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Hyperglycolysis is a known phenomenon after severe subarachnoid hemorrhage (SAH) and after brain injury. It is characterized by decreased oxidative metabolism and relatively increased anaerobic glycolysis. Metabolic suppressive therapy reduces the cerebral metabolic rate of oxygen (CMRO(2)) and the cerebral metabolic rate of glucose (CMRGluc). If CMRO(2) is suppressed after SAH, withdrawal of metabolic suppressive therapy could lead to the accumulation of lactate. In this project, we assessed the relationship between the withdrawal of metabolic suppressive therapy and cerebrospinal fluid (CSF) lactate concentration. A prospective observational database containing 262 patients with SAH was retrospectively analyzed. CSF lactate levels were compared with the daily dose of metabolic suppressive therapy. Outcome was assessed with the Glasgow Outcome Scale (GOS). In 56% of patients an increase in CSF lactate (mean: 3.2 ± 0.9 mmol/L) after withdrawal of metabolic suppressive therapy was observed. Mean Glasgow Outcome Score (GOS) was lower in patients with an increase in CSF lactate concentration (>0.5 mmol/L) after withdrawal of metabolic suppressive therapy (p = 0.095). In 88% of patients who died during the first 30 days after SAH, a CSF lactate elevation of more than 0.5 mmol/L after withdrawal of metabolic suppressive therapy was found (p = 0.071).

Background: Although propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression., Methods: Theoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model., Results: Compared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%., Conclusion: The integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.

A sensitive gas chromatography-mass spectrometry method for measuring propofol in cerebrospinal fluid is described, validated and applied to four patients after traumatic brain injury. The limit of quantitation was 2 microg/L using a volume of 0.5 mL. The inter- and intra-assay coefficients of variation were 5.9 and 5.1%, respectively. The assay covers the linear concentration range of 2-50 microg/L, which is relevant in clinical pharmacokinetic studies when propofol is used in the Intensive Care Unit as a sedative agent or to lower the intracranial pressure.

Aim: To determine propofol concentration in the cerebral spinal fluid (CSF) of neurosurgical patients and carry out a preliminary population pharmacodynamic study., Methods: Twenty-seven elective neurosurgical patients (12 men and 15 women) aged 17-74 years received propofol in a bolus dose of 2 mg/kg for 5 min and an infusion of 10 mg/kg per h for 5 min. Frequent CSF samples were drawn and assayed for propofol concentration. The bispectral index (BIS) was used to measure the drug effect. All data were analyzed first with the Excel software package, then pharmacodynamics modeling was performed using the NONMEM software package., Results: The CSF concentration was related to the drug effect with linear and sigmoid Emax models. The parameters for the linear addictive model were a=1.11 and b=95.4. The parameters for the linear exponential model were a=1.05 and b=92.7. The parameters for the sigmoid E(max) model were E(max)=119, EC(50)=53.6 ng/mL, and N=1.51. When the covariates of age, weight and sex were considered, the parameters of models, objective function, the standard error of the mean and the prediction error were not optimized., Conclusion: Linear additive, linear exponential and sigmoid E(max) models can be used to describe the pharmacodynamics of propofol with respect to the concentration in CSF. In this small population, age (17-74 years), weight (47-98 kg) and sex did not influence any of the pharmacodynamic parameters of propofol. To verify these preliminary results, a larger study population is required.

Objective: To establish a method for determining propofol in human cerebrospinal fluid (CSF)., Methods: Reverse phase high-performance liquid chromatography (HPLC) with fluorescence detection was applied to quantitative analysis. CSF samples were centrifuged (12,500 r/min for 3 min) and filtered (the diameter of the filter is 0.45 microm). Twenty mul of supernatant was directly injected and separated by Supelco Discovery C(18)column. The mobile phase was composed of methanol-water (80:20); the flow rate was 1 ml/min, and the column temperature was 30 degree. The fluorescence detective waves were: lambda ex=276 nm and lambda em=310 nm., Results: The linear range of propofol in CSF was 5-200 ng/ml (r=0.9994). The recovery rates for high, intermediate and low concentrations were 101.2%, 99.8%, 98.8%, respectively. The RSD of inter-day assay was 1.55%, 1.73%, 6.01% and it of intra-day assay was 1.69%, 2.37%, 8.60%. The limit of detection proved to be 2 ng/ml., Conclusion: The method is rapid, simple, accurate and sensitive for measurement of propofol concentration in CSF.

