A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies.

We aimed to identify biomarkers in skin punch biopsies that could be used to monitor progression of diabetic peripheral neuropathy (DPN), and, in future studies, to assess the efficacy of agents that may reduce progression. Patients with DPN were studied with clinical assessments, skin biopsies, quantitative sensory testing (QST), histamine-induced skin flare, nerve conduction studies and contact heat-evoked potentials (CHEPS). Skin biopsies were performed on two visits with a 6 month interval (n=29 patients) to quantify intraepidermal (IENF) and subepidermal (SENF) nerve fibres immunoreactive for: protein gene product 9.5 (PGP9.5), a pan-neuronal marker; transient receptor potential cation channel vanilloid 1 (TRPV1), the heat and capsaicin receptor; and growth associated protein-43 (GAP-43), a marker of regenerating fibres. The IENF were counted along the length of four non-consecutive sections, and results were expressed as fibres per millimetre length of section. SENF were measured by image analysis, and the area of highlighted immunoreactivity was obtained as a percentage (% area) of the field scanned. QST, skin flare and CHEPS were also performed at the two visits. We found that IENF and SENF were significantly reduced for both PGP9.5 and TRPV1 between the first and second skin biopsy over 6months. The annual rate ± standard error of the mean of IENF loss was 3.76 ± 1.46 fibres/mm for PGP9.5, and 3.13 ± 0.58 fibres/mm for TRPV1. The other tests did not show significant changes. Strongly positive GAP-43 nerve fibres were found in deep dermis in the patients with diabetes, even in those with an absence of IENF. We conclude that PGP9.5 and TRPV1 IENF and SENF in skin biopsies are useful markers of progression in DPN, whereas GAP-43 SENF could potentially help detect nerve regeneration in severe neuropathy.

Patient-controlled analgesia during SWL treatments.

PURPOSE: To identify the factors that influence analgesic consumption during SWL on the Dornier Lithotripter U/50. PATIENTS AND METHODS: In Group 1 (N = 152), analgesia was induced with propofol 0.8 mg/kg and alfentanil 8 microg/kg. In Groups 2 (N = 78) and 3 (N = 250), the induction dose was reduced by 20%. For all patients, the maintenance dose was propofol 0.25 mg/kg and alfentanil 5 mg/kg administered with a patient-controlled analgesia (PCA) device. Groups 1 and 2 had SWL with the EMSE 220 shockwave emitter, whereas Group 3 was treated with the EMSE F150. Data were collected on treatment, total drug doses, and side effects. RESULTS: There was no significant difference in PCA dose among the groups, but analgesic consumption was lower in patients treated with the EMSE F150. Except in Group 2, analgesic consumption tended to decrease with age until age <70. The 20% reduction in the induction dose did not cause an increase in PCA usage. Analgesic consumption was higher for kidney than for ureteral stones and was highest for stones in renal pelvis. Consumption was lower for larger stones than for smaller stones and higher for patients receiving more shockwaves. Almost one quarter of patients in Group 1 exhibited transient O2 desaturation during induction, an effect that was less common in the other groups. Ventricular premature beats were detected only during treatment of stones above the ureteropelvic junction. CONCLUSIONS: Intravenous administration of a combination of alfentanil and propofol via a PCA device is an elegant, reliable, and safe method of analgesosedation for SWL. Patient satisfaction is high, and side effects are uncommon. Faster turnover of patients is possible.

An economic evaluation of Tomudex (raltitrexed) and 5-fluorouracil plus leucovorin in advanced colorectal cancer.

Our objective was to establish the balance between costs and effects of treatment with Tomudex (raltitrexed) as an alternative to treatment with 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with advanced colorectal cancer. Data were used from an international, open label randomized clinical trial. Costs were calculated by multiplying resource utilization data with Dutch estimates of unit costs. Effects have been expressed in terms of 6 months and 1 year survival, and in terms of the number of patients without severe adverse events including WHO grade 3 and 4 leucopenia, mucositis, anemia and severe asthenia. Cost effectiveness is expressed in terms of costs per additional day of survival and costs per additional patient without any severe adverse event. The clinical results did not show significant survival differences implying great uncertainty about the cost-effectiveness of raltitrexed in terms of additional costs per additional life-year gained. However, 80% of the initially higher cost of raltitrexed ($3132 per patient) is compensated by savings due to a more convenient administration scheme leading to a net cost of $626 per patient treated. Weighed against the decrease in adverse events, a cost-effectiveness ratio results of $3936 per additional patient free of any severe adverse event. More favorable estimates result when the convenience of the administration scheme is valued in positive monetary terms.

