Modeling adult COX-2 cerebrospinal fluid pharmacokinetics to inform pediatric investigation.

AIM: Hysteresis is reported between plasma concentration and analgesic effect from nonsteroidal anti-inflammatory drugs. It is possible that the temporal delay between plasma and CSF nonsteroidal anti-inflammatory drugs mirrors this hysteresis. The temporal relationship between plasma and CSF concentrations of COX-inhibitors (celecoxib, rofecoxib, valdecoxib) has been described. The purpose of this secondary data analysis was to develop a compartmental model for plasma and CSF disposition of these COX-2 inhibitors. METHODS: Plasma and CSF concentration-time profiles and protein binding data in 10 adult volunteers given oral celecoxib 200 mg, valdecoxib 40 mg and rofecoxib 50 mg were available for study. Nonlinear mixed effects models with a single plasma compartment were used to link a single CSF compartment with a transfer factor and an equilibration rate constant (Keq). To enable predictive modeling in pediatrics, celecoxib pharmacokinetics were standardized using allometry. RESULTS: Movement of all three unbound plasma COX-2 drugs into CSF was characterized by a common equilibration half-time (T1/2 keq) of 0.84 h. Influx was faster than efflux and a transfer scaling factor of 2.01 was required to describe conditions at steady-state. Estimated celecoxib clearance was 49 (95% CI 34-80) L/h/70 kg and the volume of distribution was 346 (95% CI 237-468) L/70 kg. The celecoxib absorption half-time was 0.35 h with a lag time of 0.62 h. Simulations predicted a 70-kg adult given oral celecoxib 200 mg with maintenance 100 mg twice daily would have a mean steady-state total (bound and unbound) plasma concentration of 174 µg L-1 and CSF concentration of 1.1 µg L-1 . A child (e.g., 25 kg, typically 7 years) given oral celecoxib 6 mg kg-1 with maintenance of 3 mg kg-1 twice daily would have 282 and 1.7 µg L-1 mean plasma and CSF concentrations, respectively. CONCLUSIONS: Transfer of unbound COX-2 inhibitors from plasma to CSF compartment can be described with a delayed effect model using an equilibration rate constant to collapse observed hysteresis. An additional transfer factor was required to account for passage across the blood-brain barrier. Use of a target concentration strategy for dose and consequent plasma (total and unbound) and CSF concentration prediction could be used to inform pediatric clinical studies.

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.

Measurement of patient-reported outcomes after laparoscopic cholecystectomy: a systematic review.

BACKGROUND: Patient-reported outcome (PRO) measures (PROMs) are increasingly used as endpoints in surgical trials. PROs need to be consistently measured and reported to accurately evaluate surgical care. Laparoscopic cholecystectomy (LC) is a commonly performed procedure which may be evaluated by PROs. We aimed to evaluate the frequency and consistency of PRO measurement and reporting after LC. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for prospective studies reporting PROs of LC, between 2013 and 2016. Data on the measurement and reporting of PROs were extracted. RESULTS: A total of 281 studies were evaluated. Forty-five unique multi-item questionnaires were identified, most of which were used in single studies (n = 35). One hundred and ten unique rating scales were used to assess 358 PROs. The visual analogue scale was used to assess 24 different PROs, 17 of which were only reported in single studies. Details about the type of rating scale used were not given for 72 scales. Three hundred and twenty-three PROs were reported in 162 studies without details given about the scale or questionnaire used to evaluate them. CONCLUSIONS: Considerable variation was identified in the choice of PROs reported after LC, and in how they were measured. PRO measurement for LC is focused on short-term outcomes, such as post-operative pain, rather than longer-term outcomes. Consideration should be given towards the development of a core outcome set for LC which incorporates PROs.

A target concentration strategy to determine ibuprofen dosing in children.

BACKGROUND: Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood. METHODS: Published clearance estimates from different aged patients determined after administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed-effects models. A target concentration strategy was used to estimate maintenance dose at different ages. RESULTS: There were three publications reporting an estimate of individual clearance estimates in premature neonates, three reporting population clearances in infants, 11 in children 2-15 years (1 with individual and 9 with population clearances), and 13 adult studies (1 with individual and 12 with population clearances). Clearance maturation, standardized to a 70 kg person was described using the Hill equation. Mature clearance was 3.81 (CV 15.5%, 95%CI 3.72, 3.92) L/h/70 kg. The maturation half-time was 36.8 (CV 9.2%, 95%CI 34.7, 40.9) weeks postmenstrual age and the Hill coefficient 11.5 (95%CI 8.1, 15). A target effect of four units (visual analogue scale 0-10) correlated with an effect site concentration of 6.3 mg/L: a concentration achieved at trough after 400 mg 8 hourly in adults. CONCLUSION: Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. Maturation of ibuprofen clearance was rapid and was 90% of adult values by the first month of life in term neonates (ie, 44 weeks postmenstrual age) and 98% of standardized adult estimates by 3 months of age (53 weeks postmenstrual age). Clearance informed dosing predictions in all ages (premature neonate to adult) and matched those doses in common use in children older than 3 months.

