Disposition Of Propofol Research Articles

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.

Propofol and children – what we know and what we do not know

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps.

In Vivo Glucuronidation Activity of Drugs in Neonates: Extensive Interindividual Variability Despite Their Young Age

Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.

Recovery and long-term renal excretion of propofol, its glucuronide, and two di-isopropylquinol glucuronides after propofol infusion during surgery

BackgroundThe metabolism of the short-acting anaesthetic agent propofol has been described over the first 24 h. However, the long-term disposition of propofol and its metabolites is unclear. We describe the pharmacokinetics (renal excretion rates and renal clearance) of propofol and its metabolites over 60 h. MethodsTen patients undergoing lung surgery were included in the study. They received anaesthesia with continuous i.v. propofol at an average rate of 10 mg min−1. During surgery and 60 h thereafter, we sampled blood and urine. Propofol and its metabolites were measured using gradient high performance liquid chromatography (HPLC). ResultsIn nine patients, propofol and its glucuronides were found in the plasma over the first 15 h. In the urine, however, even after 60 h, propofol and its quinol glucuronides were still detectable. One patient had a markedly different pharmacokinetic profile, showing a limited renal excretion or absorption of 12% of the dose. ConclusionsAfter an infusion of propofol, patients excrete propofol and its metabolites in the urine over a period in excess of 60 h. We hypothesize that (re)absorption of propofol and its metabolites by the kidney is a major process in elimination and that the reabsorbed compounds are gradually conjugated in the kidney and excreted in the urine. One patient showed a different pharmacokinetic profile for which we currently have no explanation.

Propofol pharmacokinetics in preterm and term neonates: the relevance of both postmenstrual and postnatal age

Although disposition of propofol has been extensively studied in different populations of adult and paediatric age, data are still very limited. Preliminary data in neonates suggested that propofol clearance is significantly different compared with toddlers and children, with important interindividual variability in propofol clearance in neonates [1]. We therefore wanted to document covariates that contribute to interindividual variability in propofol pharmacokinetics in preterm and term neonates.

Maturational pharmacokinetics of single intravenous bolus of propofol

Our aim was to document propofol pharmacokinetics in preterm and term neonates following a single intravenous bolus and compare these estimates with pharmacokinetics findings in toddlers and young children. Newly collected observations following intravenous bolus administration of propofol in preterm and term neonates (n = 9) were compared with earlier reported pharmacokinetic estimates in toddlers and young children. Data are reported by median and range. Mann-Whitney U-test or correlation was used to analyze differences in pharmacokinetic findings between neonates, toddlers and young children. Concentration-time profiles obtained were interpreted by two-stage analysis as a three compartment open model in nine neonates with a median weight of 2.51 (range 0.91-3.8) kg and a median postmenstrual age (PMA) of 36 (range 27-43) weeks. Median clearance (CL) was 13.6 (range 3.7-78.2) ml.min(-1).kg(-1) and median apparent volume of distribution at steady state (V(ss)) was 3.7 (1.33-7.96) l.kg(-1). Following allometric scaling and standardization to 70 kg, median CL was 442 (range 97-2184) ml.min(-1).70 kg(-1). Compared with earlier reported observations in toddlers and children, median clearance (kg.min(-1)) was significantly lower in neonates (P < 0.01) and these differences remained significant after allometric scaling (70 kg.min(-1)) while V(ss) (l.kg(-1)) was significantly lower in neonates (P < 0.01). Propofol disposition is significantly different in neonates compared with toddlers and young children, reflecting both ontogeny and differences in body composition. Based on the reduced clearance of propofol, a longer recovery time is more likely to occur in neonates.

A Physiologically Based, Recirculatory Model of the Kinetics and Dynamics of Propofol in Man

The disposition of propofol in man is commonly described using a three-compartment mamillary model. However, these models do not incorporate blood flows as parameters. This complicates the representation of the changes in blood flows that may occur in surgical patients. In contrast, complex physiologically based models are derived from data sets (e.g., tissue:blood partition coefficients) that may not be readily collected in man. Alternatively, the authors report a recirculatory model of propofol disposition in a "standard" man that incorporates detailed descriptions of the lungs and brain, but with a lumped description of the remainder of the body. The model was parameterized from data in the literature using a "meta-modeling" approach. The first-pass passage of propofol through the venous vasculature and the lungs was a function of the injected drug mixing with cardiac output and passing through a three-"tank in series" model for the lungs. The brain was represented as a two-compartment model defined by cerebral blood flow and a permeability term. The Bispectral Index was a linear function of the mean brain concentration. The remainder of the body was represented by compartment systems for the liver, fast distribution and slow distribution. The model was a good fit of the data and was able to predict other data not used in the development of the model. The model may ultimately find a role in improving the fidelity of patient simulators currently used to train anesthetists and for clinical practice simulation to optimize dosing and management strategies.

