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Background: Anaesthesia for awake craniotomy aims for an unconscious patient at the beginning and end of surgery but a rapidly awakening and responsive patient during the awake period. Therefore, an accurate pharmacokinetic/pharmacodynamic (PK/PD) model for propofol is required to tailor depth of anaesthesia., Objective: To compare the predictive performances of the Marsh and the Schnider PK/PD models during awake craniotomy., Design: A prospective observational study., Setting: Single university hospital from February 2009 to May 2010., Patients: Twelve patients undergoing elective awake craniotomy for resection of brain tumour or epileptogenic areas., Intervention: Arterial blood samples were drawn at intervals and the propofol plasma concentration was determined., Main Outcome Measures: The prediction error, bias [median prediction error (MDPE)] and inaccuracy [median absolute prediction error (MDAPE)] of the Marsh and the Schnider models were calculated. The secondary endpoint was the prediction probability PK, by which changes in the propofol effect-site concentration (as derived from simultaneous PK/PD modelling) predicted changes in anaesthetic depth (measured by the bispectral index)., Results: The Marsh model was associated with a significantly (P = 0.05) higher inaccuracy (MDAPE 28.9 ± 12.0%) than the Schnider model (MDAPE 21.5 ± 7.7%) and tended to reach a higher bias (MDPE Marsh -11.7 ± 14.3%, MDPE Schnider -5.4 ± 20.7%, P = 0.09). MDAPE was outside of accepted limits in six (Marsh model) and two (Schnider model) of 12 patients. The prediction probability was comparable between the Marsh (PK 0.798 ± 0.056) and the Schnider model (PK 0.787 ± 0.055), but after adjusting the models to each individual patient, the Schnider model achieved significantly higher prediction probabilities (PK 0.807 ± 0.056, P = 0.05)., Conclusion: When using the 'asleep-awake-asleep' anaesthetic technique during awake craniotomy, we advocate using the PK/PD model proposed by Schnider. Due to considerable interindividual variation, additional monitoring of anaesthetic depth is recommended., Trial Registration: ClinicalTrials.gov identifier: NCT 01128465.

Background: Target-controlled infusions (TCIs) of propofol are commonly used for general anaesthesia. The Marsh model pharmacokinetic parameter set incorporated in TCI devices for propofol could increase bias when used in obese patients., Objective: The purpose of this study was to assess the optimal predicted blood concentration (Cp) of 4.0 μg ml of propofol using a correction formula including BMI and to evaluate the influences on propofol concentration in obese patients., Design: An open-label, comparative study., Setting: Sapporo Medical University Hospital, Japan, from October 2011 to December 2013., Patients: Seventy-five adults scheduled for elective surgery under general anaesthesia with the following exclusion criteria: less than 30 or more than 65 years of age; American Society of Anesthesiologists status 3 to 5; allergy to propofol; the daily use of psychoactive drugs; known or suspected drug or alcohol abuse; and cardiac, hepatic, renal or neurological impairment., Intervention: Propofol was administered and maintained at a Cp of 4.0 μg ml using a TCI device programmed with the Marsh pharmacokinetic model. Arterial blood samples were collected at 15, 30, 60, 90, 120, 150 and 180 min after the start of the infusion, and the measured propofol concentration (Cm) was determined. After calculation of the adjustment formula using the corrected Cp of 69 patients, we then applied the corrected Cp to five other obese patients., Main Outcome Measures: The median performance error (MDPE) and median absolute performance error (MDAPE) were calculated to measure bias at each time point., Results: We analysed 333 samples from the 69 individuals. There was a significant correlation between BMI and Cm, which tended be greater than 4.0 μg ml in obese patients. Our new method improved MDPE and MDAPE from a range of 20 to 40 for both, to ranges of -11.3 to -1.8 and 8.8 to 11.5, respectively., Conclusion: BMI influences blood propofol concentrations, leading to the possibility of overdosage of propofol in obese patients when the Marsh model is used to assess propofol concentration. Our new method using corrected Cp might improve this bias in obese, Japanese patients.

