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PubMed2005

A dopamine infusion decreases propofol concentration during epidural blockade under general anesthesia.

PURPOSE: It is common clinical practice to use dopamine to manage the reduction in blood pressure accompanying epidural blockade. As propofol is a high-clearance drug, propofol concentrations can be influenced by cardiac output (CO). The purpose of the present study was to investigate the effects of dopamine infusions on propofol concentrations administered by a target-controlled infusion system during epidural block under general anesthesia. METHODS: 12 patients undergoing abdominal surgery were enrolled in this study. Anesthesia was induced with propofol and vecuronium 0.1 mg.kg(-1), and maintained using 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 6.0 microg.mL(-1) at intubation and 2.0 microg.mL(-1) after intubation. Before and after the administration of 10 mL of 1.5% mepivacaine from the epidural catheter and dopamine infusion at 5 microg.kg(-1).min(-1), CO and effective liver blood flow (LBF) were measured using indocyanine green. Blood propofol concentration was also determined using high-performance liquid chromatography. RESULTS: At one hour after epidural block and dopamine infusion, CO was significantly increased from 4.30 +/- 1.07 L.min(-1) to 5.82 +/- 0.98 L.min(-1) (P < 0.0001), and effective LBF was increased 0.75 +/- 0.17 L.min(-1) to 0.96 +/- 0.18 L.min(-1) (P < 0.0001). Propofol concentration was significantly decreased from 2.13 +/- 0.24 microg.mL(-1) to 1.59 +/- 0.29 microg.mL(-1) (P < 0.0001). CONCLUSIONS: Propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.

Aged↗
PubMed2002

Propofol decreases cerebral blood flow velocity in anesthetized children.

PURPOSE: Propofol, by virtue of its favourable pharmacokinetic profile, is suitable for maintenance of anesthesia by continuous infusion during neurosurgical procedures in adults. It is gaining popularity for use in pediatric patients. To determine the effects of propofol on cerebral blood flow in children, middle cerebral artery blood flow velocity (Vmca) was measured at different levels of propofol administration by transcranial Doppler (TCD) sonography. METHODS: Twelve ASA I or II children, aged one to six years undergoing elective urological surgery were randomized to receive one of two propofol dosing regimens. Half of the patients received propofol in an escalating fashion, initially targeting an estimated steady-state serum concentration of 3 microg x mL-1, which was then doubled. The other half received propofol designed initially to target the high concentration followed by the lower one. In each child anesthesia was induced and maintained with propofol according to the protocol, rocuronium was given to facilitate tracheal intubation, and a caudal epidural block was performed. A TCD probe was placed appropriately to measure Vmca. Cerebral blood flow velocity (CBFV), mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously at both levels of propofol administration. RESULTS: Twelve patients were studied. At the higher estimated target serum propofol concentration there were significant decreases in Vmca (17%, P < 0.001), MAP (6%, P < 0.002) and HR (8%, P < 0.05) when compared to the lower targeted concentration. CONCLUSION: This study shows that a higher rate of propofol infusion is associated with lower CBFV and MAP values in children. Propofol's cerebral vasoconstrictive properties may be responsible for this finding.

Anesthesia↗
PubMed2004

[Propofol infusion syndrome].

Propofol infusion syndrome has not only been observed in patients undergoing long-term sedation with propofol, but also during propofol anesthesia lasting 5 h. It has been assumed that the pathophysiologic cause is propofol's impairment of oxidation of fatty acid chains and inhibition of oxidative phosphorylation in the mitochondria, leading to lactate acidosis and muscular necrosis. It has been postulated that propofol might act as a trigger substrate in the presence of priming factors. Severe diseases in which the patient has been exposed to high catecholamine and cortisol levels have been identified as trigger substrates. Once the development of propofol infusion syndrome is suspected, propofol infusion has to be stopped immediately and specific therapeutic measures initiated, including cardiocirculatory stabilization and correction of metabolic acidosis. To increase elimination of propofol and its potential toxic metabolites, hemodialysis or hemofiltration are recommended. Due to its possible fatal side effects, the use of propofol for long-term sedation in critically ill patients should be reconsidered. In cases of unexplained lactate acidosis occurring during continuous propofol infusion, propofol infusion syndrome must be taken into consideration.

