cases of known mortality or new morbidities were reviewed. Validity was assessed by using postreview surveys with a Likert scale. Reliability was assessed by percent agreement and interrater reliability., Results: The primary reviewers agreed or strongly agreed in 94.9% of reviews that the information to form a conclusion about pathophysiological processes and therapeutic advances could be adequately found. They agreed or strongly agreed in 93.2% of the reviews that conclusions were easy to make, and confidence in the process was 94.2%. Secondary reviewers made modifications to 36.6% of cases. Duplicate reviews ( n = 41) revealed excellent percent agreement for the causes (80.5%-100%) and therapeutic advances (68.3%-100%). κ statistics were strong for the pathophysiological categories but weaker for the therapeutic categories., Conclusions: A structured chart review by knowledgeable primary reviewers, followed by a brief secondary review, can be valid and reliable., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tenofovir Disoproxil Fumarate (TDF) and tenofovir Alafenamide (TAF) are prodrugs of tenofovir and have excellent long-term efficacy and tolerability for the treatment of HIV. An objective marker of adherence to tenofovir-based therapy could be clinically useful in supporting adherence to TDF-based HIV pre-Exposure Prophylaxis (PrEP) in populations in whom, self-report has been shown to be unreliable, and could play a role in resource-limited settings to support HIV and hepatitis B treatment adherence. A semi-quantitative high-performance liquid chromatographymass spectrometry method for tenofovir quantification of urine samples was developed. This assay detects tenofovir concentration in log10 levels between 1 and 10,000 ng/mL, and was shown to distinguish between recent adherence and low/non-adherence to both TDF and TAF, with a concentration of >1000 ng/mL, highly predictive of medication ingestion in the last 24-48 hours. This assay was validated relative to other markers of adherence including dried blood spot and selfreport in a highly adherent population of PrEP patients, and tenofovir was shown to be stable at room temperature in urine for at least 14 days. The assay was successfully used in a clinical setting to maintain high PrEP adherence and retention in care of 50 young men who have sex with men (MSM) over 48 weeks, to assess PrEP adherence in youth with mental health conditions, and to monitor drug levels relative to plasma levels in a case study of chewed TDF/FTC (tenofovir/emtricitabine) for PrEP. Further studies are underway to implement the tenofovir urine assay to monitor adherence and pre-exposure prophylaxis, nationally and internationally., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Ongoing adult sepsis clinical trials are assessing therapies that target three inflammation phenotypes including 1) immunoparalysis associated, 2) thrombotic microangiopathy driven thrombocytopenia associated, and 3) sequential liver failure associated multiple organ failure. These three phenotypes have not been assessed in the pediatric multicenter setting. We tested the hypothesis that these phenotypes are associated with increased macrophage activation syndrome and mortality in pediatric sepsis., Design: Prospective severe sepsis cohort study comparing children with multiple organ failure and any of these phenotypes to children with multiple organ failure without these phenotypes and children with single organ failure., Setting: Nine PICUs in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network., Patients: Children with severe sepsis and indwelling arterial or central venous catheters., Interventions: Clinical data collection and twice weekly blood sampling until PICU day 28 or discharge., Measurements and Main Results: Of 401 severe sepsis cases enrolled, 112 (28%) developed single organ failure (0% macrophage activation syndrome 0/112; < 1% mortality 1/112), whereas 289 (72%) developed multiple organ failure (9% macrophage activation syndrome 24/289; 15% mortality 43/289). Overall mortality was higher in children with multiple organ and the phenotypes (24/101 vs 20/300; relative risk, 3.56; 95% CI, 2.06-6.17). Compared to the 188 multiple organ failure patients without these inflammation phenotypes, the 101 multiple organ failure patients with these phenotypes had both increased macrophage activation syndrome (19% vs 3%; relative risk, 7.07; 95% CI, 2.72-18.38) and mortality (24% vs 10%; relative risk, 2.35; 95% CI, 1.35-4.08)., Conclusions: These three inflammation phenotypes were associated with increased macrophage activation syndrome and mortality in pediatric sepsis-induced multiple organ failure. This study provides an impetus and essential baseline data for planning multicenter clinical trials targeting these inflammation phenotypes in children.

