Application of a pharmacokinetics-pharmacodynamics approach to the free propofol plasma levels during coronary artery bypass grafting surgery with hypothermic cardiopulmonary bypass

OBJECTIVES: The objective of this study was to apply a pharmacokinetics-pharmacodynamics approach to investigate the free propofol plasma levels in patients undergoing coronary artery bypass grafting under hypothermic conditions compared with the off-pump procedure. METHODS: Nineteen patients scheduled for on-pump coronary artery bypass grafting under hypothermic conditions (n=10) or the equivalent off-pump surgery (n=9) were anesthetized with sufentanil and propofol target-controlled infusion (2 μg/mL) during surgery. The propofol concentration was then reduced to 1 μg/mL, and a pharmacokinetics-pharmacodynamics analysis using the maximum-effect-sigmoid model obtained by plotting the bispectral index values against the free propofol plasma levels was performed. RESULTS: Significant increases (two- to five-fold) in the free propofol plasma levels were observed in the patients subjected to coronary artery bypass grafting under hypothermic conditions. The pharmacokinetics of propofol varied according to the free drug levels in the hypothermic on-pump group versus the off-pump group. After hypothermic coronary artery bypass was initiated, the distribution volume increased, and the distribution half-life was prolonged. Propofol target-controlled infusion was discontinued when orotracheal extubation was indicated, and the time to patient extubation was significantly higher in the hypothermic on-pump group than in the off-pump group (459 versus 273 min, p=0.0048). CONCLUSIONS: The orotracheal intubation time was significantly longer in the hypothermic on-pump group than in the off-pump group. Additionally, residual hypnosis was identified through the pharmacokinetics-pharmacodynamics approach based on decreases in drug plasma protein binding in the hypothermic on-pump group, which could explain the increased hypnosis observed with this drug in this group of patients.

Pharmacodynamic Estimate of Propofol-Induced Sedation and Airway Obstruction Effects in Obstructive Sleep Apnea-Hypopnea Syndrome

PURPOSE: Sedatives must be carefully titrated for patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) as oversedation may lead to disastrous respiratory outcomes. This study aimed to investigate the relations between the effect-site concentration (Ce) of propofol and sedation and airway obstruction levels in patients with OSAHS. MATERIALS AND METHODS: In 25 patients with OSAHS, sedation was induced by 2% propofol using target-controlled infusion. Sedation and airway obstruction levels were assessed using the Observer's Assessment of Alertness/Sedation Scale and a four-category scale, respectively. The relationships between propofol Ce and sedation and airway obstruction were evaluated using a sigmoid Emax model. Pharmacodynamic modeling incorporating covariates was performed using the Nonlinear Mixed Effects Modeling VII software. RESULTS: Increased propofol Ce correlated with the depth of sedation and the severity of airway obstruction. Predicted Ce50(m) (Ce associated with 50% probability of an effect> or =m) for sedation scores (m> or =2, 3, 4, and 5) and airway-obstruction scores (m> or =2, 3, and 4) were 1.61, 1.78, 1.91, and 2.17 microg/mL and 1.53, 1.64, and 2.09 microg/mL, respectively. Including the apnea-hypopnea index (AHI) as a covariate in the analysis of Ce50(4) for airway obstruction significantly improved the performance of the basic model (p<0.05). CONCLUSION: The probability of each sedation and airway obstruction score was properly described using a sigmoid Emax model with a narrow therapeutic range of propofol Ce in OSAHS patients. Patients with high AHI values need close monitoring to ensure that airway patency is maintained during propofol sedation.

Effects of cardiopulmonary bypass on propofol pharmacokinetics and bispectral index during coronary surgery

PURPOSE: Cardiopulmonary bypass is known to alter propofol pharmacokinetics in patients undergoing cardiac surgery. However, few studies have evaluated the impact of these alterations on postoperative pharmacodynamics. This study was designed to test the hypothesis that changes in propofol pharmacokinetics increase hypnotic effects after cardiopulmonary bypass. METHODS: Twenty patients scheduled for on-pump coronary artery bypass graft (group, n=10) or off-pump coronary artery bypass graft (group, n=10) coronary artery bypass grafts were anesthetized with sufentanil and a propofol target controlled infusion (2.0 µg/mL). Depth of hypnosis was monitored using the bispectral index. Blood samples were collected from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma propofol concentrations were measured using high-performance liquid chromatography, followed by a non-compartmental propofol pharmacokinetic analysis. Data were analyzed using ANOVA, considering p<0.05 as significant. RESULTS: After cardiopulmonary bypass, despite similar plasma propofol concentrations in both groups, bispectral index values were lower in the on-pump coronary artery bypass graft group. Time to extubation after the end of propofol infusion was greater in the on-pump coronary artery bypass graft group (334 ± 117 vs. 216 ± 85 min, p = 0.04). Patients undergoing cardiopulmonary bypass had shorter biological (1.82 ± 0.5 vs. 3.67 ± 1.15h, p < 0.01) and terminal elimination (6.27 ± 1.29 vs. 10.5h ± 2.18, p < 0.01) half-life values, as well as higher total plasma clearance (28.36 ± 11.40 vs.18.29 ± 7.67 mL/kg/min, p = 0.03), compared to patients in the off-pump coronary artery bypass graft group. CONCLUSION: Aside from the increased sensitivity of the brain to anesthetics after cardiopulmonary bypass, changes in propofol pharmacokinetics may contribute to its central nervous system effects.

Propofol pharmacokinetics in infants

Infant and children differ markedly from adult patients. Since the production of propofol, it has gained popularity as an agent for both induction and maintenance of anaesthesia for adults and children. There has been a lack of pharmacokinetic studies in children less than 3 years. Was to determine the complete pharmacokinetic profile of propofol in infants [2-24 months]. Forty eight patients were randomly assigned into 4 groups, each group has 12 patients. They were scheduled to undergo superficial body surgery of I hour expected duration. Venous blood samples were collected and analyzed used high performance liquid chromatography [HPLC].Non linear mixed effects modelling [NONMEM] software program was used to analyze the pharmacokinetic data. The pharmacokinetic of propofol in infants followed two compartement model with systemic clearance -[Cl] 29.77 +/- 9.46 ml kg[-1] min[-1], central volume of distribution [Vc] 0.62 +/- 0.24 l kg[-1], and the volume at steady state [Vss] 1.67 +/- 0.26 l kg[-1]. The context sensitive half life [HL] was 0.24 +/- 0.02 h. The infants have a larger volume of distribution and a higher clearance of propofol. Therefore, the induction and maintenance doses should be increased in this young age with using population based pharmacokinetic parameters for accurate propofol dosing strategy

Development of a gas chromatography-mass spectrometry method for the quantification of propofol in blood / 法医学杂志

OBJECTIVE@#A rapid and selective method has been developed for the determination of propofol in blood by gas chromatography-mass spectrometry (GC-MS).@*METHODS@#The blood was extrasted with the solution of internal standard, the extracted residue was analyzed by gas chromatography-mass spectrometry using selected-ion monitoring mode.@*RESULTS@#The linear range was 0.1-10 microg/mL. The coefficient(R2) was 0.993 1. The detection limit was 0.05 microg/mL.@*CONCLUSION@#The method is simple and rapid, offering superior sensitivity and selectivity for propofol. The method can be used successfully during clinical and forensic toxicology.