The influence of target concentration, equilibration rate constant (ke0 ) and pharmacokinetic model on the initial propofol dose delivered in effect-site target-controlled infusion.

One advantage of effect-site target-controlled infusion is the administration of a larger initial dose of propofol to speed up the induction of anaesthesia. This dose is determined by the combination of the pharmacokinetic model parameters, the target setting and the blood-effect time-constant, ke0 . With the help of computer simulation, we determined the ke0 values required to deliver a range of initial doses with three pharmacokinetic models for propofol. With an effect site target of 4 µg.ml(-1) , in a 35-year-old, 170-cm tall, 70-kg male subject, the ke0 values delivering a dose of 1.75 mg.kg(-1) with the Marsh, Schnider and Eleveld models were 0.59 min(-1) , 0.20 min(-1) and 0.26 min(-1) , respectively. These ke0 values have the attractive feature that, when used to simulate the administration schemes used in two previous studies, predicted effect site concentrations at loss of consciousness were close to those required for maintenance of anaesthesia.

A comparison of the predictive performance of three pharmacokinetic models for propofol using measured values obtained during target-controlled infusion.

We compared the predictive performance of the existing Diprifusor and Schnider models, used for target-controlled infusion of propofol, with a new modification of the Diprifusor model (White) incorporating age and sex covariates. The bias and inaccuracy (precision) of each model were determined using computer simulation to replicate the infusion profiles in an earlier study of 41 patients undergoing surgery with propofol administered by target-controlled infusion and in which timed, measured blood propofol concentrations were available. Bias with the White model (5%) was significantly less (p < 0.0001) than with the Diprifusor (16%) or Schnider (15%) models. The White model showed a significant improvement in accuracy (inaccuracy 19%, p < 0.0001) relative to the Diprifusor (26%). Temporal changes were such that with all three models, bias differed at induction and recovery. None of the models accounted fully for the extent of inter-individual variation in propofol clearance, but the improved performance with the White model suggests it has merit.

A novel technique to determine an 'apparent ke0 ' value for use with the Marsh pharmacokinetic model for propofol.

Debate continues over the most appropriate blood-brain equilibration rate constant (ke0) for use with the Marsh pharmacokinetic model for propofol. We aimed to define the optimal ke0 value. Sixty-four patients were sedated with incremental increases in effect-site target concentration of propofol while using six different ke0 values within the range 0.2-1.2 min(-1). Depth of sedation was assessed by measuring visual reaction time. A median 'apparent ke0' value of 0.61 min(-1) (95% CI 0.37-0.78 min(-1)) led to the greatest probability of achieving a stable clinical effect when the effect-site target was fixed at the effect-site concentration displayed by the target-controlled infusion system, at the time when a desired depth of sedation had been reached. By utilising a clinically relevant endpoint to derive this value, inter-individual pharmacokinetic and pharmacodynamic variability may be accounted for.

Induction of general anaesthesia by effect-site target-controlled infusion of propofol: influence of pharmacokinetic model and ke0 value.

We studied the use of a new ke0 value (0.6 min(-1)) for the Marsh pharmacokinetic model for propofol. Speed of induction and side-effects produced were compared with three other target-controlled infusion systems. Eighty patients of ASA physical status 1-2 were studied in four groups in a prospective, randomised study. Median (IQR [range]) induction times were shorter with the Marsh model in effect-site control mode with a ke0 of either 0.6 min(-1) (81 (61-101 [49-302])s, p < 0.01), or 1.2 min(-1) (78 (68-208 [51-325])s, p < 0.05), than with the Marsh model in blood concentration control (132 (90-246 [57-435])). The Schnider model in effect-site control produced induction times that were longer (298 (282-398 [58-513])s) than those observed with the Marsh model in blood control (p < 0.05), or either effect-site control mode (p < 0.001). There were no differences in the magnitude of blood pressure changes or frequency of apnoea between groups.

Evaluation of the predictive performance of four pharmacokinetic models for propofol.

BACKGROUND: This study has compared the predictive performance of four pharmacokinetic models, two of which are currently incorporated in commercial target-controlled infusion pumps for the administration of propofol. METHODS: Arterial propofol concentrations and patient characteristic data were available from nine patients who, in a published study, had received a standardized infusion of propofol. Predicted concentrations with 'Diprifusor' (Marsh), 'Schnider', 'Schuttler', and 'White' models were obtained by computer simulation. The predictive performance of each model was assessed overall and over the following phases: rapid infusion (1-5 min), early (1-21 min), maintenance (21-min end-infusion), and recovery (2-20 min post-infusion). RESULTS: The overall assessment, based on 29-36 samples from each patient, indicated that all four models were clinically acceptable. However, the negligible bias (-0.1%) with the 'Schnider' model was accompanied by overprediction in the rapid infusion phase and underprediction during recovery. This changing bias over time was not detected as 'divergence' when assessed on absolute performance error (APE), (1.4% h(-1)) but became significant (13.2% h(-1)) when based on changes in signed PE over time. The 'Schuttler' model performed well at most phases but overpredicted concentrations during recovery. The White model led to a marginal improvement over 'Diprifusor' and would be expected to reduce the positive bias usually seen with 'Diprifusor' systems. CONCLUSIONS: In assessing the predictive performance of pharmacokinetic models, additional information can be obtained by analysis of bias at different phases of an infusion. The evaluation of divergence should involve linear regression analysis of both absolute and signed PEs.