Background: Propofol target-controlled infusion (TCI) in effect site mode has become popular since it became commercially available., Objective: We have performed a study to assess the pharmacokinetic performance of the Marsh model in effect site mode in an unselected group of patients during neurosurgery during the maintenance phase of anaesthesia., Design: Fifty American Society of Anesthesiologists (ASA) physical status classes 1 to 3 adults underwent elective neurosurgery receiving propofol TCI using the Marsh model in effect site mode. Propofol dose titration and level of patient monitoring was determined by the attending anaesthesiologist. Arterial blood was sampled at regular intervals during the maintenance phase of anaesthesia and measured plasma propofol concentrations were compared with those estimated using TCI., Setting: Large tertiary referral centre in Birmingham, UK, with a specialist neuroanaesthesia service., Patients: Fifty ASA status I to III adult patients undergoing elective neurosurgery., Main Outcome Measures: Performance of Marsh model as assessed by median performance error (bias) and median absolute performance error (imprecision)., Results: Performance of the Marsh model showed a positive bias (median performance error) of 27.6%, and imprecision (median absolute performance error) of 29.4%. Analysis of pooled data demonstrated greatest bias in the early phase (15 to 30 min) of anaesthesia (mean prediction error of 51.6%). Analysis of covariates demonstrated that obesity (BMI >30 kg m(-2)) contributed around half of the bias detected (mean prediction error 47 vs. 23%, P < 0.001). Patients with advanced age and significant comorbidity (ASA physical status class >2) actually demonstrated significantly lower prediction errors., Conclusion: Pharmacokinetic analysis suggests that the performance of the Marsh model in effect site mode is poor in this broad patient population. The greatest bias demonstrated occurred in the early maintenance phase of anaesthesia. Of the covariates analysed, obesity contributed most significantly to an increased bias. Despite overall poor performance of the Marsh model, attending anaesthesiologists modified targeted propofol concentrations only 0.3 times per hour on average, using remifentanil dose modification nine times more frequently, with good surgical conditions in all patients.

Background and Objective: The impact of anaesthesia using target-controlled infusion with propofol on intraoperative stability, recovery and cost compared to manually controlled infusion has been evaluated with inconsistent results. We studied a new device that allows more individual titration of propofol target-controlled infusion by using the effect-site concentration at the loss of eyelash reflex to predict the maintenance infusion rate (FM-TCI)., Methods: Fifty-six patients undergoing major abdominal surgery lasting >2 h were randomly assigned to receive either FM-TCI (n = 28) or MCI-controlled (n = 28) anaesthesia. Both groups were Bispectral Index-monitored and thoracic epidural analgesia was established. Anaesthetic stability, incidence of haemodynamic abnormalities, time to extubation, propofol consumption and patient satisfaction were assessed., Results: In the FM-TCI group, a significantly improved anaesthetic stability was achieved (0.43 +/- 0.44 vs. 1.31 +/- 0.78 adjustments of propofol infusion per patient per hour, P = 0.003) and time to extubation was significantly shorter (9.6 +/- 2.1 vs. 15.7 +/- 9.6 min P = 0.011). With FM-TCI, propofol consumption was significantly lower. Haemodynamic stability and patient satisfaction did not differ between the groups., Conclusion: FM-TCI helps to provide more stable anaesthesia conditions requiring less-frequent adjustments of the propofol infusion compared to manually controlled infusion in patients undergoing major abdominal surgery.

Background and Objective: The objectives of this study were, firstly, to characterize the inter-patient variability in the dose of propofol required to achieve a bispectral index <70 and 'time to eye opening' following propofol infusion and, secondly, to determine if the pharmacodynamic parameter 'time to achieve bispectral index <70' was influenced by genotype of the sex-linked drug receptor gene GABRE or if pharmacokinetic parameters such as clearance and 'time to eye opening' were influenced by the genotype of the metabolizing enzyme CYP2B6., Methods: One hundred and fifty patients received a standardized anaesthetic. Apparent systemic clearance values were estimated. Correlation was sought between carriers of different CYP2B6 and GABRE genotypes and apparent systemic clearance, 'time to achieve bispectral index <70' and 'time to eye opening'., Results: Propofol induction/emergence characteristics varied, with slow recovery times in a subset of males. Time to loss of verbal contact and time to bispectral index <70 varied 6.6- and 4.3-fold, respectively. At emergence, there was a 15.5- to 111-fold variability in the measured time intervals. Clearance varied from 9.1 to 55.8 mL min-1 kg-1. The CYP2B6 C1459T (R487C) genotype frequencies were TT 1%, TC 22% and CC 67%. The three major haplotypes of CYP2B6 (R487C, K262R and Q172H variants) were not significantly associated with time to eye opening or clearance. Clearance was similar in 487C carriers and 487RR genotypes. There was no statistically significant correlation between the four major haplotypes of GABRE variants investigated ([mRNA358]G/T, 20118C/T, 20326C/T and 20502 A/T) and the observed anaesthesia induction time., Conclusions: Great inter-patient variability exists in the dose of propofol required to achieve bispectral index <70, apparent systemic propofol clearance and time to eye opening. Common haplotypic differences at the CYP2B6 and GABRE genes do not appear to account for the majority of the observed inter-patient variability.

