Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics.
AIMS: Propofol is a widely used i.v. anaesthetic agent. However, its binding properties to blood components have not been fully studied. METHODS: We studied the binding of propofol to erythrocytes, to human serum and to isolated serum proteins. Because propofol bound to ultrafiltration and equilibrium dialysis membranes, we used a co-binding technique with dextran coated charcoal and with erythrocytes. RESULTS: Propofol free fraction in blood was 1.2-1.7% at total concentrations ranging from 2.80 to 179 microM (0.5 to 32 microg ml(-1)). Fifty percent was bound to erythrocytes and 48% to serum proteins, almost exclusively to human serum albumin. In the clinical range of concentrations (0.5-16 microg ml(-1)) 40% of the molecules bound to erythrocytes are on the red blood cells membranes. No binding to lipoproteins occurred and binding to alpha1-acid glycoprotein was less than 1.5% CONCLUSIONS: We conclude that hypoalbuminaemia may increase propofol free fraction particularly during prolonged administration. Since propofol is non-restrictively cleared, no change in clearance is expected to occur, and the increase in free fraction will not be compensated by a parallel increase in clearance. It is also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment. (+info)
Benzodiazepine premedication: can it improve outcome in patients undergoing breast biopsy procedures?
BACKGROUND: Women awaiting needle-guided breast biopsy procedures may experience high anxiety levels. A randomized, double-blind, placebo-controlled study was designed to evaluate the ability of midazolam and diazepam (in a lipid emulsion [Dizac]) to improve patient comfort during needle localization and breast biopsy procedures. METHODS: Ninety women received two consecutive doses of a study medication, one before the mammographic needle localization and a second before entering the operating room. Patients were assigned randomly to receive saline, 2.0 ml intravenously, at the two time points; midazolam, 1.0 mg intravenously and 2.0 mg intravenously; or diazepam emulsion, 2.0 mg intravenously and 5.0 mg intravenously, respectively. Patients assessed their anxiety levels before the needle localization, before entering the operating room, and on arrival in the operating room. Patients completed a questionnaire evaluating their perioperative experience at the time of discharge. RESULTS: Patient satisfaction during needle localization was significantly improved in both benzodiazepine treatment groups (vs. saline). The incidence of moderate-to-severe discomfort during needle localization was lower in the midazolam (20%) and diazepam emulsion (6%) groups compared with the saline group (70%) (P<0.05). The preoperative visual analogue scale anxiety scores were similar in all three groups. In the operating room, however, anxiety scores were 55% and 68% lower after midazolam (21+/-19) and diazepam emulsion (15+/-14) compared with saline (46+/-28). Finally, there was no difference in the time to achieve home-readiness or actual discharge time among the three groups. CONCLUSIONS: Premedication with midazolam or diazepam emulsion improved patients' comfort during needle localization procedures and significantly reduced intraoperative anxiety levels before breast biopsy procedures without prolonging discharge times. Use of diazepam emulsion may be an effective alternative to midazolam in this population. (+info)
Postoperative behavioral outcomes in children: effects of sedative premedication.
BACKGROUND: Although multiple studies document the effect of sedative premedication on preoperative anxiety in children, there is a paucity of data regarding its effect on postoperative behavioral outcomes. METHODS: After screening for recent stressful life events, children undergoing anesthesia and surgery were assigned randomly to receive either 0.5 mg/kg midazolam in 15 mg/kg acetaminophen orally (n = 43) or 15 mg/kg acetaminophen orally (n = 43). Using validated measures of anxiety, children were evaluated before and after administration of the intervention and during induction of anesthesia. On postoperative days 1, 2, 3, 7, and 14, the behavioral recovery of the children was assessed using the Post Hospitalization Behavior Questionnaire. RESULTS: The intervention group demonstrated significantly lower anxiety levels compared with the placebo group on separation to the operating room and during induction of anesthesia (F[1,77] = 3.95, P = 0.041). Using a multivariate logistic regression model, the authors found that the presence or absence of postoperative behavioral changes was dependent on the group assignment (R = 0.18, P = 0.0001) and days after operation (R = -0.20, P = 0.0001). Post hoc analysis demonstrated that during postoperative days 1-7, a significantly smaller number of children in the midazolam group manifested negative behavioral changes. At week 2 postoperatively, however, there were no significant differences between the midazolam and placebo groups. CONCLUSIONS: Children who are premedicated with midazolam before surgery have fewer negative behavioral changes during the first postoperative week. (+info)
Mechanisms of bronchoprotection by anesthetic induction agents: propofol versus ketamine.
