Considerations for Intravenous Anesthesia Dose in Obese Children: Understanding PKPD.

The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body mass. Fat-free mass, lean body mass and ideal body mass are not drug specific and fail to recognize the variable impact of fat mass contributing to body composition in children, both lean and obese. Normal fat mass, used in conjunction with allometry, may prove a useful size metric but computation by clinicians for the individual child is not facile. Dosing is further complicated by the need for multicompartment models to describe intravenous drug pharmacokinetics and the concentration effect relationship, both beneficial and adverse, is often poorly understood. Obesity is also associated with other morbidity that may also influence pharmacokinetics. Dose is best determined using pharmacokinetic-pharmacodynamic (PKPD) models that account for these varied factors. These models, along with covariates (age, weight, body composition), can be incorporated into programmable target-controlled infusion pumps. The use of target-controlled infusion pumps, assuming practitioners have a sound understanding of the PKPD within programs, provide the best available guide to intravenous dose in obese children.

Acetaminophen pharmacokinetics in infants and children with congenital heart disease.

BACKGROUND: Acetaminophen is routinely used for perioperative analgesia in children undergoing major surgical procedures. There are few estimates of acetaminophen pharmacokinetic parameters in children with congenital heart disease, especially those with cyanotic heart disease. AIMS: The current study prospectively investigated differences in acetaminophen pharmacokinetics following surgery using cardiopulmonary bypass in children with cyanotic and acyanotic congenital heart disease. METHODS: Children (2-6 years, 9-23 kg) presenting for median sternotomy for Fontan palliation (cyanotic patients) or two ventricle surgical repair (acyanotic patients) were eligible for inclusion. A single intravenous dose of acetaminophen (15 mg/kg) was administered at the start of sternal closure after separation from cardiopulmonary bypass. The time-course of acetaminophen concentrations were described using non-linear mixed effects models. One and two-compartment disposition models with first-order elimination were tested. Pharmacokinetic parameter estimates were scaled using allometry and standardized to a 70 kg person. RESULTS: There were 208 acetaminophen concentrations assayed from 30 children, 15 with cyanotic, and 15 with acyanotic heart disease. A 2-compartment model best described acetaminophen PK. Parameter estimates (population parameter variability, PPV%; 95% confidence interval, CI) were clearance CL 15.3 L.h-1.70 kg-1 (22.2%; 13.8-16.7), intercompartment clearance Q 45.4 L.h-1.70 kg-1 (22.4%; 25.2-61.9), central volume of distribution V1 33.5 L.70 kg-1 (23.2%; 25.9-38.8), peripheral volume of distribution V2 32.1 L.70 kg-1 (21.7%; 25.9-38.8). Neither clearance nor volume parameters differed between cyanotic and acyanotic patients. CONCLUSIONS: Acetaminophen pharmacokinetics were characterized using a 2-compartment model with first-order elimination following cardiac bypass surgery in children. Population pharmacokinetic parameter estimates were similar to other studies in children. No differences were detected between patients with cyanotic and acyanotic heart disease.

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice.

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

Population Pharmacokinetic Modelling of Acetaminophen and Ibuprofen: the Influence of Body Composition, Formulation and Feeding in Healthy Adult Volunteers.

BACKGROUND AND OBJECTIVE: Combined acetaminophen and ibuprofen are common antipyretic and analgesic drugs. Formulation and feeding affect drug absorption. Drug clearance has a nonlinear relationship with total body weight. The covariate effect of fat mass on acetaminophen and ibuprofen pharmacokinetics remains unexplored. This study sought to quantify acetaminophen and ibuprofen pharmacokinetics with intravenous, tablet, sachet and oral suspension formulations in fed and fasted states. METHODS: Pooled time-concentration data for acetaminophen and ibuprofen were available from fasting and fed healthy adults. Data from intravenous, tablet, sachet and suspension formulations were analysed using nonlinear mixed-effects models. Body composition was considered as a covariate on clearances and volumes of distribution (Vd). Size metrics investigated were total body weight, fat and fat-free mass. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A factor on absorption half-life and lag time quantified delays due to feeding for oral formulations. Pharmacokinetic-pharmacodynamic simulations were used to explore the time courses of pain response for acetaminophen and ibuprofen for each formulation. RESULTS: Pooled data included 116 individuals (18-49 years, 49-116 kg) with 6095 acetaminophen and 6046 ibuprofen concentrations available for analysis. A two-compartment pharmacokinetic model with first-order elimination described disposition for both drugs. Normal fat mass was the best covariate to describe acetaminophen clearance (CL), with a factor for fat contribution (FFATCL) of 0.816. Acetaminophen volume of distribution was described using total body weight. Normal fat mass was the best covariate to describe ibuprofen clearance (FFATCL = 0.863) and volume of distribution: (FFATV = 0.718). Clearance and central volume of distribution were 24.0 L/h/70 kg and 43.5 L/h/70 kg for acetaminophen. Ibuprofen clearance and central volume of distribution were 3.79 L/h/70 kg and 10.5 L/h/70 kg. Bioavailability and absorption half-life were 86% and 12 min for acetaminophen and 94% and 27 min for ibuprofen. Absorption lag times were 5.3 min and 6.7 min for acetaminophen and ibuprofen, respectively. Feeding increased both absorption half-life and absorption lag time when compared to the tablet formulation under fasting conditions. Feeding had the most pronounced effect on the lag time associated with tablet formulation for both drugs. Time to a pain score reduction of 2 points (visual analogue score, 0-10) differed by only 5-10 min across all formulations for acetaminophen and ibuprofen. CONCLUSION: Fat mass was an important covariate to describe acetaminophen and ibuprofen pharmacokinetics. The absorption half-lives of acetaminophen and ibuprofen were increased in fed states. The delay in absorption, quantified by a lag time, was protracted for both drugs.

