Plasma Propofol Concentrations Research Articles

Influence of hemorrhage on propofol pseudo-steady state concentration.

A small induction dose has been recommended in cases of hemorrhagic shock. However, the influence of hemorrhage on the amplitude of plasma propofol concentration has not yet been fully investigated during continuous propofol infusion. The authors hypothesized that the effect of hemorrhage on plasma propofol concentration is variously influenced by the different stages of shock. After 120 min of steady state infusion of propofol at a rate of 2 mg x kg(-1) x h(-1), nine instrumented immature swine were studied using a stepwise increasing hemorrhagic model (200 ml of blood every 30 min until 1 h, then additional stepwise bleeding of 100 ml every 30 min thereafter, to the point of circulatory collapse). Hemodynamic parameters and plasma propofol concentration were recorded at every step. Before total circulatory collapse, it was possible to drain 976 +/- 166 ml (mean +/- SD) of blood. Hemorrhage of less than 600 ml (19 ml/kg) was not accompanied by a significant change in plasma propofol concentration. At individual peak systemic vascular resistance, when cardiac output and mean arterial pressure decreased by 31% and 14%, respectively, plasma propofol concentration increased by 19% of its prehemorrhagic value. At maximum heart rate, when cardiac output and mean arterial pressure decreased by 46% and 28%, respectively, plasma propofol concentration increased by 38%. In uncompensated shock, it increased to 3.75 times its prehemorrhagic value. During continuous propofol infusion, plasma propofol concentration increased by less than 20% during compensated shock. However, it increased 3.75 times its prehemorrhagic concentration during uncompensated shock.

THIS MONTH IN ANESTHESIOLOGY

THIS MONTH IN ANESTHESIOLOGY

Propofol in a Medium- and Long-Chain Triglyceride Emulsion: Pharmacological Characteristics and Potential Beneficial Effects

Hypertriglyceridemia is a possible unwanted effect during long-term propofol sedation while using a formulation containing long-chain triglycerides (LCT) from soybean oil. The use of propofol formulated in a solvent consisting of medium-chain triglycerides (MCT) and LCT might reduce the risk. Because a new solvent may affect the pharmacological profile of propofol, in this prospective, randomized, controlled, and double-blinded study we compared the pharmacodynamic and kinetic characteristics of propofol diluted in MCT/LCT fat solution with those of propofol formulated in LCT fat emulsion. In addition, serum triglyceride levels were measured during and after the administration of both drugs. Thirty patients likely to require mechanical ventilation over at least 48 h were randomized to receive either propofol 2% MCT/LCT (Group 1) or propofol 2% LCT (Group 2). Infusion rates of propofol (2.34 ± 0.83 mg · kg−1 · h−1 in Group 1 versus 2.31 ± 0.6 mg · kg−1 · h−1 in Group 2), the plasma propofol concentrations during infusion (0.95 ± 0.53 versus 0.98 ± 0.32 μg/mL), and the concentrations and arousal behavior after discontinuation of the drug did not show significant differences. Plasma triglyceride concentrations during sedation did not differ between the groups, whereas there was a tendency toward a more rapid triglyceride elimination in Group 1 after termination of the propofol administration.

Dose-Related Changes in Plasma Propofol Concentration and Burst Suppression Ratio on Electroencephalography during Normothermic Cardiopulmonary Bypass

Dose-Related Changes in Plasma Propofol Concentration and Burst Suppression Ratio on Electroencephalography during Normothermic Cardiopulmonary Bypass

Progressive electroencephalogram frequency deceleration despite constant depth of propofol-induced sedation*