Background: Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing., Methods: We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml -1 ), medium (400-500 pg ml -1 ), and high (600-700 pg ml -1 ) DEX plasma concentrations., Results: Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min -1 70 kg -1 . Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml -1 ., Conclusions: When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection., Clinical Trials Registration: NCT01915277., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Medical cannabis is increasingly used for the treatment of various ailments in children and adults. Three major cannabinoids in cannabis are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). There is a growing need to develop and utilize a patient-centric blood microsampling methodology to enable clinical trials and facilitate therapeutic drug monitoring. We have employed the volumetric absorptive microsampling (VAMS™) devices that enables accurate and precise collection of a fixed volume (20 µL) of blood, minimizing the impact of hematocriton accurate quantitation. We developed an ultra-performance liquid chromatographic method with tandem mass spectrometry detection for the quantification of three cannabinoids (THC, CBD, and CBN) employing deuterium labelled internal standards (THC-D 3 , CBD-D 3 , and CBN-D 3 ). Sample extraction of VAMS™ devices, followed by solid phase extraction, reverse phase chromatographic separation, and selective detection using tandem mass spectrometry with a 6-minute runtime per sample was developed. Standard curves were linear between 1 and 500 ng/mL for THC and 0.5-500 ng/mL for CBD and CBN. Intra-day accuracies were within 91.3-112% while inter-day accuracies were within 94.4-107% with both having precisions (CV (%)) of <13% based on quality control samples in a three day validation study for all three cannabinoids. Analytes were stable in human whole blood under assay conditions (60 h at room temperature and 24 h in autosampler post-extraction). Dried microsamples were stable for one week at 40 °C, two weeks (15 days) under different storage conditions (room temperature, 4, -20 and -78 °C), one month (29 days) at -20 and -78 °C and three months (68 days) at -78 °C. This assay provides an efficient quantitation of THC, CBD, and CBN in VAMS™ devices and is currently being implemented for pediatric clinical trials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To identify medications administered to pediatric patients on extracorporeal membrane oxygenation and to review the available pharmacokinetics and pharmacodynamics literature for the most commonly administered medications., Design: Retrospective single-center study., Setting: ICUs at Children's Hospital of Philadelphia., Patients: Pediatric patients supported by extracorporeal membrane oxygenation between October 1, 2014, and September 30, 2018., Interventions: None., Measurements and Main Results: Drug exposure was described according to age group (< 1 mo, 1 mo to < 2 yr, 2 to < 12 yr, and > 12 yr) and ICU (cardiac, neonatal, pediatric). The association of drug exposure with patient's characteristics was examined using one-way analysis of variance for categorical variables and linear regression for continuous variables. All pharmacokinetics and pharmacodynamics literature for the 50 most commonly administered medications on extracorporeal membrane oxygenation was reviewed, with inclusion of studies that reported dosing regimens in conjunction with pharmacokinetics or pharmacodynamics data. A total of 179 different medications were administered to 254 children. Cumulative drug exposure increased with the duration of extracorporeal membrane oxygenation from a median (interquartile) of 10 drugs (6-14) at 1 week to 31 drugs (21-45) at 5 weeks following cannulation. There were significant differences in total drug exposure between age groups and ICUs. With exclusion of in vitro studies, published literature was available to support the use of 40% (20/50) of the most commonly administered medications. Dosing guidance was available for 20% (10/50) of medications and was primarily based on simulations and retrospective studies focusing on neonates and infants., Conclusions: This study highlights specific needs for future pharmacokinetics and pharmacodynamics studies. Dosing guidelines are essential to optimize the care of critically ill children supported by extracorporeal membrane oxygenation., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the pharmacokinetics profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure-response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage., Objective: This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention., Study Design: This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours post dose. Primary outcome was concentration/time profile of serum progesterone., Results: Median (range) maternal age was 27 (21.5-33.3) years, median body mass index was 26.5 (23.3-29.0) kg/m 2 , and median gestational age was 22.9 (21.0-23.4) weeks. Median baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to 239., Conclusion: Unlike in nonpregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels, with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0-20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge., Methods: This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. "Immediate hypertension" was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge., Results: Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16-7.69)., Conclusions: In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats ( n  = 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve [AUC], 0.662; P  < 0.001) and clusterin (AUC, 0.706; P  < 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage., (Copyright © 2019 American Society for Microbiology.)

Dexmedetomidine (Dex), a highly selective α 2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C 18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery., (© 2019 John Wiley & Sons, Ltd.)