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.

Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy.

BACKGROUND: The impact of tramadol in children given acetaminophen-ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy. METHODS: Children undergoing tonsillectomy were given oral paracetamol and ibuprofen perioperatively. Blood was taken for paracetamol and ibuprofen drug assay on up to six occasions over 6 h after the initial dose. Tramadol was administered by caregivers for unacceptable postoperative pain. Pain was measured using the Parent's Postoperative Pain Measurement rating two hourly on the first postoperative day. A first-order absorption, one-compartment linear model with first-order elimination was used to describe acetaminophen and ibuprofen disposition. Analgesia was described using an EMAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models. RESULTS: Pharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (EMAX ) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C50,ACET ) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C50 (C50,IBU ) 3.95 (95%CI 2.57, 7.53) mg/L. The Hill coefficient was 1.48 (95%CI 0.92, 2.62) and an interaction term was fixed at zero (additivity). The half-time (t1/2 keo) for equilibration between the plasma and effect site was 0.34 hour (95%CI 0.23, 1.98) for acetaminophen and 1.04 hour (95%CI 0.75, 1.77) for ibuprofen. Tramadol had a C50,TRAM of 0.07 (95%CI 0.048, 1.07) mg/L with a t1/2 keo,TRAM 1.78 hour (95%CI 1.06, 1.96). CONCLUSION: Ibuprofen has an EC50 for analgesia in children similar to that of adults (3.95 mg/L; 95%CI 2.57-7.53, vs 5-10 mg/L adults). The maximum effect from combination therapy (ie, 65% reduction in pain score) achieves satisfactory analgesia with commonly used doses but increased dose adds little additional benefit. The addition of tramadol to this analgesic mixture prolongs analgesia duration.

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.

Reporting of complications after laparoscopic cholecystectomy: a systematic review.

BACKGROUND: Consistent measurement and reporting of outcomes, including adequately defined complications, is important for the evaluation of surgical care and the appraisal of new surgical techniques. The range of complications reported after LC has not been evaluated. This study aimed to identify the range of complications currently reported for laparoscopic cholecystectomy (LC), and the adequacy of their definitions. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for prospective studies reporting clinical outcomes of LC, between 2013 and 2016. RESULTS: In total 233 studies were included, reporting 967 complications, of which 204 (21%) were defined. One hundred and twenty-two studies (52%) did not provide definitions for any of the complications reported. Conversion to open cholecystectomy was the most commonly reported complication, reported in 135 (58%) studies, followed by bile leak in 89 (38%) and bile duct injury in 75 (32%). Mortality was reported in 89 studies (38%). CONCLUSION: Considerable variation was identified between studies in the choice of measures used to evaluate the complications of LC, and in their definitions. A standardised set of core outcomes of LC should be developed for use in clinical trials and in evaluating the performance of surgical units.

Retesting the Hypothesis of a Clinical Randomized Controlled Trial in a Simulation Environment to Validate Anesthesia Simulation in Error Research (the VASER Study).

BACKGROUND: Simulation has been used to investigate clinical questions in anesthesia, surgery, and related disciplines, but there are few data demonstrating that results apply to clinical settings. We asked "would results of a simulation-based study justify the same principal conclusions as those of a larger clinical study?" METHODS: We compared results from a randomized controlled trial in a simulated environment involving 80 cases at three centers with those from a randomized controlled trial in a clinical environment involving 1,075 cases. In both studies, we compared conventional methods of anesthetic management with the use of a multimodal system (SAFERsleep; Safer Sleep LLC, Nashville, Tennessee) designed to reduce drug administration errors. Forty anesthesiologists each managed two simulated scenarios randomized to conventional methods or the new system. We compared the rate of error in drug administration or recording for the new system versus conventional methods in this simulated randomized controlled trial with that in the clinical randomized controlled trial (primary endpoint). Six experts were asked to indicate a clinically relevant effect size. RESULTS: In this simulated randomized controlled trial, mean (95% CI) rates of error per 100 administrations for the new system versus conventional groups were 6.0 (3.8 to 8.3) versus 11.6 (9.3 to 13.8; P = 0.001) compared with 9.1 (6.9 to 11.4) versus 11.6 (9.3 to 13.9) in the clinical randomized controlled trial (P = 0.045). A 10 to 30% change was considered clinically relevant. The mean (95% CI) difference in effect size was 27.0% (-7.6 to 61.6%). CONCLUSIONS: The results of our simulated randomized controlled trial justified the same primary conclusion as those of our larger clinical randomized controlled trial, but not a finding of equivalence in effect size.