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Summary 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

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.

Summary 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.

Summary 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

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 '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.

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.

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.

We have studied the effects of graded infusion rates of propofol (0.2-0.5 mg kg-1 min-1) on left ventricular global and regional function, in eight acutely instrumented dogs. Global function was assessed by measurement of aortic and left ventricular pressure, LV dP/dtmax, aortic blood acceleration and stroke volume. Regional function was assessed by measurement of systolic shortening and the end-systolic pressure-length relationship. The response of the coronary circulation to short periods of occlusion was also assessed. Administration of propofol significantly reduced left ventricular preload, as indicated by reductions in end-diastolic pressure and length; contractility was depressed, the depression being greater in the apex than in the base of the left ventricle. High infusion rates impaired relaxation. Regulation of coronary blood flow was not disrupted. Reductions in preload and contractility contributed to the propofol-induced hypotension. After 60 min, recovery from the greatest infusion rate was incomplete.

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.

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.

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.

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.

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.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.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.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.

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.

Studies with an emulsion formulation of ICI 35 868 (2,6- diisopropylphenol ) indicate that this new formulation has anaesthetic properties in rats and mice, and haemodynamic effects in the mini-pig which are similar to those of the previously available Cremophor formulation. Administration of the emulsion formulation to dogs produced no untoward effect, whereas the Cremophor formulation produced a marked increase in plasma histamine concentration. In the mini-pig, no adverse response was produced by the repeated administration of the emulsion formulation of ICI 35 868, whereas the Cremophor formulation produced anaphylactoid responses when a second injection was given 1 week after an uneventful first exposure to this formulation. Behavioural responses in the rat suggest that the emulsion formulation may produce less discomfort on i.v. injection.

Summary A minimum fresh gas flow of I litre per minute per mask and an inspired concentration of 2-3% halothane was required to induce anaesthesia in rats in 1-2 min. Anaesthesia was maintained with an inspired concentration of 1·5-2% halothane. Arterial carbon dioxide concentration increased during anaesthesia and was not reduced by increasing the flow of fresh gas. Using the apparatus described here, halothane vapour concentration in the operator's breathing zone was 5 ppm. Prior to its introduction, levels of 250 ppm had been recorded in a poorly-ventilated animal room. Although it has been suggested that trace concentrations of anaesthetics may affect the psychomotor performance of operating theatre personnel (Bruce, Bach & Arbit, 1974), the balance of experimental evidence indicates that concentrations of halothane much higher than to ppm are required to produce detrimental effects (Smith & Shirley, 1978). A recent review of possible hazards in operating theatres concluded that the risk of spontaneous abortion appeared to be increased in association with anaesthetic practice (Spence & Knill-Jones, 1978). Although there is no direct evidence to implicate contamination by anaesthetics, it is sensible to take reasonable precautions to reduce that contamination. The system commonly used to anaesthetize rats with gaseous agents utilizes a continuous flow of a vapour mixture, delivered through a face mask. This invariably leads to a considerable escape of anaesthetic vapour into the operator's breathing zone. Our objective was to evaluate the effectiveness of a system designed to limit this atmospheric contamination to an acceptable and reasonable level.

The authors investigate the applicability of the relationship Nsh = A + B NmReNnSc to determine over-all mass transfer rates in forced convection from single solid spheres, where A, B, m and n are presumed to be constants. This expression is shown to be not entirely adequate and, in particular, the changing importance of the wake with increasing Reynolds number and turbulence in the boundary layer will affect these constants.

Summary A number of design modifications have been made to an extraction system for use with inhalation anaesthesia techniques in rats and other small laboratory animals. These changes necessitated a re-evaluation of the effectiveness of this equipment in limiting the operator's exposure to the anaesthetic vapours used. With a given fresh gas flow. the halothane vapour concentration in the operator's breathing zone was dependent on the design of the oronasal mask. With the optimum configuration the atmospheric concentration of halothane was less than 1 ppm. Previous work with a scavenging system designed for use with inhalation anaesthesia techniques in rats indicated that the halothane vapour concentration in an operator's breathing zone could be limited to 5 ppm (Glen, Cliff & Jamieson, 1980). The system as originally designed utilized a charcoal adsorber in the horizontal position and could have allowed anaesthetic vapour to pass across the upper surface of the charcoal in the adsorber. To ensure more effective adsorption the apparatus has been modified to allow the adsorber to be placed in a vertical position. Further changes have been made to the electric fan used to draw vapour through the adsorber and to the dimensions of the tubing used to deliver anaesthetic to the oronasal mask. Because of these changes it was necessary to re-evaluate the effectiveness of the apparatus in limiting the operator's exposure to the anaesthetic vapours used. Materials and methods The apparatus ('Fluovac': International Market Supply, 183 Crompton Road, Macclesfield, Cheshire SK 11 8EH) as currently constructed is shown in Fig. 1. When used with halothane the anaesthetic vapour is delivered from a calibrated vaporizer to an oronasal mask (Fig. 2) via polythene tubing placed within a piece of larger bore flexible tubing. An electric fan is used to draw waste anaesthetic gases through this outer tubing to the adsorber ('Cardiff Aldasorber'; Shirley Aldred and Co. Ltd, Worksop, Nottinghamshire