Acid-Base Imbalance↗
PubMed1995

[Postoperative pulmonary function after lung surgery. Total intravenous anesthesia with propofol in comparison to balanced anesthesia with isoflurane].

After lung resection, early extubation and the rapid return of the patients ability to cooperate is the predominant goal. Propofol anaesthesia is characterised by rapid awakening and recovery of cognitive and psychomotor functions and is consequently desirable for such operations. Experience so far in lung surgery, however, is limited. Besides the level of consciousness we investigated various spirometric parameters after lung resection. Total intravenous anaesthesia was performed with propofol, while balanced anaesthesia was performed with isoflurane. METHODS. A total of 93 patients evaluated electively for wedge excision or lobectomy were enrolled in an open, prospective, randomised, interindividual comparative study. Sixty-three patients could be evaluated with complete data sets. In the evening and the morning before the operation the patients were premedicated orally with clorazepate 0.5-0.7 mg/kg. Anaesthesia was induced in group 1 with propofol (1.0-2.5 mg/kg) and maintained with propofol (4-12 mg/kg) in 50% O2/air. The patients in group 2 received methohexital (1-2 mg/kg) for induction and isoflurane (0.4-2.0 vol%) in 50% O2/air for the maintenance of general anaesthesia. In both groups analgesia was achieved by using fentanyl (up to 10 micrograms/kg) and muscle relaxation by using atracurium. Psychomotor tests (minimal mental state, reaction time) were performed the day before the operation (t1), immediately prior to induction of anaesthesia (t2) and 5 min, 30 min, 60 min, 90 min, 24 h, and 7 days after extubation (t3-t8). Spirometry (forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC; peak expiratory flow, PEF) was carried out at times t1, t2 and t5-t8. RESULTS. The two groups were comparable regarding preoperative status (age, sex, preoperative risk score, psychomotor tests, and spirometric values) and the operation performed (wedge excision/lobectomy, duration of anaesthesia). The extubation time was slightly shorter in the propofol group (18 +/- 8 min) than in the isoflurane group (20 +/- 6 min). Also, the results of the psychomotor tests were somewhat better in the propofol group than those in the isoflurane group. The clearest differences were found in the early postoperative period, but not all differences were significant. Statistically highly significant differences between the two groups were found for the three spirometric parameters. Based on the FEV1 value of the 7th postoperative day, FEV1 taken 60 min after extubation declined by 27.9% in the propofol group vs. 51.7% in the isoflurane group (P = 0.01). At 90 min after extubation the corresponding decline in the propofol group was 26.6%, in the isoflurane group 51.1% (P = 0.003). In addition, the decline of FVC and PEF measured 60 min and 90 min after extubation was significantly smaller in the propofol group than in the isoflurane group. CONCLUSION. The postoperative impairment of lung function after lung resection under propofol anaesthesia is statistically significantly smaller than under isoflurane anaesthesia. Total intravenous anaesthesia with propofol is particularly suitable for this kind of operation.

Adult↗
PubMed2003

Effect of propofol on adhesion of activated platelets to leukocytes in human whole blood.

OBJECTIVE: To investigate the effect of propofol and its solvent Intralipid on the adhesion of activated platelets to leukocytes in vitro. DESIGN AND SETTING: Prospective study in an experimental laboratory. PARTICIPANTS: Sixteen healthy volunteers. INTERVENTIONS: Whole blood was incubated for 60 min with propofol (4, 40 micro g/ml), an equal volume of Intralipid 10% or phosphate-buffered saline (PBS). After stimulation with adenosine-5-diphosphate (ADP) platelet-leukocyte adhesion and platelet surface expression of P-selectin, GPIb and fibrinogen-binding to platelets were evaluated by flow cytometry. MEASUREMENTS AND RESULTS: The 4 micro g/ml concentration of propofol did not alter binding of platelets to leukocytes, expression of P-selectin, GPIb and fibrinogen binding to platelets. The 40 micro g/ml concentration of propofol reduced spontaneous and ADP-induced formation of platelet-neutrophil conjugates compared with PBS and the equal volume of Intralipid. In addition, binding of ADP-activated platelets to monocytes were also inhibited by 40 micro g/ml propofol. Following incubation with propofol, platelets showed reduced binding of fibrinogen in the unstimulated and ADP-stimulated blood samples as well as a lower percentage of platelets with bound fibrinogen. Effects dependent on the solvent Intralipid were enhanced adhesion of platelets to monocytes in comparison with propofol (40 micro g/ml) and PBS. CONCLUSION: In clinically used concentrations, propofol does not alter the adhesion of platelets to leukocytes in vitro. At ten-fold anesthetic concentration propofol reduced the formation of platelet-neutrophil and platelet-monocyte conjugates. We suggest that this effect is due to an inhibition of fibrinogen-binding to platelets by propofol. These effects were all independent of the propofol carrier Intralipid.

