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Introduction: As a result of drug sequestration and increased volume of distribution, the extracorporeal membrane oxygenation (ECMO) procedure might lead to a decrease in drug concentrations during a patient's treatment. The aim of this study was to evaluate sedative, antibiotic and immunosuppressive drug loss in ECMO circuit using ex-vivo and in-vitro experiments., Methods: Blood concentrations of propofol, midazolam, cyclosporine and vancomycin were measured in an ex-vivo ECMO circuit primed with whole human blood, and compared to controls stored in polypropylene tubes. In vitro experiments were also conducted to further explore the role of temperature, oxygen exposure and polyvinylchloride surfaces on propofol loss in the ECMO circuit., Results: Propofol concentration decreased rapidly; 70% of its baseline concentration was lost after only 30 minutes, and only 11% remained after five hours (P <0.001 for the comparison with control polypropylene tube propofol concentration). Further experiments demonstrated that oxygen exposure and contact with polyvinylchloride tubing were respectively responsible for 70% and 85% of propofol loss after 45 minutes. Midazolam concentration also rapidly decreased in the ECMO circuit, with only 54% and 11% of baseline concentration being detected at 30 minutes and 24 hours respectively (P = 0.01 versus control). Alternatively, cyclosporine concentration remained stable for the five first hours, then decreased to 78% and 73% of the baseline value after 24 hours and 48 hours, (P = 0.35 versus control). Lastly, vancomycin concentration remained stable in the ECMO circuit for the 48-hour experimental protocol., Conclusions: We observed important losses of propofol and midazolam, while cyclosporine concentration decreased slowly and moderately, and vancomycin concentration remained unchanged in the ex-vivo ECMO circuit primed with whole human blood. These data might help intensive care unit physicians planning clinical trials with a final objective to better adapt doses of these drugs while treating critically ill ECMO patients.

Background: Chronic alcoholic patients are frequently presented for anesthesia and surgery. These patients require higher doses of propofol than control patients for induction of anesthesia, but whether this is because of changes in pharmacokinetics or pharmacodynamics is not known. This study was designed to investigate the influence of chronic ethanol intake on propofol pharmacokinetics., Methods: Fifteen chronic alcoholic and 15 control patients, receiving propofol by target-controlled infusion for otolaryngologic surgery, were studied. Blood propofol concentrations were measured at regular intervals during and after the propofol infusion. Nonlinear mixed-effects population models (NONMEM) examining the influence of alcoholism were constructed. The influence of recovery on propofol pharmacokinetic parameters was also addressed., Results: The total amount of propofol and the predicted and measured concentrations during all phases of anesthesia did not differ between the two groups. The fact that the measured concentrations at the time of opening eyes were similar further confirmed that the potency of propofol was not modified by the alcoholic status of the patients. Chronic alcoholism was associated with only mild changes in propofol pharmacokinetics (increase in rapid intercompartmental clearance and greater interindividual variability in the central volume of distribution). The rebound in concentration frequently observed during the recovery phase could be related to decreased propofol peripheral volumes of distribution despite an increase in elimination clearance., Conclusions: Chronic alcoholism induces only mild changes in the pharmacokinetics of propofol. Conversely, propofol pharmacokinetics are markedly different during anesthesia and surgery or after opening eyes in the recovery period.

Background: No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change., Methods: This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg.kg(-1))plus fentanyl (2.5 microg.kg(-1)) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 microl were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 thereafter injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed effects population model, and standard two-stage analysis., Results: Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013l.kg(-1).min(-1), volume of distribution at steady state9.5 +/- 3.7l.kg(-1),and residence time 188 +/- 85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l.kg(-).min(-1), volume of central compartment 1.03 versus 0.95 l.kg(-1), volume of steady state 8.09 versus 8.17 l.kg(-1)., Conclusions: The volume of the central compartment and the systemic clearance were both greater than all values reported in older children and adults. This is consistent with the increased propofol requirements for both induction and maintenance of anesthesia in children 1-3 yr. (Key words: Anesthesia: pediatric. Pharmacokinetics: propofol.)