Evaluation of a new method of assessing depth of sedation using two-choice visual reaction time testing on a mobile phone.

The utility of two-choice visual reaction time testing using a specially programmed mobile telephone as a measure of sedation level was investigated in 20 healthy patients sedated with target controlled infusions of propofol. At gradually increasing target concentrations visual reaction time was compared with patient-assessed visual analogue scale sedation scores and an observer-rated scale. Propofol sedation caused dose-dependent increases in visual reaction time and visual analogue scale scores that were statistically significant when the calculated effect-site concentration reached 0.9 microg.ml(-1) (p < 0.05) and 0.5 microg.ml(-1) (p < 0.01) respectively. While visual analogue scale scores were more sensitive at lower levels of sedation than visual reaction time, the latter demonstrated marked increase in values at higher levels of sedation. Visual reaction time may be useful for identifying impending over-sedation.

Propofol sedation using Diprifusor target-controlled infusion in adult intensive care unit patients.

This multicentre, non-comparative study investigated the range of target blood propofol concentrations required to sedate 122 adult intensive care patients when propofol was administered using Diprifusor target-controlled infusion systems together with opioid analgesia. Depth of sedation was assessed with a modified Ramsay score and the target blood propofol setting was adjusted to achieve the sedation desired for each patient. A desired level of sedation was achieved for 84% of the sedation period. In postcardiac surgery patients the median time-weighted average propofol target setting was 1.34 microg.ml(-1) (10th - 90th percentiles: 0.79-1.93 microg.ml(-1)). Values in brain injured and general ICU patients were 0.98 (10th - 90th percentiles: 0.60-2.55) microg.ml(-1) and 0.42 (10th - 90th percentiles: 0.16-1.19) microg.ml(-1), respectively. Measured propofol concentrations were generally close to values predicted by the Diprifusor system. Target settings in the range of 0.2-2.0 microg.ml(-1) are proposed for propofol sedation in this setting with titration as required in individual patients.

Evaluation and optimisation of a target-controlled infusion system for administering propofol to dogs as part of a total intravenous anaesthetic technique during dental surgery.

The performance of a modified target-controlled infusion system was investigated in 16 dogs undergoing routine dental work, by comparing the predicted concentrations of propofol in venous blood samples with direct measurements; the optimum targets for the induction and maintenance of anaesthesia were also identified. The performance of a target-controlled infusion system is considered clinically acceptable when the median prediction error, a measure of bias, is not greater than +/-10 to 20 per cent, and the median absolute performance error, a measure of the accuracy, is not greater than 20 to 30 per cent. The results fell within these limits indicating that the system performed adequately. The optimal induction target was 3 microg/ml, and anaesthesia of adequate depth and satisfactory quality was achieved with maintenance targets of between 2.5 and 4.7 microg/ml propofol. The system was easy to use and the quality of anaesthesia was adequate for dental work.

The development of 'Diprifusor': a TCI system for propofol.

The 'Diprifusor' target controlled infusion system has been developed as a standardised infusion system for the administration of propofol by target controlled infusion. A preferred set of pharmacokinetic parameters for propofol was selected using computer simulation of a known infusion scheme with pharmacokinetic parameters described in published literature. The selected model was included in a 'Diprifusor' module that was interfaced with, and later incorporated into, a computer-compatible infusion pump. Clinical trials with such systems led to guidance on appropriate target concentrations for the administration of propofol by 'Diprifusor' target controlled infusion for inclusion in drug prescribing information. Standardisation of the delivery performance (+/- 5%) of commercial systems has been achieved with a laboratory performance specification. Clinical studies indicate that the actual blood concentrations achieved were about 16% greater than the calculated values displayed by the system. In an individual patient, titration of the target concentration is required in the same manner as an anaesthetic vapouriser is adjusted to obtain a specific pharmacodynamic effect.

Evaluation of the predictive performance of a 'Diprifusor' TCI system.