To investigate a possible time-dependent effect of propofol sedation on electroencephalographic activity, we analyzed the electroencephalogram frequency behavior while keeping patients at a constant level of sedation. Prospective, controlled trial. Intensive care unit of a university hospital. Twenty patients without neurologic or metabolic disorders. During sedation with propofol (1-4 mg x kg(-1) x hr(-1)), a bifrontally recorded processed electroencephalogram was obtained. For 48 hrs, sedation was kept constant at a level according to Ramsay Scale 3 while we adjusted the dosage of propofol given per hour. At hours 6, 18, 30, and 42, blood samples were taken to assess the plasma concentration of propofol. The electroencephalogram values of 60 mins obtained during 1 hr before blood sampling were taken for further calculation. From the data, relative band power of the beta-, alpha-, theta, and delta-bands, spectral median frequency, and spectral edge frequency 90 and 95 were computed. For statistical analysis, a polynomial three-factorial repeated-measures analysis of variance with covariates was performed. Relative power of beta- and alpha-wavebands showed a constant and significant decrease over time (beta, 15.5%, 10.3%, 10.3%, 7.6%; alpha, 14.8%, 13.4%, 10.0%, 8.3%), whereas relative delta power increased (delta, 56.4%, 63.4%, 70.7%, 72.3%). The theta-waveband remained unchanged. Accordingly, spectral edge frequency 90 and 95 and spectral median frequency decreased significantly. From hours 6 to 18, a significant increase of the plasma propofol concentration was found. Subsequently, the level remained constant. Despite constant sedation, a longer period of propofol application induces a time-dependent electroencephalogram frequency deceleration. The use of electroencephalogram derivatives to monitor depth of sedation in the intensive care unit thus should be regarded cautiously.

Influence of cardiac output on plasma propofol concentrations during constant infusion in swine.

As propofol is a high-clearance drug, plasma propofol concentrations can be influenced by cardiac output (CO), which can easily change in response to several factors. If propofol is metabolized in the lungs, the difference between pulmonary and arterial propofol concentrations might also be affected by CO. The objective of the current study was to assess how much plasma propofol concentrations are affected by CO and to determine how much the lungs take part in propofol elimination and in concentration changes affected by CO in anesthetized swine. Thirteen swine were studied. Propofol was administered via a peripheral vein at a rate of 6 mg x kg(-1) x h(- 1), and blood samples were simultaneously collected from pulmonary and femoral arteries at 0, 2, 3.5, 5, 7, 10, 20, and 30 min and at 20-min intervals up to 270 min. After 90 min of sampling (baseline 1), CO increased in response to a continuous infusion of dobutamine (20 microg x kg(-1) x min(- 1); high-CO state); the infusion was then stopped, and CO was allowed to return to baseline (baseline 2). Finally, CO decreased with the administration of propranolol (2.0-4.0 mg administered intravenously; low-CO state). Each hemodynamic status was maintained for 1 h. As CO increased 36% from baseline 1, plasma propofol concentrations decreased by 18% from baseline 1, and as CO decreased 42% from baseline 1, plasma propofol concentrations increased by 70% from baseline 1. Plasma propofol concentrations can be expressed by the following equation: plasma propofol concentration (micrograms per milliliter) = 6.51/CO (l/min) + 1.11 (r = 0.78, P < 0.0001). No significant differences were observed between plasma propofol concentrations in pulmonary and femoral arteries in any state, and CO caused no apparent differences between pulmonary and arterial propofol concentrations. An inverse relation was observed between CO and propofol concentrations. The lungs appear to have a minor effect on plasma propofol concentrations during constant infusion in anesthetized swine.

Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography.

The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis. Using H(2)(15)O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC(50), or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 microg/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation. Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36-53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7-16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62-70%, with minor further effects. In the SPM analysis of the "awake to 1 MAC/EC(50)" step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices. Both anesthetic agents caused a global reduction of rCBF (propofol > sevoflurane) at the 1 MAC/EC(50) level. The effect was maintained at higher propofol concentrations, whereas 2 MAC sevoflurane caused noticeable flow redistribution. Despite the marked global changes, SPM analysis enabled detailed localization of regions with the greatest relative decreases.

Cerebral Blood Flow During Propofol Induced Sedation

Purpose: This work determined if 2, 6-diisopropylphenol (propofol) selectively affects cerebral blood flow in regions associated with wakefulness. Procedures: Cerebral blood flow (CBF) was measured with positron emission tomography (PET) using the 15O-water bolus technique in 10 subjects while awake and during light and deep sedation. Arterial blood was sampled for CBF estimation, blood gases and propofol plasma concentrations. Results: Global CBF decreased under deep sedation. A regression analysis of CBF vs. propofol concentration showed significant decreases in CBF in the thalamus and posterior cingulate and increases in the hippocampus and cerebellum. An ANCOVA analysis on condition (controlling for pCO 2 levels) showed mean CBF decreased in the thalamus and posterior cingulate cortex and increased in the primary motor and hippocampal areas during the light and deep sedation compared to awake conditions. Conclusions: These data support the hypothesis that propofol preferentially alters CBF in specific brain regions necessary to maintain wakefulness. (Mol Imag Biol 2002;4:139–146)

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects

Background and objective: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. Methods: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg−1 min−1. Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. Results: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 μg mL−1 min−1, Km = 2.65 μg mL−1, k12 = 0.30 min−1, k21 = 0.063 min−1, Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 μg mL−1, γ = 2.3, ke0 = 0.36 min−1) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. Conclusions: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects.

Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

Flumazenil reduces the hypnotic dose of propofol in male patients under spinal anesthesia

Flumazenil has been reported to produce a partial benzodiazepine-agonist-like effect in some psychopharmacological examinations. This study investigated the effect of flumazenil on the hypnotic activity of propofol in 60 men scheduled for minor surgical procedures done under spinal anesthesia. After a steady state of spinal anesthesia had been reached, patients were pretreated with saline or flumazenil, 5 microg.kg(-1), followed by the administration of saline or midazolam, 10 microg.kg(-1). Then, 250 microg.kg(-1).min(-1) of propofol was infused until hypnosis was achieved. Loss of response to a simple command with a slight stimulus, served as the end-point for hypnosis. Immediately after achievement of the end-point, propofol infusion was discontinued, and a 2-ml venous blood sample was obtained from the dorsal pedis vein to determine plasma propofol concentration. Flumazenil significantly decreased the dose of propofol required and the time required to achieve hypnosis compared with values in the control group (55 +/- 10 [mean +/- SD] vs 71 +/- 14 mg and 212 +/- 42 vs 268 +/- 48 s, respectively; P < 0.05), whereas flumazenil attenuated the effect of midazolam in reducing the plasma concentration of propofol at hypnosis (2.9 +/- 0.5 and 2.5 +/- 0.6 microg.ml(-1), respectively; P < 0.05). These results suggested that flumazenil may potentiate the hypnotic properties of propofol, despite flumazenil having an antagonistic effect on the enhanced hypnotic activity of propofol induced by the coadministration of midazolam.

The Optimal Target Propofol and Alfentanil Concentrations during Plastic Surgery

Background: Propofol and alfentanil are frequently combined to provide total intravenous anesthesia (TIVA). The goals of this study were to determine the target plasma concentration (predicted plasma concentration) of propofol required to provide satisfactory anesthesia in the presence of nitrous oxide over a range of alfentanil infusions for analgesia and to determine the dosing rates required to achieve adequate anesthesia. Methods: Sixty patients undergoing plastic surgery were anesthetized with 50% nitrous oxide, alfentanil (0 [A0 group] or 5g/kg loading followed by 0.12g/kg/min [A5 group] or 10g/kg loading followed by 0.25g/kg/min [A10 group] or 20g/kg loading followed by 0.5g/kg/min [A20 group]) and propofol using a target-controlled infusion (TCI). The mean target concentration and infusion rate of propofol, and induction and recovery time according to changes of the alfentanil regimen were checked. Results: Induction and recovery time were prolonged in the A0 group more than other groups, and recovery time was shortened in the A10 group more than the other three groups (P 0.05). The infusion rate and mean target concentration of propofol had significant impact among the groups (P 0.05). Side effects did not differ among the groups. Conclusions: The optimal target plasma propofol concentrations and infusion rates of alfentanil, both with satisfactory intraoperative anesthetic conditions and speed of recovery, are 3.51, 3.02, 2.35g/ml and 0.12, 0.25, 0.5g/kg/min with 5, 10, 20g/kg loading in plastic surgery patients. We recommand 0.25g/kg infusion with 10g/kg loading of alfentanil combined with 3.02g/ml of target plasma concentration of propofol as the best combination dosage to shorten recovery time.