Anesthetics, Intravenous↗
PubMedDate not supplied

Recovery following outpatient anesthesia: use of enflurane versus propofol.

STUDY OBJECTIVE: To compare the intraoperative conditions and postoperative recovery of patients following the use of either propofol-nitrous oxide (N2O) or enflurane-N2O for maintenance of outpatient anesthesia. DESIGN: Randomized, single-blind study. SETTING: University hospital outpatient surgery center. PATIENTS: 61 ASA physical status I and II, healthy female outpatients undergoing laparoscopic surgery. INTERVENTIONS: Patients were randomly assigned to one of three anesthetic regimens. Group 1 (control) received thiopental sodium 4 mg/kg intravenously (i.v.), followed by 0.5% to 1.5% enflurane and 67% N2O in oxygen (O2). Group 2 received propofol 2 mg/kg i.v., followed by 0.5% to 1.5% enflurane and 67% N2O in O2. Group 3 received propofol 2 mg/kg i.v., followed by propofol 50 to 160 micrograms/kg/min i.v. and 67% N2O in O2. All patients received succinylcholine 1 mg/kg i.v. to facilitate tracheal intubation and atracurium 10 to 20 mg i.v. to provide adequate relaxation during the maintenance period. MEASUREMENTS AND MAIN RESULTS: Recovery from anesthesia was assessed by a research nurse who was unaware of the anesthetic technique used. The mean +/- SD time to eye opening was significantly longer in the thiopental-enflurane-N2O group (Group 1) than in the propofol-propofol-N2O group (Group 3) (6.1 +/- 2.5 minutes vs. 3.5 +/- 2.8 minutes, respectively). In addition, the mean time to respond to verbal commands was significantly shorter in the propofol induction groups compared with the thiopental induction group. However, the use of enflurane versus propofol for maintenance of anesthesia did not significantly prolong the time from arrival in the recovery room to sitting, tolerating oral fluids, walking, or being judged "fit for discharge." There were no differences among the three groups with respect to postoperative pain or analgesic requirements. Finally, patients who received enflurane for maintenance of anesthesia had a significantly higher frequency of nausea and vomiting than the propofol maintenance group. CONCLUSION: Induction of anesthesia with propofol is associated with a more rapid emergence from anesthesia than induction with thiopental. Maintenance of anesthesia with enflurane did not prolong recovery compared with maintenance with propofol, but enflurane was associated with increased frequency of postoperative nausea and vomiting.

Adult↗
PubMed2004

Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding.

OBJECTIVE: Cardiopulmonary bypass is known to result in a reduction in the plasma binding of drugs. The resulting effect on the hepatic clearance of drugs with low extraction is well understood. However, the situation with those that are highly extracted is less clear. Studies were, therefore, undertaken with one such drug, propofol, for which plasma binding was changed during cardiac surgery with cardiopulmonary bypass. METHODS: After induction of anesthesia with midazolam in 19 patients, propofol was infused continuously at a rate of 4 mg. kg(-1). h(-1) during surgery. Propofol's concentration was measured by HPLC in blood samples collected from the radial artery and hepatic vein during surgery at predetermined intervals. The drug's unbound fraction in arterial plasma was estimated via equilibrium dialysis. RESULTS: The total concentration of propofol in blood was unchanged during surgery except shortly after the initiation of cardiopulmonary bypass. By contrast, the fraction of unbound propofol in blood increased by 2-fold during cardiopulmonary bypass and then decreased after the completion of cardiopulmonary bypass. The hepatic extraction ratio of propofol was greater than 0.8 and remained constant throughout surgery. The ratio of propofol concentration in erythrocytes to that in blood increased by 1.6-fold during cardiopulmonary bypass. CONCLUSIONS: During cardiopulmonary bypass, a significant increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood. The effect of the changes of propofol's protein binding on its kinetics was consistent with the predictions based on the well-stirred model of hepatic elimination for an intravenously infused high-clearance drug. Our finding on propofol pharmacokinetics may be the first example demonstrating the theoretic prediction of the well-stirred model.