We have studied the development of tolerance to the anaesthetic effects of propofol in rats. In the first set of experiments, three groups of rats (A, B and C) received i.v. propofol 10 mg kg-1, 15 mg kg-1 and 20 mg kg-1, respectively. The durations of anaesthesia were recorded, the rats were killed and blood was collected to measure the concentrations of propofol. In a second set of experiments, rats received propofol 10 mg kg-1 i.v. repeated 24 h (group D), 48 h (group E) or 72 h (group F) later. Sleeping times were recorded after the first and the second administration and concentrations of propofol at awakening were measured after the second dose, when rats were killed. Sleeping times were significantly longer in groups B (22.4 min) and C (25.9 min) compared with group A (13.7 min) (P < 0.001 for both). Durations of anaesthesia in groups D, E and F were 14.7, 14.5 and 14.3 min, respectively, after the first dose of propofol and 11.6, 12.1, and 14.9 min, respectively, after the second dose. The rats in groups D and E exhibited shorter sleeping times after the second dose of propofol than after the first (P < 0.01 for both). Concentrations of propofol at awakening did not differ between groups A, B and C or between groups D, E and F. The results suggest lack of changes in susceptibility of the CNS to the anaesthetic effects of propofol.

Only few publications consider physio-chemical interactions and stability of propofol. On the basis of current experience, this agent is safe for use in polypropylene or polypropylene/polystyrene syringes, diluted 1 in 5 in 5% dextrose if necessary. The potential hazards are as follows: 1. Propofol may undergo oxidation when not stored under nitrogen, or when in contact with oxidizing agents (active ingredients or excipients of other preparations). 2. The emulsion may be destabilised by contact with mineral or organic cations (calcium, magnesium, dibasic amino acids etc.) or acids (citric acid etc.). 3. Losses of propofol may occur by adsorption-diffusion (surface adherence combined with penetration of plastic material) during storage in PVC bags or during administration by means of PVC infusion sets. Most of these hazards have still to be evaluated under controlled conditions.

The doses of propofol that produce loss of consciousness were investigated in 26 patients with chronic alcoholism and in 20 patients with a history of small alcoholic intake undergoing ear, nose, and throat surgery under general anesthesia. Last ethanol consumption by the alcoholics was 24 h preoperatively, as they had no access to alcohol when admitted to the hospital. Propofol was infused at a rate of 1200 mL/h (200 mg/min). The doses required to produce (a) loss of verbal contact and (b) loss of ability to grasp a 20-mL syringe filled with water were recorded. At this time a 2-mL venous blood sample was collected to detect propofol blood concentrations. A painful stimulus was applied to the abdomen, and a positive or negative response was noted. The mean +/- SD dose of propofol required for loss of verbal contact was 2.7 +/- 0.42 mg/kg in the alcoholic group and 2.2 +/- 0.43 mg/kg in the control group (P < 0.001). The dose of propofol required for dropping the syringe was significantly higher in the alcoholic group, 4.2 +/- 1.02 mg/kg versus 3.2 +/- 0.75 mg/kg in the control group (P < 0.01). The two groups did not differ significantly regarding the propofol blood concentrations at loss of consciousness, or the frequency of response or no response to painful stimulus. These findings suggest that the doses of propofol required to induce anesthesia in chronic alcoholic patients are more than in patients who drink socially.

Background: The pharmacokinetic and pharmacodynamic properties of propofol indicate that this may be an appropriate agent for induction and maintenance of anesthesia in obese patients. This study was designed to assess the rates of recovery and the pharmacokinetics of propofol infusions in morbidly obese patients., Methods: Anesthesia was induced and maintained using a stepwise infusion regimen of propofol in eight morbidly obese patients. The patients' lungs were ventilated with nitrous oxide:oxygen (66:34%). Pharmacokinetic parameters were calculated from iterative blood sampling during the propofol infusion and during 8 h after its completion., Results: Results were compared with those from a concurrent study of propofol pharmacokinetics in nonobese adults. The initial volume of distribution of propofol was not modified in obese patients. Total body clearance increase was correlated to body weight (R = 0.76, 25.4 +/- 6.5 ml.kg-1.min-1, mean +/- SD). Volume of distribution at steady state was also correlated to body weight (R = 0.61, 1.63 +/- 0.54 l.kg-1, mean +/- SD). Propofol concentration at the time of eye opening in response to verbal command was 0.94 +/- 0.26 mg.l-1., Conclusions: Results from this study confirm the absence of propofol accumulation in morbidly obese patients when the current dosing scheme is used. Dosing schemes expressed in mg.kg-1 are the same as those in normal patients.