The anaesthetic properties of propofol ('Diprivan') have been described previously. This report summarizes additional studies designed to investigate some aspects of the general pharmacology of propofol. Following recovery from anaesthesia with propofol there was no evidence of any central anticholinergic or anticonvulsant effect in mice. An anti-convulsant effect followed thiopentone anaesthesia. In mice anaesthetized with propofol 24 h after the last of 4 daily doses of phenelzine, amitriptyline, diazepam or alcohol, no marked potentiation of anaesthesia was found. Pretreatment with alcohol on the day of anaesthesia potentiated thiopentone but not propofol anaesthesia. Oral doses of propofol up to 300 mg/kg failed to induce anaesthesia in mice. The acute administration of the beta-adrenoceptor antagonists, atenolol or propranolol was well tolerated during anaesthesia with propofol in pigs. In the cat the arrhythmia threshold to adrenaline was greater than that in cats anaesthetized with halothane and no ganglion blocking or alpha-adrenoceptor antagonist properties were demonstrated. No potent or specific agonist or antagonist properties were detected in the range of in vitro systems examined. Neither propofol nor thiopentone had any effect on ADP-induced platelet aggregation or whole blood clotting time. Bronchomotor tone and gastrointestinal motility were unaffected by propofol. Tests of renal function indicated only a slight reduction in sodium excretion, similar to that seen with thiopentone. A normal corticosterone response to ACTH was seen in rats anaesthetized for 90 min with an infusion of propofol.

This randomized study compared the effects of the emulsion formulation of propofol with those of the Cremophor-containing agent Althesin. Plasma histamine concentration, immunoglobulin levels, total complement C3 and complement C3 conversion were measured prior to and following induction of anaesthesia in 32 male volunteers with either 2 mg/kg propofol or 0.05 ml/kg Althesin. In only one volunteer, in the Althesin group, was an increase in plasma histamine to a value greater than 1 ng/ml associated with a relatively large increase over the base line value. Cutaneous signs, such as flushing, did not correlate with the plasma concentrations of histamine. No changes consistent with a propensity to produce anaphylactoid reactions could be seen from measurements of immunoglobulin levels, complement C3 or plasma histamine concentration in the propofol treated subjects.

Fifty consecutive cases of salivary mucocoeles in dogs were investigated. Twenty-four dogs were presented with both cervical and sublingual mucocoeles; in twenty-three cases a cervical swelling only was noted and in three cases a sublingual mucocoele (ranula) existed on its own. Sialography demonstrated sublingual gland, or duct, defects in forty cases. In seven of the remaining ten cases, normal mandibular sialograms were obtained on the affected side. Bilateral sublingual gland involvement was confirmed by sialography in eight cases and suggested by circumstantial evidence in a further two cases. Surgical excision of the mandibular and sublingual glands on the affected side, combined with drainage of the mucocoele contents, has proved to be a reliable approach to treatment.

SUMMARY Cortisol utilization by salivary glands, kidneys and adrenals of various mammals has been compared by using a standard histochemical technique for the demonstration of hydroxysteroid dehydrogenases. 11β-Hydroxysteroid dehydrogenase activity was localized in salivary gland ducts, renal collecting and convoluted tubules and in the adrenal cortex of some species. There was no obvious relationship between the levels of enzyme activity in the salivary glands, kidneys and adrenals. Neither was the presence of 11β-hydroxysteroid dehydrogenase in salivary glands particularly associated with mucous or serous secretion, nor were sex differences in levels of activity evident.