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PubMed1993

Effects of propofol and thiopental on maternal and fetal cardiovascular and acid-base variables in the pregnant ewe.

BACKGROUND: The effects of propofol on uterine blood flow are not understood well. This is a relatively new agent that is finding increased use for nonobstetric surgical procedures during pregnancy and induction of anesthesia for cesarean section. METHODS: The effects of induction and maintenance of anesthesia with propofol were studied on maternal and fetal cardiovascular and acid-base variables in a chronically instrumented pregnant sheep model. Anesthesia was induced with a 2 mg/kg bolus of propofol and maintained with of one of three continuous infusions: 150, 300, and 450 micrograms.kg-1 x min-1. The control group received thiopental for induction, and anesthesia was maintained with isoflurane. RESULTS: The use of propofol did not adversely affect maternal or fetal mean arterial pressure, heart rate, or base excess, fetal heart rate variability, or uterine blood flow. Uterine blood flow transiently decreased during induction and intubation with thiopental but remained stable during induction with propofol. However, administration of succinylcholine for intubation in the presence of propofol resulted in a transient, but severe, maternal bradycardia. Continuous infusion of 300 micrograms.kg-1.min-1 of propofol appeared to provide satisfactory anesthesia in the ewe. CONCLUSIONS: Assuming the applicability of ovine data to humans, these findings suggest that induction and maintenance of anesthesia with propofol and 50% nitrous oxide in oxygen has no adverse fetal effects but warrants caution because of the potential risk of severe maternal bradycardia during induction of anesthesia using the combination of propofol and succinylcholine.

Acid-Base Equilibrium↗
PubMed1993

Propofol activates GABAA receptor-chloride ionophore complex in dissociated hippocampal pyramidal neurons of the rat.

BACKGROUND: The molecular mechanism of propofol anesthesia has been related to facilitation of the inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). In the current study, the authors examined the direct actions of propofol on the acutely dissociated mammalian central neurons. METHODS: Hippocampal pyramidal neurons were dissociated after enzymatic treatment of the brain slices of the rat. Single neurons were voltage-clamped using the whole cell configuration of the patch clamp technique, and drugs were applied with a rapid drug-application system. RESULTS: In the pyramidal neurons voltage-clamped at -60 mV, propofol evoked a transmembrane inward current, which desensitized at high concentrations of the anesthetic. The peak amplitude of the current increased sigmoidally with increasing doses of propofol applied. A least-squares fitting gave a dissociation constant of 1.2 x 10(-5) M and a Hill coefficient of 1.8, thereby indicating that clinical concentrations of propofol evoke the current, and that the anesthetic cooperatively activates the channel. The threshold concentration was less than 10(-6) M. The reversal potential for the current shifted according to the chloride equilibrium potential predicted by the Nernst equation, indicating that the current was carried by chloride ions. Bicuculline and strychnine suppressed the current in a concentration-dependent manner, in which the former was almost 40-fold more potent than the latter. The propofol-induced current cross-desensitized with the GABA-induced current, but no such interaction was observed with the glycine-induced current. Ro15-1788 (10(-6) M), an allosteric benzodiazepine antagonist, had no effect on the response. Diazepam (10(-6) M) enhanced the propofol-induced current, but pentobarbital (10(-6) M and 3 x 10(-5) M) did not affect the current. CONCLUSIONS: Propofol at clinically relevant concentrations directly activates the GABAA receptor-chloride ionophore complex in the mammalian central neurons and, hence, increases the chloride conductance, which may contribute to anesthesia produced by the agent. The desensitization of the GABAA receptor in the presence of high concentrations of propofol may result in a suppression of the GABAA inhibitory system.

Animals↗
PubMed1993

The dose of propofol required to prevent children from moving during magnetic resonance imaging.

