Pharmacokinetics Of Propofol Research Articles

Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats

ObjectiveTo compare the pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol administered intravenously (IV) as a single induction dose in cats. Study designProspective experimental study. AnimalsSix healthy adult cats, three female intact, three male castrated, weighing 4.8 ± 1.8 kg. MethodsCats received 8 mg kg−1 IV of propofol (P) or propofol with 2% benzyl alcohol (P28) using a randomized crossover design. Venous blood samples were collected at predetermined time points to 24 hours after drug administration to determine drug plasma concentrations. Physiologic and behavioral variables were also recorded. Propofol and benzyl alcohol concentrations were determined using high pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were described using a 2-compartment model. Pharmacokinetic and pharmacodynamic parameters were analyzed using repeated measures anova (p < 0.05). ResultsPlasma concentrations of benzyl alcohol were below the lower limits of quantification (LLOQ) at all time points for two of the six cats (33%), and by 30 minutes for the remaining four cats. Propofol pharmacokinetics, with or without 2% benzyl alcohol, were characterized by rapid distribution, a long elimination phase, and a large volume of distribution. No differences were noted between treatments with the exception of clearance from the second compartment (CLD2), which was 23.6 and 38.8 mL kg−1 minute−1 in the P and P28 treatments, respectively. Physiologic and behavioral variables were not different between treatments with the exception of heart rate at 4 hours post administration. Conclusions and clinical relevanceThe addition of 2% benzyl alcohol as a preservative minimally altered the pharmacokinetics and pharmacodynamics of propofol 1% emulsion when administered as a single IV bolus in this group of cats. These data support the cautious use of propofol with 2% benzyl alcohol for induction of anesthesia in healthy cats.

Propofol: a review of its role in pediatric anesthesia and sedation.

Propofol is an intravenous agent used commonly for the induction and maintenance of anesthesia, procedural, and critical care sedation in children. The mechanisms of action on the central nervous system involve interactions at various neurotransmitter receptors, especially the gamma-aminobutyric acid A receptor. Approved for use in the USA by the Food and Drug Administration in 1989, its use for induction of anesthesia in children less than 3years of age still remains off-label. Despite its wide use in pediatric anesthesia, there is conflicting literature about its safety and serious adverse effects in particular subsets of children. Particularly as children are not "little adults", in this review, we emphasize the maturational aspects of propofol pharmacokinetics. Despite the myriad of propofol pharmacokinetic-pharmacodynamic studies and the ability to use allometrical scaling to smooth out differences due to size and age, there is no optimal model that can be used in target controlled infusion pumps for providing closed loop total intravenous anesthesia in children. As the commercial formulation of propofol is a nutrient-rich emulsion, the risk for bacterial contamination exists despite the Food and Drug Administration mandating addition of antimicrobial preservative, calling for manufacturers' directions to discard open vials after 6h. While propofol has advantages over inhalation anesthesia such as less postoperative nausea and emergence delirium in children, pain on injection remains a problem even with newer formulations. Propofol is known to depress mitochondrial function by its action as an uncoupling agent in oxidative phosphorylation. This has implications for children with mitochondrial diseases and the occurrence of propofol-related infusion syndrome, a rare but seriously life-threatening complication of propofol. At the time of this review, there is no direct evidence in humans for propofol-induced neurotoxicity to the infant brain; however, current concerns of neuroapoptosis in developing brains induced by propofol persist and continue to be a focus of research.

Robust control of burst suppression for medical coma

Objective. Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed-loop anesthesia delivery (CLAD) system to control medical coma. Approach. We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment. Main results. In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [−0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg−1. The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg−1 h−1. Performance fell within clinically acceptable limits for all measures. Significance. A CLAD system designed using robust control theory achieves clinically acceptable performance in the presence of realistic unmodeled disturbances and in spite of realistic model uncertainty, while maintaining infusion rates within acceptable safety limits.

Pharmacokinetics and pharmacodynamics of propofol in cancer patients undergoing major lung surgery.

Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol–fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, biochemical and hemodynamic parameters was collected for the purpose of covariate analysis. Nonlinear mixed effect modeling in NONMEM was used to analyze the collected data. A three-compartment model was sufficient to describe PK of propofol. The anesthetic effect (AAI index) was linked to the propofol effect site concentrations through a sigmoidal E max model. A slightly higher value of clearance, a lower value of distribution clearance, and a decreased volume of peripheral compartment were observed in our patients, as compared with the literature values reported for healthy volunteers by Schnider et al. and by Eleveld et al. Despite these differences, both models led to a clinically insignificant bias of −8 and −1 % in concentration predictions, as reflected by the median performance error. The C e50 and propofol biophase concentration at the time of postoperative orientation were low and equaled 1.40 and 1.13 mg/L. The population PK/PD model was proposed for cancer patients undergoing a major lung surgery. The large body of studied covariates did not affect PK/PD of propofol significantly. The modification of propofol dosage in the group of patients under study is not necessary when TCI-guided administration of propofol by means of the Schnider model is used.Electronic supplementary materialThe online version of this article (doi:10.1007/s10928-015-9404-6) contains supplementary material, which is available to authorized users.

Effects of Genetic Polymorphism of CYP2B6 and UGT1A9 and Sex Differences on Pharmacokinetics of Propofol

Effects of Genetic Polymorphism of CYP2B6 and UGT1A9 and Sex Differences on Pharmacokinetics of Propofol

Performance of propofol target-controlled infusion models in the obese: pharmacokinetic and pharmacodynamic analysis.

Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese patients and to characterize the Bispectral Index (BIS) response in this population. Twenty obese patients (body mass index >35 kg/m), aged 20 to 60 years, scheduled for laparoscopic bariatric surgery, were studied. Anesthesia was administered using propofol by target-controlled infusion and remifentanil by manually controlled infusion. BIS data and propofol infusion schemes were recorded. Arterial blood samples to measure propofol were collected during induction, maintenance, and the first 2 postoperative hours. Median performance errors (MDPEs) and median absolute performance errors (MDAPEs) were calculated to measure model performance. A PKPD model was developed using NONMEM to characterize the propofol concentration-BIS dynamic relationship in the presence of remifentanil. We studied 20 obese adults (mean weight: 106 kg, range: 85-141 kg; mean age: 33.7 years, range: 21-53 years; mean body mass index: 41.4 kg/m, range: 35-52 kg/m). We obtained 294 arterial samples and analyzed 1431 measured BIS values. When total body weight (TBW) was used as input of patient weight, the Eleveld allometric model showed the best (P < 0.0001) performance with MDPE = 18.2% and MDAPE = 27.5%. The 5 tested PK models, however, showed a tendency to underestimate propofol concentrations. The use of an adjusted body weight with the Schnider and Marsh models improved the performance of both models achieving the lowest predictive errors (MDPE = <10% and MDAPE = <25%; all P < 0.0001). A 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (ke0) adequately described the propofol concentration-BIS data. A lag time parameter of 0.44 minutes (SE = 0.04 minutes) to account for the delay in BIS response improved the fit. A simulated effect-site target of 3.2 μg/mL (SE = 0.17 μg/mL) was estimated to obtain BIS of 50, in the presence of remifentanil, for a typical patient in our study. The Eleveld allometric PK model proved to be superior to all other tested models using TBW. All models, however, showed a trend to underestimate propofol concentrations. The use of adjusted body weight instead of TBW with the traditional Schnider and Marsh models markedly improved their performance achieving the lowest predictive errors of all tested models. Our results suggest no relevant effect of obesity on both the time profile of BIS response and the propofol concentration-BIS relationship.

Pharmacogenetics, Plasma Concentrations, Clinical Signs and EEG During Propofol Treatment

A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high-performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9-promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (subdelta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9-331C/T had a higher propofol clearance than those without (p=0.03) and required a higher induction dose (p=0.03). The patients with UGT1A9-1818T/C required a longer time to LOC (p=0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p=0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern.