Human Kidneys Play an Important Role in the Elimination of Propofol

Extrahepatic clearance of propofol has been suggested because its total body clearance exceeds hepatic blood flow. However, it remains uncertain which organs are involved in the extrahepatic clearance of propofol. In vitro studies suggest that the kidneys contribute to the clearance of this drug. The purpose of this study was to confirm whether human kidneys participate in propofol disposition in vivo. Ten patients scheduled to undergo nephrectomy were enrolled in this study. Renal blood flow was measured using para-aminohippurate. Anesthesia was induced with vecuronium (0.1 mg/kg) and propofol (2 mg/kg) and then maintained with nitrous oxide (60%), sevoflurane (1 approximately 2%) in oxygen, and an infusion of propofol (2 mg . kg . h). Radial arterial blood for propofol and para-aminohippurate analysis was collected from a cannula inserted in the radial artery. The renal venous sample and the radial arterial sample were obtained at the same time after the steady state of propofol was established. The renal extraction ratio of propofol was 0.58 +/- 0.15 (mean +/- SD). The renal clearance of propofol was 0.41 +/- 0.15 l/min (mean +/- SD), or 27 +/- 9.9% (mean +/- SD) of total body clearance. Human kidneys play an important role in the elimination of propofol.

Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model

To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. Prospective, randomized animal study. University research laboratory. Five adult female merino sheep. Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 microg/min) and dopamine (10, 20, 40 microg x kg x min) in 3 x 5 min intervals followed by a 30-min washout period. Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146-169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95 % CI, p < 0.05): epinephrine to 41.8% of baseline (11.4-72), norepinephrine to 63 % (27-99) and dopamine to 52.9 % (18.5-87.3). There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The lowest blood concentrations were associated with emergence from anesthesia. Arterial concentrations were inversely related to the simultaneously determined cardiac output (r2 = 0.74, p < 0.0001). Comparison of the data with the predictions of a previously developed recirculatory model of propofol disposition in sheep showed the data were consistent with a mechanism based on increased first pass dilution and clearance of propofol secondary to the increased cardiac output. Catecholamines produced circulatory changes that reversed propofol anesthesia. These observations have potential clinical implications for the use of propofol in hyperdynamic circulatory conditions, either induced by exogenous catecholamine infusions or pathological states.

Pulmonary disposition of propofol in surgical patients.

The lungs have been mentioned as a possible site contributing to the extrahepatic clearance of propofol. The objective of the present study was to clarify the pulmonary disposition of propofol directly in human lungs by investigating both the first-pass uptake and pulmonary extraction at pseudo-steady state. Nine patients were enrolled in the first-pass uptake study. Propofol (5 mg) and indocyanine green (ICG; 15 mg) were simultaneously administered via a central venous catheter within 1 s, and sequential arterial blood samples were obtained from the radial artery at 1-s intervals up to 45 s. Eleven patients were included in the infusion study, and propofol was infused via the jugular vein at a rate of 50 microgram. kg-1. min-1. Blood samples were simultaneously collected from pulmonary and radial arteries up to 60 min. A pronounced difference in the dilution curves between propofol and ICG was observed, and 28.4 +/- 11.6% (mean +/- SD) of propofol was taken up during the single passage through the human lung. The mean pulmonary transit time of propofol (31.3 +/- 6.0 s) was significantly longer than that of ICG (22.4 +/- 2.7 s; P < 0.01), indicating that some of the propofol trapped by lungs returned to the circulation by back diffusion. In the constant infusion study, no significant differences were observed with the plasma concentrations of propofol between pulmonary and radial arteries except for that at 2 min. The area under the curve of pulmonary and radial arterial concentration curves to 60 min were 59.1 +/- 14.8 and 56.8 +/- 12.5 microg. ml-1. min-1, respectively. No significant difference was observed with the area under the curve, suggesting that metabolism was not involved in the pulmonary uptake in human lungs. Most of the propofol that undergoes pulmonary uptake during the first pass was released back to the circulation by back diffusion. Metabolism was not involved in the pulmonary uptake in human lungs.