BACKGROUND: Intravenous propofol offers several advantages as an anesthetic for children undergoing magnetic resonance imaging. However, the dose of propofol required to prevent movement during magnetic resonance imaging is likely to be less than that required for surgical anesthesia. METHODS: Thirty children between the ages of 1 and 10 years, undergoing elective magnetic resonance imaging as outpatients were randomly assigned to receive a propofol infusion at a rate of 50, 75, or 100 micrograms.kg-1.min-1 during the imaging procedure. Anesthesia was induced with inhalation of halothane, nitrous oxide, and oxygen, and a 2 mg.kg-1 loading dose of propofol. Immediately after insertion of an intravenous catheter, inhaled anesthetics were discontinued and the propofol infusion started. The children then were observed for movement during the scan. RESULTS: There were no significant differences among the three groups with respects to mean age (4.4 +/- 2.0 yr), weight (17.6 +/- 5.1 kg), induction time (11 +/- 3 min), scan duration (55 +/- 26 min), or recovery time (30 +/- 8 min). Five of ten patients who received 50 micrograms.kg-1 x min-1 moved during the scan, three of ten patients who received 75 micrograms.kg-1 x min-1 moved, and none of the children who received 100 micrograms.kg-1 x min-1 moved. Two patients experienced a decrease of arterial oxygen saturation to less than 95% after receiving the initial bolus of propofol. The arterial oxygen saturation returned to normal within 15 s without specific treatment other than continued supplemental oxygen. There were no episodes of hypoxemia during image acquisition. None of the children experienced nausea or vomiting. CONCLUSIONS: Following induction of anesthesia with halothane, nitrous oxide, and a 2 mg.kg-1 loading dose of propofol, infusion of propofol at a rate of 100 micrograms.kg-1 x min-1 effectively prevents children from moving during elective magnetic resonance imaging. A transient decrease in arterial oxygen saturation can occur after the initial bolus of propofol. Recovery from anesthesia is rapid and without nausea or vomiting.

Ambulatory Care↗
PubMed1994

Propofol induces changes in the cytosolic free calcium concentration and the cytoskeletal organization of cultured human glial cells and primary embryonic rat brain cells.

BACKGROUND: The site of action of the intravenous anesthetic drug propofol is uncertain. Therefore, we examined the effects of propofol on the cytosolic free calcium levels of cultured primary embryonic rat brain cells (80-85% neurons), and on the organization of the cytoskeleton in these rat cells and in a model system of cultured human glial cells (astrocytes). METHODS: Propofol was added to the cells as the clinically available solution Diprivan. Cytosolic free calcium changes in neurons were studied using Fura2 and a single-cell microfluorometric method. Fluorescence microscopy was used to study the organization of actin filaments and tubulin in detergent-extracted cells. RESULTS: An increase in the cytosolic free calcium concentration of 116 +/- 39 nM was seen shortly after the addition of 0.3 microgram.ml-1 propofol, and a propofol concentration of 0.03 microgram.ml-1 resulted in an increase in cytosolic free calcium concentration of the same magnitude, 119 +/- 42 nM. Most of the calcium (60-75%) came from the extracellular environment, and the rest was from intracellular stores. When neurons were depleted of intracellular calcium by 1,2-bis-5-methyl-amino-phenoxylethane-N,N'-tetra-acetoxymethyla cetate (MAPT/AM), no changes were seen in the actin organization of the cytoskeleton. Actin organization was affected by all concentrations of propofol, 0.3-50 micrograms.ml-1 (1.7-280 microM), when exposure to the drug was achieved by a 30-min incubation. After the incubation, the exposed cells were more rounded and exhibited increased ruffling activity, both at the periphery and on the cellular surface, and ring-shaped actin structures were also seen. These effects were concentration dependent and reversible, and reached a maximum after 20 min of incubation. Propofol had no apparent effect on the organization of tubulin. CONCLUSIONS: Propofol induced changes in the cytoskeletal organization of actin in cultured rat neurons and human glial cells. These changes must have been due to the increase in intracellular calcium seen shortly after the addition of propofol, since no effects on actin organization were seen when intracellular calcium was depleted.

Actins↗
PubMed1995

Propofol has no direct effect on sinoatrial node function or on normal atrioventricular and accessory pathway conduction in Wolff-Parkinson-White syndrome during alfentanil/midazolam anesthesia.