Prostate specific antigen density of the transition zone for early detection of prostate cancer.

PURPOSE: We compare the ability of several prostate specific antigen (PSA) parameters, including PSA density of the whole prostate and of the transition zone, percent free PSA and PSA velocity, to enhance the specificity for prostate cancer detection and to reduce unnecessary biopsies in men with serum PSA levels of 4 to 10.0 ng./ml. MATERIALS AND METHODS: This prospective study included 559 consecutive men referred for early prostate detection or lower urinary tract symptoms who had a serum PSA of 4.0 to 10.0 ng./ml. All men underwent prostatic ultrasonography and sextant biopsy with 2 additional transition zone biopsies. Specific biopsies of abnormal findings on digital rectal examination were also performed. In all cases if first biopsies were negative an additional set of biopsies was performed within 6 weeks. The ability of PSA density, PSA transition zone, PSA velocity and percent free PSA to improve the power of PSA in the detection of prostate cancer was evaluated with univariate and multivariate analyses as well as receiver operating characteristics (ROC) curves. RESULTS: Of 559 patients 342 had histologically confirmed benign prostatic hyperplasia and 217 had prostate cancer. Mean serum PSA, PSA velocity, PSA density and PSA transition zone were statistically higher (p <0.018, p <0.037, p <0.0001 and p <0.0001, respectively) and percent free PSA was statistically lower (p <0.0001) in patients with prostate cancer than in those with benign disease. Multivariate analysis and ROC curves showed that PSA transition zone and percent free PSA were the most powerful and highly significant predictors of prostate cancer. Areas under the ROC curve for PSA transition zone and percent free PSA were 0.827 and 0.778, respectively (p=0.01 McNemar test). Combination of free-to-total PSA with PSA transition zone significantly increased the area under the ROC curve compared to PSA transition zone alone (p=0.020). With a 95% sensitivity for prostate cancer detection a PSA transition zone cutoff of 0.25 ng./ml./cc would result in the lowest number of unnecessary biopsies (47% PSA transition zone specificity) compared to all other PSA parameters. However, total prostate volume (greater than 30 cc in 422 men or less than 30 cc in 137) was an important factor in predicting the statistical performance of PSA transition zone. In fact, PSA transition zone did not outperform free percent PSA in sensitivity and specificity when the entire prostate gland volume was less than 30 cc (p=0.094 McNemar test). CONCLUSIONS: PSA density of the transition zone enhances the specificity of serum PSA for prostate cancer detection in referred patients with a serum PSA of 4.0 to 10.0 ng./ml. compared to other PSA parameters currently available. While PSA transition zone was more effective in prostates greater than 30 cc and percent free PSA was more effective in prostates less than 30 cc, the combination of percent free PSA with PSA transition zone further increased prostate cancer prediction.

Emergence from target-controlled anesthesia with propofol and sufentanil in patients undergoing intracranial surgery.

The study was designed to characterise the emergence from target-controlled anesthesia assessed by the recovery of spontaneous breathing, eye opening to command, and extubation in 18 adult patients undergoing intracranial surgery. Total intravenous anesthesia was induced and maintained with propofol and sufentanil. Target plasma concentration of propofol ranged between 3.0 and 5.5 micrograms.ml-1 and infusion was stopped after head dressing. The initial target plasma sufentanil concentration of 0.50 ng.ml-1 was decreased to 0.15 ng.ml-1 after craniotomy; sufentanil infusion was discontinued at the dura closure. The time from the end of surgery (head dressing) to recovery of spontaneous breathing was 8.3 +/- 6.5 min, and the time to eye opening and extubation was 14.7 +/- 10.0 min. At the end of surgery, the calculated plasma propofol concentration was 3.42 +/- 0.26 micrograms.ml-1. It significantly decreased to 2.11 +/- 0.51 micrograms.ml-1 at recovery of spontaneous breathing and to 1.81 +/- 0.41 micrograms.ml-1 at eye opening and extubation. The calculated plasma sufentanil concentration was 0.108 +/- 0.019 ng.ml-1 at the end of surgery but did not change significantly between recovery of spontaneous breathing (0.089 +/- 0.013 ng.ml-1), eye opening and extubation (0.087 +/- 0.013 ng.ml-1). The calculated plasma propofol concentrations recorded at emergence were not correlated with patient age, total dose of propofol, and duration of infusion; corresponding calculated sufentanil concentrations were not correlated with age and total dose of sufentanil. An inverse relationship (p < 0.05) was found between the duration of sufentanil infusion and the calculated sufentanil concentrations at emergence. No correlation was observed between calculated concentrations of propofol and sufentanil at emergence.