Objective: Investigation of the propofol concentration changes in cerebrospinal fluid (CSF) after the termination of the drug infusion., Methods: Nine patients (American Society of Anesthesiologists classes I-III) scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation, the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (fraction of inspired oxygen = 0.33). Arterial blood and CSF samples (from an intraventricular drain) were taken simultaneously at the end of propofol infusion and then at 15, 30, 45, 60, 90, and 120 minutes after the end of infusion., Results: A pronounced decrease of the anesthetic concentration in plasma (P < 0.001) was observed during the first 15 minutes after infusion termination, followed by further yet slower decrease of the drug concentration. At the end of propofol infusion, the concentration of propofol in CSF was 65.59 ng/mL (SD, 26.91 ng/mL) and remained almost stable for approximately 30 minutes; afterward, a slow decrease of CSF propofol concentration was observed., Conclusion: The statement that CSF can be regarded as a significant route for drugs delivery to the brain is disputable for propofol. The obtained results show that, in contrast to the situation from induction of anesthesia, back transport of the drug from CSF to blood is markedly slower, supporting the thesis about propofol transport from blood to CSF by passive diffusion.

Objective: The aim of this paper is to compare the propofol concentration in plasma and cerebrospinal fluid (CSF) in patients scheduled for intracranial tumor removal and anaesthetized using propofol as part of a total intravenous anaesthesia technique., Methods: Twenty-seven patients (ASA I-II) scheduled for elective intracranial tumor removal were studied. Anesthesia was induced with 2 mg/kg propofol for 5 min and infused at 10 mg/(kg x h) for 5 min and then stopped. CSF and arterial blood were collected simultaneously before infusion of propofol and at different time points after infusion of propofol according to bispectral index (BIS) values. Concentrations of propofol in plasma and CSF were measured by HPLC with fluorescence detection. The correlation coefficient and regression equation between plasma and CSF concentration of propofol were worked out by linear simple regression., Results: The propofol CSF concentration that we measured was 1.46% of the plasma concentration. The coefficient of relation between plasma and CSF concentration was 76.7%., Conclusions: The propofol CSF concentration was positively correlated with and much lower than the plasma concentration. Discrepancies may result from high plasma protein binding of propofol, intracranial pathology and sampling volume.

Background: Propofol is one of the most frequently applied intravenous anesthetics. Although it has been used for a long period, its pharmacokinetics, especially central nervous system pharmacokinetics, are not fully recognized., Objective: Investigation of the relationships between total propofol concentration in blood, total propofol concentration in cerebrospinal fluid (CSF), free propofol concentration in blood, and free anesthetic concentration in CSF in patients undergoing elective neurosurgery and anesthetized with propofol., Methods: Eleven patients scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (Fi O2 = 0.33). CSF and blood were taken at the moment of intraventricular drainage application., Results: The unbound propofol concentration in plasma is 1.12% (SD 0.61%; SEM 0.18%) of the total concentration in plasma, and the free propofol concentration in plasma is 71.6% (SD 61.0%; SEM 18.4%) of the total CSF propofol concentration. The free anesthetic concentration in CSF is 30.9% (SD 15.7%; SEM 4.7%) of the total CSF propofol concentration, and 61.8% (SD 34.9%; SEM 10.5%) of the free propofol concentration in plasma., Conclusion: The relationship between unbound drug concentrations in plasma and in CSF determined in this study leads to the postulate that propofol is transported from blood to CSF by passive diffusion.