BACKGROUND: Propofol has been implicated as causing intraoperative bradyarrhythmias. Furthermore, the effects of propofol on the electrophysiologic properties of the sinoatrial (SA) node and on normal atrioventricular (AV) and accessory pathways in patients with Wolff-Parkinson-White syndrome are unknown. Therefore, this study examined the effects of propofol on the cardiac electrophysiologic properties in humans to determine whether propofol promotes bradyarrhythmias and its suitability as an anesthetic agent in patients undergoing ablative procedures. METHODS: Twelve patients with Wolff-Parkinson-White syndrome undergoing radiofrequency catheter ablation were studied. Anesthesia was induced with alfentanil (50 micrograms/kg), midazolam (0.15 mg/kg), and vecuronium (20 mg) and maintained with alfentanil (2 micrograms.kg-1.min-1) and midazolam (1-2 mg, every 15 min, as needed). A electrophysiologic study was performed consisting of measurement of the effective refractory period of the right atrium, AV node, and accessory pathway and the shortest cycle length of the AV node and accessory pathway during antegrade stimulation plus the effective refractory period of the right ventricle and accessory pathway and the shortest cycle length of the accessory pathway during retrograde stimulation. Determinants of SA node function including sinus node recovery time, corrected sinus node recovery time, and SA conduction time; intraatrial conduction time and atrial-His interval also were measured. Reciprocating tachycardia was induced by rapid right atrial or ventricular pacing, and the cycle length and atrial-His, His-ventricular, and ventriculoatrial intervals were measured. Alfentanil/midazolam was then discontinued. Propofol was administered (bolus 2 mg/kg + 120 micrograms.kg-1.min-1), and the electrophysiologic measurements were repeated. RESULTS: Propofol caused a statistically significant but clinically unimportant prolongation of the right atrial refractory period. The effective refractory periods of the AV node, right ventricle, and accessory pathway, as well as the shortest cycle length, were not affected. Parameters of SA node function and intraatrial conduction also were not affected. Sustained reciprocating tachycardia was inducible in 8 of 12 patients, and propofol had no effect on its electrophysiologic properties. All accessory pathways were successfully identified and ablated. CONCLUSIONS: Propofol has no clinically significant effect on the electrophysiologic expression of the accessory pathway and the refractoriness of the normal AV conduction system. In addition, propofol has no direct effect on SA node activity or intraatrial conduction; therefore, it does not directly induce bradyarrhythmias. It is thus a suitable agent for use in patients undergoing ablative procedures who require either a neuroleptic or general anesthetic.

Adolescent↗
PubMed1996

Propofol attenuates hydrogen peroxide-induced mechanical and metabolic derangements in the isolated rat heart.

BACKGROUND: Oxygen-derived free radicals are involved in tissue damage during myocardial ischemia and reperfusion. Recent in vitro studies have demonstrated that a beneficial effect of propofol lies on its free radical scavenging properties. The current study, therefore, examined whether propofol is effective against the mechanical and metabolic damage induced by exogenously administered hydrogen peroxide in the isolated rat heart. METHODS: Rat hearts were perfused aerobically with Krebs-Henseleit bicarbonate buffer at a constant flow rate according to Langendorff's technique, while being paced electrically. Hearts were studied in control Krebs-Henseleit bicarbonate buffer, with Intralipid vehicle, with 25 microM or 50 microM propofol for 40 min, and with 50 microM propofol for 30 min followed by Intralipid for 10 min. A similar set of hearts was treated with hydrogen peroxide for 4 min, either in the absence of or beginning 10 min after Intralipid or propofol infusion. Left ventricular pressure was recorded as an index of mechanical function. The tissue concentrations of adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, and creatine phosphate were measured as indices of energy metabolism. The tissue concentration of malondialdehyde was measured to evaluate lipid peroxidation. RESULTS: Hydrogen peroxide (600 microM) significantly increased the left ventricular end-diastolic pressure, decreased the left ventricular developed pressure (i.e., it produced mechanical dysfunction), and decreased tissue concentrations of adenosine triphosphate and creatine phosphate (i.e., metabolic damage). Hydrogen peroxide also increased the tissue concentration of malondialdehyde. These mechanical and metabolic alterations induced by hydrogen peroxide were significantly attenuated by propofol (25 microM or 50 microM), while the increase in malondialdehyde was completely suppressed by propofol. CONCLUSIONS: The current study demonstrates that in the isolated heart, propofol attenuates both mechanical and metabolic changes induced by exogenously applied hydrogen peroxide. The beneficial action of propofol is probably correlated with reduction of the hydrogen peroxide-induced lipid peroxidation.