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review.

BACKGROUND: Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. AIM: To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. DESIGN: A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. REVIEW SOURCES: PubMed (1960-2020); EMBASE (1980-2020); IPA (1973-2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. RESULTS: The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4-88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. CONCLUSIONS: We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4-13 years.

Pharmacokinetic modeling and simulation to understand diamorphine dose-response in neonates, children, and adolescents.

Pharmacokinetic-pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure-response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children. Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure-response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6-monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time-concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg-1 was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 µg.L-1 can be achieved by a diamorphine intravenous infusion in neonates 14 µg.kg-1 .h-1 , in a 5-year-old child 42 µg.kg-1 .h-1 and in an 15 year-old-adolescent 33 µg.kg-1 .h-1 .

Propofol context-sensitive decrement times in children.

Plasma drug concentration is the variable linking dose to effect. The decrement time required for plasma concentration of anesthetic agents to decrease by 50% (context-sensitive half-time) correlates with the time taken to regain consciousness. However, the decrement time to consciousness may not be 50%. An effect compartment concentration is associated more closely with return of consciousness than plasma concentration. An alternative decrement time, the time required for propofol to decrease to a predetermined effect compartment concentration associated with movement (eg, 2 µg.ml-1 ), was used to simulate time for the concentration to decrease from steady state at a typical targeted effect compartment concentration 3.5 µg.ml-1 in children. These times were short and reflected a decrement time to consciousness (CSTAWAKE ) increase that was small with longer infusion time. CSTAWAKE ranged from 7.5 min in 1-year-old infant given propofol for 15 min to 13.5 min in a 15-year-old adolescent given a 2-hour infusion. Changes in decrement time with age reflect maturation of drug clearance. Neonates had prolonged increment times, 10 min after 15 min infusion and 18 min after 120 min infusion using a target concentration of 3.5 µg.ml-1 . Decrement times to a targeted arousal concentration are context-sensitive. Use of a higher target concentration of 6 µg.ml-1 doubled decrement times. Decrement times are associated with variability: delayed recovery beyond these simulated times is likely more attributable to the use of adjuvant drugs or the child's clinical status. An understanding of propofol decrement times can be used to guide recovery after anesthesia.

Population pharmacokinetics of oxycodone: Premature neonates to adults.

BACKGROUND: Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified. METHODS: Pooled oxycodone time-concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed-effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A maturation function described the increase in clearance in neonates and infants. RESULTS: There were 237 subjects (24 weeks postmenstrual age to 75 years; 0.44-110 kg) providing 1317 plasma concentrations. A three-compartment model with first-order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h-1 .70 kg-1 (CV 71%); intercompartmental clearances (Q2) 220 L.h-1 .70 kg-1 (CV 64%); Q3 1.45 L.h-1 .70 kg-1 ; volume of distribution in the central compartment (V1) 98.2 L.70 kg-1 (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70 kg-1 (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70 kg-1 . Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (TABS ) were: 1.1 minutes for intramuscular, 70 minutes for epidural, 82 minutes for nasogastric, and 159.6 minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7 minutes. CONCLUSIONS: Clearance matured with age; 8% of the typical adult value at 24 weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat-free mass.

Oxycodone target concentration dosing for acute pain in children.

