A pharmacokinetic framework describing antibiotic adsorption to cardiopulmonary bypass devices.

Cardiopulmonary bypass (CPB) can alter pharmacokinetic (PK) parameters and the drug may adsorb to the CPB device, altering exposure. Cefazolin is a beta-lactam antibiotic used for antimicrobial prophylaxis during cardiac surgery supported by CPB. Adsorption of cefazolin could result in therapeutic failure. An ex vivo study was undertaken using CPB devices primed and then dosed with cefazolin and samples were obtained over 1 hour of recirculation. Twelve experimental runs were conducted using different CPB device sizes (neonate, infant, child, and adult), device coatings (Xcoating™, Rheoparin®, PH.I.S.I.O), and priming solutions. The time course of saturable binding, using Bmax (binding capacity), Kd (dissociation constant), and T2off (half-time of dissociation), described cefazolin adsorption. Bmax estimates for the device sizes were neonate 40.0 mg (95% CI 24.3, 67.4), infant 48.6 mg (95% CI 5.97, 80.2), child 77.8 mg (95% CI 54.9, 103), and adult 196 mg (95% CI 191, 199). The Xcoating™ Kd estimate was 139 mg/L (95% CI 27.0, 283) and the T2off estimate was 98.4 min (95% CI 66.8, 129). The Rheoparin® and PH.I.S.I.O coatings had similar binding parameters with Kd and T2off estimates of 0.169 mg/L (95% CI 0.01, 1.99) and 4.94 min (95% CI 0.17, 59.4). The Bmax was small (< 10%) relative to a typical total patient dose during cardiac surgery supported by CPB. A dose adjustment for cefazolin based solely on drug adsorption is not required. This framework could be extended to other PK studies involving CPB.

Time-Varying Clearance in Milrinone Pharmacokinetics from Premature Neonates to Adolescents.

BACKGROUND AND OBJECTIVES: Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300 µg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection. METHODS: Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1). RESULTS: There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8 L/70 kg [95% CI 15.8-19.9] and volume 20.4 L/h/70 kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0 h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977 days [95% CI 0.833-1.12]. CONCLUSION: Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.

A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation. We compared the percentage of time spent in the international normalized ratio acceptable range (%TIR) during the first 28 days following warfarin initiation, and %TIR and count of bleeding events over the entire follow-up period. Two hundred thirty-four participants were followed up to day 28 (NextDose: 116 and standard of care: 118), and 228 participants (114 per arm) were followed up to the final study visit. Median %TIR tended to be higher for participants receiving NextDose guided warfarin management during the first 28 days (63 vs. 56%, P = 0.13) and over the entire follow-up period (74 vs. 71%, P = 0.04). The hazard of clinically relevant minor bleeding events was lower for participants in the NextDose arm (hazard ratio: 0.21, P = 0.041). In NextDose, there were 89.3% of proposed doses accepted by prescribers. NextDose guided dose management in cardiac surgery patients requiring warfarin was associated with an increase in %TIR across the full follow-up period and fewer hemorrhagic events. A theory-based, pharmacologically guided approach facilitates higher quality warfarin anticoagulation. An important practical benefit is a reduced requirement for clinical experience of warfarin management.

Safety and efficacy of intraosseous ropivacaine in lower extremity (SORE) study.

BACKGROUND: Day stay surgery for anterior cruciate ligament (ACL) reconstructions is an increasingly common practice and has driven clinicians to develop postoperative pain regimes that allow same day mobilization and a safe and timely discharge. There is a paucity of literature surrounding the use of intraosseous (IO) ropivacaine used as a Bier's block to provide both intraoperative and postoperative analgesia in lower limb surgery. METHODS: This patient blinded, pilot study randomized 15 patients undergoing ACL reconstruction to receive either IO ropivacaine 1.5 or 2.0 mg/kg; or 300 mg of ropivacaine as local infiltration. The primary outcome for this study was arterial plasma concentration of ropivacaine. Samples were taken via an arterial line at prespecified times after tourniquet deflation. Secondary outcomes included immediate postoperative pain scores using the visual analogue scale and perioperative opioid equivalent consumption. RESULTS: All patients in the intervention group receiving IO ropivacaine had plasma concentrations well below the threshold for central nervous system (CNS) toxicity (0.60 µg/mL). The highest plasma concentration was achieved in the intervention group receiving 1.5 mg/kg dose of ropivacaine reaching 2.93 mg/mL. This would equate to 0.18 µg/mL of free plasma ropivacaine. There were no differences across the three groups regarding pain scores or perioperative opioid consumption. CONCLUSIONS: This study demonstrates that IO ropivacaine is both safe and effective in reducing perioperative pain in patients undergoing ACL reconstruction. There may be scope to increase the IO dose further or utilize other analgesics via the IO regional route to improve perioperative pain relief.

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.

Days alive and out of hospital after laparoscopic cholecystectomy.