The predictive performance of a 'Diprifusor' target controlled infusion system for propofol was examined in 46 patients undergoing major surgery, divided into three age groups (18-40, 41-55 and 56-80 years). Measured arterial propofol concentrations were compared with values calculated (predicted) by the target controlled infusion system. Performance indices (median performance error and median absolute performance error) were similar in the three age groups, with study medians of 16.2% and 24.1%, respectively. Mean values for 'divergence' and 'wobble' were -7.6%.h-1 and 21.9%, respectively. Measured concentrations tended to be higher than calculated concentrations, particularly following induction or an increase in target concentration. The mean (SD) propofol target concentration of 3.5 (0.7) micrograms.ml-1 during maintenance was lower in older patients, compared with higher target concentrations of 4.2 (0.6) and 4.3 (0.7) micrograms.ml-1 in the two younger age groups, respectively. The control of depth of anaesthesia was good in all patients and the predictive performance of the 'Diprifusor' target controlled infusion system was considered acceptable for clinical purposes.

Administration of propofol by target-controlled infusion in patients undergoing coronary artery surgery.

OBJECTIVES: To study the predictive performance of a target-controlled infusion (TCI) system of propofol in patients undergoing coronary bypass graft (CABG) surgery, using a referenced pharmacokinetic set derived from healthy patients. Also, to determine the propofol concentrations required for clinically acceptable induction and maintenance of anesthesia when combined with midazolam as premedication and a continuous alfentanil infusion and to study the hemodynamic stability of this technique. DESIGN: Prospective noncomparative study analysis. SETTING: Operating room at a university hospital. PARTICIPANTS: Twenty-on patients with good left ventricular function undergoing coronary artery surgery. INTERVENTIONS: Patients were anesthetized using a continuous infusion of alfentanil (mean infusion rate: 1 microgram/kg/min) and propofol administered by TCI. MEASUREMENTS AND MAIN RESULTS: The predictive performance of the TCI system (212 arterial samples) was measured at specified time points before, during, and after bypass. The TCI system underestimated the measured blood propofol concentrations with a bias of +21.2% and +9.6% during the prebypass and the bypass periods, respectively. The predictive inaccuracy, expressed by the median absolute prediction error, was 23% and 18.5%, respectively. Mean target propofol concentrations required to induce and maintain anesthesia before bypass were 0.92 microgram/mL and 3.64 micrograms/mL, respectively. In the period during and after bypass, the mean target concentrations required to maintain anesthesia was 2.22 micrograms/mL. The administration of propofol by TCI was still associated with some short episodes of hemodynamic instability that were easily controlled by adjusting the target concentration in the majority of the patients. Therefore, the overall quality and ease of control of anesthesia were considered as being good or adequate. CONCLUSIONS: In this group of patients undergoing CABG surgery, the TCI system used underestimated the measured propofol concentrations. However, the predictive performance of the selected mean pharmacokinetic parameters derived from healthy patients was acceptable during the whole surgical procedure.

Total intravenous anaesthesia with propofol or inhalational anaesthesia with isoflurane for major abdominal surgery. Recovery characteristics and postoperative oxygenation--an international multicentre study.

Two hundred and ten adult patients undergoing open cholecystectomy, vagotomy or gastrectomy were included in a randomised multicentre study to compare postoperative nausea and vomiting, oxygen saturations for the first three postoperative nights, time to return of gastrointestinal function, mobilisation, and discharge from the hospital following induction and maintenance of anaesthesia with propofol and alfentanil or with thiopentone, nitrous oxide, isoflurane and alfentanil. Recovery from anaesthesia was significantly faster in the propofol group (mean (SD) times to eye opening and giving correct date of birth of 14.0 (SD 13.8) and 25.5 (SD 29.5) minutes, and 18.5 (SD 14.8) and 35.5 (SD 37.2) minutes in the propofol and isoflurane groups respectively). There was significantly less nausea in the propofol group (15.4%) than in the isoflurane group (33.7%) in the first two postoperative hours (p < 0.003) but not thereafter. There were no significant differences between the groups in any other recovery characteristics. The incidence of hypoxaemia (arterial oxygen saturation less than 93%) was close to 70% in both groups for the first three postoperative nights, indicating the need for oxygen therapy after major abdominal surgery.

Manual compared with target-controlled infusion of propofol.