Clinical usefulness of the bispectral index for titrating propofol target effect-site concentration.

The bispectral index, a new processed electroencephalographic parameter which may give information on depth of anaesthesia, was used in 58 patients undergoing outpatient gynaecological surgery in order to study if the addition of bispectral index monitoring to standard clinical monitoring could improve the titration of target propofol concentration when using effect-site target-controlled propofol infusion for sedation. In Group 1 (n = 30), the bispectral index was recorded but the anaesthetist was unaware of the readings and therefore only classical signs of depth of anaesthesia were used to guide the anaesthetist in controlling the effect-site concentration. In Group 2 (n = 28), bispectral index readings were available to the anaesthetist and effect-site concentration was adjusted to ensure that bispectral index was maintained between 40 and 60. Similar propofol induction and maintenance doses, blood and effect-site concentrations and mean bispectral index were found in the two groups. A greater percentage of bispectral index readings lying outside the target range (i.e. < 40 or > 60) and more movement at incision and during maintenance were found in Group 1. There was a trend towards more implicit awareness in patients in Group 1. Bispectral index was found to be useful for measuring depth of sedation when using propofol target-controlled infusion. Propofol dosage could not be decreased but a more consistent level of sedation could be maintained due to a more satisfactory titration of target effect-site concentration.

Propofol infusion for induction and maintenance of anaesthesia in patients with end-stage renal disease.

We have investigated the pharmacokinetics and pharmacodynamics of propofol in 11 patients with end-stage renal disease (ESRD) compared with nine healthy patients during and after a manually controlled three-stage infusion of propofol 21, 12 and 6 mg kg-1 h-1 lasting a minimum of 2 h. Mean total body clearance was not reduced significantly in the ESRD group (30.66 (SD 8.47) ml kg-1 min-1) compared with the control group (33.75 (7.8) ml kg-1 min-1). ESRD patients exhibited a greater, but not statistically significant, volume of distribution at steady state compared with patients in the control group (11.25 (8.86) vs 5.79 (2.14) litre kg-1, respectively). Elimination half-life values were unchanged by renal failure. Mean times to induction of anaesthesia were similar in both groups: 177 (SD 57) and 167 (58) s for the ESRD and control groups, respectively. Waking time after cessation of propofol infusion was significantly shorter in the ESRD group (474 (156) s) compared with the control group (714 (240) s) (P < 0.05). Mean plasma concentrations on waking were similar. We conclude that the pharmacokinetic and pharmacodynamic profiles of propofol after infusion were not markedly affected by renal failure.

Antihypertensive treatment based on conventional or ambulatory blood pressure measurement. A randomized controlled trial. Ambulatory Blood Pressure Monitoring and Treatment of Hypertension Investigators.