BACKGROUND: Propofol and ketamine have been purported to decrease bronchoconstriction during induction of anesthesia and intubation. Whether they act on airway smooth muscle or through neural reflexes has not been determined. We compared propofol and ketamine to attenuate the direct activation of airway smooth muscle by methacholine and limit neurally mediated bronchoconstriction (vagal nerve stimulation). METHODS: After approval from the institutional review board, eight sheep were anesthetized with pentobarbital, paralyzed, and ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, 5 mg/ml concentrations of propofol, ketamine, and thiopental were infused into the bronchial artery at rates of 0.06, 0.20, and 0.60 ml/min. After 10 min, airway resistance was measured before and after vagal nerve stimulation and methacholine given via the bronchial artery. Data were expressed as a percent of baseline response before infusion of drug and analyzed by analysis of variance with significance set at P< or =0.05. RESULTS: Systemic blood pressure was not affected by any of the drugs (P>0.46). Baseline airway resistance was not different among the three agents (P = 0.56) or by dose (P = 0.96). Infusion of propofol and ketamine into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction to 26+/-11% and 8+/-2% of maximum, respectively (P<0.0001). In addition, propofol caused a significant decrease in the methacholine-induced bronchoconstriction to 43+/-27% of maximum at the highest concentration (P = 0.05) CONCLUSIONS: The local bronchoprotective effects of ketamine and propofol on airways is through neurally mediated mechanisms. Although the direct effects on airway smooth muscle occur at high concentrations, these are unlikely to be of primary clinical relevance. (+info)
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. (+info)
Effects of inhaled oxygen concentration on fat metabolism during propofol infusion in rabbits.
We have investigated the effect of inhaled oxygen tension on lipid metabolism during propofol infusion. Propofol is supplied as a lipid emulsion containing 10% soybean oil, which is rich in triglycerides (TG). Infused TG are metabolized via three pathways in the liver cell; Krebs cycle, ketogenesis and release as very low density lipoproteins (VLDL) into the blood. For this reason, we measured TG and the products of the three pathways; carbon dioxide, ketone bodies and VLDL. Thirty-two rabbits were anaesthetized under four different conditions: propofol under hyperoxia, normoxia, hypoxia and isoflurane anaesthesia under hyperoxia. Our results indicated that hyperoxia produced more ketone bodies, normoxia more PaCO2 and hypoxia more free fatty acids (FFA) and TG compared with the other propofol infusion groups. We conclude that hyperoxia during propofol infusion facilitated fat metabolism through ketogenesis, while normoxia did so via the Krebs cycle. Also, hypoxia suppressed utilization of TG and VLDL production in the liver. (+info)
Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta.
ATP-sensitive potassium channel openers are used as vasodilators in the treatment of cardiovascular disorders. The effects of i.v. anaesthetics on arterial relaxation induced by ATP-sensitive potassium channel openers have not been studied. Therefore, in this study, we have examined if thiopental (thiopentone) and propofol affect the vascular response to the ATP-sensitive potassium channel openers, cromakalim and pinacidil, in the isolated rat aorta. Rings of rat thoracic aortas without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative manner. During submaximal contractions with phenylephrine 0.3 mumol litre-1, relaxation after cromakalim 0.1-30 mumol litre-1, pinacidil 0.1-30 mumol litre-1 and papaverine 0.1-300 mumol litre-1 was demonstrated. Thiopental 30-300 mumol litre-1, propofol 10-100 mumol litre-1, 10% Intralipid 45 microliters or glibenclamide 5 mumol litre-1 were applied 15 min before addition of phenylephrine. During contractions with phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxation. A selective ATP-sensitive potassium channel antagonist, glibenclamide 5 mumol litre-1, abolished this relaxation, whereas it did not affect relaxation produced by papaverine. Thiopental concentrations > 30 mumol litre-1 significantly impaired relaxation produced by cromakalim or pinacidil. Propofol concentrations > 10 mumol litre-1 also significantly reduced relaxation produced by cromakalim or pinacidil, whereas Intralipid was ineffective. Thiopental 300 mumol litre-1 and propofol 100 mumol litre-1 did not alter relaxation produced by papaverine. These results suggest that the i.v. anaesthetics, thiopental and propofol, impaired vasodilatation mediated by ATP-sensitive potassium channels in vascular smooth muscle cells. (+info)
Effect of remifentanil on the auditory evoked response and haemodynamic changes after intubation and surgical incision.
We have observed the effect of intubation and incision, as measured by the auditory evoked response (AER) and haemodynamic variables, in 12 patients undergoing hernia repair or varicose vein surgery who received remifentanil as part of either an inhaled anaesthetic technique using isoflurane or as part of a total i.v. technique using propofol. Anaesthesia was induced with remifentanil 1 microgram kg-1 and propofol, neuromuscular block was achieved with atracurium 0.6 mg kg-1 before intubation, and anaesthesia was maintained with a continuous infusion of remifentanil in combination with either a continuous infusion of propofol or inhaled isoflurane. The AER and haemodynamic variables were measured before and after intubation and incision. The effects of intubation and incision on the AER and haemodynamic variables were not significantly different between the remifentanil-propofol and remifentanil-isoflurane groups. However, the study had a low power for this comparison. When the data for the two anaesthetic combinations were pooled, the only significant effects were increases in diastolic arterial pressure and heart rate immediately after intubation; these were not seen 5 min after intubation. There were no cardiovascular responses to incision. There were no significant changes in the AER after intubation or incision. (+info)