Objective: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure., Design: Prospective pharmacokinetic-pharmacogenomic observational study., Setting: Thirteen PICUs across the United States., Patients: Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions., Interventions: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation., Measurements and Main Results: Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified., Conclusions: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.

Objectives: To develop a prognostic model for predicting mortality at time of extracorporeal membrane oxygenation initiation for children which is important for determining center-specific risk-adjusted outcomes., Design: Multivariable logistic regression using a large national cohort of pediatric extracorporeal membrane oxygenation patients., Setting: The ICUs of the eight tertiary care children's hospitals of the Collaborative Pediatric Critical Care Research Network., Patients: Five-hundred fourteen children (< 19 yr old), enrolled with an initial extracorporeal membrane oxygenation run for any indication between January 2012 and September 2014., Interventions: None., Measurements and Main Results: A total of 514 first extracorporeal membrane oxygenation runs were analyzed with an overall mortality of 45% (n = 232). Weighted logistic regression was used for model selection and internal validation was performed using cross validation. The variables included in the Pediatric Extracorporeal Membrane Oxygenation Prediction model were age (pre-term neonate, full-term neonate, infant, child, and adolescent), indication for extracorporeal membrane oxygenation (extracorporeal cardiopulmonary resuscitation, cardiac, or respiratory), meconium aspiration, congenital diaphragmatic hernia, documented blood stream infection, arterial blood pH, partial thromboplastin time, and international normalized ratio. The highest risk of mortality was associated with the presence of a documented blood stream infection (odds ratio, 5.26; CI, 1.90-14.57) followed by extracorporeal cardiopulmonary resuscitation (odds ratio, 4.36; CI, 2.23-8.51). The C-statistic was 0.75 (95% CI, 0.70-0.80)., Conclusions: The Pediatric Extracorporeal Membrane Oxygenation Prediction model represents a model for predicting in-hospital mortality among children receiving extracorporeal membrane oxygenation support for any indication. Consequently, it holds promise as the first comprehensive pediatric extracorporeal membrane oxygenation risk stratification model which is important for benchmarking extracorporeal membrane oxygenation outcomes across many centers.

Background: Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury., Objective: We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest., Methods: This was a retrospective cohort study of children aged 30 days-17 years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24 h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2-3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR)., Results: Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7 mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29 mL/min/1.73 m 2 [interquartile range (IQR) 23-47] vs. 52 [IQR 50-57]; p = 0.03) but well below normal in both., Conclusions: In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population.

BACKGROUND AND OBJECTIVE: Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people., Methods: We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care., Results: Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants., Conclusion: Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.

Voriconazole is a broad-spectrum antifungal triazole drug for the treatment of invasive fungal infections. It is extensively metabolized by hepatic drug metabolizing enzymes cytochrome (CYP) 2C19 and CYP3A4. Selective inhibition of intestinal CYP3A4 by grapefruit juice may increase the oral bioavailability of voriconazole in children. To test this hypothesis it is necessary to develop a sensitive assay for measuring voriconazole and its major metabolites in a small volume of blood. Mitra® devices from Neoteryx were employed to develop and validate the assay for the quantitation of voriconazole and voriconazole N-oxide. Mitra® devices utilize volumetric absorptive microsampling (VAMS™) technology that enables accurate and precise collection of a fixed volume (10 μL of blood), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed an ultra-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of voriconazole and voriconazole N-oxide. Sample extraction of Mitra® devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4.00 minute runtime per sample was employed. Standard curves were linear between 10.0 to 10,000 ng/mL for both voriconazole and voriconazole N-oxide. Intra- and inter-day accuracy were within 87-102% and precision (CV) was <12% based on a 3-day validation study. Recoveries were ≥94 % for voriconazole and ≥87 % for voriconazole N-oxide. Voriconazole and voriconazole N-oxide were stable in human whole blood under assay conditions (19 h at room temperature and 24 h in autosampler). Voriconazole was stable for 1-month in dried microsamples under different conditions (4, -20 and -78 °C). This assay provides an efficient quantitation of voriconazole and voriconazole N-oxide and is ready to be implemented for the analysis of whole blood microsamples in a pediatric clinical trial investigating the impact of intestinal inhibition of CYP3A4 on voriconazole pharmacokinetics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling., Design: Multicenter, prospective observational study., Setting: The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network., Patients: Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled., Interventions: None., Measurements and Main Results: A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator., Conclusions: Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT&#95;minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.