Animals↗
PubMed1996

Propofol alters left ventricular afterload as evaluated by aortic input impedance in dogs.

BACKGROUND: Systemic vascular resistance incompletely describes left ventricular afterload because of the phasic nature of arterial pressure and blood flow. Aortic input impedance is an experimental description of left ventricular afterload that incorporates the frequency- dependent characteristics and viscoelastic properties of the arterial system. The effects of propofol on aortic input impedance were examined using three variables derived from the three-element Windkessel model: characteristic aortic impedance, total arterial compliance, and total arterial resistance. METHODS: Eight dogs were chronically instrumented for measurement of aortic pressure, left ventricular pressure, +dP/dt, subendocardial segment length, and aortic blood flow. Systemic hemodynamics and aortic blood pressure and flow waveforms were recorded in the conscious state and after a bolus of 5 mg x kg(-1) propofol and infusion for 15 min at 25, 50 and 100 mg x kg(-1) x h(-1). Aortic input impedance spectra were generated using power spectral analysis of aortic pressure and flow waveforms corrected for the phase responses of the pressure and flow transducers. Characteristic aortic impedance, total arterial resistance, and total arterial compliance were calculated from the aortic input impedance spectrum and the aortic pressure waveform. Parameters describing the net site and magnitude or arterial wave reflection were determined from aortic impedance. RESULTS: Propofol decreased total arterial resistance (3.05 +/- 0.20 during control to 2.29 +/- 0.18 dynes x s x cm(-5) x 10(3) at the high dose) and increased total arterial compliance (0.53 +/- 0.04 during control to 1.15 +/- 0.17 ml x mmHg(-1) at the high dose) in a dose- related manner. Propofol increased characteristic aortic impedance (1.49 +/- 0.15 during control to 2.20 +/- 0.20 dynes x s x cm(-5) x 10(2) at the high dose). The net site and the magnitude of arterial wave reflection were unchanged by the propofol. CONCLUSIONS: In chronically instrumented dogs, propofol decreased total arterial resistance, a property of arteriolar resistance vessels, consistent with the known actions of this drug on systemic vascular resistance. Propofol also increased total arterial compliance and characteristic aortic impedance, indicating that this anesthetic affects the mechanical properties of the aorta. Propofol had no effect on arterial wave reflection patterns. The results indicate that propofol reduces left ventricular afterload via decreases in peripheral resistance and increases in arterial compliance.

Anesthetics, Intravenous↗
PubMed1996

Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The Multicenter Study of Perioperative Ischemia Research Group.

BACKGROUND: Propofol is increasingly used for cardiac anesthesia and for perioperative sedation. Because pharmacokinetic parameters vary among distinct patient populations, rational drug dosing in the cardiac surgery patient is dependent on characterization of the drug's pharmacokinetic parameters in patients actually undergoing cardiac procedures and cardiopulmonary bypass (CPB). In this study, the pharmacokinetics of propofol was characterized in adult patients undergoing coronary revascularization. METHODS: Anesthesia was induced and maintained by computer-controlled infusions of propofol and alfentanil, or sufentanil, in 41 adult patients undergoing coronary artery bypass graft surgery. Blood samples for determination of plasma propofol concentrations were collected during the predefined study periods and assayed by high-pressure liquid chromatography. Three-compartment model pharmacokinetic parameters were determined by nonlinear extended least-squares regression of pooled data from patients receiving propofol throughout the perioperative period. The effect of CPB on propofol pharmacokinetics was modeled by allowing the parameters to change with the institution and completion of extracorporeal circulation and selecting the optimal model on the basis of the logarithm of the likelihood. Predicted propofol concentrations were calculated by convolving the infusion rates with unit disposition functions using the estimated parameters. The predictive accuracy of the parameters was evaluated by cross-validation and by a prospective comparison of predicted and measured levels in a subset of patients. RESULTS: Optimal pharmacokinetic parameters were: central compartment volume = 6.0 l; second compartment volume = 49.5 l; third compartment volume = 429.3 l; Cl1 (elimination clearance) = 0.68 l/min; Cl2 (distribution clearance) = 1.97 l/min1; and Cl3 (distribution clearance) = 0.70 l/min. The effects of CPB were optimally modeled by step changes in V1 and Cl1 to values of 15.9 and 1.95, respectively, with the institution of CPB. Median absolute prediction error was 18% in the cross-validation assessment and 19% in the prospective evaluation. There was no evidence for nonlinear kinetics. Previously published propofol pharmacokinetic parameter sets poorly predicted the observed concentrations in cardiac surgical patients. CONCLUSIONS: The pharmacokinetics of propofol in adult patients undergoing cardiac surgery with CPB are dissimilar from those reported for other adult patient populations. The effect of CPB was best modeled by an increase in V1 and Cl1. Predictive accuracy of the derived pharmacokinetic parameters was excellent as measured by cross-validation and a prospective test.

