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PubMed2004

Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics.

BACKGROUND: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. METHODS: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. RESULTS: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. CONCLUSIONS: Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

Adult↗

PubMed2004

Impact of bispectral index monitoring on stress response and propofol consumption in patients undergoing coronary artery bypass surgery.

BACKGROUND: Bispectral Index (BIS)-titrated administration allows a reduction of propofol infusion rates in patients undergoing surgery. Resulting differences in anesthetic depth might affect the stress response to surgery involving neural circuitry not reflected in the electroencephalogram. METHODS: Forty patients scheduled to undergo elective coronary artery bypass grafting receiving a background infusion of remifentanil (0.3 microg . kg . min) were anesthetized with intravenous propofol delivered by target-controlled infusion according to the Marsh pharmacokinetic model under BIS monitoring. In a randomized, prospective design, 20 patients received propofol at a target concentration of 3 microg/ml, whereas in 20 patients propofol was titrated to maintain a BIS value of 40-50. Plasma concentrations of propofol (by means of gas chromatography-mass spectrometry), epinephrine, norepinephrine (by means of high-pressure liquid chromatography), cortisol (by means of radioimmunoassay), and interleukins 6 and 10 (by means of enzyme-linked immunosorbent assay) were measured repeatedly throughout surgery. RESULTS: BIS monitoring allowed a 30% reduction of propofol infusion rates and a similar decrease in plasma propofol concentrations in the BIS group without affecting the stress response to surgery for the group mean. None of the patients reported awareness during a standardized interview. Interestingly, propofol-remifentanil anesthesia blunted the release of epinephrine and cortisol to bypass surgery completely even when the propofol infusion rate was reduced according to BIS values. CONCLUSIONS: Total intravenous anesthesia using propofol-remifentanil effectively attenuates the neurohumoral stress response to coronary bypass surgery involving cardiopulmonary bypass. Titration of propofol using BIS allows for significant reduction of propofol consumption, with only minor effects on stress response under these conditions.

Aged↗

PubMedDate not supplied

Relationships between total and unbound propofol in plasma and CSF during continuous drug infusion.

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.

Adult↗

PubMed1997

Predictive accuracy of continuous propofol infusions in neurosurgical patients: comparison of pharmacokinetic models.

The performance of 10 pharmacokinetic models in predicting blood propofol concentrations was evaluated in patients during neurosurgical anesthesia. Eight patients-ASA category I or II, aged 49 +/- 18-years, weighing 71 +/- 20 kg, and scheduled for routine neurosurgery-were anesthetized with propofol and sufentanil using Ohmeda pumps controlled with a personal computer. Sufentanil was administered as a bolus of 0.3 microgram.kg-1, 5 min before induction of anesthesia, and infused at a constant rate of 0.5 microgram.kg-1.h-1 throughout the study. At induction, propofol was administered as a bolus of 1.5 mg.kg-1 followed by a continuous infusion of 6 mg.kg-1.h-1. During surgery, the propofol infusion rate was deliberately increased by 2 mg.kg-1.h-1 every 15 min up to 12 mg.kg-1.h-1. Arterial blood samples were drawn at the end of each infusion step for measurement of propofol concentrations by high-performance liquid chromatography. Measured propofol concentrations were compared with theoretical concentrations derived from 10 published pharmacokinetic models designed in different clinical settings. Each model has been assessed by calculating the median of the performance error, the median of the absolute performance error, and their 10th and 90th percentiles. Models designed for certain categories, such as children, young, or elderly patients who received propofol as a bolus injection, showed a bad predictive accuracy. The models of Gepts et al. (Anesth Analg 1987; 66:1256-1263, Anaesthesia 1988; 43(suppl):8-13), Tackley et al. (Br J Anaesth 1989;62:46-53), and Cockshott (Postgrad Med J 1985;61:55), derived from healthy patients receiving continuous propofol infusions, provided the best agreement between expected and measured propofol concentrations; they showed bias and inaccuracy lower than 17%. In conclusion, the accurate prediction of blood propofol concentrations from different continuous infusion rates in ASA I or II patients requires the selection of appropriate pharmacokinetic models derived from similar categories of patients and using a similar technique of propofol administration. However, in clinical practice, the selection of a specific set among the appropriate models is balanced by the interindividual variability in blood propofol concentrations adjusted to clinical effects.