Background and Objective: Propofol has been shown to inhibit a variety of functions of neutrophils in vitro, but there is a lack of in vivo data. To analyse the effects of propofol on neutrophil function in vivo we chose to investigate cataract surgery since it represents a small surgical procedure with minimal immunomodulatory effects induced by surgery. We sought to analyse any immunosuppressive effects of propofol after short-term administration in vivo in comparison to local anaesthesia as well as to in vitro effects of propofol., Methods: The study was designed as an open randomized trial enrolling 20 patients undergoing general or local anaesthesia. The neutrophil oxidative response and propofol plasma concentration were assessed prior, during and after anaesthesia. Neutrophil function was determined flow cytometrically based on dihydrorhodamine 123 oxidation., Results: Propofol concentrations which yielded a marked suppression in vitro did not alter the neutrophil oxidative response during cataract surgery in vivo. However, after local anaesthesia the neutrophil oxidative response declined to 37%, compared to the control response prior to anaesthesia., Conclusions: Although we could detect the well established suppression of neutrophil function by propofol in vitro it was not evident in vivo. This may be due to compensating effects on neutrophil function during surgery in vivo. The decline in the neutrophil oxidative response in the local anaesthesia group might be due to increased stress and catecholamine concentrations or a direct interaction of local anaesthetics with neutrophil intracellular signalling.

Background and Objective: High doses of opioid associated with low doses of hypnotic is a popular anaesthetic technique since the use of remifentanil has become widespread. This type of anaesthesia could result in a higher incidence of implicit memory., Methods: Ten patients were anaesthetised with a target-controlled infusion of remifentanil (target concentration of 8 ng mL(-1)) combined with a target-controlled infusion of propofol with progressive stepwise increases until loss of consciousness was reached. A tape containing 20 words was then played to the patients. Bispectral index (BIS, Aspect Medical Systems, Newton, MA, USA) was continuously monitored during the whole study period. Implicit and explicit memories were tested between 2 and 4 h after recovery., Results: Loss of consciousness was obtained with a mean calculated propofol plasma concentration of 1.3 +/- 0.4 microg mL(-1). At this low hypnotic concentration no implicit or explicit memory was found in the three postoperative memory tests. Median (range) BIS value during word presentation was 93 (80-98)., Conclusions: In our group of young American Society of Anesthesiologists (ASA) I/II patients, no explicit or implicit memory was found when the calculated concentration of propofol combined with a high concentration of remifentanil was maintained at the level associated with loss of consciousness with high BIS values.

Background and Objective: Although percutaneous nephrolithotomy has many advantages over open surgery, some endocrine and haemodynamic responses have been reported. However, the effects of anaesthetic agents on these responses have not previously been reported. This study compared the effects of sevoflurane and total intravenous anaesthesia using propofol and alfentanil on the haemodynamic and hormonal changes during percutaneous nephrolithotomy., Methods: Forty-two ASA I-II patients aged between 15 and 65 yr were studied. Sevoflurane in Group S (21 patients) or TIVA in Group TIVA (21) was used for the maintenance of anaesthesia. Haemodynamic variables and serum concentrations of sodium and potassium were measured before, during and after the procedure. Arterial blood-gas status, plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were measured before and during the procedure., Results: Mean heart rate was lower during percutaneous nephrolithotomy in Group TIVA compared with Group S (P < 0.01). The mean systolic and diastolic arterial pressures were not different in both groups at any stage of measurement (P < 0.05). Plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were increased during percutaneous nephrolithotomy in both groups, but the increase was greater in Group S (P < 0.05)., Conclusions: In the sevoflurane group, the concentrations of renin, aldosterone and adrenocorticotrophic hormone were significantly higher after 15 min of irrigation compared with the total intravenous anaesthesia group. Although the clinical significance of this difference was not clear, these changes should be considered in certain patient groups.

Background and Objective: We ascertained whether dreams during short general anaesthesia influence subsequent patient satisfaction and anxiety., Methods: Fifty female patients were randomized into two groups to test for a difference between intravenous and inhalational anaesthesias. In Group Propo, anaesthesia was induced and maintained with propofol; in Group Metho-Iso, anaesthesia was induced with methohexital and maintained with isoflurane. Satisfaction and anxiety with anaesthesia were evaluated using a visual analogue scale from 0 to 100. Dream incidence rate, satisfaction and anxiety were assessed from immediately after waking until 3 months later., Results: Seventeen patients (34%) dreamed during anaesthesia. There were no significant differences in satisfaction or anxiety after anaesthesia between the dreaming and non-dreaming patients (satisfaction, 92.3 +/- 21.6 versus 92.1 +/- 21.6; anxiety, 21.1 +/- 21.1 versus 30.3 +/- 32.1), or between Group Propo and Group Metho-Iso (satisfaction, 94.4 +/- 19.3 versus 90.0 +/- 23.4; anxiety, 26.0 +/- 27.6 versus 28.4 +/- 30.7). There was no significant difference in the incidence rate of dreaming with the type of anaesthesia used (Group Propo, 11 patients; Group Metho-Iso, 6 patients)., Conclusions: Dreaming during general anaesthesia is common but does not influence satisfaction or anxiety after anaesthesia.