Objectives: Opioid pharmacotherapy is the cornerstone of postoperative analgesia. Despite its effectiveness, it has a variety of potential adverse effects. Therefore, a multimodal approach with non-opioid analgesics would be optimal. The aim of this study was to determine if intravenous (IV) acetaminophen would reduce opioid requirements and improve clinical outcomes in children after surgery., Methods: A single-center, randomized, double-blind study was conducted in 57 children (10-18 years old) undergoing posterior spine fusion surgery between July 2011 to May 2014. All subjects received either acetaminophen or placebo at the end of surgery, followed by repeated doses every 6 hours for a total of 8 doses., Results: In the first 24 postoperative hours, the average opioid consumption was lower for the active group compared with the placebo group (p = 0.02). The total unadjusted time to patient controlled analgesia (PCA) discontinuation was also longer in the placebo group than the active group (90 hours vs. 73 hours, p = 0.02); however, this was not statistically significant after normalizing for body weight. Additionally, time to first solid intake was longer without the use of acetaminophen (69 hours vs. 49 hours, p = 0.01)., Conclusions: Postoperative use of IV acetaminophen was associated with earlier time to diet advancement and discontinuation of IV analgesics and may result in lower opioid consumption., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all data and take responsibility for the integrity and accuracy of the data analysis.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Background: Clinicians recognise that some critically ill children are difficult-to-sedate. It may be possible to identify this clinical phenotype for sedation response using statistical modelling techniques adopted from machine learning. This requires identification of a finite number of variables to include in the statistical model., Objective: To establish face and content validity for 17 candidate variables identified in the international literature as characteristic of the difficult-to-sedate child phenotype., Methods: Paediatric critical care clinicians rated the relevance of 17 variables characterising the difficult-to-sedate child using a four-point scale ranging from not (1) to highly relevant (4). Face and content validity of these variables were assessed by calculating a mean score for each item and computing an item-level content validity index. Items with a mean score >1 were rated as having adequate face validity. An item-level content validity index ≥0.70 indicated good to excellent content validity., Setting and Participants: Web-based survey emailed to members of the Pediatric Acute Lung Injury and Sepsis Investigators Network or the Society of Critical Care Medicine Pediatric Sedation Study Group., Results: Of 411 possible respondents, 121 useable surveys were returned for a response rate of 29%. All items had a mean score >1, indicating adequate face validity. Ten of 17 items scored an item-level content validity index ≥0.70. The highest scoring items were requiring three or more sedation classes simultaneously, daily modal sedation score indicating agitation, sedation score indicating agitation for 2 consecutive hours, receiving sedatives at a dose >90th percentile of the usual starting dose, and receiving intermittent paralytic doses for sedation., Conclusions: Computation of an item-level content validity index validated variables to include in statistical modelling of the difficult-to-sedate phenotype. The results indicate consensus among paediatric critical care clinicians that the majority of candidate variables identified through literature review are characteristic of the difficult-to-sedate child., (Copyright © 2018 Australian College of Critical Care Nurses Ltd. All rights reserved.)

A study was implemented to describe the pharmacokinetics (PK) of ketamine (K) and its metabolite norketamine (NK) in critically ill adults. Conducting studies in these subjects is hindered by the immediate need to process and freeze samples obtained in a busy intensive care setting. The ability to store unprocessed samples at room temperature for an extended time period would overcome this barrier. Stability and blood to plasma partitioning of K and NK were investigated in whole blood for up to 120 h at room temperature and 4°C. Whole blood was spiked with K and NK (1000 ng/mL each). Blood samples were aliquoted at different time points (0-120 h), extracted and analyzed using a validated high-performance liquid chromatography tandem mass spectrometry assay. The study demonstrated the stability of both K and NK in whole blood up to 120 h. These in vitro studies suggest that the concentrations of K and NK measured in the PK samples are reliable. The established stability results were successfully employed to investigate K and NK pharmacology studies in critically ill adults., (Copyright © 2017 John Wiley & Sons, Ltd.)