Target-Controlled Infusion of Alfentanil and Propofol for Total Abdominal Hysterectomy

Background: Alfentanil has been shown to act synergistically if combined with propofol, with or without nitrous oxide, or if combined with potent inhalation anesthetics. The goal of this study was to determine the dosing rate and target plasma concentration of propofol to supplement nitrous oxide in the presence of varying concentrations of alfentanil and to determine the optimal combination of propofol and alfentanil. Methods: Sixty patients undergoing a total abdominal hysterectomy (TAH) were anesthetized with nitrous oxide, and given a target-controlled infusion (TCI) of alfentanil [target plasma concentrations of 0 (A0 group), 50 ng/ml (A50 group), and 100 ng/ml (A100 group)], and propofol at rates varied up and down depending on the bispectal index (BIS). The mean target concentration (Tc) and infusion rate of propofol according to changes of concentrations of alfentanil were determined. Recovery time (from infusion stop to eye opening) and side effects were compared. Results: Induction time and recovery time were shortened in the A50 group and A100 group compared with the A0 group (P 0.05). The infusion rate and mean target concentration of propofol were significantly lower in the A100 group (7.5 mg/kg/h, 3.4g/ml) than the A0 (12.6 mg/kg/h, 4.5g/ml) and A50 (10.2 mg/kg/h, 4.0g/ml) groups (P 0.01). Side effects did not differ among the three groups. Conclusions: The optimal blood propofol and plasma alfentanil concentration, with respect to satisfactory intraoperative anesthetic conditions and speed of recovery, are 4.0g/ml and 50 ng/ml or 3.4g/ ml and 100 ng/ml in TAH patients.

Titration of Effect Site Concentration of Propofol for Conscious Sedation in Elderly Patients

Background: Propofol is used for sedation during local and regional anesthesia. In order to evaluate the depth of sedation the bispectral index (BIS) and observer's sedation scoring (OAA/S) are widely used. However, there are few studies focused on elderly surgical patients during propofol-induced sedation for regional anesthesia. The goal of this study was to examine the effect site concentration of propofol for conscious sedation using the bispectral index (BIS) and hemodynamic changes in elderly patients. Methods: Sixteen patients aged 65 yrs or older presenting for elective surgery requiring regional anesthesia were studied. After performing spinal anesthesia, target plasma concentration of propofol was set at 2.5/ml. Effect site concentration was titrated by increasing and decreasing the target plasma concentration to maintain a BIS of 75-80. Effect site concentration, the OAA/S score, mean arterial pressure (MAP) and heart rate were measured for 1 hour every 5 minutes. Statistical analysis was performed using repeated measurement of ANOVA and correlation analysis. Results: The mean effect site concentrations was 1.3 0.2/ml and OAA/S score was 2.8 0.5 when the BIS was maintained between 75-80. The correlation coefficient for the effect site concentration versus the BIS was r = - 0.79. The MAP significantly decreased with an effect site concentration of propofol 1.0 and 1.2/ml and the heart rate significantly decreased at 1.2/ml. MAP decreased significantly at the level of conscious sedation. Conclusions: The mean effect site concentration of propofol was 1.3 0.2/ml when the BIS was 75-80. There were significant correlation between the effect site concentration and BIS.

Effects of Hypothermic Cardiopulmonary Bypass on Bispectral Analysis

Background: Patient awareness is a particular problem in cardiac anesthesia with cardiopulmonary bypass (CPB). Transformed electroencephalogram monitors, such as the Bispectral index (BIS) monitor, has been advocated as a tool that may reduce the incidence of unexpected intraoperative recall. The authors studied the effects of hypothermia during CPB on the BIS score and the BIS can be a useful monitor to measure anesthetic depth and requirement during hypothermic CPB. Methods: Eighteen consenting volunteers scheduled for an elective cardiac surgery were studied. Volunteers were randomly allocated to one of two groups. All patients were given propofol by a target controlled infusion system, Diprifusor, with fentanyl (0.6 /kg/min). In group A, before and during CPB propofol was infused at a predetermined target plasma concentration (2.0 /ml), the BIS score and temperature were monitored. In group B, before and during CPB, to maintain the BIS score at 30-40 units, changing propofol plasma concentrations and temperature were monitored. Then we asked patients about intraoperative awareness. Results: In group A, compared with before the start of CPB, the BIS score was decreased by the temperature (P