CONTEXT: Ambulatory blood pressure (ABP) monitoring is used increasingly in clinical practice, but how it affects treatment of blood pressure has not been determined. OBJECTIVE: To compare conventional blood pressure (CBP) measurement and ABP measurement in the management of hypertensive patients. DESIGN: Multicenter, randomized, parallel-group trial. SETTING: Family practices and outpatient clinics at regional and university hospitals. PARTICIPANTS: A total of 419 patients (> or =18 years), whose untreated diastolic blood pressure (DBP) on CBP measurement averaged 95 mm Hg or higher, randomized to CBP or ABP arms. INTERVENTIONS: Antihypertensive drug treatment was adjusted in a stepwise fashion based on either the average daytime (from 10 AM to 8 PM) ambulatory DBP (n=213) or the average of 3 sitting DBP readings (n=206). If the DBP guiding treatment was above (>89 mm Hg), at (80-89 mm Hg), or below (<80 mm Hg) target, 1 physician blinded to the patients' randomization intensified antihypertensive treatment, left it unchanged, or reduced it, respectively. MAIN OUTCOME MEASURES: The CBP and ABP levels, intensity of drug treatment, electrocardiographic and echocardiographic left ventricular mass, symptoms reported by questionnaire, and cost. RESULTS: At the end of the study (median follow-up, 182 days; 5th to 95th percentile interval, 85-258 days), more ABP than CBP patients had stopped antihypertensive drug treatment (26.3% vs 7.3%; P<.001), and fewer ABP patients had progressed to sustained multiple-drug treatment (27.2% vs 42.7%; P<.001). The final CBP and 24-hour ABP averaged 144.1/89.9 mm Hg and 129.4/79.5 mm Hg in the ABP group and 140.3/89.6 mm Hg and 128.0/79.1 mm Hg in the CBP group. Left ventricular mass and reported symptoms were similar in the 2 groups. The potential savings in the ABP group in terms of less intensive drug treatment and fewer physician visits were offset by the costs of ABP monitoring. CONCLUSIONS: Adjustment of antihypertensive treatment based on ABP monitoring instead of CBP measurement led to less intensive drug treatment with preservation of blood pressure control, general well-being, and inhibition of left ventricular enlargement but did not reduce the overall costs of antihypertensive treatment.

Trough-to-peak versus surface ratio in the assessment of antihypertensive agents. APTH Investigators. Ambulatory Blood Pressure and Treatment of Hypertension.

This study investigated whether the 'surface ratio', a novel index to characterize long-acting antihypertensive agents, would provide a more reproducible estimate of the duration of the antihypertensive effect than the more commonly used trough-to-peak ratio. In 66 hypertensive patients (diastolic pressure on conventional measurement > 95 mmHg), the ambulatory blood pressure was measured on a placebo at baseline and 2 months later, while the patients took 10 mg lisinopril once a day between 7 p.m. and 11 p.m. Diurnal treatment effect curves were obtained by subtracting the blood pressure at baseline from the corresponding value at 2 months for all time intervals considered in the analysis. In order to calculate the surface ratio, the area under the treatment effect curve was divided by the product of the maximal blood pressure lowering effect and the dosing interval (24 h). Reproducibility of the trough-to-peak and surface ratios was investigated by the Bland and Altman techniques. At 2 months, lisinopril reduced (+/- standard deviation) the 24 h pressure by 13 +/- 16 mmHg systolic and by 8 +/- 8 mmHg diastolic (p < 0.001). According to the usual approach, disregarding inter-individual variability, the trough-to-peak ratio was 0.7 for systolic and diastolic pressure. When in individual patients diurnal treatment effects curves with a 1 h resolution were investigated, the median trough-to-peak ratio was 0.30 for systolic pressure (5th-95th percentile interval [PI]: -0.51, 0.82) and 0.28 for diastolic pressure (PI: -0.37, 0.78); the corresponding values for the surface ratio were 0.33 (PI: 0.03, 0.58) and 0.30 (PI: -0.01, 0.55). In the same manner, the trough-to-peak ratios and surface ratios became larger when the individual blood pressure profiles were progressively smoothed by substituting 1 h averages by 2 h moving averages, 2 h averages, 3 h moving averages or by 3 h averages. The distributions of the trough-to-peak ratios and surface ratios were non-normal in 37 of 40 instances (p < 0.001, Shapiro-Wilk's test). Consistency was higher (p < 0.001) for the surface than for the trough-to-peak ratios. The within-subject reproducibility of the surface ratios tended to be superior to that of the corresponding trough-to-peak ratios. In conclusion, the surface ratio provides an index of the duration of action of antihypertensive agents. Moreover, in the present patients, the surface ratio tended to be characterized by a higher within-subject reproducibility than the trough-to-peak ratio.

Intra- and interobserver variability of a fast on-line quantitative coronary angiographic system.