Disposition of propofol between red blood cells, plasma, brain and cerebrospinal fluid in rabbits.

The disposition of propofol in the blood and brain of New Zealand rabbits was studied in three groups of six rabbits. One group received a single anaesthetic dose; a second group received a 1-h infusion; and a third group was studied after the rabbits were judged to have recovered from a 1-h infusion. There was a high concentration of propofol in the red blood cell fraction and in the brain, however, the red blood cell concentration largely exceeded the one found in the brain in all groups of animals. This is consistent with the high fat solubility of diisopropylphenol. The possible effects of propofol sequestered in red blood cells is discussed.

Disposition of propofol between red blood cells, plasma, brain and cerebrospinal fluid in rabbits

The disposition of propofol in the blood and brain of New Zealand rabbits was studied in three groups of six rabbits. One group received a single anaesthetic dose; a second group received a 1-h infusion; and a third group was studied after the rabbits were judged to have recovered from a 1-h infusion. There was a high concentration of propofol in the red blood cell fraction and in the brain, however, the red blood cell concentration largely exceeded the one found in the brain in all groups of animals. This is consistent with the high fat solubility of diisopropylphenol. The possible effects of propofol sequestered in red blood cells is discussed.

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

Disposition of propofol after medetomidine premedication in beagle dogs

SUMMARY Propofol by infusion was administered to 6 adult beagle dogs on 2 separate occasions. The dogs received either no premedication or 20 μg/kg im medetomidine 15 min before induction of anaesthesia, with propofol given at 7 mg/kg/min to permit tracheal intubation. After tracheal intubation the infusion rate was maintained for 120 min at 0.4 mg/kg/min in the non-premedicated, and 0.2 mg/kg/min in the premedicated dogs. The latter group received atipamezole 50 μg/kg im immediately at the end of the infusion. After induction of anaesthesia, a 7F balloon catheter designed for thermal dilution measurement of cardiac output was inserted via the right jugular vein. Blood propofol concentrations were measured by HPLC with fluorescence detection and kinetic variables calculated using non-compartmental moment analysis. The induction dose of propofol was 7.00 (sem 0.55) mg/kg in non-premedicated compared with 3.09 (0.25) mg/kg in premedicated dogs. There were differences in systemic clearance and mean residence time (MRTiv); 47.5 (6.2) ml/kg/min vs 29.0 (4.4) ml/kg/min (non-premedicated vs premedicated) and 132.3 (5.2) min vs 152.4 (3.1) min (P

A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient.

To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children. A prospective clinical study. A pediatric intensive care unit (ICU) in a university hospital. Clinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation. A stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patient's level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography. Twenty-nine patients were enrolled into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propofol loading dose; 28 patients completed the study. All patients were sedated immediately after the first 2.5-mg/kg propofol loading dose. Eight patients were adequately sedated with the starting propofol dose regimen, whereas five patients required downward dose adjustment and 11 patients required dosage increases to achieve optimal sedation. Four patients failed to achieve adequate sedation after five dose escalations and the drug was stopped. Recovery from sedation (COMFORT score of > or = 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but < or = 1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2 and V3, which are two-and 20-fold greater in volume, respectively, than V1. Redistribution from V2 and V3 into V1 was much slower than ingress, underscoring the importance of the propofol concentration in V1 as reflective of the drug's sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment. We conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2 and V3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.

In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat.

The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigated. Propofol (4.9-5.1 mg.kg-1) was administered to groups of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by the gut wall (fG), liver (fH) and lung (fL) were calculated. In addition, transport experiments were carried out using Caco-2 cell monolayers to rule out the possibility that intestinal permeability is limiting the oral absorption of propofol. Values for fG, fH and fL were the following: 0.21 +/- 0.07, 0.61 +/- 0.13, and 0.82 +/- 0.09, respectively. The apparent permeability coefficient of propofol across Caco-2 cell monolayers was 24.2 +/- 0.3 x 10(-6) cm.sec-1, which is similar to the apparent permeability coefficient obtained for propranolol (30.7 +/- 1.7 x 10(-6) cm.sec-1), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be demonstrated during the flux experiments across the Caco-2 cell monolayers. The intestinal mucosa is the main site of first pass metabolism following oral administration of propofol in the rat. Intestinal metabolism could therefore also contribute to the systemic clearance of propofol.