Propofol anaesthesia for surgery in late gestation pony mares

ObjectiveTo characterize propofol anaesthesia in pregnant ponies. AnimalsFourteen pony mares, at 256 ± 49 days gestation, undergoing abdominal surgery to implant fetal and maternal vascular catheters. Materials and methodsPre-anaesthetic medication with intravenous (IV) acepromazine (20 µg kg−1), butorphanol (20 µg kg−1) and detomidine (10 µg kg−1) was given 30 minutes before induction of anaesthesia with detomidine (10 µg kg−1) and ketamine (2 mg kg−1) IV Maternal arterial blood pressure was recorded (facial artery) throughout anaesthesia. Arterial blood gas values and plasma concentrations of glucose, lactate, cortisol and propofol were measured at 20-minute intervals. Anaesthesia was maintained with propofol infused initially at 200 µg kg−1 minute−1, and at 130–180 µg kg−1 minute−1 after 60 minutes, ventilation was controlled with oxygen and nitrous oxide to maintain PaCO2 between 5.0 and 6.0 kPa (37.6 and 45.1 mm Hg) and PaO2 between 13.3 and 20.0 kPa (100 and 150.4 mm Hg). During anaesthesia flunixin (1 mg kg−1), procaine penicillin (6 IU) and butorphanol 80 µg kg−1 were given. Lactated Ringer's solution was infused at 10 mL kg−1 hour−1. Simultaneous fetal and maternal blood samples were withdrawn at 85–95 minutes. Recovery from anaesthesia was assisted. ResultsArterial blood gas values remained within intended limits. Plasma propofol levels stabilized after 20 minutes (range 3.5–9.1 µg kg−1); disposition estimates were clearance 6.13 ± 1.51 L minute−1 (mean ± SD) and volume of distribution 117.1 ± 38.9 L (mean ± SD). Plasma cortisol increased from 193 ± 43 nmol L−1 before anaesthesia to 421 ± 96 nmol L−1 60 minutes after anaesthesia. Surgical conditions were excellent. Fetal umbilical venous pH, PO2 and PCO2 were 7.35 ± 0.04, 6.5 ± 0.5 kPa (49 ± 4 mm Hg) and 6.9 ± 0.5 kPa (52 ± 4 mm Hg); fetal arterial pH, PO2 and PCO2 were 7.29 ± 0.06, 3.3 ± 0.8 kPa (25 ± 6 mm Hg) and 8.7 ± 0.9 kPa (65 ± 7 mm Hg), respectively. Recovery to standing occurred at 46 ± 17 minutes, and was generally smooth. Ponies regained normal behaviour patterns immediately. Conclusions and clinical relevancePropofol anaesthesia was smooth with satisfactory cardiovascular function in both mare and fetus; we believe this to be a suitable anaesthetic technique for pregnant ponies.

The influence of blood sample storage time on the propofol concentration in plasma and solid blood elements.

In order to describe the changes of propofol concentration in whole blood and in its components during the blood storage we examined venous blood samples collected from patients anaesthetized either with or without propofol. Blood samples from patients anaesthetized without propofol were spike with propofol 45 min before analysis. Propofol concentration was examined in whole blood, plasma, rinsed formed elements and rinsed and lysed formed blood elements by means of HPLC after 1, 4, 7, 13, 21, 25 and 28 days of storage. There was significant decrease in plasma concentration of propofol during the first few days of sample storage followed by its increase during subsequent days. The opposite phenomenon was observed for formed blood elements. The findings support the hypothesis that propofol distribution between blood components changes in time.

Determination of the median effective concentration (EC50) of propofol during oesophagogastroduodenoscopy in children.

Propofol is commonly used to provide anaesthesia for children undergoing oesophagogastroduodenoscopy (OGD). Despite this, the plasma concentration-response relationships for propofol used in this setting have not been established. In order to determine the EC50 of propofol during OGD, we studied 12 children aged 3-10 years. No premedication was given. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a paediatric pharmacokinetic model. The 'up-and-down' method described by Dixon was used to determine the EC50. Accordingly, the target plasma propofol concentration for each patient, beginning with the second subject, was determined by the response of the previous patient. A patient was considered a 'responder' if there was minimal movement and the heart rate (HR) and blood pressure (BP) remained < or = 120% of baseline during the procedure. Patients who moved excessively, i.e. requiring more than gentle restraint, or who manifest HR and BP >120% of baseline, were considered 'nonresponders'. The EC50 of propofol during OGD was 3.55 microg.ml(-1) in this study. The plasma propofol concentration associated with adequate anaesthesia for OGD in 50% of unpremedicated children is 3.55 microg.ml(-1). This concentration is higher than that required for OGD in adult patients.