A general purpose pharmacokinetic model for propofol.

Pharmacokinetic (PK) models are used to predict drug concentrations for infusion regimens for intraoperative displays and to calculate infusion rates in target-controlled infusion systems. For propofol, the PK models available in the literature were mostly developed from particular patient groups or anesthetic techniques, and there is uncertainty of the accuracy of the models under differing patient and clinical conditions. Our goal was to determine a PK model with robust predictive performance for a wide range of patient groups and clinical conditions. We aggregated and analyzed 21 previously published propofol datasets containing data from young children, children, adults, elderly, and obese individuals. A 3-compartmental allometric model was estimated with NONMEM software using weight, age, sex, and patient status as covariates. A predictive performance metric focused on intraoperative conditions was devised and used along with the Akaike information criteria to guide model development. The dataset contains 10,927 drug concentration observations from 660 individuals (age range 0.25-88 years; weight range 5.2-160 kg). The final model uses weight, age, sex, and patient versus healthy volunteer as covariates. Parameter estimates for a 35-year, 70-kg male patient were: 9.77, 29.0, 134 L, 1.53, 1.42, and 0.608 L/min for V1, V2, V3, CL, Q2, and Q3, respectively. Predictive performance is better than or similar to that of specialized models, even for the subpopulations on which those models were derived. We have developed a single propofol PK model that performed well for a wide range of patient groups and clinical conditions. Further prospective evaluation of the model is needed.

Utilization of Optimal Study Design for Maternal and Fetal Sheep Propofol Pharmacokinetics Study: A Preliminary Study

Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates.

Review of pharmacokinetic models for target controlled infusions in anesthesia

Intravenous injection of anesthetic drugs dates back to the 17 th Century when opium and chloral hydrate have been injected intravenously. It was not until the 1930s intravenous anesthesia became popular with the invention of barbiturates.Early intravenous anesthetic agents such as barbiturates were ideal for induction of anesthesia, but not suitable for maintenance of anesthesia. Most of these drugs accumulated significantly with increasing durations of infusion and also resulted in cardiorespiratory depression. The invention of propofol and shorter acting opioid analgesics such as remifentanil and alfentanil have revolutionized intravenous anesthesia. The rapid onset and offset of these drugs lends itself to being suitable agents for maintenance of anesthesia over prolonged periods of time. 1,2 Detailed understanding of the pharmacokinetics of propofol and remifentanil, combined with technological advances in intravenous pumps capable of accurate delivery of drugs have resulted in great development of the field of total intravenous anesthesia and target controlled infusions. I would like to discuss, in this article, the pharmacokinetics and pharmacokinetic models behind these intravenous infusion pumps.

Effects of gender on pharmacokinetics of propofol

Objective To evaluate the effects of gender on the pharmacokinetics of propofol in patients.Methods Twenty ASA physical status Ⅰ or Ⅱ patients of both sexes (10 male,10 female),aged 42-59 yr,weighing 46-76 kg,scheduled for elective surgery for gastrointestinal cancer,were randomly divided into 2 gender groups (n =10 each):male group and female group.Combined intravenous-inhalational anesthesia was performed during surgery.Anesthesia was induced with iv injection of 2％ propofol 2 mg/kg,remifentanil 1.5 μg/kg,and suxamethonium chloride 1.5 mg/kg.The patients were tracheally intubated and mechanically ventilated.Anesthesia was maintained with inhalation of the mixture of 1％-2 ％ isoflurane and nitrous oxide (N2 O ∶ O2 =1 ∶ 1.),iv infusion of remifentanil 0.2-0.3 μg/kg and intermittent iv boluses of atracurium.Blood samples were taken from the central vein before propofol administration,and at 1,2,3,4,6,10,15,30,45,60,90,120,180,240,360 and 720 min after propofol administration for determination of the plasma concentration of propofol by high-performance liquid chromatography.The blood concentration-time curve of propofol was drawn and the pharmacokinetic parameters were calculated.Results The blood concentrations of propofol were significantly lower at each time points within 10 rmin after administration of the single bolus of propofol in female group than in male group (P ＜0.05).The blood concentration-time curves of propofol were fitted to a three-compartment open model in the 2 groups.The central volume of distribution and clearance rate were significantly larger in female patients than in male patients (P ＜ 0.05).Conclusion After iv injection of propofol,the blood concentration of propofol is lower,and the central volume of distribution and clearance rate are larger in female than in male,suggesting that gender has significant effect on pharmacokinetics of propofol. Key words: Sex factor; Propofol; Pharmacokinetics