Pharmacokinetic, pharmacodynamic and pharmacogenomic studies of midazolam are currently being performed in critically ill children to find suitable dose regimens. Sensitive assays using small volumes of plasma are necessary to determine the concentrations of midazolam and its respective metabolites in pediatric studies. Midazolam is metabolized to hydroxylated midazolam isomers, which are present as free as well as the corresponding glucuronide conjugates. A high-performance liquid chromatographic method with tandem mass spectrometry has been developed and validated for the quantification of midazolam, and free and total 1-hydroxymidazolam and 4-hydroxymidazolam metabolites in small volumes of plasma. Cleanup consisted of 96-well μ-elution solid phase extraction (SPE). The analytes were separated by gradient elution using a C 18 analytical column with a total run time of 5min. Multiple reaction monitoring was employed using precursor to product ion transitions of m/z 326.2→291.3 for midazolam, m/z 342.1→203.0 for 1-hydroxymidazolam, m/z 342.1→325.1 for 4-hydroxymidazolam and m/z 330.2→295.3 for 2 H 4 -midazolam (internal standard). Since authentic hydroxymidazolamglucuronide standards are not available, samples were hydrolyzed with β-glucuronidase under optimized conditions. Assay conditions were modified and optimized to provide appropriate recovery and stability because 4-hydroxymidazolam was very acid sensitive. Standard curves were linear from 0.5 to 1000ng/mL for all three analytes. Intra- and inter day accuracy and precision for quality control samples (2, 20, 200 and 800ng/mL) were within 85-115% and 15% (coefficient of variation), respectively. Stability in plasma and extracts were sufficient under assay conditions. Plasma samples were processed and analyzed for midazolam, and free 1-hydroxymidazolam and 4-hydroxymidazolam metabolites. Plasma samples that were hydrolyzed with β-glucuronidase were processed and analyzed for midazolam, and total 1-hydroxymidazolam and 4-hydroxymidazolam metabolites under the same assay conditions. The difference in concentration between the total and free hydroxymidazolam metabolites provided an estimate of conjugated hydroxymidazolam metabolites. The combination of 96-well μ-elution SPE and LC-MS/MS allows reliable quantification of midazolam and its metabolites in small volumes of plasma for pediatric patients. This assay is currently being successfully utilized for analysis of samples from ongoing clinical trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sedation is a mainstay of therapy for critically ill children. Although necessary in the care of the critically ill child, sedative drugs are associated with adverse effects, such as disruption of circadian rhythm, altered sleep, delirium, potential neurotoxicity, and immunosuppression. Optimal approaches to the sedation of the critically ill child should include identification of sedation targets and sedation interruptions, allowing for a more individualized approach to sedation. Further research is needed to better understand the relationship between critical illness and sedation pharmacokinetics and pharmacodynamics, the impact of sedation on immune function, and the genetic implications on drug disposition and response., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes., Design: Observational cohort study of HIV-infected adults initiating efavirenz-based regimens in Botswana., Methods: The primary endpoint was a composite of death or loss to care or HIV RNA more than 25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured by using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint., Results: A total of 801 individuals included 406 (51%) men, median age 37 years, median baseline CD4 cell count 195 cells/μl, and plasma HIV RNA 4.9 log10 copies/ml. 288 (36%) reached the endpoint, including 34 (4%) deaths, 151 (19%) lost to care, 11 (1%) lost to the study, but alive and in care, and 92 (11%) with plasma HIV RNA more than 25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences., Conclusion: Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate central nervous system toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.

Background: CYP2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYP2B6 516G>T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana., Setting: We performed a case-control study that included 1338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between July 2013 and April 2014., Methods: Cases experienced late HIV failure, defined as plasma HIV RNA >1000 copies/mL after maintaining viral suppression (<400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA <400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G>T genotype., Results: After adjustment for the confounding variables age and CD4 count, the CYP2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95% CI: 0.50 to 0.97., Conclusion: The CYP2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYP2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.