Adult↗
PubMed1996

Effect of propofol on affective state as assessed by place conditioning paradigm in rats.

BACKGROUND: Whether propofol produces a pleasant affective state remains unclear from clinical studies. In the current study, the effect on affective state of subanesthetic and anesthetic doses of propofol was assessed at a preclinical level with rats in a place conditioning paradigm. Propofol was compared with methohexital. METHODS: In the place conditioning paradigm, propofol-induced effect was repeatedly paired with one of two distinguishable compartments of the apparatus, whereas the vehicle-induced effect was repeatedly paired with the other compartment. During a subsequent free-choice test, a preference for the drug-paired compartment over the vehicle-paired compartment would be indicative of pleasant state induced by the drug. For all experiments, the conditioning session lasted 8 days and consisted of four pairings of the drug with one compartment and four pairings of the equivalent volume of vehicle with the other compartment. In experiment 1A, four groups of rats were designated according to the dose of propofol that they received intraperitoneally: 0,30,60, or 90 mg/kg. In experiment 1B, the same procedure was used with subanesthetic doses of intraperitoneal methohexital: 0,10,20, or 30 mg/kg. In experiment 2, the rats were conditioned during the recovery period from short-term anesthesia. For one group, anesthesia was induced by propofol (100 mg/kg) whereas for the other group, anesthesia was induced by an equivalent anesthetic dose of methohexital (40 mg/kg). RESULTS: In experiment 1A, the 30-mg/kg, 60-mg/kg, and 90-mg/kg groups showed a place preference for the drug-paired compartment, but only the group conditioned with 60 mg/kg propofol significantly differed from the 0-mg/kg group. In experiment 1B, the groups conditioned with methohexital showed no place preference for the drug-paired compartment. In experiment 2, the rats showed a place preference for the compartment in which they recovered from propofol-induced anesthesia but no place preference for the compartment in which they recovered from methohexital-induced anesthesia. CONCLUSIONS: Propofol, but not methohexital, induced a pleasant affective state in rats at subanesthetic doses as well as during recovery from an anesthetic dose.

Affect↗
PubMed1997

Alterations in canine left ventricular-arterial coupling and mechanical efficiency produced by propofol.

BACKGROUND: Propofol reduces blood pressure by decreasing left ventricular (LV) afterload and myocardial contractility. This investigation tested the hypothesis that propofol preserves LV-arterial coupling and mechanical efficiency because of these simultaneous hemodynamic actions. METHODS: Experiments were conducted in open-chest dogs (n = 8) instrumented for measurement of aortic and LV pressure, dP/dtmax, and LV volume. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (En; the ratio of end systolic arterial pressure to stroke volume), stroke work (SW), and pressure-volume area (PVA) were determined from the LV pressure-volume relationships. Dogs were studied 30 min after instrumentation and after 15-min intravenous infusions of propofol at 5, 10, 20, and 40 mg.kg-1.h-1. RESULTS: Propofol caused dose-dependent decreases in Ees (4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dosage) and dP/dtmax, indicating a direct negative inotropic effect. Ea increased at the 10 mg.kg-1.h-1 dose of propofol but decreased at higher dosages. Propofol decreased the ratio of Ees to Ea (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dosage), consistent with impairment of LV-arterial coupling. Propofol also reduced the ratio SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg.kg-1.h-1), suggesting a decline in LV mechanical efficiency. SW and PVA recovered toward baseline values at the 40 mg.kg-1.h-1 dose. CONCLUSIONS: Although propofol depresses mechanical matching of the LV to the arterial system and reduces LV efficiency, these alterations plateau at higher dosages of propofol because reductions in afterload begin to offset further declines in myocardial contractile function.