A small dose of midazolam decreases the time to achieve hypnosis without delaying emergence during short-term propofol anesthesia

Study Objective: To evaluate the effect of a small dose of midazolam (10 μg kg −1 ) on induction and emergence during short-term propofol anesthesia and to investigate the effects of subsequent administration of flumazenil. Design: Double-blinded, prospective, randomized study. Setting: Operating room of a medical college hospital. Patients: 30 male ASA physical status I and II patients (ages 51 to 75) scheduled for minor surgery under spinal anesthesia. Interventions: Patients were randomly allocated to one of three groups: the placebo-propofol-placebo (PP) group, the midazolam-propofol-placebo (MP) group, or the midazolam-propofol-flumazenil (MF) group. After administering placebo or midazolam (10 μg kg −1), propofol 250 μg kg −1 min −1 was infused. Immediately after confirming that the patient was hypnotized, we terminated the propofol infusion and administered placebo or flumazenil (5 μg kg −1). Measurements: The dose and the times required to achieve hypnosis (the first endpoint) and to emerge from anesthesia (the second endpoint). The plasma concentration at each endpoint was determined. Main Results: Midazolam significantly decreased the dose and time needed to achieve hypnosis [PP vs . MP, 66 ± 14 vs . 48 ± 15 mg, 260 ± 55 vs . 179 ± 44 sec, respectively (mean ± SD)]. Thus, the plasma concentration of propofol at hypnosis was significantly lower (PP vs. MP, 3.31 ± 0.78 vs. 2.41 ± 0.57 μg mL −1 ). The time to emerge from anesthesia was not prolonged by midazolam, and was further shortened by administration of flumazenil (PP, MP vs . MF, 237 ± 77, 207 ± 71 s vs . 126 ± 56 sec, respectively). Flumazenil also reversed the reduction in propofol concentration induced by midazolam at emergence (PP, MP, and MF, 0.54 ± 0.17, 0.37 ± 0.15, and 0.59 ± 0.22 μg mL −1, respectively). Conclusions: Coadministration of 10 μg kg −1 midazolam decreases the dose and time required to achieve hypnosis with propofol induction without delaying emergence from anesthesia. Additional administration of flumazenil further shortens the time to emerge from midazolam-propofol anesthesia.

Propofol and remifentanil pharmacodynamic interaction during orthopedic surgical procedures as measured by effects on bispectral index

Study Objective: To identify and quantify the interaction between propofol and remifentanil during surgical procedures with a bispectral index (BIS) of 50 that was chosen as a continuous surrogate measure for “adequate depth” of anesthesia. Design: Prospective, open-label study. Setting: Department of orthopedics of a university hospital. Patients: 20 patients undergoing orthopedic surgery. Interventions: Anesthesia was induced and maintained with propofol and remifentanil, both administered by target-controlled infusion (TCI). Initial target concentrations of propofol (1.5–8 μg/mL) and remifentanil (2–15 ng/mL) were chosen and alternated in order to maintain the BIS between 45 and 55. If constant target concentrations had been maintained for 20 minutes and the BIS did not depart from the desired range, blood samples were taken to determine propofol concentrations, and the BIS value was recorded. Isobolographic interaction models were fitted to the infusion rates of remifentanil and propofol, predicted target concentrations of both drugs, and measured propofol concentrations versus predicted remifentanil concentrations. Main Results: The isobole for the interaction of propofol and remifentanil in the concentration range investigated (propofol 1.5–8 μg/mL and remifentanil 1–30 ng/mL) is a concave up hyperbola ((0.15 · C prop) 3.13 · C rem = 1) with C prop = propofol plasma concentration [μg/mL] and C rem = remifentanil blood concentration [ng/mL]). Use of predicted (=TCI target) concentrations or the respective infusion rates did not alter the general shape of the interaction isobole. Conclusions: The interaction between propofol and remifentanil for maintenance of a BIS value between 45 and 55 during surgery is synergistic. This finding applies regardless of whether measured concentrations (for propofol), predicted concentrations of the infusion device, or infusion rates are used as model input. Notably, the interaction isobole of the (clinically readily available) infusion rates provides a useful dosing recommendation for the coadministration of propofol and remifentanil during maintenance of anesthesia.