Objectives: Limited data exist on the effects of therapeutic hypothermia on renal function and pharmacokinetics in pediatric patients after cardiac arrest. The objective was to describe the differences in vancomycin disposition in pediatric patients following cardiac arrest treated with either therapeutic hypothermia or normothermia using population pharmacokinetic modeling., Design: Single-center, retrospective cohort study., Setting: A tertiary care hospital pediatric and cardiac ICU., Patients: Fifty-two pediatric patients (30 d to 17 yr old) who experienced a cardiac arrest, received vancomycin, and were treated with therapeutic hypothermia (32-34°C) or normothermia (36.3-37.6°C) between January 1, 2010, and September 30, 2014, were reviewed., Interventions: None., Measurements and Main Results: A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data despite high variability due to the small sample size. The typical value of clearance in this study was 4.48 L/hr (0.19 L/hr/kg) for a normothermic patient weighing 70 kg and a glomerular filtration rate of 90 mL/min/1.73 m. Patients treated with normothermia but with reduced or poor renal function (≤ 90 mL/min/1.73 m) had up to an 80% reduction in vancomycin clearance compared to those with normal renal function (90-140 mL/min/1.73 m). Patients with normal renal function but treated with therapeutic hypothermia versus normothermia experienced up to 25% reduction in vancomycin clearance. Patients treated with therapeutic hypothermia and with poor renal function experienced up to an 84% reduction in vancomycin clearance., Conclusions: Patients receiving hypothermia and/or with decreased renal function had lower vancomycin clearances based on a retrospectively fitted two-compartment model in children who experience cardiac arrest.

Objective  To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design  Randomized, open label pilot study. Setting  Multicenter; level 3 and level 4 neonatal intensive care units. Patients  Six infants ≥34 weeks' gestational age and < 10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention  Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results  The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion  The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure., Competing Interests: Off-Label Disclosure: In this study, milrinone was used off-label for PPHN under IND #108332., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Neuroblastoma is a pediatric malignancy, and most tumor cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. Meta-iodobenzylguanidine (MIBG) is a NET-specific ligand used as a highly specific imaging agent and targeted radiotherapeutic. Patients with neuroblastoma frequently require sedation during targeted radiotherapy. Dexmedetomidine has been increasingly used to achieve efficacious sedation. There are theoretical concerns that this highly selective alpha-2 adrenergic receptor agonist may interfere with active uptake of MIBG through the NET transporter. In this study, we analyzed the impact of [125-iodine]-labeled MIBG ([ 125 I]MIBG) uptake in the presence of dexmedetomidine in human neuroblastoma-derived cellular models., Procedure: Carrier-free [ 125 I]MIBG was synthesized using UltraTrace® resin (Molecular Insight Pharmaceuticals, Inc., Tarrytown, NY) through radioiododestannylation from a tin precursor bound by a solid-state polymer. NET (SLC6A2) protein expression was determined in human neuroblastoma cell lines (BE2C, SKNSH and IMR5). [ 125 I]MIBG internalization studies were performed using [ 125 I]MIBG alone or in combination with either desipramine or dexmedetomidine. Dexmedetomidine and desipramine competitive inhibition studies were performed and concentration at 50% maximal inhibition was calculated. Finally, NET inhibitor dissociation studies were performed in which after pre-incubation with either desipramine or dexmedetomidine, cells were washed and [ 125 I]MIBG was added., Results: We show dose-dependent inhibition of [ 125 I]MIBG uptake by dexmedetomidine, but at several logs lower potency than the known NET inhibitor desipramine. A review of pediatric dexmedetomidine pharmacokinetic data shows that the concentrations achieved in the serum are much lower than those required to block MIBG uptake., Conclusion: We conclude that dexmedetomidine will not interfere with therapeutic [ 131 I]MIBG efficacy., (© 2016 Wiley Periodicals, Inc.)

Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF; Truvada ® ) given as pre-exposure prophylaxis (PrEP) successfully blocks HIV when taken once daily prior to potential HIV exposure. A 22-year-old male reported difficulty swallowing FTC/TDF for PrEP and subsequently began chewing the FTC/TDF tablets. Monthly urine samples assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated tenofovir levels >1,000 ng/ml, indicative of protection from HIV acquisition, over a 48-week period. Data from observational studies of HIV-positive patients details the successful treatment of HIV using crushed FTC/TDF delivered via feeding and gastronomy tubes while small, randomized trials of healthy volunteers demonstrate bioequivalence between whole and crushed FTC/TDF.