Adult↗

PubMed1995

Prilocaine reduces injection pain caused by propofol.

Propofol, which is commonly used for outpatient anaesthesia, may evoke pain during infusion. Forty-eight patients (ASA-I-II) undergoing elective uterine dilatation and curettage received randomly in a standardised fashion: A: Propofol mixed with prilocaine; B: Propofol and lidocaine; C: Propofol with prilocaine+lidocaine (equal amounts) or D: Propofol and saline. The final ratio of propofol:local anaesthetic/saline was 9:1 in all mixtures. Pain on injection was significantly decreased in the three groups receiving propofol and local anaesthetic(s) compared to the one given propofol and saline. Propofol is required in greater amounts when mixed with lidocaine than when mixed with saline. A binding between the algesic part of the propofol molecule and the local anaesthetic agent may explain these findings. Another twenty-two comparable patients were given 30 mg of ketorolac or an equal volume of saline intramuscularly 45-60 minutes prior to propofol. Ketorolac given before propofol did not reduce pain on injection. This indicates that inhibition of the cyclooxygenase pathway of arachidonic acid metabolism does not play a major role in the reduction of this pain.

Adult↗

PubMed1993

Propofol at a subanesthetic dose may have abuse potential in healthy volunteers.

We conducted a study in which the rewarding effects of propofol were assessed in humans, using a discrete-trials choice procedure. Normal healthy volunteers (n = 12) were exposed in a blind fashion to acute bolus injections of 0.6 mg/kg of propofol twice and to a similar volume of Intralipid twice. Then, for the next three sessions, subjects chose which drug (identified by a color code) they wished to receive. We defined propofol choosers if individuals chose propofol two or three times, and nonchoosers if they chose propofol once or not at all. By using a chi 2 goodness-of-fit test of a random choice model, the choice distribution differed significantly from a random choice distribution (P < 0.005). Six subjects were choosers: four subjects chose propofol on all three choice occasions and two subjects chose the drug on 2/3 occasions (referred to hereafter as propofol choosers). Six subjects were nonchoosers: five subjects chose Intralipid on all three choice occasions, and one subject chose Intralipid twice (referred to hereafter as propofol nonchoosers). During sampling sessions, propofol choosers reported pleasant acute effects and no unpleasant residual effects, whereas propofol nonchoosers reported either unpleasant acute subjective effects and/or residual effects from propofol. We conclude that 1) propofol may be rewarding (reinforcing) in some individuals without a history of drug abuse, and 2) further abuse liability testing is needed with this drug.

Adult↗

PubMed2006

Nitrous oxide and anesthetic requirement for loss of response to command during propofol anesthesia.

The blood concentration associated with loss of response (LOR) to command in 50% of subjects (CP50(LOR)) is an important measure of anesthetic potency. We therefore determined the CP50(LOR) in 40 healthy surgical patients, aged 18-60 yr old, receiving propofol alone or propofol with 67% nitrous oxide (N2O). Patients were randomized to receive 100% oxygen or 67% N2O in oxygen via facemask. Three minutes later, a target-controlled propofol infusion was commenced at a concentration determined by the response of the previous patient in the same group. Fifteen minutes later, response to command was assessed by a blinded observer. Arterial blood samples were taken for propofol assay, and the bispectral index (BIS) was monitored continuously. At testing for response to command, both the measured and target propofol concentrations were significantly larger and BIS values significantly smaller in the propofol-alone group compared with the propofol-N2O group. The CP50(LOR) of propofol in the propofol-alone group was 4.58 mug/mL (95% confidence interval [CI], 1.14-15.36) and 2.67 microg/mL (95% CI, 2.28-3.17) in the propofol-N2O group. The BIS value when 50% of patients responded to command was 60 (95% CI, 55-65) in the propofol-alone group and 75 (95% CI, 73-83) in the propofol-N2O group.

Adult↗

PubMed2002

Pharmacokinetics of propofol in elderly coronary artery bypass graft patients under total intravenous anesthesia.