BACKGROUND: Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals. METHODS: We assumed a target concentration of 35 mcg.L-1 (acceptable range ±20%) to be associated with adequate analgesia without increased risk of adverse effects from respiratory depression. Pharmacokinetic simulation was used to estimate dose in neonates through to obese adults given intravenous or parenteral oxycodone. RESULTS: There were 84% of simulated oxycodone concentrations within the acceptable range during maintenance dosing. Variability around the simulated target concentration decreased with age. The maturation of oxycodone clearance is reflected in changes to context-sensitive halftime where clearance is immature in neonates compared with older children and adults. The intravenous loading and maintenance doses for a typical 5-year-old child are 100 mcg.kg-1 and 33 mcg.kg-1 .h-1 . In a typical adult, the loading dose is 100 mcg.kg-1 and maintenance dose 23 mcg.kg-1 .h-1 . CONCLUSION: Simulation was used to suggest loading and maintenance doses to attain an oxycodone concentration of 35 mcg.L-1 predicted in adults. Although the covariates age and weight contribute 92% variability for clearance, there remains variability accounting for 16% of concentrations outside the target range. Duration of analgesic effect after ceasing infusion is anticipated to be longer in neonates where context-sensitive halftime is greater than older children and adults.

Estimation of the Loading Dose for Target-Controlled Infusion of Dexmedetomidine. Reply to Eleveld et al. Comment on "Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480".

The parameters for a three-compartment model described by Morse and colleagues [...].

Pharmacokinetic concepts for dexmedetomidine target-controlled infusion pumps in children.

Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) to describe concentration changes with time in a population and are specific to that population. Simulation using these models and their parameter estimates can enrich understanding of drug behavior and serve as a basis for study design. Pharmacokinetic concepts are presented pertaining to future designs of dexmedetomidine target-controlled infusion pumps in children. This manuscript provides the pediatric anesthesiologist with an understanding of the nuances that should be considered when using target-controlled infusion pumps; how the central volume may differ between populations, how clearance changes with age, and the impact of adverse effects on dose. In addition, the ideal loading dose and rate of delivery to achieve target concentration without adverse cardiovascular effects are reviewed, and finally, dose considerations for obese children, based on contact-sensitive half-time, are introduced. An understanding of context-sensitive half-time changes with age enables anesthetic practitioners to better estimate duration of effect after cessation of dexmedetomidine infusion. Use of these known pharmacokinetic parameters and covariate information for the pediatric patient could readily be incorporated into commercial target-controlled infusion pumps to allow effective and safe open-loop administration of dexmedetomidine in children.

A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults.

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

Bioavailability of oxycodone by mouth in coronary artery bypass surgery patients - a randomized trial.

OBJECTIVE: Pain after coronary artery by-pass (CAB) surgery is severe. Analgesic administration by mouth is unreliable until after gastrointestinal function has recovered. We evaluated the bioavailability of oxycodone co-administered with naloxone by mouth in patients after CAB surgery using either a conventional extracorporeal circulation (CECC) or off-pump surgery (OPCAB). METHODS: Twenty-four patients, 50-73 years, 12 with CECC and 12 with OPCAB, were administered a 10/5 mg oxycodone-naloxone controlled-release tablet by mouth on the preoperative day and for the first seven postoperative days (PODs) thereafter. Blood samples were collected up to 24 h after the preoperative administration, and then randomly either on POD1 and POD3 or on POD2 and POD4. The oxycodone concentration in plasma was analyzed using liquid chromatography-mass spectrometry. RESULTS: On POD1 oxycodone absorption was markedly delayed in five of six patients after CECC and in all six patients after OPCAB surgery; median of tmax after CECC 630 [range 270-1420] minutes and after OPCAB 1020 [720-1410] minutes, compared to median of 120-315 min preoperatively and on POD2-POD4. The carry-over corrected AUC0-24 values on the PODs did not differ from the preoperative values, but were higher on POD3 compared with POD1 in both CECC and OPCAB groups. The rate and extent of oxycodone absorption equaled preoperative values on POD2 and onwards in patients with CAB surgery. CONCLUSIONS: Bioavailability of oxycodone by mouth was similar after CAB surgery via CECC or having OPCAB. Data indicate that POD2 is an appropriate time to start oxycodone administration by mouth after CAB surgery.

Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects.

Introduction: The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development.Areas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment.Expert opinion: The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.

A manual propofol infusion regimen for neonates and infants.

AIMS: Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. METHODS: Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3 years. Simulated steady state concentrations were 6-8 µg.mL-1 in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3 µg.mL-1 was determined using a heuristic approach. RESULTS: A manual dosing regimen predicted to achieve steady-state plasma concentration of 3 µg.mL-1 comprised a loading dose of 2 mg.kg-1 followed by an infusion rate of 9 mg.kg-1 .h-1 for the first 15 minutes, 7 mg.kg-1 .h-1 from 15 to 30 minutes, 6 mg.kg-1 .h-1 from 30 to 60 minutes, 5 mg.kg-1 .h-1 from 1 to 2 hours in neonates (38-44 weeks postmenstrual age). Dose increased with age in those aged 1-2 years with a loading dose of 2.5 mg.kg-1 followed by an infusion rate of 13 mg.kg-1 .h-1 for the first 15 minutes, 12 mg.kg-1 .h-1 from 15 to 30 minutes, 11 mg.kg-1 .h-1 from 30 to 60 minutes, and 10 mg.kg-1 .h-1 from 1 to 2 hours. CONCLUSION: Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg-1 ) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.