Anesthetics, Intravenous↗
PubMed1998

Cardiovascular effects of propofol in dogs with dilated cardiomyopathy.

BACKGROUND: The authors tested the hypothesis that propofol improves left ventricular diastolic function in dogs with dilated cardiomyopathy by reducing left ventricular preload and afterload. METHODS: Seven dogs were instrumented for left ventricular and aortic pressures, aortic blood flow, and subendocardial segment length. Left ventricular afterload and contractility were quantified with aortic input impedance and preload recruitable stroke work, respectively. Diastolic function was evaluated with a time constant of left ventricular relaxation (tau); segment-lengthening velocities and time-velocity integrals during early left ventricular filling (dL/dtE and TVI-E, respectively) and atrial systole (dL/dtA and TVI-A, respectively); and a regional chamber stiffness constant (K). Dogs were paced at 240 beats/min for 18 +/- 3 days, and hemodynamics were recorded in sinus rhythm in the conscious state. Anesthesia was induced with propofol (5 mg/kg) and maintained with propofol infusions at 25, 50, and 100 mg x kg-1 x h-1, and hemodynamics were recorded after 15 min of equilibration at each dose. RESULTS: Propofol decreased mean arterial pressure, left ventricular end-diastolic pressure, and K but did not change heart rate. Propofol reduced total arterial resistance and increased total arterial compliance derived from aortic input impedance. Propofol also reduced preload recruitable stroke work. The lowest dose of propofol decreased tau. Propofol decreased dL/dtE and TVI-E and reduced the dL/dt-E/A and TVI-E/A ratios. CONCLUSIONS: Propofol reduces left ventricular preload, afterload, and regional chamber stiffness, causes direct negative inotropic effects, and impairs early-diastolic left ventricular filling in dogs with dilated cardiomyopathy.

Anesthetics, Intravenous↗
PubMed1998

The pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses to skin incision, peritoneum incision, and abdominal wall retraction.

BACKGROUND: Sufficient propofol or fentanyl doses necessary to prevent the response to skin incision do not necessarily attenuate hemodynamic responses during surgery. The goal of this study was to characterize the pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses after three stimuli: skin incision, peritoneum incision, and abdominal wall retraction. METHODS: Propofol and fentanyl were administered via computer-assisted continuous infusion to provide equilibration between plasma-blood and biophase concentrations. Patients were randomized to nine groups that received predetermined concentrations of fentanyl (from 0 to 9 ng/ml). Each patient was administered different target concentrations of propofol. Somatic and hemodynamic responses were measured before and after each of three different stimulations: skin incision (si), peritoneum incision (pi), and abdominal wall retraction (ret). The propofol plasma concentrations at which 50% of the patients did not respond to each type of stimulation (Cp50si, Cp50pi, and Cp50ret) were calculated by fitting the Loewe synergistic model. RESULTS: For propofol alone, Cp50si, Cp50pi, and Cp50ret were 12.9, 17.1, and 19.4 microg/ml, respectively. Increasing the fentanyl concentration markedly reduced propofol Cp50si, Cp50pi, and Cp50ret for somatic response, indicating the potential synergistic interaction of both drugs. During the prestimulation period, fentanyl did not decrease systolic blood pressure; however, propofol specifically decreased systolic blood pressure. Both drugs had a synergistic drug interaction on the systolic blood pressure increase after various surgical stimulations. Fentanyl and propofol concentrations that suppressed both the 50% probability of somatic response and the 50% probability of moderate hemodynamic change defined by the 15% systolic blood pressure increase over the prestimulation value were 3.6 ng/ml and 2.5 microg/ml for skin incision, 8.4 ng/ml and 1.6 microg/ml for peritoneum incision, and 5.9 ng/ml and 5.1 microg/ml for wall retraction, respectively. CONCLUSIONS: The anesthesia requirements for stimuli that are more intense than skin incision should be considered during abdominal surgery. Somatic and hemodynamic responses varied depending on the type of surgical stimuli.