To evaluate intra- and interobserver variability of an on-line quantitative coronary angiographic system, 2 independent observers measured 166 primary lesions excluding total occlusions before and after coronary angioplasty. Each observer repeated his measurement 3 times at 14 days interval. The average percent diameter stenosis results obtained by observer 1 and 2 were almost identical, before (62.2% +/- 12.0% and 62.6% +/- 11.4%, NS) and after (27.1% +/- 12.0% and 26.9% +/- 11.3%, NS) angioplasty. Variability was expressed as 95% limits of agreement (mean difference +/- 2 x SD). The intra-observer variability of observer 1 ranged from -6.6% to 6.6% before angioplasty and from -9.6% to 9.6% after angioplasty. The corresponding limits of observer 2 were -8.0% to 7.5% and -8.3% to 8.5%, respectively. The interobserver variability ranged from -10.4% to 9.6% before versus -12.5% to 13.1% after angioplasty. This variability was not influenced by vessel size. The widening of the limits observed after angioplasty was largely due to an increased variability in the measurements of the absolute minimal luminal diameter but not of the reference segment. We conclude that the intra- and interobserver variability of measurements obtained with an on-line quantitative angiographic system used for guiding coronary interventions is acceptable and without systematic bias in any direction for a wide range of primary coronary stenoses. However, the variability increases when images are acquired immediately after angioplasty.

Acute haemodynamic effects of lisinopril and captopril in patients with severe congestive heart failure.

The acute haemodynamic effects of several equivalent dosages of lisinopril and captopril were compared in patients with severe class III or IV congestive heart failure. The evaluation was started with a low dose of 2.5 mg lisinopril o.d. or 6.25 mg captopril t.i.d. and subsequent daily increases to 5 and 10 mg lisinopril o.d. or 12.5 and 25 mg captopril t.i.d. Captopril had an earlier onset of action compared to lisinopril and caused larger diurnal fluctuations of the haemodynamic parameters. Lisinopril provoked a more pronounced decrease in pulmonary capillary wedge pressure (PCWP) than captopril and only lisinopril increased the cardiac index significantly. Side-effects of hypotension or increase in serum creatinine leading to withdrawal according to protocol were noted in 3 patients on each drug. Increases in dosage caused very little increase in haemodynamic effect, suggesting that complete suppression of the angiotensin-converting enzyme may not be necessary for an optimal clinical response.

Propofol requirements for induction of anesthesia in children of different age groups.

To demonstrate any age-related differences in propofol requirements for induction of anesthesia, 150 healthy children aged 3-5 yr (n = 50), 6-9 yr (n = 50), and 10-15 yr (n = 50) scheduled for outpatient surgery were randomly assigned to receive an induction dose of propofol of 1.5, 2.0, 2.5, 3.0, or 3.5 mg/kg. To limit pain during injection, alfentanil (5 micrograms/kg) was administered before the propofol. Patients were classified as asleep or not asleep 30 s after the propofol. Incidence of excitation, injection pain, and apnea during induction of anesthesia were noted; arterial blood pressure and heart rate were recorded for 5 min after induction. More than 95% of the children were asleep in the dose groups receiving > or = 2.5 mg/kg. The number of patients falling asleep after receiving 1.5 mg/kg of propofol increased significantly with increasing age (P < 0.05); the difference between the oldest and the youngest age groups was the most significant (P < 0.05). Significant decreases in mean arterial blood pressure and heart rate occurred after induction in all dose and age groups without any systematic intergroup differences. Apnea occurred more frequently in older children (P < 0.01) and with larger doses (P < 0.01). The most frequent side effect was erythema near the site of injection, and its occurrence was dose dependent. The authors conclude that 2.5 mg/kg of propofol, if preceded by 5 micrograms/kg of alfentanil, is an appropriate induction dose for children aged 3-15 yr and that the sleep response to 1.5 mg/kg is more in older children.

Plasma vitamin E, total lipids and myeloperoxidase levels during spinal surgery. A comparison between two anesthetic agents: propofol and isoflurane.

Plasma levels of vitamin E (Vit. E), total lipids (TL), Vit. E to TL ratio and myeloperoxidase (MPO) were studied in 20 patients undergoing lumbar spinal surgery and randomly allocated to two anesthetic groups: propofol (bolus dose + continuous infusion and thiopental/isoflurane. Peripheral blood samples were withdrawn prior to induction, each hour during anesthesia and 1 h after the end of surgery. Mean Vit. E and TL levels as well as mean Vit. E to TL ratios remained in the normal range over the entire period of study whatever the anesthetic regimen. MPO levels rose significantly in the post-operative period only, but without statistical difference between the two groups. Therefore, anesthesia with propofol or thiopental/isoflurane modifies neither total lipid concentrations nor plasma Vit. E, which is a potent endogenous inhibitor of lipid peroxidation bound to lipoproteins. The rise of plasma MPO suggests a moderate post-operative neutrophil activation which is not influenced by anesthetic techniques.