Background: Although the performance of target-controlled infusion (TCI) have been studied extensively, the accuracy and safety of a TCI system that targets the effect site remains to be demonstrated. This study was to investigate the relations of TCI of propofol to its concentrations in cerebral spinal fluid (CSF), the effect-site concentrations and bispectral index (BIS)., Methods: Twelve mongrel dogs were used for investigations. The target effect-site concentration was set at 3 microg/ml and the infusion was lasted for 15 minutes. CSF and blood samples were then collected and propofol concentrations were determined by using high performance liquid chromatography with fluorescence detection. BIS and hemodynamic data were monitored continuously., Results: The predicted plasma concentrations were generally overestimated. Median performance error (MDPE) and absolute median performance error (MDAPE) were -10.0% and 29.9% respectively. Propofol CSF concentrations were much lower than its effect-site concentrations. Changes in BIS were consistent with propofol concentrations in CSF, both of which changed direction at 5 minutes while the effect-site concentrations relatively lagged behind. Better correlation (r(2) = 0.9195) was found between BIS and CSF concentrations, when compared with that between BIS and effect-site concentrations (r(2) = 0.554)., Conclusion: With 1% enflurane inhaled, the inconsistency of drug effect to the effect-site concentrations may result from inaccuracy of pharmacokinetic parameters. CSF may show effect-site concentrations more accurately than plasma when using target effect-site concentration infusion.

Aims: The aim of this study was to define the relationship between unbound propofol concentrations in plasma and total drug concentrations in human cerebrospinal fluid (CSF), and to determine whether propofol exists in the CSF in bound form., Methods: Forty-three patients (divided into three groups) scheduled for elective intracranial procedures and anaesthetized by propofol target control infusion (TCI) were studied. Blood and CSF samples (taken from the radial artery, and the intraventricular drainage, respectively) from group I (17 patients) were used to investigate the relationship between unbound propofol concentration in plasma and total concentration of the drug in CSF. CSF samples taken from group II (18 patients) were used to confirm the presence of the bound form of propofol in this fluid. The CSF and blood samples taken from group III (eight patients) were used to monitor the course of free and bound CSF propofol concentrations during anaesthesia., Results: For group I patients the mean (and 95% confidence interval) total plasma propofol concentration was 6113 (4971, 7255) ng ml(-1), the mean free propofol concentration in plasma was 63 (42, 84) ng ml(-1), and the mean total propofol concentration in CSF was 96 (76, 116) ng ml(-1) (P < 0.05 for the difference between the last two values). For group II patients the fraction of free propofol in CSF was 31 (26, 37)%. For group III patients the fraction of free propofol in CSF during TCI was almost constant (about 36%)., Conclusions: The unbound propofol concentration in plasma was not equal to its total concentration in CSF and cannot be directly related to the drug concentration in the brain. Binding of propofol to components of the CSF may be an additional mechanism regulating the transport of the drug from blood into CSF.

The paper compares the total propofol concentration in the cerebrospinal fluid (CSF) with the free drug concentration in plasma measured in 35 humans scheduled for elective neurosurgical procedures during propofol anaesthesia. The concentrations of total and free propofol in the blood and CSF samples were measured by means of HPLC using liquid-liquid extraction and ultrafiltration in the sample preparation procedure. The arterial blood and CSF samples (collected from intraventricular drainage) were taken at the same time. According to the obtained results, the usually expected equality between free drug concentration in plasma and its total concentration in CSF is not valid for propofol: the unbound propofol concentration in plasma is not equal to its total concentration in CSF (p < 0.05). This difference suggests a substantial contribution of active transport in propofol transfer from blood into CSF. Moreover, the paper shows the presence of bound propofol in CSF, which is a novel finding., (Copyright 2003 John Wiley & Sons, Ltd.)

Background: The aim of this paper is to compare the propofol concentration in blood and cerebrospinal fluid (CSF) in patients scheduled for different neurosurgical procedures and anaesthetized using propofol as part of a total intravenous anaesthesia technique., Methods: Thirty-nine patients (ASA I-III) scheduled for elective intracranial procedures, were studied. Propofol was infused initially at 12 mg kg(-1) h(-1) and then reduced in steps to 9 and 6 mg kg(-1) h(-1). During anaesthesia, bolus doses of fentanyl and cis-atracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (FI(O(2))=0.33). Arterial blood and CSF samples for propofol examination were obtained simultaneously directly after intracranial drainage insertion and measured using high-performance liquid chromatography. The patients were divided into two groups depending on the type of neurosurgery. The Aneurysm group consisted of 13 patients who were surgically treated for ruptured intracranial aneurysm. The Tumour group was composed of 26 patients who were undergoing elective posterior fossa extra-axial tumour removal., Results: Blood propofol concentrations in both groups did not differ significantly (P>0.05). The propofol concentration in CSF was 86.62 (SD 37.99) ng ml(-1) in the Aneurysm group and 50.81 (26.10) ng ml(-1) in the Tumour group (P<0.005)., Conclusions: Intracranial pathology may influence CSF propofol concentration. However, the observed discrepancies may also result from quantitative differences in CSF composition and from restricted diffusion of the drug in the CSF.