Evaluation of propofol anesthesia in morbidly obese children and adolescents.

BackgroundPoor characterization of propofol pharmacokinetics and pharmacodynamics in the morbidly obese (MO) pediatric population poses dosing challenges. This study was conducted to evaluate propofol total intravenous anesthesia (TIVA) in this population.MethodsAfter IRB approval, a prospective study was conducted in 20 MO children and adolescents undergoing laparoscopic surgery under clinically titrated propofol TIVA. Propofol doses/infusion rates, hemodynamic variables, times to induction and emergence, and postoperative occurrence of respiratory adverse events (RAE) were recorded, along with intraoperative blinded Bispectral Index/BIS and postoperative Ramsay sedation scores (RSS). Study subjects completed awareness questionnaires on postoperative days 1 and 3. Propofol concentrations were obtained at predetermined intra- and post-operative time points.ResultsStudy subjects ranged 9 – 18 years (age) and 97 - 99.9% (BMI for age percentiles). Average percentage variability of hemodynamic parameters from baseline was ≈ 20%. Patients had consistently below target BIS values (BIS < 40 for >90% of maintenance phase), delayed emergence (25.8 ± 22 minutes), increased somnolence (RSS ≥ 4) in the first 30 minutes of recovery from anesthesia and 30% incidence of postoperative RAE, the odds for which increased by 14% per unit increase in BMI (p ≤ 0.05). Mean propofol concentration was 6.2 mg/L during maintenance and 1.8 mg/L during emergence from anesthesia.ConclusionsOur findings indicate clinical overestimation of propofol requirements and highlight the challenges of clinically titrated propofol TIVA in MO adolescents. In this setting, it may be advantageous to titrate propofol to targeted BIS levels until more accurate weight-appropriate dosing regimens are developed, to minimize relative overdosing and its consequences.

The combined effects of midazolam and propofol sedation on muscle power

We performed a randomised, crossover study to investigate the effects of intravenous sedation on grip strength and bite force. Twenty male volunteers received a bolus intravenous injection of midazolam (0.02 mg.kg(-1)) together with a 30-min propofol infusion designed to achieve an effect-site concentration of 1.0 μg.ml(-1). Observed variables included bispectral index, observer's assessment of alertness/sedation, correct answer rate of Stroop colour-word test, grip strength and bite force. Grip strength decreased from a median (IQR [range]) of 483 (443-517 [380-586]) N to 358 (280-405 [108-580]) N (p < 0.001) during sedation and recovered following flumazenil administration, while bite force increased from 818 (593-1026 [405-1406]) N to 1377 (1243-1585 [836-2357]) N (p < 0.001) during sedation. Although bite force gradually returned to baseline following flumazenil administration, it remained increased throughout the experimental period. We conclude that bite force increased during intravenous sedation and that this may have clinical implications.