Adult↗
PubMed2005

Propofol-induced calcium signalling and actin reorganization within breast carcinoma cells.

BACKGROUND AND OBJECTIVE: MDA-MB-468 breast carcinoma cells respond to non-volatile anaesthetics such as propofol with an increased migration. Here we investigated the relationship between GABA-A receptor modulators, the mode of calcium oscillation and actin reorganization with regard to breast carcinoma cell migration. METHODS: Expression of the GABA-A receptor was determined by Western blot analysis. Calcium-imaging experiments of individual MDA-MB-468 cells as well as visualization of the F-actin distribution were performed by confocal laser scanning microscopy. Cell migration was investigated in a three-dimensional collagen matrix by time-lapse video microscopy. The GABA agonist propofol was used in a final concentration of 6 microg mL(-1). GABA-A receptor antagonist bicuculline (50 micromol) and selective L-type calcium channel blocker verapamil (5 micromol) were used to modulate the propofol effects. RESULTS: A functional GABA-A receptor is expressed by MDA-MB-468 cells. Activation with propofol resulted in sustained increased intracellular calcium concentrations concomitant with actin reorganization and induction of migration in MDA-MB-468 cells. These propofol effects were completely blocked by verapamil. Spontaneous migration of MDA-MB-468 cells (64.4 +/- 7.0%) was significantly increased by propofol to 85.0 +/- 5.0%. MDA-MB-468 cells co-treated with propofol and verapamil showed a migratory activity of 63.0 +/- 2.0% indicating that verapamil blocked the propofol effect. Similar results were achieved with the GABA-A receptor inhibitor bicuculline (control: 56.3 +/- 8.5%; propofol: 80.5 +/- 7.1%; propofol + bicuculline: 52.5 +/- 8.6%). CONCLUSION: Activation of GABA-A receptor by propofol correlated with an increased migration of MDA-MB-468 breast carcinoma cells, mediated by calcium influx via L-type calcium channels and reorganization of the actin cytoskeleton.

Actins↗
PubMed2000

Effects of propofol on desipramine-sensitive [3H]-noradrenaline uptake kinetics in rat femoral artery.

BACKGROUND: The intravenous anaesthetic propofol inhibits the neuronal uptake of noradrenaline (uptake1) from the vascular sympathetic neuromuscular junction, resulting in an enhancement of the sympathetic neurotransmission. This could be important for maintenance of blood pressure during propofol anaesthesia. The aim of the present study was to determine how propofol influences the kinetics of uptake1. METHODS: Isolated segments of rat femoral arteries were incubated with [3H]-noradrenaline in the presence or absence of propofol and the radioactivity taken up was measured in a scintillation counter. The uptake1 inhibitor, desipramine, was used to delineate the specific neuronal uptake. RESULTS: Desipramine and 10 microM propofol significantly reduced the uptake in segments incubated with 0.1 microM [3H]-noradrenaline. Propofol at 1 microM and 100 microM did not affect the uptake. Non-linear regression analysis of specific uptake yielded Km 0.50 microM, Vmax 1.6 pmol mg(-1) 15 min(-1) and Hill coefficient 1.1. Propofol (1-10 microM) increased the Km value and propofol (10-100 microM) increased the Vmax value concentration-dependently, while the Hill coefficient was not affected. CONCLUSION: Propofol seems to have a biphasic effect on the uptake of noradrenaline in the vascular sympathetic neuromuscular junction. At lower propofol concentrations there is a decrease in the affinity of the noradrenaline transporters. The resulting uptake inhibition is counteracted at higher propofol concentrations by an increase in the efficacy of the uptake.

Adrenergic Uptake Inhibitors↗
PubMed2001

Involvement of human liver cytochrome P4502B6 in the metabolism of propofol.