We have investigated extrahepatic metabolism of propofol in 10 patients undergoing orthotopic liver transplantation (group 1) (mean age 38 yr, mean weight 60 (SD 7) kg) and compared it with that in 10 patients without liver dysfunction undergoing extrahepatic abdominal surgery (group 2) (mean age 56 yr, mean weight 68 (11) kg). A single i.v. bolus dose of propofol 0.5 mg kg-1 was injected into a peripheral vein 5 min after the beginning of the anhepatic phase in group 1 and 60 min after the induction of anaesthesia in group 2. Arterial blood samples were obtained at 5, 10, 15, 20, 30, 40, 50 and 60 min after injection and urine samples were collected every 15 min. Propofol concentrations in whole blood and urine were measured by high performance liquid chromatography with fluorescence detection. Propofol glucuronide was measured in urine by incubation with a specific beta-glucuronidase. The area under the time-blood concentration curve from 0 to 60 min was found to be significantly greater in group 1 (13743 (2830) micrograms litre-1 h-1) than in group 2 (7992 (4895) micrograms litre-1 h-1) (P less than 0.05). Unchanged propofol was not detected in the urine of either group. No significant difference was found in the amount of propofol glucuronide excreted by patients in group 1 (457 (269) micrograms) and in group 2 (921 (672) micrograms). The presence of a propofol metabolite in urine when the liver was excluded from the circulation suggests that extrahepatic metabolism occurred.

The pharmacokinetics of propofol administered in continuous infusion was studied in 10 patients without left ventricular insufficiency during extracorporeal circulation (ECC) with hemodilution, for aortocoronary bypass. After a dosage of 1.5 mg.kg-1 during anaesthetic induction, the blood level was 4,800 micrograms.l-1. Under continuous infusion levels remained very high: they decreased by 40% during EEC induction and rose more than 10% when artificial ventilation started again. These modifications can be explained by physiological variations induced by EEC (non pulsated flow, redistribution, vasoconstriction, hemodilution, hypothermia) and they lead to adapt dosages in this type of anaesthesia.

We have compared the pharmacokinetics of propofol as an infusion in 10 control and 10 patients with cirrhosis. Anaesthesia was induced within 3-4 min during administration of an infusion of propofol 21 mg kg-1 h-1. After 5 min, the infusion was decreased in a stepwise manner to 12 mg kg-1 h-1 and subsequently 6 mg kg-1 h-1. The mean recovery time after discontinuation of the infusion was significantly longer in the cirrhotic group; however, when patients opened their eyes, blood concentrations of propofol were similar in both groups (1 micrograms ml-1). Pharmacokinetic analysis was performed from the beginning of infusion to 8 h after termination. Total body clearance was not reduced significantly in cirrhotic (1.56 (SD 0.48) litre min-1) compared with control (1.75 (0.32) litre min-1) patients. The volume of distribution at steady state was significantly greater in patients with cirrhosis than in control patients (202 (82) litre vs 121 (49) litre). However, this difference did not change terminal elimination half-life. The pharmacokinetics of propofol given by infusion to maintain general anaesthesia were not affected markedly by moderate cirrhosis.

The effects of propofol induction (2.5 mg kg-1) and of two continuous infusion rates of propofol (100 and 200 micrograms kg-1 min-1) on baroreflex control of heart rate and on plasma noradrenaline concentration were investigated in 11 unpremedicated patients. Baroreflex function was assessed using a pressor test (phenylephrine) and a depressor test (sodium nitroprusside). In addition, samples for subsequent determination of plasma noradrenaline levels and blood propofol levels were collected before each test. Baroreflex sensitivity and plasma noradrenaline concentrations were not significantly changed at any time of the study. By contrast, a significant and sustained resetting of baroreflex set point was observed, allowing unchanged heart rate at lower arterial pressure. It is concluded that the effects of propofol on baroreflex function and noradrenaline concentration are moderate.