Effects of propofol and remifentanil on phrenic nerve activity and nociceptive cardiovascular responses in rabbits.
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BACKGROUND: The effects of propofol, remifentanil, and their combination on phrenic nerve activity (PNA), resting heart rate (HR), mean arterial pressure (MAP), and nociceptive cardiovascular responses were studied in rabbits. METHODS: Basal anesthesia and constant blood gas tensions were maintained with alpha-chloralose and mechanical ventilation. PNA, HR, MAP, and maximum changes in HR and MAP (deltaHR, deltaMAP) evoked by electrical nerve stimulation of tibial nerves were recorded. The comparative effects were observed for propofol at infusion rates from 0.05 to 3.2 mg x kg(-1) x min(-1) (group I) and remifentanil from 0.0125 to 12.8 microg x kg(-1) x min(-1) alone (group II), and during constant infusions of propofol at rates of 0.1 and 0.8 mg x kg(-1) x min(-1) (groups III and IV, respectively). Finally, the effect of remifentanil on propofol blood levels was observed (group V). RESULTS: The infusion rates for 50% depression (ED50) of PNA, deltaHR, and deltaMAP were 0.41, 1.32, and 1.58 mg x kg-(1) x min(-1) for propofol, and 0.115, 0.125, and 1.090 microg x kg(-1) x min(-1) for remifentanil, respectively. The ratios for the ED50 values of deltaHR and deltaMAP to PNA were 3.2 and 3.9 for propofol, and 1.1 and 9.5 for remifentanil, respectively. Analysis of the expected and observed responses and isobologrms showed that although their combined effects on PNA, resting HR, and MAP, and deltaMAP were synergistic for deltaHR, they were merely additive. Remifentanil had no effect on propofol blood levels. CONCLUSION: PNA was abolished by propofol and remifentanil, alone and in combination, before significant depression of nociceptive pressor responses occurred. Their combined effects on PNA, HR, MAP, and deltaMAP are greater than additive, ie., synergistic. Unlike propofol, remifentanil obtunded pressor responses more than the resting circulation. (+info)
Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia.
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We have studied the effect of nitrous oxide on bispectral index (BIS), calculated from a bipolar encephalogram. Inhalation of 70% nitrous oxide resulted in loss of consciousness in all healthy volunteers (n = 10) but no change in BIS. Brief inhalation up to 1.2% sevoflurane also resulted in loss of consciousness in volunteers (n = 5), but with sevoflurane, BIS decreased. BIS and the haemodynamic effects of adding nitrous oxide were also measured during coronary artery bypass surgery in patients (n = 10) receiving midazolam and fentanyl infusions. Measurements were made after 0%, 33%, 66% and 0% nitrous oxide, just before skin incision and after sternotomy. Nitrous oxide caused no change in BIS. BIS may indicate a sufficient hypnotic depth to prevent awareness during surgery, but our study demonstrated that pharmacological unconsciousness-hypnosis can also be reached by mechanisms to which BIS is not sensitive. Thus BIS is a sufficient but not a necessary criterion for adequate depth of anaesthesia or prevention of awareness. (+info)
A model of the kinetics and dynamics of induction of anaesthesia in sheep: variable estimation for thiopental and comparison with propofol.
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We describe a six-compartment kinetic and dynamic physiological model of induction of anaesthesia with thiopental. The model included an accurate account of initial drug distribution by representing the inter-relationships between initial vascular mixing, lung kinetics and cardiac output, and the use of the brain as the target organ for anaesthesia (two-compartment sub-model with slight membrane limitation). It also accounted for thiopental-induced reductions in cerebral blood flow and cardiac output. Parameters for the model were estimated using hybrid modelling from an extensive in vivo data set collected in sheep. Simulations were used to compare the properties of the thiopental model with an analogous previously published model of propofol. Differences in the blood:brain equilibrium half-lives of thiopental (1.22 min) and propofol (4.32 min) contributed to significant differences in the predicted optimal rate of bolus injection of each agent for inducing anaesthesia in sheep. (+info)
Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro.
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Fentanyl decreases clearance of midazolam administered i.v., but the mechanism remains unclear. To elucidate this mechanism, we have investigated the effect of fentanyl on metabolism of midazolam using human hepatic microsomes and recombinant cytochrome P450 isoforms (n = 6). Midazolam was metabolized to l'-hydroxymidazolam (l'-OH MDZ) by human hepatic microsomes, with a Michaelis-Menten constant (K(m)) of 5.0 (SD 2.7) mumol litre-1. Fentanyl competitively inhibited metabolism of midazolam in human hepatic microsomes, with an inhibition constant (Ki) of 26.8 (12.4) mumol litre-1. Of the seven representative human hepatic P450 isoforms, CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, only CYP3A4 catalysed hydroxylation of midazolam, with a K(m) of 3.6 (0.8) mumol liter-1. Fentanyl competitively inhibited metabolism of midazolam to l'-OH MDZ by CYP3A4, with a Ki of 24.2 (6.8) mumol litre-1, comparable with the Ki obtained in human hepatic microsomes. These findings indicate that fentanyl competitively inhibits metabolism of midazolam by CYP3A4. (+info)
Detecting alveolar epithelial injury following volatile anesthetics by (99m)Tc DTPA radioaerosol inhalation lung scan.