BACKGROUND: Days alive and out of hospital (DAOH) is a metric that incorporates several outcomes into a single, standardized measure. This study aimed to explore the utility of DAOH in assessing the outcomes of a retrospective cohort of patients undergoing laparoscopic cholecystectomy (LC). METHODS: Patients undergoing LC at Auckland City Hospital between 1 January 2010 and 31 August 2015 were included. DAOH values were calculated for the 90 days from the date of surgery (DAOH90 ) and described using median and interquartile ranges (IQR). DAOH90 distributions were compared using a two-tailed (non-parametric) Wilcoxon-Mann-Whitney test. RESULTS: 1652 patients undergoing LC were studied. Patients experiencing complications (n = 70, 4.2%) had fewer DAOH90 (median 83, IQR 79, 86) than patients who underwent uncomplicated LC (median 88, IQR 86, 88), P < 0.001. Patients who were converted to open cholecystectomy (n = 70, 4.2%) also had fewer DAOH90 (median 82.5, IQR 79, 84) than patients who underwent uncomplicated LC, P < 0.001. Post-operative complications and conversion had a statistically significant effect on DAOH90 at each of the tested quantiles, except for conversion at the 0.1 quantile. CONCLUSION: DAOH90 is readily calculable from existing New Zealand administrative data sources and is sensitive to the occurrence of complications after LC.

Analysis of medication errors during anaesthesia in the first 4000 incidents reported to webAIRS.

Medication error is a well-recognised cause of harm to patients undergoing anaesthesia. From the first 4000 reports in the webAIRS anaesthetic incident reporting system, we identified 462 reports of medication errors. These reports were reviewed iteratively by several reviewers paying particular attention to their narratives. The commonest error category was incorrect dose (29.4%), followed by substitution (28.1%), incorrect route (7.6%), omission (6.5%), inappropriate choice (5.8%), repetition (5.4%), insertion (4.1%), wrong timing (3.5%), wrong patient (1.5%), wrong side (1.5%) and others (6.5%). Most (58.9%) of the errors resulted in at least some harm (20.8% mild, 31.0% moderate and 7.1% severe). Contributing factors to the medication errors included the presence of look-alike medications, storage of medications in the incorrect compartment, inadequate labelling of medications, pressure of time, anaesthetist fatigue, unfamiliarity with the medication, distraction, involvement of multiple people and poor communication. These data add to current evidence suggesting a persistent and concerning failure effectively to address medication safety in anaesthesia. The wide variation in the nature of the errors and contributing factors underline the need for increased systematic and multifaceted efforts underpinned by a strengthening of the current focus on safety culture to improve medication safety in anaesthesia. This will require the concerted and committed engagement of all concerned, from practitioners at the clinical workface, to those who fund and manage healthcare.

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.

A non-opioid analgesic implant for sustained post-operative intraperitoneal delivery of lidocaine, characterized using an ovine model.

Appropriate management of post-operative pain is an ongoing challenge in surgical practice. At present, systemic opioid administration is routinely used for analgesia in the post-operative setting. However, due to significant adverse effects and potential for misuse, there is a perceived need for the development of alternative, opioid-sparing treatment modalities. Continuous infusion of local anesthetic into the peritoneum after major abdominal surgery reduces pain and opioid consumption, and enhances recovery from surgery. Here we describe a non-opioid, poly(ethylene-co-vinyl-acetate) intraperitoneal implant for the sustained delivery of local anesthetic following major abdominal surgery. A radio-opaque core had the required mechanical strength to facilitate placement and removal procedures. This core was enclosed by an outer shell containing an evenly dispersed local anesthetic, lidocaine. Sustained release of lidocaine was observed in an ovine model over days and the movement modelled between peritoneal fluid and circulating plasma. While desirably high levels of lidocaine were achieved in the peritoneal space these were several orders of magnitude higher than blood levels, which remained well below toxic levels. A pharmacokinetic model is presented that incorporates in vitro release data to describe lidocaine concentrations in both peritoneal and plasma compartments, predicting similar release to that suggested by lidocaine concentrations remaining in the device after 3 and 7 days in situ. Histological analysis revealed similar inflammatory responses following implantation of the co-extruded implant and a commercially used silicone drain after three days. This non-opioid analgesic implant provides sustained release of lidocaine in an ovine model and is suitable for moving onto first in human trials.

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 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.

The effect of implementing an aseptic practice bundle for anaesthetists to reduce postoperative infections, the Anaesthetists Be Cleaner (ABC) study: protocol for a stepped wedge, cluster randomised, multi-site trial.