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.

The effects of propofol on mean arterial pressure, heart rate and Adelta and C somatosympathetic reflexes, recorded in renal nerves, evoked by repeated individual supramaximal electrical stimuli applied to radial nerves, were observed in anaesthetized, paralysed and artificially ventilated dogs. Propofol was infused at rates from 0.4 to 2.0 mg kg-1 min-1. Mean C and Adelta reflexes were abolished at plasma concentrations (mean, SEM) of 24.3 (3.3) and 29.2 (2.6) microg mL-1 (P < 0.05), respectively, when mean arterial pressure and mean heart rate were reduced by approximately 55% (P < 0.01) and 26% (P > 0.05), respectively. Recovery of Adelta and C reflexes occurred at plasma concentrations of 13.1 (2.3) and 9.9 (1.3) microg mL-1 (P > 0.05), respectively. There was a log- arithmically linearly related fall in mean arterial pressure by 70% up to a plasma concentration approximately 97 microg mL-1 (r 2=0.7) with a 28% reduction in heart rate which was uncorrelated with the plasma concentrations (r 2=0.12). In conclusion, propofol abolished Adelta and C responses at comparable plasma concentrations and caused a major reduction in both mean arterial pressure and heart rate which is consistent with resetting of the baroreflexes. The reduction in mean arterial pressure was logarithmically, linearly correlated with a progressive increase in plasma concentrations without evidence of a ceiling effect.

This study was designed to examine the effect of volume loading on haemodynamic responses and regional cardiac function in dogs subjected to two infusion rates of propofol. Instrumentation was established to measure aortic and left ventricular pressures, cardiac output and myocardial segmental lengths. Measurements were taken during two successive infusion rates of propofol: 0.2 (P0.2) and 0.4 (P0.4) mg kg-1 min-1. One group (VL +) (n = 6) received volume loading (dextran 40, 10 mL kg-1 h-1), the other group (VL-) (n = 6) received only basal perfusion (Ringer solution, 2 mL kg-1.h-1). Regional blood flows were measured by radio-labelled microspheres. P0.4 induced a decrease in cardiac output and in dP/dtmax. End-diastolic length decreased with propofol without any difference between groups. Regional contractility was not modified by propofol or by volume loading. P0.4 decreased endocardial and epicardial blood flow in the VL-group only. Renal, small intestine and large intestine blood flows decreased in both groups with P0.4. P0.2 did not alter regional blood flows significantly. It was concluded that in this model, propofol infusion at 0.4 mg kg-1 min-1 induced splanchnic, renal and myocardial hypoperfusion in animals not submitted to a mild fluid loading. Fluid loading allowed myocardial perfusion to be maintained but could not prevent a marked decrease in splanchnic and renal perfusion.

The antioxidant capacity of plasma taken from 10 patients before and during propofol anaesthesia was measured. Mean total plasma antioxidant activity fell from 1.73 to 1.64 mM L-1 trolox equivalents (P = 0.047). This was caused by haemodilution since mean haemoglobin concentration fell from 13.0 to 12.5 g dL-1 (P = 0.016). The time to 50% haemolysis (H50) of 10% red blood cell suspensions induced by 2,2'azo-bis(2-amidinopropane) dihydrochloride (ABAP) was measured in blood from six patients. There was no change when red cells alone were studied, but when the patients' plasma was added to red cell suspensions (producing 10% plasma and 10% red cell suspensions), mean H50 increased from 291 to 308 min (P = 0.049). Despite there being no overall increase in plasma antioxidant activity, the lipid soluble component of blood antioxidant activity appears to be increased by propofol.

The initial disposition of propofol was reported to change when the administration was preceded by fentanyl. The pharmacokinetic profile of the induction dose of propofol (2 mg kg-1 body weight) was studied in 20 ASA I patients randomly allocated to receive fentanyl 1.5 microgram kg-1 (n = 12) or not (n = 8). Anaesthesia was maintained with isoflurane in N2O/O2. Venous blood drawn from the contralateral arm was used to determine whole blood propofol concentrations. The mean propofol blood concentrations were comparable in the two groups and were best fitted by a three exponential equation in all the patients, conforming to a three-compartment open mammillary model. Distributions (T1/2 alpha) redistribution (T1/2(7)) and elimination (T1/2 beta half-lives were comparable in the groups, without significant differences in the total body clearance in the area under the time-concentration curve (zero-infinity) in the volume of distribution at steady-state, in the volume of distribution during the elimination phase or in the mean resident time. Our data support the conclusion that pretreatment with fentanyl does not affect the pharmacokinetic profile of the induction dose of propofol in ASA I patients.