Continuous infusions of propofol administered to dogs: effects on ICG and propofol disposition

We have studied the effects of stepwise increasing infusion rates of propofol 200-500 micrograms kg-1 min-1 on blood concentrations of propofol and the disposition and clearance of a bolus dose of indocyanine green (ICG) 0.5 mg kg-1 in 10 acutely instrumented dogs. Drug concentrations and ICG clearance were measured 30 min after each change of infusion rate and after reverting for 60 min to the basal propofol infusion rate. Increasing infusion rates resulted in significant prolongation of the elimination half-life of ICG and decrease in ICG clearance at the largest infusion rate (500 micrograms kg-1 min-1) compared with the basal rate. Similarly, there were greater than predicted blood concentrations of propofol at the largest infusion rate. When the infusion rate reverted to 200 micrograms kg-1 min-1, and continued for 60 min, there was a significant difference between the initial blood concentration of propofol at this basal infusion rate and this latter value (P < 0.01). These changes reflect the persistent myocardial depression observed during the recovery phase.

Pharmacokinetics of propofol in mixed-breed dogs and Greyhounds

Summary Pharmacokinetics and recovery characteristics of propofol in Greyhounds and mixed-breed dogs were compared. In all dogs, disposition of propofol was adequately described by a 2-compartment open model, with a rapid distribution phase followed by a slower elimination phase. When findings in Greyhounds were compared with those in mixed-breed dogs, significant differences were observed in mean concentrations of propofol in blood, recovery characteristics, and estimates for apparent volume of distribution, volume of distribution at steady state, and total body clearance. In addition, Greyhounds recovered from anesthesia at higher concentrations of propofol than did mixed-breed dogs. A secondary peak in blood propofol concentration was observed in 8 of 10 Greyhounds and in 5 of 8 mixed-breed dogs. This peak corresponded to the time of return of the righting reflex.

Disposition of propofol infusions for caesarean section

The disposition of propofol was studied in women undergoing elective Caesarean section. Indices of maternal recovery and neonatal assessment were correlated with venous concentrations of propofol. After induction of anaesthesia with propofol 2.0 mg.kg-1, ten patients received propofol 6 mg.kg-1.hr-1 with nitrous oxide 50 per cent in oxygen (low group) and nine were given propofol 9 mg.kg-1.hr-1 with oxygen 100 per cent (high group). Pharmacokinetic variables were similar between the groups. The mean +/- SD Vss = 2.38 +/- 1.16 L.kg-1, Cl = 39.2 +/- 9.75 ml.min-1.kg-1 and t1/2 beta = 126 +/- 68.7 min. At the time of delivery (8-16 min), the concentration of propofol ranged from 1.91-3.82 micrograms.ml-1 in the maternal vein (MV), 1.00-2.00 micrograms.ml-1 in the umbilical vein (UV) and 0.53-1.66 micrograms.ml-1 in the umbilical artery (UA). Neonates with high UV concentrations of propofol at delivery had lower neurologic and adaptive capacity scores 15 minutes later. The concentrations of propofol were similar between groups during the infusion but they declined at a faster rate in the low group postoperatively. Maternal recovery times did not depend on the total dose of propofol but the concentration of propofol at the time of eye opening was greater in the high group than the low group (1.74 +/- 0.51 vs 1.24 +/- 0.32 micrograms.ml-1, P less than 0.01). The rapid placental transfer of propofol during Caesarean section requires propofol infusions to be given cautiously, especially when induction to delivery times are long.

HEPATIC AND EXTRAHEPATIC DISPOSITION OF PROPOFOL IN PATIENTS UNDERGOING CORONARY BYPASS SURGERY

In order to clarify the relative contribution of the liver to the short term disposition of propofol, hepatic blood flow was measured during induction of anaesthesia with an i.v. bolus dose of propofol 2 mg kg-1. Total clearance of the drug was 2390 (SD 340) ml min-1, hepatic extraction 82% and hepatic clearance 1060 (260) ml min-1. During the 60-min period of observation, hepatic extraction of propofol increased from 79% to 92%. It is concluded that, within 1 h, only 44% of the administered dose is removed by the liver. Consequently, drug accumulation may occur with repeated dosing or infusion of propofol. The increase in extraction results presumably from slow release of propofol from the soy-bean emulsion.