AIMS: To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes. METHODS: The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform-selective substrates by liver microsomes, the effect of CYP isoform-selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined. RESULTS: The mean rate constant of propofol metabolism by liver microsomes obtained from six individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol min(-1) mg(-1) protein. The rate constants of propofol by microsomes were significantly correlated with S-mephenytoin N-demethylation, a marker of CYP2B6 (r = 0.93, P < 0.0001), but not with the metabolic activities of other CYP isoform-selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P < 0.05), while other CYP isoform-selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol min-1 nmol P450-1). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74%. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol. CONCLUSIONS: CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.

Analgesics, Opioid↗
PubMed2004

Electroencephalograph variables, drug concentrations and sedation scores in children emerging from propofol infusion anaesthesia.

BACKGROUND: Inadequate sedation or oversedation are common problems in Paediatric Intensive Care because of wide variations in drug response and the lack of objective tests for sedative depth. We undertook a pilot study to try to identify correlates of propofol drug concentration, electroencephalographic (EEG) variables and observed behaviour during a stepwise reduction in propofol infusion after paediatric cardiac surgery. METHODS: This was a prospective pilot study with 10 children (5 months to 8 years) emerging from propofol anaesthesia following cardiac surgery with cardiopulmonary bypass (CPB). Patients underwent a stepped wake-up from propofol anaesthesia during which the propofol infusion rate was decreased from 4 mg.kg(-1).h(-1) in 1 mg.kg(-1).h(-1) steps at 30 min intervals. EEG variables, propofol blood concentrations and clinical sedation scores (COMFORT scale) were recorded during the stepped wakeup. Analgesia was maintained with a standardized continuous infusion of fentanyl. RESULTS: : Mean (SD) whole blood propofol concentrations at arousal varied considerably [973 ng.ml(-1) (SD 523 ng.ml(-1))]. The summed ratio (SR) of high frequency to low frequency bands correlated with both propofol infusion rate (R2 value=0.47) and propofol blood concentrations (R2 value=0.64). The mean SR in deeply sedated patients was significantly different from that in the 5 min prior to wakening (6.84 vs 1.55, P=0.00002). There was no relationship between COMFORT scores and SR. CONCLUSIONS: In this group of patients receiving opioid analgesia and relatively high doses of propofol, sedation scores were unhelpful in predicting arousal. The SR correlated with propofol blood concentrations and clinical arousal and may have potential as a predictive tool for arousal in children.

Anesthesia Recovery Period↗
PubMed2000

Improved sedation in diagnostic and therapeutic ERCP: propofol is an alternative to midazolam.

BACKGROUND AND STUDY AIMS: Adequate sedation of the patient is required for diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). The anesthetic propofol, with its shorter half-life, affording better control, offers an alternative to the benzodiazepine midazolam. The aim of this randomized, controlled, unblinded study was to compare prospectively the quality of sedation under propofol and midazolam in patients undergoing ERCP. PATIENTS AND METHODS: A total of 80 patients were randomized to sedation with propofol alone (n = 40) or midazolam alone (n = 40). Blood pressure, pulse, and oxygen saturation were measured. Midazolam was given by the endoscopist and titrated to the patients' response during ERCP, to a maximum dose of 15 mg per patient. In the propofol group an anesthetist was present to administer the propofol and to observe the patient. Standardized testing procedures (Steward score, Trieger test) were used to determine the length of postendoscopy recovery time. Efficacy of sedation was assessed by investigators and patients, using scoring systems. RESULTS: Complete ERCP and adequate sedation was possible in 80% of patients (32 out of 40) with midazolam, and in 97.5% of patients (39 out of 40) with propofol (P<0.01). The average propofol induction dose was 1.24 mg/kg body weight, with maintenance requiring a mean dose of 9 mg/kg body weight per hour, or the equivalent of 354 mg in total. The average dose of midazolam administered was 0.12 mg/kg body weight; the total dose averaged 8 mg. Recovery time in the propofol patients was significantly shorter (P<0.01). The investigators (P<0.01) and the patients (P<0.05) both judged the quality of sedation to be better in the propofol group. There were no differences in blood pressure, pulse, or oxygen saturation between the two groups. One patient in the propofol group (79 years old) suffered a protracted apneic phase accompanied by hypotension that was managed by manual ventilation and drug therapy, and led to no complications. CONCLUSIONS: Propofol proves to be an excellent sedative for ERCP and shows a shorter recovery time than midazolam. Because of the narrow therapeutic window, we recommend close patient monitoring.