The present paper investigates the pharmacokinetics of propofol in the plasma of two elderly patients operated on under total intravenous anesthesia using propofol. A 78-year-old (patient A) and a 76-year-old (patient B), both Japanese men with unstable angina pectoris, were operated on for coronary artery bypass grafts. For the induction of anesthesia, 1.5 mg/kg propofol was administered as a single bolus infusion, and anesthesia was maintained using the step-down infusion regimens of propofol. Propofol concentration in the plasma was measured by HPLC with a fluorescence detector. The simulation curves, following the two-compartment model, fitted well to the profiles of the individual data of propofol concentrations in the plasma. When 4 mg/kg/h of propofol was administered to both patients while maintaining anesthesia, propofol concentrations in the plasma were maintained at over 1.0 microg/ml. In patient A, the propofol concentration in the plasma was 140 ng/ml at 6 h after the end of the infusion. In patient B, the propofol concentrations in the plasma were 73 ng/ml at 6 h and 35 ng/ml at 12 h after the end of the infusion. The apparent distribution volumes of patients A and B were 1.43 and 1.62 l/kg, respectively. The half-lives of propofol in the plasma of patients A and B were estimated to be 13.3 and 17.4 min as the a phase, and 10.1 and 10.5 h as the beta phase, respectively. In elderly patients with cardiac surgery, the maintenance concentrations of propofol in the plasma were enough to maintain a concentration of 1.0 microg/ml, and the half-life may be longer than previously reported values in adult patients.

Aged↗

PubMed2005

Bispectral index as a guide for titration of propofol during procedural sedation among children.

OBJECTIVE: To determine whether the bispectral index (BIS) monitor could be used to guide physicians in titrating propofol to an effective safe level of deep sedation for children undergoing painful medical procedures. DESIGN: Multiphase clinical trial. SETTING: Outpatient treatment center of a university children's hospital. PATIENTS: Pediatric outpatients undergoing painful medical procedures. INTERVENTIONS: Patients were sedated with propofol for the procedures. Patients were monitored with a BIS monitor, and the BIS score was correlated with the patient's clinical level of sedation. The BIS score was then used as a guide to titrate propofol in the last phase of the study. MEASUREMENTS AND MAIN RESULTS: The study consisted of 3 phases. In a chart review of data for 154 children who underwent 212 procedures, propofol was found to be safe and effective, with consistent dosing among the intensivists administering the medication. The children received a mean bolus dose of propofol of 1.56 mg/kg, with a mean total dose of propofol of 0.33 mg/kg per minute for the duration of the procedure. In the second phase, 21 patients ranging in age from 27 weeks to 18 years, with normal neurologic function, were sedated with propofol. An observer who was blinded to the BIS scores recorded clinical levels of sedation and reactivity (with a modified Ramsay scale and reactivity score) every 1 to 3 minutes. Another observer recorded the BIS scores at the same times. A total of 275 data points were collected and evaluated. All data points from the times at which patients were considered to be sedated adequately were used to construct a normal distribution of BIS scores. The mean BIS score was 62. This distribution was used to predict that a maximal BIS score of 47 was needed to ensure adequate sedation for 90% of the population. In the third phase of the study, an algorithm was devised to determine the target BIS score necessary for adequate sedation of 95% of the patients. We chose an initial BIS score of 50 (at which 85% of the patients in phase 2 were sedated) because of the possibility of data from phase 2 being skewed toward oversedation. Propofol was administered by an intensivist in an attempt to maintain the target BIS score. A blinded observer noted the patient's clinical level of sedation. In this group, there were 2 failures, ie, patients were clinically uncomfortable despite a BIS score of < or =50, representing only 90% success. Therefore, with the algorithm, propofol was titrated to sedate the next patients to a BIS score of 45. These patients required a mean bolus dose of 1.47 mg/kg and a mean total dose of 0.51 mg/kg per minute to maintain a BIS score of 45. They awakened in 12.75 minutes. All patients were sedated adequately, all procedures were successful, and no patients experienced complications from the sedation. To eliminate variability in the way propofol was dosed, the next 10 patients were given propofol according to a standardized protocol. These 10 children received an initial bolus of 1 mg/kg, with incremental bolus doses of 0.5 mg/kg per dose (maximum: 20 mg) to achieve and to maintain a BIS score of 45. With this protocol, all patients were sedated adequately and none experienced complications from the sedation. The patients required a mean bolus dose of 2.23 mg/kg and a mean dose of 0.52 mg/kg per minute to maintain a BIS score of 45. The mean time until awakening was 14.9 minutes. Regarding the total dose over time and the time until awakening, there was no statistical significance between this group and the group sedated to a BIS score of 45 without the dosing protocol. CONCLUSION: The BIS monitor can be a useful monitoring guide for the titration of propofol by physicians who are competent in airway and hemodynamic management, to achieve deep sedation for children undergoing painful procedures.