Abdominal Muscles↗
PubMed1998

Isobolographic analysis of the interactions between midazolam and propofol at GABA(A) receptors in embryonic mouse neurons.

BACKGROUND: Clinical studies suggest that midazolam and propofol interact synergistically to induce hypnosis, but these drugs do not interact synergistically to prevent movement in response to noxious stimuli. The mechanisms underlying these interactions are not certain but may occur at the level of the gamma-aminobutyric acid A (GABA(A)) receptor. METHODS: The authors evaluated the interactions between propofol and midazolam in modulating GABA(A) receptor activity in embryonic hippocampal neurons. The effects of midazolam and propofol on peak current evoked by submaximal concentrations of GABA were studied using the patch clamp method. Isobolographic analysis was undertaken by constructing concentration-response curves for midazolam and propofol alone and then evaluating the potency of combinations of midazolam and propofol. In other experiments, the concentration of GABA was increased and flurazepam was substituted for midazolam. RESULTS: Isobolographic analysis confirmed that midazolam and propofol interact synergistically to enhance currents evoked by low concentrations of GABA (1 microM). However, when the concentration of GABA was increased to 3 microM, the interaction was additive. The interaction between flurazepam and propofol was also additive for enhancement of currents evoked by 3 microM GABA. CONCLUSIONS: The interaction between midazolam and propofol was critically dependent on the concentration of GABA: Synergism was evident at low concentrations of GABA, but an additive interaction was apparent when the concentration of GABA was increased. Changes in GABA(A) receptor function may underlie the synergistic interaction between propofol and midazolam for clinical effects such as hypnosis. The clinical implication of the results is that the benefits of synergism observed at one concentration ratio of these drugs may not be apparent at another.

Anesthetics, Intravenous↗
PubMed1999

The influence of age on propofol pharmacodynamics.

BACKGROUND: The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect. METHODS: The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion. RESULTS: Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively. CONCLUSIONS: Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

Adolescent↗
PubMed1999

The mechanism of inhibitory actions of propofol on rat supraoptic neurons.

BACKGROUND: In the perioperative period, plasma osmotic pressure, systemic blood pressure, and blood volume often change dramatically. Arginine vasopressin is a key factor in the regulation of these parameters. This study was performed to evaluate the direct and the mechanism of the actions of propofol on arginine vasopressin release from magnocellular neurosecretory neurons in the rat supraoptic nucleus. METHODS: Somatodendritic arginine vasopressin release from supraoptic nucleus slice preparations was measured by radioimmunoassay. Ionic currents were measured using the whole-cell mode of the patch-clamp technique in supraoptic nucleus slice preparations or in single dissociated supraoptic nucleus neurons of the rat. RESULTS: Propofol at concentrations greater than 10(-5) M inhibited the arginine vasopressin release stimulated by potassium chloride (50 mM). This inhibition by propofol was not reversed by picrotoxin, a gamma-aminobutyric acid(A)(GABA(A)) receptor antagonist, whereas arginine vasopressin release induced by glutamate (10(-3) M) was also inhibited by propofol at a clinically relevant concentration (10(-6) M). The latter effect was reversed by picrotoxin. Propofol evoked Cl- currents at concentrations ranging 10(-6) to 10(-4) M. Propofol (10(-6) M) enhanced the GABA (10(-6) M)-induced current synergistically. Moreover, propofol (10(-6) M) prolonged the time constant of spontaneous GABA-mediated inhibitory postsynaptic currents. Furthermore, propofol (10(-5) M and 10(-4) M) reversibly inhibited voltage-gated Ca2+ currents, whereas it did not affect currents induced by glutamate (10(-3) M). CONCLUSIONS: Propofol inhibits somatodendritic arginine vasopressin release from the supraoptic nucleus, and the enhancement of GABAergic inhibitory synaptic inputs and the inhibition of voltage-gated Ca2+ entry are involved in the inhibition of arginine vasopressin release.

Anesthetics, Intravenous↗
PubMed1999

Effects of propofol and remifentanil on phrenic nerve activity and nociceptive cardiovascular responses in rabbits.

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.

Anesthetics, Intravenous↗
PubMed2000

Propofol for monitored anesthesia care: implications on hypoxic control of cardiorespiratory responses.