Anesthesia Recovery Period↗
PubMed1998

Effects of propofol on human hepatic microsomal cytochrome P450 activities.

1. The potential of propofol to inhibit the activity of major human cytochrome P450 enzymes has been examined in vitro using human liver microsomes. Propofol produced inhibition of CYP1A2 (phenacetin O-deethylation), CYP2C9 (tolbutamide 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation) and CYP3A4 (testosterone 6beta-hydroxylation) activities with IC50 = 40, 49, 213 and 32 microM respectively. Ki for propofol against all of these enzymes with the exception of CYP2D6, where propofol showed little inhibitory activity, was 30, 30 and 19 microM respectively for CYPs 1A2, 2C9 and 3A4. 2. Furafylline, sulphaphenazole, quinidine and ketoconazole, known selective inhibitors of CYPs 1A2, 2C9, 2D6 and 3A4 respectively, were much more potent than propofol having IC50 = 0.8, 0.5, 0.2 and 0.1 microM; furafylline and sulphaphenazole yielded Ki = 0.6 and 0.7 microM respectively. 3. The therapeutic blood concentration of propofol (20 microM; 3-4 microg/ml) together with the in vitro Ki estimates for each of the major human P450 enzymes have been used to estimate the extent of cytochrome P450 inhibition, which may be produced in vivo by propofol. This in vitro-in vivo extrapolation indicates that the degree of inhibition of CYP1A2, 2C9 and 3A4 activity which could theoretically be produced in vivo by propofol is relatively low (40-51%); this is considered unlikely to have any pronounced clinical significance. 4. Although propofol has now been used in > 190 million people since its launch in 1986, there are only single reports of possible drug interactions between propofol and either alfentanil or warfarin. Consequently, it is difficult to conclude from either the published literature or the ZENECA safety database whether there is any evidence to indicate that propofol produces clinically significant drug interactions through inhibition of cytochrome P450-related drug metabolism.

Anesthetics, Intravenous↗
PubMed1998

In vivo effects of propofol on acetylcholine release from the frontal cortex, hippocampus and striatum studied by intracerebral microdialysis in freely moving rats.

Using in vivo microdialysis, we have investigated the effects of propofol on acetylcholine (ACh) release from various regions of the rat brain. Propofol 25 and 50 mg kg-1 i.p. decreased basal ACh release from the frontal cortex by 70% and 85%, respectively. Propofol 25 and 50 mg kg-1 i.p. decreased basal ACh release from the hippocampus by 47% and 72%, respectively. However, in rat striatum, propofol 25 mg kg-1 i.p. did not affect basal ACh release and 50 mg kg-1 i.p. produced slight inhibition of basal ACh release (by 19%) only in the second sample after i.p. injection. In addition, we also examined the pharmacological mechanisms mediating the interaction between propofol and a gamma-aminobutyric acid A (GABAA) receptor complex. In the rat hippocampus, local application of bicuculline 1 mumol litre-1, a GABAA receptor antagonist, significantly antagonized the inhibitory effects of propofol 50 mg kg-1 i.p. on basal ACh release. In the rat frontal cortex, local application of bicuculline 1 mumol litre-1 did not antagonize the inhibitory effects of propofol 50 mg kg-1 i.p. on basal ACh release, while systemic application of bicuculline 1 mg kg-1 i.p. significantly antagonized the inhibitory effects of propofol 50 mg kg-1 i.p. These results suggest that propofol has powerful depressant effects on ACh release from the rat frontal cortex and hippocampus but not from the striatum, indicating that propofol has a "region-selective" anaesthetic action. Further, these results suggest that the inhibitory effects of propofol in the rat hippocampus may involve "intra" hippocampal GABAA receptors while the inhibitory effects in the rat frontal cortex may be mediated by GABAA receptors other than "intra" frontal cortex GABAA receptors.