Adolescent↗

PubMed1988

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic.

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.

Anesthesia, Intravenous↗

PubMed2001

Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions.

This manuscript describes the pharmacokinetic and pharmacodynamic interactions between propofol and the opioids. PHARMACOKINETIC INTERACTIONS: In vitro studies describe the reduced clearance of opioids in the presence of propofol, midazolam and etomidate due to interaction at the cytochrome P450 enzyme system. In vivo, however, pharmacokinetic interaction studies by mixed effects modelling predominantly focus on haemodynamic factors affecting distribution and elimination of concomitantly administered agents. In the presence of propofol the elimination clearance and rapid and slow distribution clearance of alfentanil is decreased. Consequently, plasma alfentanil concentrations are increased in the presence of propofol. Vice versa alfentanil reduces propofol elimination clearance and increases the deep volume of distribution. PHARMACODYNAMIC INTERACTIONS: Propofol and the opioids interact in a synergistic manner for various clinical end points. The magnitude of interaction is similar between the various opioids and hypnotic agents, taken into consideration the differences in potency between the opioids. CLINICAL INTERPRETATION OF PK/PD INTERACTIONS: A. Speed of induction. Using PK/PD interaction data speed of induction can be optimised. Of importance are the magnitude of PD interaction between propofol and the various opioids, the rate of administration and the time to peak effect of the agents involved. B. Haemodynamic stability. In ASA 1-2 patients the opioid induced hypnotic dose reduction is not associated with an increased haemodynamic stability of induction of loss of consciousness. In elderly patients or patients known with cardiovascular instability high opioid-low propofol anaesthesia may be associated with improved haemodynamic stability during induction of anaesthesia, however, no data are available regarding this yet. C. Speed of recovery. Time to return of consciousness after termination of propofol-opioid infusions of various duration can be reduced using optimal propofol-opioid concentrations. In general, optimal propofol target concentrations to assure this are 5 micrograms/ml in the presence of fentanyl, 3.5 micrograms/ml in the presence of alfentanil and sufentanil and 2.5 micrograms/ml in the presence of remifentanil. D. Spontaneous respiration. For single agents some data allow proper targeting of a drug concentration that is associated with adequate intraoperative respiration. However, no data exist on drug interactions regarding the respiratory depressant effects of hypnotic-opioid combinations. CONCLUSION: The proper exploration and use of published pharmacokinetic and pharmacodynamic interaction data allows the clinical anaesthesiologist to optimise the clinical administration of propofol and the various opioids when given alone or in combination.

Analgesics, Opioid↗

PubMed2003

Propofol requirement for insertion of cuffed oropharyngeal airway versus laryngeal mask airway with and without fentanyl: a dose-finding study.