BACKGROUND: Postoperative infection is a serious problem in New Zealand and internationally with considerable human and financial costs. Also, in New Zealand, certain factors that contribute to postoperative infection are more common in Maori and Pacific populations. To date, most efforts to reduce postoperative infection have focussed on surgical aspects of care and on antibiotic prophylaxis, but recent research shows that anaesthesia providers may also have an impact on infection transmission. These providers sometimes exhibit imperfect hand hygiene and frequently transfer the blood or saliva of their patients to their work environment. In addition, intravenous medications may become contaminated whilst being drawn up and administered to patients. Working with relevant practitioners and other experts, we have developed an evidence-informed bundle to improve key aseptic practices by anaesthetists with the aim of reducing postoperative infection. The key elements of the bundle are the filtering of compatible drugs, context-relevant hand hygiene practices and enhanced maintenance of clean work surfaces. METHODS: We will seek support for implementation of the bundle from senior anaesthesia and hospital leadership and departmental "champions". Anaesthetic teams and recovery room staff will be educated about the bundle and its potential benefits through presentations, written material and illustrative videos. We will implement the bundle in operating rooms where hip or knee arthroplasty or cardiac surgery procedures are undertaken in a five-site, stepped wedge, cluster randomised, quality improvement design. We will compare outcomes between approximately 5000 cases before and 5000 cases after implementation of our bundle. Outcome data will be collected from existing national and hospital databases. Our primary outcome will be days alive and out of hospital to 90 days, which is expected to reflect all serious postoperative infections. Our secondary outcome will be the rate of surgical site infection. Aseptic practice will be observed in sampled cases in each cluster before and after implementation of the bundle. DISCUSSION: If effective, our bundle may offer a practical clinical intervention to reduce postoperative infection and its associated substantial human and financial costs. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618000407291 . Registered on 21 March 2018.

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.

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.

Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy-A randomised, double blind, active control, double-dummy clinical comparison with intravenous administration.

AIMS: Early pain after laparoscopy is often severe. Oxycodone is a feasible analgesic option after laparoscopy, but there are sparse data on epidural administration. The aim was to evaluate the analgesic efficacy and pharmacokinetics of a single dose of epidural oxycodone as a part of multimodal analgesia after gynaecological laparoscopy. METHODS: Women (n = 60), aged 23-71 years, undergoing elective gynaecological laparoscopy, were administrated either epidural oxycodone 0.1 mg kg-1 and intravenous (i.v.) saline (EPI-group n = 31), or epidural saline and i.v. oxycodone 0.1 mg kg-1 (IV-group = 29) in a randomised, double blind, active control, double dummy clinical trial. A pharmacokinetic model was developed using population modelling of plasma and cerebrospinal fluid (CSF) concentrations obtained in these patients and data of 2 published studies. The primary outcome was the amount of i.v. fentanyl for rescue analgesia during the first 4 hours. RESULTS: Twenty of the 31 patients in the EPI-group and 26 of the 29 patients in the IV-group needed i.v. fentanyl for rescue analgesia, P = .021. The median (interquartile range) number of fentanyl doses were 1.0 (1.0-3.0) in the EPI-group and 2.5 (1.0-4.0) doses in the IV-group, P = .008. Plasma concentrations were similar, but CSF concentrations were 100-fold higher in the EPI-group. The population model indicated that 60% of oxycodone injected into the epidural space enters into CSF and 40% is absorbed into the systemic circulation. CONCLUSIONS: The data support superiority of epidural administration of oxycodone compared to i.v. administration during the first hours after laparoscopic surgery. This is likely to be based on enhanced permeation into the central nervous system after epidural administration.

Improving the quality of administration of the Surgical Safety Checklist: a mixed methods study in New Zealand hospitals.

While the WHO Surgical Safety Checklist (the Checklist) can improve patient outcomes, variable administration can erode benefits. We sought to understand and improve how operating room (OR) staff use the Checklist. Our specific aims were to: determine if OR staff can discriminate between good and poor quality of Checklist administration using a validated audit tool (WHOBARS); to determine reliability and accuracy of WHOBARS self-ratings; determine the influence of demographic variables on ratings and explore OR staff attitudes to Checklist administration. DESIGN: Mixed methods study using WHOBARS ratings of surgical cases by OR staff and two independent observers, thematic analysis of staff interviews. PARTICIPANTS: OR staff in three New Zealand hospitals. OUTCOME MEASURES: Reliability of WHOBARS for self-audit; staff attitudes to Checklist administration. RESULTS: Analysis of scores (243 participants, 2 observers, 59 cases) supported tool reliability, with 87% of WHOBARS score variance attributable to differences in Checklist administration between cases. Self-ratings were significantly higher than observer ratings, with some differences between professional groups but error variance from all raters was less than 10%. Key interview themes (33 interviewees) were: Team culture and embedding the Checklist, Information transfer and obstacles, Raising concerns and 'A tick-box exercise'. Interviewees felt the Checklist could promote teamwork and a safety culture, particularly enabling speaking up. Senior staff were of key importance in setting the appropriate tone. CONCLUSIONS: The WHOBARS tool could be useful for self-audit and quality improvement as OR staff can reliably discriminate between good and poor Checklist administration. OR staff self-ratings were lenient compared with external observers suggesting the value of external audit for benchmarking. Small differences between ratings from professional groups underpin the value of including all members of the team in scoring. We identified factors explaining staff perceptions of the Checklist that should inform quality improvement interventions.