Validation of pharmacokinetic model of propofol in Indian population

The pharmacokinetics of propofol has been evaluated extensively in a variety of patients groups after either bolus doses or continuous infusions. Presently there are multiple models available based on western data including China. So far, the pharmacokinetics of propofol has not been studied in the Indian population. With this background we planned to evaluate pharmacokinetics of propofol in Indian patients which will help in better management of these patients undergoing surgery using propofol infusion in total intravenous anesthesia. Venous blood samples (3 ml) for estimation of propofol concentrations were taken at different time intervals. Plasma propofol concentration was estimated by using High Performance Liquid Chromatography (HPLC) method. Maximum performance error occurred at 2 min with a median of -3.85 and it varied from -1.7 to -9.5 showing a consistent over prediction of the concentration at two minutes after the loading dose and start of infusion. Subsequently the error decreased to median of -0.9 (-0.9 to 4.6) at 10 minutes and median of -0.3 (range-0.3 to 2.8) at 30 and in 60 min -1.55(-0.28 to 1). When we compare the performance of our pharmacokinetic model of propofol in this study with other western studies, we observed less error with our pharmacokinetic model. Key words: Propofol, pharmacokinetics, median performance error (MDPE), median absolute performance error (MDAPE).

False selection of syringe-brand compatibility and the method of correction during target-controlled infusion of propofol

BackgroundWe evaluated volumetric differences of syringe brand compatibilities, and investigated the impact of false brand settings on target-controlled infusion (TCI) and their methods of correction.MethodsGravimetric measurement of 10 ml bolus infusions was performed using BD Plastipak (BDP) and Terumo compatible syringes, while setting to 7 different kinds of brand compatibilities (BDP, Sherwood Monoject, BD Perfusion, Braun Perfusor, Braun Omnifix, Fresenius Injectomat, and Terumo). To investigate the performance of TCI using BDP with a false setting to Terumo (BDPTERUMO) and Terumo to BDP (TERUMOBDP), 24 TCI targeting 4.0 µg/ml of effect-site concentration (Ceff) of propofol were performed. Subsequently, another 24 TCI were evaluated for simple corrections of false settings at 30 min. We also investigated 24 TCI using active corrections (fill-up for BDPTERUMO, evacuation for TERUMOBDP) based on the pharmacokinetics of propofol. The Ceff at 30 min of TCI and time to normalize to ± 5% of target concentration (T±5%target) were compared.ResultsThe Ceff of BDPTERUMO showed negative bias and 17.2% inaccuracy, and the Ceff of TERUMOBDP showed positive bias and 19.5% inaccuracy. The Ceff at 30 min showed no difference between the methods of correction in BDPTERUMO or TERUMOBDP. The T±5%target in both the active corrections was significantly shorter than that of each simple corrections (P < 0.001).ConclusionsFalse brand setting of syringe proportionally maintained different predicted concentrations as much as the volumetric differences of syringe brand. Based on the results, it is proposed that correction methods based on pharmacokinetics could effectively normalize the differences, without giving up the wrong TCI.

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Propofol Clearance in Morbidly Obese Children and Adolescents : Influence of Age and Body Size.

Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM® was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46kg/m2 (range 31-63 kg/m2) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min)= 1.70 × (TBW/70)0.8]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT00948597.

Propofol Clearance in Morbidly Obese Children and Adolescents

Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM(®) was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46 kg/m(2) (range 31-63 kg/m(2)) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min) = 1.70 × (TBW/70)(0.8)]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function.

Real time monitoring of propofol blood concentration in ponies anaesthetized with propofol and ketamine

This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh-cross ponies (weighing 135-300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20-40 μg/kg/min). Blood samples (<2 mL) were collected prior to, during and after the infusion, and on assuming standing position. Anaesthesia was uneventful; with the duration of infusion 31-89 min. Blood propofol concentrations during the infusion ranged between 1.52 and 7.65 μg/mL; pseudo-steady state concentrations 3.64-6.78 μg/mL, and concentrations on assuming standing position 0.75-1.40 μg/mL. Propofol clearance and volume of distribution were 31.4 (SD 6.1) mL/min/kg and 220.7 (132.0) mL/kg, respectively. The propofol analyser allows titration of propofol to a given concentration; and may be useful for anaesthesia in animals where kinetics are unknown; in disease states; and where intercurrent therapies affect propofol disposition.