BACKGROUND: The cuffed oropharyngeal airway (COPA) is a modified Guedel-type oral airway with a cuff at its distal end. The objectives of this prospective, randomized study were to compare the COPA and the laryngeal mask airway (LMA) in terms of propofol requirement with and without fentanyl pretreatment for smooth insertions. METHODS: Seventy-five patients undergoing general anaesthesia were randomly assigned to either a COPA (n=38) or LMA (n=37) group for airway management, and each group was further randomized to a saline-propofol or fentanyl-propofol group for anaesthesia induction. The saline-propofol group received i.v. saline and the fentanyl-propofol group received i.v. fentanyl 1 micro g kg(-1) followed 30 s later by i.v. propofol. Insertion of the device was attempted 90 s after propofol administration without the use of neuromuscular blocking agents or other adjuvants, and the responses of 'movement' or 'no movement' were judged by three observers blinded to the drug dose. Each dose of propofol at which insertion was attempted was predetermined by modification of Dixon's up-and-down method with 0.5 mg kg(-1) as the step size, and 2 mg kg(-1) as an initial dose. RESULTS: Without fentanyl pretreatment, propofol requirement [mean (SD), 95% CI] for COPA placement [2.17 (0.38), 1.77-2.56 mg kg(-1)] was significantly less than for LMA insertion [3.42 (0.26), 3.15-3.69 mg kg(-1), P<0.001]. In contrast, propofol requirements after fentanyl were comparable between the COPA and LMA groups [1.50 (0.42), 1.06-1.94 and 1.42 (0.26), 1.15-1.69 mg kg(-1), respectively], but were less than for the placebo group with both devices (P<0.05). Haemodynamic changes and duration of apnoea were similar with both devices irrespective of fentanyl pretreatment. CONCLUSIONS: Insertion of the COPA can be accomplished with a smaller bolus dose of propofol compared with the LMA, but propofol requirements are similar with both devices after a small dose of fentanyl.

Adolescent↗

PubMed2003

[Effect of propofol on the electric discharge of inspiratory neurons in the brainstem of neonatal rats].

OBJECTIVE: To investigate the effects of propofol on the electric discharge of the inspiratory neurons in the neonatal rat brainstem slices and its possible mechanism. METHODS: Experiments were performed on in vitro neonatal rat (of either sex, 0 to 30 d old) brainstem slices perfused with modified Kreb's solution (MKS), and the rhythmical discharge activity of the inspiratory neurons in the hypoglossal nerve was recorded by suction electrode. Thirty-six slices positive of respiratory-related rhythmic activity were randomly divided into 6 equal groups consisting of a control group (group I) with MKS perfusion, 4 propofol groups (groups II to V) with propofol treatment delivered via continuous MKS perfusion for 3 min at the doses of 5, 20, 50, 100 micromol/L respectively, and a bicuculline-propofol group (group VI) with the continuous perfusion of bicuculline (20 micromol/L) and propofol (20 micromol/L). The discharge time course of inspiratory, expiratory, peak inspiratory discharge and the frequency of respiration were recorded before and 1, 3, 5, 10, 15, 30 min after propofol or bicuculline-propofol perfusion. RESULTS: In control group, no significant changes took place in all Hreparameters in the whole course of the experiment. In groups II to IV, the discharge time was significantly reduced after propofol perfusion and at 5 min, and the discharge was arrested in 4 out of the 6 slices in group V, showing a concentration-dependent inhibition of the inspiratory discharge time by propofol. In contrast, the expiratory time course was prolonged and frequency of respiration decreased in the period of 3 to 30 min after propofol perfusion. Combined treatment of bicuculine and propofol produced no significant changes in the discharge time and expiratory time courses of the inspiratory neurons. CONCLUSION: Propofol inhibits the discharge of inspiratory neurons in a concentration-dependent manner and GABA A receptor may play an important role in this process.

Anesthetics, Intravenous↗

PubMed2006

Propofol significantly attenuates iNOS, CAT-2, and CAT-2B transcription in lipopolysaccharide-stimulated murine macrophages.