Acetylcholine↗
PubMed1999

Propofol concentrations in follicular fluid during general anaesthesia for transvaginal oocyte retrieval.

Propofol (Diprivan) is an i.v. anaesthetic used for general anaesthesia. The purpose of this study was to measure the propofol concentration in arterial blood and follicular fluid in patients during transvaginal oocyte retrieval. After approval by the University Ethics Committee, 30 women participated in this prospective study. Following induction of anaesthesia with 0.5 mg alfentanil and 2 mg.kg-1 propofol i.v., a continuous infusion of propofol at 10 mg.kg-1.h-1 was used for maintenance of anaesthesia. Follicular fluid and arterial blood samples were aspirated simultaneously at fixed intervals during the surgical procedure and propofol assayed by high pressure liquid chromatography (HPLC). The mean follicular fluid concentration of propofol increased linearly with time from 0.10 +/- 0.02 microgram.ml-1 to 0.57 +/- 0.06 microgram.ml-1 and was strongly related to the cumulative dose of propofol administered. The absorption of propofol was time-dependent. There was no correlation between the concentration of propofol in the follicular fluid and the arterial blood concentration of the drug. In conclusion, a propofol-based anaesthetic technique resulted in significant concentrations of this agent in follicular fluid, related to the dose administered and to the duration of propofol administration.

Adult↗
PubMed1997

Eltanolone as an alternative to propofol for ambulatory anesthesia.

UNLABELLED: The intravenous (i.v.) steroid anesthetic, eltanolone, compares favorably to propofol with respect to its induction characteristics. This double-blind investigation was designed to compare the induction and recovery profile of eltanolone (versus propofol) when it was used for both induction and maintenance of ambulatory anesthesia. Eighty-three consenting ASA physical status I-III outpatients undergoing minor gynecologic or urologic procedures lasting 10-40 min were randomly assigned to one of three anesthetic treatment groups. All patients received midazolam, 2 mg i.v., and fentanyl, 50 micrograms i.v., before induction of anesthesia. The control group (Group 1) was induced with propofol, 2.4 mg/kg i.v. (18-60 yr or ASA physical status I or II) or 1.6 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus doses of 0.6 mg/kg i.v. in combination with N2O 67% for maintenance of anesthesia. In Group 2, anesthesia was induced with eltanolone, 0.75 mg/kg i.v., (18-60 yr and/or ASA physical status I or II) or 0.5 mg/kg i.v. (61-80 yr and/or ASA physical status III), and maintained with intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. Group 3 received eltanolone, 1.0 mg/kg i.v. (18-60 yr and/or ASA physical status I or II), or 0.75 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. In addition to recording the induction and recovery times and side effects, psychomotor testing was performed before and at 30-min intervals after anesthesia. Induction times (57 +/- 23, 67 +/- 26, and 61 +/- 22s, respectively) were similar in all three groups. Although eltanolone produced no pain on injection (versus 52% in the propofol group), 10% of the eltanolone-treated patients (versus none in the propofol group) developed transient cutaneous (rash-like) reactions. The total dose of study medication used during the anesthetic period was 9.2 +/- 3.7 mg.kg-1.h-1 in the propofol group compared with 3.3 +/- 1.4 mg.kg-1.h-1 and 3.3 +/- 1.9 mg.kg-1.h-1 in Groups 2 and 3, respectively. Early recovery times were significantly shorter after propofol anesthesia. However, times to ambulation, micturition, and being judged "fit for discharge," as well as recovery of cognitive function, were similar in all three groups. Although ethanolone seems to be a safe and effective i.v. anesthetic, these data suggest that it is unlikely to replace propofol in the ambulatory setting. IMPLICATIONS: Eltanolone is an investigational steroid anesthetic that causes less pain on injection and less cardiovascular depression than propofol (the most widely used intravenous anesthetic in the outpatient setting). Unfortunately, emergence from anesthesia after ambulatory surgery is slower with eltanolone compared with propofol. Therefore, it is unlikely that eltanolone will replace propofol for outpatient anesthesia.

Adult↗
PubMed1998

Propofol sedation produces dose-dependent suppression of lidocaine-induced seizures in rats.