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BACKGROUND: Many volatile anesthetics have long been thought to affect alveolar epithelial permeability. OBJECTIVE: The purpose of this study was to examine the acute effects of volatile anesthetics on the permeability of the alveolocapillary barrier to (99m)Tc DTPA. METHODS: Twenty-seven patients (24 females, 3 males, age 29-73 years) undergoing operation were enrolled in this study and grouped according to the type of anesthesia received. Group 1 patients were administered 1% halothane. Group 2 patients were given 1.5% isoflurane. Intravenous anesthesia without volatile anesthetics were used for group 3 patients. Before and after anesthesia, (99m)Tc DTPA radioaerosol inhalation lung scans were performed to detect alveolar epithelial injury due to volatile anesthetics. The negative slope of the regression line was designated as the (99m)Tc DTPA pulmonary clearance rate and was expressed in terms of percentage decrease in radioactivity per minute. RESULTS: In group 1, the (99m)Tc DTPA clearance rates were 1.26 +/- 0.34 and 1.29 +/- 0.38 before and after anesthesia, respectively. The difference was not significant (p > 0.05). In group 2, the rates were 0.76 +/- 0.20 and 1.10 +/- 0. 37, before and after anesthesia, respectively. The difference was significant (p < 0.05). In group 3, the clearance rates were 1.07 +/- 0.38 and 1.21 +/- 0.48, before and after anesthesia, respectively. The difference was not significant. CONCLUSIONS: Following isoflurane administration, the more rapid pulmonary clearance of (99m)Tc DTPA indicates that isoflurane increases the permeability of the alveolo-capillary barrier. (+info)
Diazepam increases calcium sensitivity of the skinned cardiac muscle fiber in guinea pig.
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Influences of diazepam, a benzodiazepine derivative, on the contractile response to calcium in skinned trabecular fibers of guinea pig heart were examined. Diazepam (100 microM) enhanced the contractile response of the skinned fiber to calcium and shifted the concentration-response curve to the left. The pCa50 values were 6.07+/-0.03 and 6.28+/-0.03 (P<0.05) in the absence and presence of diazepam, respectively. This result suggests that diazepam increases calcium sensitivity of contractile proteins in heart muscles. (+info)
Pulmonary oedema produced by scorpion venom augments a phenyldiguanide-induced reflex response in anaesthetized rats.
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1. The involvement of pulmonary oedema produced by scorpion venom in augmenting a phenyldiguanide (PDG)-induced reflex response was evaluated in urethane-anaesthetized rats. 2. PDG-induced bradycardiac, hypotensive and apnoeic responses, expressed as time-response area, exhibited similarities before or after venom treatment. Hence, the time-response area of bradycardia was taken as a reflex parameter. Pulmonary oedema was determined by physical evaporation and histological methods. 3. Exposure to Indian red scorpion (Buthus tamulus, BT; i.v.) venom for 30 min increased the pulmonary water content (P < 0.05; Student's t test) and augmented the PDG-induced bradycardiac reflex response by more than 2 times (P < 0.001). The increase of pulmonary water content was maximal with 100 microg kg-1 of venom and the augmentation was maximal with 10 microg kg-1. In a separate series of experiments, the venom (100 microg kg-1)-induced pulmonary oedema was confirmed by histological and physical methods. In this group also, the venom augmented the reflex to the same magnitude. 4. Pulmonary oedema (physical and histological) and augmentation of the bradycardiac reflex response after BT venom (100 microg kg-1; i.v.) were absent in animals pretreated with aprotinin, a kallikrein-kinin inhibitor (6000 KIU; i. v.). 5. Ondansetron (10 microg kg-1; i.v.), a 5-HT3 receptor antagonist, failed to block the venom-induced pulmonary oedema (physical and histological) but blocked the venom-induced augmentation of the reflex. 6. The results of this study indicate that the venom-induced augmentation of the PDG reflex is associated with pulmonary oedema involving kinins utilizing 5-HT3 receptors. (+info)
Alfentanil causes less postoperative nausea and vomiting than equipotent doses of fentanyl or sufentanil in outpatients.
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BACKGROUND: The relative potencies of alfentanil, fentanyl, and sufentanil as a risk factor for postoperative nausea and vomiting have not been determined. They were compared in a randomized study designed to obtain equipotent plasma concentrations of these three opioids at the beginning of the recovery period. METHODS: The study included 274 patients treated on an outpatient basis. The steady state opioid plasma concentration providing a predicted 50% reduction of the minimum alveolar concentration of isoflurane was used to determine the relative potency of the opioids. The opioids were prepared in equal volumes at concentrations of alfentanil 150 microg/ml, fentanyl 50 microg/ml, and sufentanil 5 microg/ml and were administered in vol/kg. Anesthesia was induced in a blinded fashion with a bolus of the study opioid (0.05 ml/kg) and 4-6 mg/kg thiopental and was maintained with isoflurane (0.6-1%) in a nitrous oxide-oxygen mixture with a continuous infusion of the study opioid (0.06 ml x kg(-1) x h(-1)). If necessary, up to five additional boluses of opioid (0.02 ml/kg) could be given. This opioid administration protocol was tested by pharmacokinetic simulations. RESULTS: The incidence of postoperative nausea and vomiting was not different in the postanesthesia care unit, but in the ambulatory surgery unit it was significantly lower for alfentanil compared with fentanyl and sufentanil (12, 34, and 35%, respectively P < 0.005). Pharmacokinetic modeling showed that the end-anesthesia opioid plasma concentrations were approximately equipotent in the three groups. However, modeling does not support that the difference between groups in the postoperative period can be explained by a more rapid disappearance of alfentanil from the plasma. CONCLUSIONS: Alfentanil, compared with approximately equipotent doses of fentanyl and sufentanil, is associated with a lower incidence of postoperative nausea and vomiting in outpatients. (+info)