BACKGROUND: Propofol significantly inhibits inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) biosynthesis in stimulated macrophages. L-arginine transport mediated by the isozymes of type-2 cationic amino acid transporter (including CAT-2 and CAT-2B) has been reported to play a crucial role in regulating iNOS activity. We sought to evaluate the effects of propofol on L-arginine transport and transcription of CAT-2 and CAT-2B. METHODS: Confluent murine macrophages (RAW264.7 cells) were stimulated with lipopolysaccharide (LPS) to induce NO production, L-arginine transport and the transcriptions of iNOS, CAT-2, and CAT-2B. Propofol (25, 50, and 75 microM) was added to the cells 4 hours before, immediately after, or 4 hours after LPS administration. After reacting with LPS for 18 hours, cell cultures were harvested and assayed. RESULTS: Propofol administered 4 hours before LPS had no significant effects on NO production, L-arginine transport, and the transcriptions of iNOS and CAT-2. To our surprise, NO production and iNOS transcription were significantly enhanced by 25 microM propofol administered immediately after LPS. NO production and iNOS transcription were not affected by 50 microM propofol but significantly inhibited by 75 microM propofol administered immediately after LPS. CAT-2 transcription and L-arginine transport were significantly inhibited by 50 and 75 microM but not 25 microM propofol administered immediately after LPS. When administered 4 hours after LPS, 75 but not 25 and 50 microM propofol significantly inhibited NO production, L-arginine transport, and the transcription of iNOS and CAT-2. In addition, CAT-2B transcription was significantly inhibited by propofol that was administered 4 hours before, immediately after, or 4 hours after LPS. CONCLUSIONS: Propofol had significantly inhibitory effects on LPS-induced NO production, L-arginine transport, and the expressions of iNOS, CAT-2 and CAT-2B in stimulated murine macrophages in a dose-dependent manner. In addition, timing of administration also affected this regulatory effect of propofol.

Animals↗

PubMed1990

[Propofol infusion for sedation in regional anesthesia. A comparison with midazolam].

50 non-premedicated ASA class I or II patients were allocated randomly into two groups and received either a variable infusion of propofol or midazolam for sedation during orthopaedic surgery with regional blockade. To achieve a well-sedated patient with eyes closed and able to follow commands, the dose requirements for propofol were 1.25 mg/kg +/- 0.5 as a loading dose followed by a mean infusion rate of 3.17 mg kg-1 h-1 +/- 1.4 and for midazolam 0.073 mg/kg +/-0.02 and 0.074 mg kg-1 h-1 +/- 0.14. Steady-state plasma concentrations of propofol averaged 1.23 micrograms/kg +/- 0.75 and of midazolam 134 ng/ml +/- 62. Recovery was significantly shorter for propofol: 3.42 +/- 2.5 versus 8.05 min +/6.2 for midazolam. Perioperative cooperation was similar in both groups providing good or excellent conditions in 76% with propofol and in 52% with midazolam. 2h after discontinuation of the infusion 92% of the propofol patients were alert, while 36% of the midazolam were sleeping again. Cardiovascular effects of both drugs were minimal; however significant respiratory depression and/or airway obstruction developed in both groups (propofol 48%, midazolam 52%) requiring therapeutic intervention. Additional undesirable effects were: severe cough (propofol 40%, midazolam 20%), inadvertent movements (propofol 36%, midazolam 24%), confusion (propofol 24%, midazolam 20%), euphoria (propofol 44%), pain on injection (propofol 32%). The results of the study indicate that both drugs are useful and controllable sedative agents for surgery under regional anaesthesia, provided that measures for continuous monitoring of respiration and emergency care are guaranteed.

Anesthesia, Epidural↗

PubMed1994

Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons.

Propofol (2,6 di-isopropylphenol) is an alkyphenol recently introduced for use as a general anesthetic. The modulation of GABAA receptor activation and desensitization by propofol was studied using a rapid perfusion system and whole-cell voltage-clamp recordings from mouse hippocampal neurons. The effects of concentrations of propofol used clinically on single-channel and synaptic currents were also examined. Propofol evoked current responses (EC50 = 61 microM) and shifted the dose-response curve of GABA-activated current to the left without altering the maximum of the GABA response. Preincubation with propofol and GABA led to desensitization of the GABA response (EC50 = 454 microM and 23 microM, respectively). Saturating concentrations of GABA (600 microM) evoked currents that peaked and then declined in a biexponential fashion with fast and slow time constants of tau f = 1.0 sec and tau s = 3.5 sec. Propofol (10 microM) did not change the amplitude of the peak response but decreased the rates of decay approximately 1.5-fold and enhanced the steady-state current proportionately. Recovery from desensitization was also biexponential (tau f = 11 sec, tau s = 69 sec) but not influenced by propofol. Single-channel recordings from outside-out patches demonstrated that both propofol and GABA activated channels with a 30 pS and 21 pS open state. Propofol increased the frequency but not the duration or conductance of GABA-activated events. Miniature inhibitory postsynaptic currents (mlPSCs) were evoked by the application of hypertonic sucrose to the cell soma. Propofol (2 microM) prolonged the decay time of mlPSCs to an extent similar to which it increased the open probability of GABA-activated channels (2.3- vs 3-fold). A sequential model, based on a previous scheme of GABA receptor gating (Weiss and Magelby, 1989), is presented to summarize propofol's actions on GABAA receptor function. We show through simulation that the model reliably reproduced the whole-cell tracings. Our results indicate that propofol's neurodepressive actions will be associated with enhancement of inhibitory synaptic transmission.