The use of midazolam versus propofol for short-term sedation following coronary artery bypass grafting.

Midazolam and propofol were compared in an open randomized study for postoperative sedation during 12 h of mechanical ventilation in 40 patients following coronary artery bypass grafting. After an intravenous loading dose of midazolam (50 micrograms.kg-1) or propofol (500 micrograms.kg-1), a titrated continuous infusion was administered of midazolam (mean dose 38.1 micrograms.kg-1.h-1 (SEM 2.6)) or propofol (mean dose 909 micrograms.kg-1.h-1 (SEM 100)) together with a narcotic analgesic infusion. During mechanical ventilation midazolam and propofol produced a similar quality of sedation, but recovery (midazolam 66 min (SEM 16); propofol 24 min (SEM 7)) and weaning from the ventilator (midazolam 243 min (SEM 44); propofol 154 min (SEM 33)) where faster with propofol. In the 2 groups administration of an intravenous loading dose caused a significant decrease in mean arterial pressure but hemodynamic tolerance during maintenance infusion was good.

Propofol infusion with or without fentanyl supplementation for microlaryngoscopy.

20 patients (ASA I to III) scheduled for microlaryngoscopy were randomly allocated to receive by infusion either 12-15 mg/kg/h propofol alone (group A) or 6-9 mg/kg/h with fentanyl supplementation (group B). All patients were premedicated with oral diazepam one hour before the procedure; they received an induction dose of 2 mg/kg propofol, preceded in group B by a bolus dose of fentanyl 1 microgram/kg. Significant hypotension was observed at induction in both groups to a similar degree (A:--26%; B:--30.2% compared to baseline). Placement of the laryngoscope induced sustained hypertension throughout the procedure in both groups (A: +28%; B: +20%) subsiding only at the removal of the instrument. Heart rate was never significantly altered. Arterial blood concentrations of propofol at induction reached high peak values (A: 16.82 +/- 8.52 micrograms/ml--B: 19.52 +/- 8.87 micrograms/ml--mean +/- SD) then remained stable throughout the procedure (A: 5.44 +/- 1.40 micrograms/ml--B: 2.91 +/- 1.06 micrograms/ml). At awakening, they were lower in group B (0.62 +/- 0.2 micrograms/ml) than in group A (1.17 +/- 0.55 micrograms/ml--p less than 0.05). Recovery was a little faster in group A (at the limit of significance). Though patients may present some excitation at awakening, recovery was usually very pleasant and characterized by swift return to consciousness, alertness and of all reflexes. We conclude that a propofol infusion is particularly suitable for microlaryngeal surgery. The addition of a narcotic agent allows reduction of the propofol dose range and does not alter recovery significantly. The proper dose of narcotic agent necessary to abolish cardiovascular reactivity to laryngoscopy must still be ascertained.

Does nitrous oxide affect the hemodynamic effects of anesthesia induction with propofol?

Anesthesia was induced in 20 patients, ASA physical status I and II, with either propofol (2.5 mg.kg-1), vecuronium (100 micrograms.kg-1), and 100% oxygen (Group A), or with equal doses of propofol and vecuronium but with 70% nitrous oxide in oxygen (Group B). All patients were premedicated with lorazepam 2 mg orally. In both groups systolic arterial pressure decreased after 3 minutes (P less than 0.05) due to decreases in cardiac output and stroke volume (P less than 0.05). Systemic vascular resistance in both groups did not change immediately after administration of propofol but increased (P less than 0.05) following intubation. Addition of nitrous oxide did not alter hemodynamic parameters associated with propofol induction.

Pharmacokinetics of propofol during continuous infusion for pediatric anesthesia.

The blood concentrations of propofol have been examined during anesthesia by continuous infusion of 12 mg/hg/hr. A bolus dose of 3 mg/kg body weight propofol was used to induce anesthesia. The mean concentrations at apparent steady state were in the range of 4.3 to 5.6 micrograms/ml during the infusion. The mean total body clearance, derived from the apparent steady state concentrations in the blood, was 0.0394 litres/kg/minute. The mean propofol blood concentration at awakening was found to be 2.3 micrograms/ml.