Pharmacokinetic-pharmacodynamic population modelling in paediatric anaesthesia and its clinical translation.

PURPOSE OF REVIEW: Pharmacokinetic-pharmacodynamic (PKPD) population modelling has advanced adult anaesthesia. Current literature was reviewed to discern use of this analytic technique for benefit in the perioperative management of children. RECENT FINDINGS: Variability in drug response, selection of a dose that achieves a desired target concentration and optimizing sampling protocols for further studies are all facets of paediatric anaesthesia that have benefitted from modelling approaches. PKPD models have driven the maintenance dose rate in target-controlled infusion pumps used for total intravenous anaesthesia. Although many of the models used in these pumps were developed in adults, translation for paediatric use has followed, including subgroups, such as neonates and obese children. The use of drug effect measures (e.g. bispectral index) has improved the predictive performance of pharmacodynamic models. Simulation studies have facilitated an increase in safety by quantifying drug variability, and identifying where possible adverse drug events may occur. SUMMARY: Modelling and simulation continue to have an important role optimizing drug use during anaesthesia. Models incorporating influential covariates that better describe drug pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify drug role and impact. Their use developing paediatric clinical studies improves trial conduct, often with fewer subjects required for study.

Compliance with perioperative prophylaxis guidelines and the use of novel outcome measures.

Postoperative wound infections represent an important source of morbidity and mortality in children. Perioperative antibiotic prophylaxis has been shown to decrease the risk of developing infections and hospital guidelines surrounding antibiotic use exist to standardize patient care. Despite supporting evidence, rates of compliance with guidelines vary. Quality improvement initiatives have been introduced to improve compliance with intraoperative antibiotic guidelines. Thorough infection surveillance, including antibiotic provision in presurgical checklists, computerized voice antibiotic administration prompts, and national feedback systems are now increasingly common. Few studies have been conducted investigating the effectiveness of prophylactic antibiotics in children. Outcome measures such as morbidity and mortality and return to the operating room can be used to examine the relationship between antibiotic use and patient outcome but these measures are limited in that they occur infrequently or are subjective and difficult to measure. Metrics such as days alive out of hospital and length of hospital stay may be useful alternatives for ongoing monitoring of infections and identifying improvements in patient outcomes. Guidelines on antibiotic prophylaxis have facilitated an increase in the correct provision of perioperative antibiotics and a reduction in the incidence of postoperative infection. Measures of patient outcome such as days alive out of hospital and length of hospital stay are easy to collect and calculate but further work is needed to confirm the utility of these measures for monitoring infection rates.

Bulk iron pyrite as a catalyst for the selective hydrogenation of nitroarenes.

Bulk iron pyrite (FeS2) functions as an inexpensive, Earth-abundant, off-the-shelf catalyst capable of selectively hydrogenating a broad scope of substituted nitroarenes to their corresponding aniline derivatives using molecular hydrogen.

Semi-preparative asymmetrical flow field-flow fractionation: A closer look at channel dimensions and separation performance.

The design and performance of a semi-preparative asymmetrical flow field-flow fractionation (SP-AF4) channel are investigated with the objective of better understanding and exploiting the relationship between channel dimensions, sample loading, and resolution. Most size-based separations of nanometer and submicrometer particles are currently limited to analytical scale quantities (<100µg). However, there is a strong need to fractionate and collect larger quantities so that fundamental properties of the more narrowly dispersed fractions can be studied using additional characterization methods and for subsequent applications. In this work, dimensions of the spacer that defines the form of SP-AF4 channels are varied and their performances are assessed with respect to sample focusing position and loading. Separations are performed in aqueous and organic carrier fluids. A critical evaluation of channel dimensions showed that increasing the channel breadth is a practical and effective route to maintaining separation resolution while increasing sample loads to milligram quantities. Good size resolution (∼1.0) is achieved for separations of 10mg of 50 and 100nm silica nanoparticles suspended in water and up to 0.6mg of ∼10 to 35nm inorganic hybrid nanoparticles suspended in tetrahydrofuran. This work represents important advances in the understanding of SP-AF4 separations and extends sample loading capacities in both aqueous and organic solvents.