Animals↗

PubMed1996

Co-administration of midazolam decreases propofol dose during anesthesia in endoscopic laryngeal microsurgery.

BACKGROUND: Propofol is commonly used in total intravenous anesthesia (TIVA) for brief surgical procedures because it offers rapid recovery and has fewer side effects. However, concomittent use of other adjuvant agents has been considered so that the same anesthetic effects can be achieved at lower doses of propofol which is more expensive without compromising rapid recovery and increasing the adverse effects. This study was therefore designed to evaluate the co-administration of midazolam and propofol during anesthesia for endoscopic microsurgery and test its influences on the consumption of propofol and the quality of anesthesia. METHODS: Forty-two patients receiving selective endoscopic microsurgery were enrolled in this study. All patients received high frequency jet ventilation (HFJV) under TIVA. The control group (n = 21) received propofol (20 mg/5 s) during induction and 10 mg/kg/h as maintenance. The study group (n = 21) received midazolam (0.06 mg/kg) and propofol (20 mg/5 s) for induction with propofol 8 mg/kg/hr for maintenance. Doses of propofol, vital signs, recovery time, post-anesthetic high cortical function, and adverse events were evaluated and compared. RESULTS: Co-administration of midazolam and propofol in TIVA could reduce the induction dose and the total dose of propofol by 51% and 26% respectively but still achieve the same anesthetic effects. Vital signs and recovery were not influenced, and incidence of adverse effects did not increase. CONCLUSIONS: Our result suggests that co-administration of midazolam and propofol in TIVA appears to be safe, effective, and economic alternative to that with propofol alone. The effects were synergic but side effects were not.

Adult↗

PubMed1999

The influence of hypoxia and hyperoxia on the kinetics of propofol emulsion.

PURPOSE: To study the effect of hypoxia and hyperoxia on the pharmacokinetics of propofol emulsion, hepatic blood flow and arterial ketone body ratio in the rabbit. METHODS: Twenty four male rabbits were anesthetized with isoflurane (1.5-2%) in oxygen. After the surgical procedure, isoflurane administration was discontinued and intravenous propofol infusion (30 mg x kg(-1) x hr(-1)) was started. The infusion rate of propofol was maintained throughout the study. After an initial 90 min period of propofol infusion, rabbits were randomly allocated to one of three groups: hypoxia (F(I)O2 = 0.1), normoxia (F(I)O2 = 0.21), and hyperoxia (F(I)O2 = 1.0). Propofol infusion was continued under the allocated F(I)O2 for 60 min. Propofol concentrations in arterial blood, total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were measured. RESULTS: The mean arterial propofol concentration at the end of infusion was higher in the hypoxia group (15.2 +/- 2.8 microg x mL(-1), mean +/- SD) than in the normoxia (7.4 +/- 1.7) and hyperoxia (8.0 +/- 1.9) groups (P < 0.05). Total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were all reduced in the hypoxia group (P < 0.05). Total ketone body concentration in arterial blood increased in the hyperoxia group (P < 0.01). CONCLUSION: Hypoxia produced an accumulation of propofol in blood and reduced propofol clearance. These changes could result from decreased hepatic blood flow and low cellular energy charge in the liver. Hyperoxia, on the other hand, increased total ketone body in arterial blood.

Anesthetics, Intravenous↗