BACKGROUND: Hypoxia has a dual effect on ventilation: an initial period of hyperventilation, the acute hypoxic response, is followed after 3-5 min by a slow decline, the hypoxic ventilatory decline. Because of hypoxic ventilatory decline, subsequent acute hypoxic responses are depressed. In this study, the influence of a sedative concentration of propofol on ventilation was studied if hypoxia was sustained and intermittent. METHODS: Ten healthy young male volunteers performed two hypoxic tests without and with a target controlled infusion of propofol. The sustained hypoxic test consisted of 15 min of isocapnic hypoxia followed by 2 min of normoxia and 3 min of hypoxia. The test of hypoxic pulses involved six subsequent exposures to 3 min hypoxia followed by 2 min of normoxia. The bispectral index of the electroencephalogram was measured to obtain an objective measure of sedation. RESULTS: Blood propofol concentrations varied among subjects but were stable over time (mean blood concentration 0.6 microg/ml). The sustained hypoxic test showed that propofol decreased acute hypoxic response by approximately 50% and that the magnitude of hypoxic ventilatory decline relative to acute hypoxic response was increased by > 50%. Propofol increased the depression of the acute hypoxic response after 15 min of hypoxia by approximately 25%. In control and propofol studies, no hypoxic ventilatory decline was generated during exposure to hypoxic pulses. The bispectral index-acute hypoxic response data suggest that subjects were either awake (with minimal effect on acute hypoxic response) or sedated (with 50-60% reduction of acute hypoxic response). CONCLUSIONS: The depression of acute hypoxic response results from an effect of propofol at peripheral or central sites involved in respiratory control or secondary to the induction of sedation or hypnosis by propofol. The relative increase in hypoxic ventilatory decline is possibly related to propofol's action at the gamma-aminobutyric acid A (GABA(A)) receptor complex, causing increased GABAergic inhibition of ventilation during sustained (but not intermittent) hypoxia.

Adult↗
PubMed2000

Propofol stimulates ciliary motility via the nitric oxide-cyclic GMP pathway in cultured rat tracheal epithelial cells.

BACKGROUND: Airway ciliary motility is impaired by inhaled anesthetics. Recent reports show that nitric oxide (NO) induces upregulation in ciliary beat frequency (CBF), and others report that propofol, an intravenous anesthetic, stimulates NO release; this raises the possibility that propofol increases CBF by stimulating the NO-cyclic guanosine monophosphate (cGMP) signal pathway. In this study, the authors investigated the effects of propofol on CBF and its relation with the NO-cGMP pathway using the pharmacologic blockers NG-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor; 1H-[1,2,4]oxidazole[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor; and KT5823, a cGMP-dependent protein kinase inhibitor, in cultured rat tracheal epithelial cells. METHODS: Rat tracheal tissues were explanted and cultured for 3-5 days. Images of ciliated cells were videotaped using a phase-contrast microscope. Baseline CBF and CBF 25 min after exposure to propofol or blocker were measured using video analysis. RESULTS: Vehicle (0.1% dimethyl sulfoxide; n = 11) increased CBF by 0.2 +/- 1.7% (mean +/- SD) from baseline. Propofol stimulated CBF significantly (P < 0.01) and dose dependently (1 microM, 2.0 +/- 1. 9%, n = 6; 10 microM, 8.2 +/- 6.7%, n = 9; 100 microM, 14.0 +/- 4.7%, n = 10). Intralipid (0.05%), the clinical vehicle of propofol, did not affect CBF (-0.2 +/- 2.2%; n = 5). The enhancement of CBF with use of 100 microm propofol was abolished (P < 0.01) by coadministration of 10 mmicroM l-NMMA (2.4 +/- 3.6%; n = 5), 100 microM ODQ (-0.3 +/- 2.2%; n = 6) or 30 microM KT5823 (-0.1 +/- 4. 1%; n = 8). l-NMMA, ODQ, or KT5823 alone did not change CBF. CONCLUSIONS: These results show that propofol stimulates CBF viathe NO-cGMP pathway in rat tracheal epithelial cells, suggesting a possible advantage of propofol in decreasing respiratory risk.

Anesthetics, Intravenous↗