Introduction: Pediatric critical illness and associated alterations in organ function can change drug pharmacokinetics (PK). Extracorporeal membrane oxygenation (ECMO), a life-saving therapy for severe cardiac and/or respiratory failure, causes additional PK alterations that affect drug disposition., Areas Covered: The purposes of this review are to discuss the PK changes that occur during ECMO, the associated therapeutic implications, and to review PK literature relevant to pediatric ECMO. We discuss various classes of drugs commonly used for pediatric patients on ECMO, including sedatives, analgesics, antimicrobials and cardiovascular drugs. Finally, we discuss future areas of research and recommend strategies for future pediatric ECMO pharmacologic investigations., Expert Opinion: Clinicians caring for pediatric patients treated with ECMO must have an understanding of PK alterations that could lead to either therapeutic failures or increased drug toxicity during this life-saving therapy. Limited data currently exist for optimal drug dosing in pediatric populations who are treated with ECMO. While there are clear challenges to conducting and analyzing data associated with clinical pharmacokinetic-pharmacodynamic studies of children on ECMO, we present techniques to address these challenges. Improved understanding of the physiology and drug disposition during ECMO combined with PK-PD modeling will allow for more adaptable and individualized dosing schemes.

Background: Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery., Methods: This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated., Results: Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) µg ml(-1) within 30-60 min after the first cefazolin 30 mg kg(-1) dose. For patients who received a second 30 mg kg(-1) dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) µg ml(-1) within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively., Conclusions: For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug-drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs., Design: Retrospective cohort study using the Pediatric Health Information System database., Setting: Forty-two freestanding children's hospitals throughout the United States., Patients: A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included., Measurements and Main Results: PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p < 0.001), presence of complex chronic conditions (p < 0.001), increasing number of total distinct drugs used (p < 0.001), increasing length of stay in PICU (p < 0.001), and white race (p < 0.001)., Conclusions: Many PICU patients are exposed to substantial polypharmacy and potential drug-drug interactions. Future research should identify the risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug-drug interaction exposures., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery., Methods: Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics., Results: Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70) mL/min, intercompartmental clearance of 6780 × (weight/70) mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt., Conclusions: Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were well tolerated after open heart surgery.

Objectives: To determine the incidence of cardiopulmonary resuscitation in PICUs and subsequent outcomes., Design, Setting, and Patients: Multicenter prospective observational study of children younger than 18 years old randomly selected and intensively followed from PICU admission to hospital discharge in the Collaborative Pediatric Critical Care Research Network December 2011 to April 2013., Results: Among 10,078 children enrolled, 139 (1.4%) received cardiopulmonary resuscitation for more than or equal to 1 minute and/or defibrillation. Of these children, 78% attained return of circulation, 45% survived to hospital discharge, and 89% of survivors had favorable neurologic outcomes. The relative incidence of cardiopulmonary resuscitation events was higher for cardiac patients compared with non-cardiac patients (3.4% vs 0.8%, p <0.001), but survival rate to hospital discharge with favorable neurologic outcome was not statistically different (41% vs 39%, respectively). Shorter duration of cardiopulmonary resuscitation was associated with higher survival rates: 66% (29/44) survived to hospital discharge after 1-3 minutes of cardiopulmonary resuscitation versus 28% (9/32) after more than 30 minutes (p < 0.001). Among survivors, 90% (26/29) had a favorable neurologic outcome after 1-3 minutes versus 89% (8/9) after more than 30 minutes of cardiopulmonary resuscitation., Conclusions: These data establish that contemporary PICU cardiopulmonary resuscitation, including long durations of cardiopulmonary resuscitation, results in high rates of survival-to-hospital discharge (45%) and favorable neurologic outcomes among survivors (89%). Rates of survival with favorable neurologic outcomes were similar among cardiac and noncardiac patients. The rigorous prospective, observational study design avoided the limitations of missing data and potential selection biases inherent in registry and administrative data.

Background: Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts., Aim: The purposes of this study were to determine the plasma and tissue concentrations with standard of care, perioperative cefazolin dosing in an immature porcine model of pediatric cardiac surgery, and to determine the feasibility of this model., Methods: Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB + DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of the skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, noncompartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed., Results: Following the first intravenous dose, maximal cefazolin concentrations in the subcutaneous tissue and skeletal muscle were similar between groups with peak tissue concentrations 15-30 min after administration. After the second cefazolin dose given with the initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle- and subcutaneous-unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed subcutaneous and skeletal muscle concentrations of cefazolin >16 μg·ml(-1) while this percentage was 78-79% for the CPB + DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP + DHCA (P = 0.03)., Conclusions: The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of the cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations., (© 2015 John Wiley & Sons Ltd.)