Unlabelled: We studied the changes in the propofol concentration in the cerebrospinal fluid (CSF) in 14 patients, undergoing elective intracranial procedures, who were anesthetized with propofol administered by target-controlled infusion. During anesthesia, fentanyl and cisatracurium were administered as required. After intubation of the trachea, the lungs of the patients were ventilated to normocapnia with an oxygen-air mixture (FIO(2) = 0.33). Arterial blood and CSF samples (from an intraventricular drain) were collected between 90-180 min after the induction of anesthesia. Blood propofol concentrations were stable, between 5.0 +/- 1.89 and 4.5 +/- 1.7 microg/mL (mean +/- SD). There was a significant decrease in the CSF propofol concentration, from 52.2 +/- 35.01 ng/mL at 90 min to 28.6 +/- 21.9 ng/mL at 150 min (P < 0.05). The CSF propofol concentration at 180 min (21.4 +/- 14.0 ng/mL) was not significantly different from the concentration at 150 min. Some possible reasons for this decrease after commencing continuous intraventricular drainage are discussed., Implications: Propofol concentrations in the cerebrospinal fluid in neurosurgical patients Propofol concentration in cerebrospinal fluid of investigated patients decreased significantly after starting intraventricular drainage, despite relatively steady blood propofol concentrations. These results supplement the limited information about propofol pharmacokinetics in the human central nervous system.

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.

Background: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45-min infusion (10 mg/min)., Methods: Six sheep were prepared with arterial and sagittal sinus (effluent from the brain) blood sampling catheters and a Doppler flow probe for measuring an index of cerebral blood flow. Propofol concentrations in arterial and sagittal sinus blood during and after the infusions were measured using high-performance liquid chromatography with fluorescence detection. Brain concentrations were calculated from these concentrations and cerebral blood flow using direct mass balance methods., Results: There was dysequilibrium between the arterial blood and brain concentrations until approximately 30 min after the start of the infusion, with marked hysteresis between the arterial blood and brain concentrations for the duration of the study. The equilibrium half-life between the blood and the brain was 3.5 min, which is comparable to the value of 4.3 min derived from the earlier rapid administration data, suggesting there was no time dependency in the kinetics of cerebral uptake. The mass of propofol entering the brain via arterial blood was the same as the mass leaving the brain via sagittal sinus blood, suggesting minimal metabolism of propofol in the brain of sheep., Conclusion: It is clear that pharmacokinetic analysis based on arterial blood concentrations alone cannot accurately account for the concentrations of propofol at its site of action in the brain.

The concentration of propofol in and surrounding the human brain during propofol anaesthesia is unknown. We measured simultaneously the concentration of propofol in cerebrospinal fluid (CSF) from an indwelling intraventricular catheter and the concentration in arterial blood in five neurosurgical patients before, during induction (at 2.5 and 5 min) and during a maintenance propofol infusion (at 15 and 30 min). After induction of anaesthesia with propofol 2 mg kg-1, anaesthesia was maintained with an infusion of 8 mg kg-1 h-1 for 15 min and then reduced to 6 mg kg-1 h-1. The plasma concentration of propofol increased rapidly during induction and reached a plateau concentration of mean 2.24 (SD 0.66) micrograms ml-1 after 5 min. The concentration of propofol in CSF showed a slower increase during induction and remained almost constant at 35.5 (19.6) ng ml-1 at 15-30 min after induction. The CSF concentration of propofol that we measured was 1.6% of the plasma concentration and consistent with the high protein binding of the drug in plasma.