We studied 160 ASA I-II patients, anaesthetized with propofol by infusion, using either a manually controlled or target-controlled infusion system. Patients were anaesthetized by eight consultant anaesthetists who had little or no previous experience of the use of propofol by infusion. In addition to propofol, patients received temazepam premedication, a single dose of fentanyl and 67% nitrous oxide in oxygen. Each consultant anaesthetized 10 patients in sequential fashion with each system. Use of the target-controlled infusion resulted in more rapid induction of anaesthesia and allowed earlier insertion of a laryngeal mask airway. There was a tendency towards less movement in response to the initial surgical stimulus and significantly less movement during the remainder of surgery. Significantly more propofol was administered during both induction and maintenance of anaesthesia with the target-controlled system. This was associated with significantly increased end-tidal carbon dioxide measurements during the middle period of maintenance only, but recovery from anaesthesia was not significantly prolonged in the target-controlled group. With the exception of a clinically insignificant difference in heart rate, haemodynamic variables were similar in the two groups. Six of the eight anaesthetists found the target-controlled system easier to use, and seven would use the target-controlled system in preference to a manually controlled infusion. Anaesthetists without prior experience of propofol infusion anaesthesia quickly became familiar with both manual and target-controlled techniques, and expressed a clear preference for the target-controlled system.

Pharmacokinetic model selection for target controlled infusions of propofol. Assessment of three parameter sets.

BACKGROUND: Computer-assisted target controlled infusions (TCI) result in prediction errors that are influenced by pharmacokinetic variability among and within patients. It is uncertain whether the selection of a propofol pharmacokinetic parameter set significantly influences drug concentrations and clinical acceptability. METHODS: Thirty patients received similar propofol TCI regimens after being randomly allocated to one of three parameter sets. Arterial and venous concentrations were measured and prediction errors calculated from pooled and intrasubject data. RESULTS: Arterial propofol concentrations in the Dyck group revealed greater bias (mean 43%) than did those in the Marsh (-1%) and Tackley (-3%) groups. The Dyck group also showed greater inaccuracy (mean:47%) than the Marsh (29%) and Tackley (24%) groups. There was little tendency for measured concentrations to vary from targeted values over time (divergence). Variability about an observed mean in individual patients (wobble) was low. Venous propofol concentrations were initially much less than arterial concentrations, but this difference decreased over time. CONCLUSIONS: Although it may be preferable to administer propofol TCI by using a locally derived parameter set, it is acceptable to use a model from elsewhere. The Marsh and Tackley models produced equally good performance and are appropriate for propofol TCI within the range of 3-6 micrograms/ml. The Dyck model was less accurate at maintaining anesthetic concentrations, possibly because it was derived from low concentrations. Concentrations in blood, the most sensitive indicators of performance, demonstrated differences among the parameter sets. Clinically, TCI worked well, and by clinical criteria, the choice of pharmacokinetic model did not appear to make a difference.

Propofol administered by a manual infusion regimen.

We have evaluated the clinical utility and blood propofol concentrations produced with two different infusion regimens for propofol, given to supplement 67% nitrous oxide-morphine anaesthesia. Patients received a standardized three-step infusion of propofol based either on body weight (weight-corrected group) or on a mean body weight of 70 kg (standard dose group). Both groups showed similar cardiovascular stability and recovery times. In the 48 patients studied, isoflurane was used as a supplement in nine (two in the weight-corrected group). Apparent steady state blood propofol concentrations were 3.41 (SD 0.69) micrograms ml-1 in the weight-corrected group and 3.46 (0.79) microgram ml-1 in the standard dose group. These results suggest that for patients weighing 60-90 kg body weight, a standard dose infusion regimen may be a suitable starting point. In routine clinical practice, the need for isoflurane supplementation may be avoided by subsequent titration of the infusion rate according to clinical response. Computer simulation of the actual infusion rates used in each patient has allowed retrospective comparison of the predictive performance of different pharmacokinetic descriptors for propofol. The variables described by Tackley and colleagues provided a more accurate prediction of the measured blood propofol concentration than did the variable set reported by Gepts and colleagues.

Disposition and pharmacology of propofol glucuronide administered intravenously to animals.

1. Propofol glucuronide (PG) is the major human metabolite of the i.v. anaesthetic propofol, 2,6-diisopropylphenol. 2. Bolus i.v. doses of 14C-PG (1 mg/kg) to rat and dog were eliminated in urine (40 and 66% respectively) and faeces (48 and 19%); 25 and 48% of the dose were excreted unchanged in urine. 3. In dog, PG was distributed from plasma (t 1/2 4 min) into a volume equivalent to extracellular water and eliminated with t 1/2 80 min. Total body clearance was 1.8 ml/min per kg, and renal clearance about 20% GFR. In rat, plasma 14C concentrations were about one-tenth those in dog, thus PG levels were not quantified. 4. Propofol was not detected in the plasma showing that PG is hydrolytically stable. Enterohepatic circulation of PG occurred in rat and to a lesser extent in dog. Metabolites, mainly side-chain hydroxylation products, were evident in both species from 4 h after dosing. 5. Bolus i.v. doses of PG (200 mg/kg) showed no hypnotic activity in mice.