Objective: The inclusion of dexmedetomidine in the operative and postoperative management of infants with congenital heart defects has lessened the need for opioids that may cause respiratory depression. Our objective was to show that a dexmedetomidine bolus at or about the time of sternal closure is associated with a decrease in the use of mechanical ventilation in the immediate postoperative period., Design: Retrospective cohort study., Setting: Single pediatric tertiary cardiac center., Patients: Infants undergoing surgical intervention for congenital heart defects requiring cardiopulmonary bypass, age 30-365 days in a 5-year time period from June 1, 2008, to December 31, 2012., Interventions: None., Measurements and Main Results: Of 1,057 total encounters, 441 met inclusion criteria and were evenly distributed over the 5-year time period. Dexmedetomidine had been given at or about the time of sternal closure in 57% of patients. When the exposed and unexposed groups were compared in terms of mechanical ventilation immediately postoperative, there was a statistically significant effect of using dexmedetomidine on the odds of receiving mechanical ventilation (p = 0.0019). This difference remained significant after adjusting for covariates affecting the decision for mechanical ventilation, including year of the procedure, age and weight of subject, cardiopulmonary bypass time, the use of deep hypothermic circulatory arrest, intraoperative fentanyl dose, and the Risk Adjustment for Congenital Heart Surgery Score 1 (p = 0.0317). The odds of receiving mechanical ventilation are estimated to be two times higher for patients who did not receive dexmedetomidine than for patients who received dexmedetomidine after adjusting for variables., Conclusion: The use of dexmedetomidine bolus in the operating room at the time of sternal closure in infants undergoing open heart surgery is associated with reduced need for mechanical ventilation in the immediate postoperative period.

Background: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations., Methods: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics., Results: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics., Conclusions: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted., Clinical Trial Registration: NCT01408823., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Special populations, including women (non-pregnant and pregnant), pediatrics, and the elderly, require additional consideration with regard to clinical research. There are very specific regulatory laws, which protect these special populations, that need to be understood and adhered to in order to perform clinical research. This review provides a broad overview of some of the physiological differences in special populations and discusses how these differences may affect study design and regulatory considerations. These various special populations, with respect to regulatory affairs, are clearly defined within the Code of Federal Regulations. The definition of "special population" exists to provide enhanced awareness of their vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury or outright harm. Currently, progress is being made to be more inclusive of special populations in clinical trials. This reflects changing attitudes towards drug information, with it being more representative of those patients that will ultimately be prescribed or exposed to the therapy. However, all research undertaken in these populations should be performed in a manner that ensures all protections of each participant are upheld.

Objective: To describe the pharmacokinetics and tissue disposition of prophylactic cefazolin into skeletal muscle in a pediatric population undergoing cardiac surgery., Methods: The subjects included 12 children, with a median age of 146 days (interquartile range, 136-174) and median weight of 5.5 kg (interquartile range, 5.2-7.3) undergoing cardiac surgery and requiring cardiopulmonary bypass with or without deep hypothermic circulatory arrest. Institutional cefazolin at standard doses of 25 mg/kg before incision and 25 mg/kg in the bypass prime solution were administered. Serial plasma and skeletal muscle microdialysis samples were obtained intraoperatively and the unbound cefazolin concentrations measured. Noncompartmental pharmacokinetic analyses were performed and the tissue disposition evaluated., Results: After the first dose of cefazolin, the skeletal muscle concentrations peaked at a median microdialysis collection interval of 30 to 38.5 minutes. After the second dose, the peak concentrations were delayed a median of 94 minutes in subjects undergoing deep hypothermic circulatory arrest. Skeletal muscle exposure to cefazolin measured by the area under concentration time curve 0-last measurement was less in the subjects who underwent deep hypothermic circulatory arrest than in those who received cardiopulmonary bypass alone (P = .04). The skeletal muscle concentrations of cefazolin exceeded the goal concentrations for methicillin-sensitive Staphylococcus aureus prophylaxis; however, the goal concentrations for gram-negative pathogens associated with surgical site infections were achieved only 42.1% to 84.2% and 0% to 11.2% of the intraoperative time in subjects undergoing cardiopulmonary bypass alone or deep hypothermic circulatory arrest, respectively., Conclusions: This cefazolin dosing strategy resulted in skeletal muscle concentrations that are likely not effective for surgical prophylaxis against gram-negative pathogens but are effective against methicillin-sensitive S aureus in infants undergoing cardiac surgery., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)