UNLABELLED: The association of propofol with excitatory motor activity, such as myoclonic jerking and opisthotonus, in humans and in animals suggests that it may aggravate clinical seizure activity in some circumstances, although evidence suggests that under other circumstances, propofol inhibits seizure activity. In the current study, we assessed the effect of sedating doses of propofol on lidocaine-induced seizure activity in spontaneously breathing rats receiving no other anesthetics. Adult Sprague-Dawley male rats, 300-400 g, were divided into a control group and three experimental groups representing three graded levels of propofol sedation. The control rats then received a lidocaine infusion at the rate of 150 mg x kg(-1) x h(-1), resulting in a slow, progressive increase in systemic lidocaine concentrations. At the onset of electroencephalographic (EEG) seizure activity, arterial lidocaine concentrations were obtained. The treated rats received propofol according to three different dose schedules: Dose 1 = 10 mg x kg(-1) x h(-1) after a 2.5-mg/kg bolus; Dose 2 = 20 mg x kg(-1) x h(-1) after a 5-mg/kg bolus; Dose 3 = 40 mg x kg(-1) x h(-1) after a 10-mg/kg bolus. After 30 min, a steady level of sedation, dependent on the dose of propofol, was achieved. The lidocaine infusion was then started, and systemic lidocaine levels were obtained at the onset of EEG seizure activity. The lidocaine was continued until the onset of death by cardiac arrest. Plasma lidocaine was measured by gas chromatography. Analysis of variance and Dunnett's t-test were used for comparisons with the control values. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 +/- 3.5 mg/kg (mean +/- SEM) to 52.5 +/- 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 +/- 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3. The lethal dose of lidocaine, 89.4 +/- 10.5 mg/kg control versus 108.7 +/- 10.3 mg/kg (Dose 1), 98.3 +/- 10.1 mg/kg (Dose 2), and 93.5 +/- 10.4 mg/kg (Dose 3) did not differ among groups. The lidocaine levels at seizure threshold were increased in the propofol-treated rats: 16.9 +/- 0.5 microg/mL control versus 19.2 +/- 0.7 microg/mL (Dose 1, P = not significant) and 23.7 +/- 1.8 microg/mL (Dose 2, P < 0.05). Continuous propofol sedation in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dose-dependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions. IMPLICATIONS: The i.v. anesthetic drug propofol, given to rats to produce sedation, was found to suppress seizure activity caused by overdosage of the local anesthetic lidocaine.

Anesthetics, Local↗
PubMed1998

The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the Bispectral Index.

UNLABELLED: The Bispectral Index (BIS) correlates well with the level of consciousness with single anesthetic drugs. We studied the effect of the interaction of propofol with alfentanil on propofol concentration and BIS associated with 50% probability of loss of consciousness and lack of recall (Cp50 and BIS50, respectively). We studied 40 consenting volunteers at two institutions who were randomly assigned to receive stepped increases of propofol (10 subjects at each site), propofol plus alfentanil 50 ng/mL (10 subjects at Emory site), or propofol plus alfentanil 100 ng/mL (10 subjects at Duke site) by using a target-controlled infusion device. Measures of sedation, BIS, deltaBIS (absolute change of BIS after a painful stimulus), memory, and drug concentration were obtained at each target drug concentration. The relation among BIS, measured drug concentration, sedation score, and presence or absence of recall was determined by linear and logistic regression for different drug regimens, and the prediction probability (Pk) was calculated. The addition of alfentanil in increasing doses did not significantly affect the BIS50 and propofol Cp50 values for loss of consciousness and lack of recall. DeltaBIS was significantly decreased by both an increase in the concentration of propofol and the presence of alfentanil. The Pk for BIS was >0.93 with all drug regimens, better than those of the target and measured propofol concentrations. We conclude that BIS correlated well with the hypnotic component of anesthesia independent of the presence of an opioid. Moreover, the level of consciousness, and, therefore, the BIS index, is affected by a painful stimulus, and this response is ablated either by opioids or increasing propofol concentration. IMPLICATIONS: In volunteers, the sedation and changes in memory function produced by propofol correlated well with changes in the Bispectral Index. This relationship was not altered by the addition of an analgesic (alfentanil). However, in moderately sedated patients who received a painful stimulus, the Bispectral Index increased, but this response was blocked by the analgesic or increasing propofol concentrations.

Adult↗