Gas chromatograph-surface acoustic wave for quick real-time assessment of blood/exhaled gas ratio of propofol in humans.

BACKGROUND: Although pilot studies have reported that exhaled propofol concentrations can reflect intraoperative plasma propofol concentrations in an individual, the blood/exhaled partial pressure ratio RBE varies between patients, and the relevant factors have not yet been clearly addressed. No efficient method has been reported for the quick evaluation of RBE and its association with inter-individual variables. METHODS: We proposed a novel method that uses a surface acoustic wave (SAW) sensor combined with a fast gas chromatograph (GC) to simultaneously detect propofol concentrations in blood and exhaled gas in 28 patients who were receiving propofol i.v. A two-compartment pharmacokinetic (PK) model was established to simulate propofol concentrations in exhaled gas and blood after a bolus injection. Simulated propofol concentrations for exhaled gas and blood were used in a linear regression model to evaluate RBE. RESULTS: The fast GC-SAW system showed reliability and efficiency for simultaneous quantitative determination of propofol in blood (correlation coefficient R(2)=0.994, P<0.01) and exhaled gas (R(2)=0.991, P<0.01). The evaluation of RBE takes <50 min for a patient. The distribution of RBE in 28 patients showed inter-individual differences in RBE (median 1.27; inter-quartile range 1.07-1.59). CONCLUSIONS: Fast GC-SAW, which analyses samples in seconds, can perform both rapid monitoring of exhaled propofol concentrations and fast analysis of blood propofol concentrations. The proposed method allows early determination of the coefficient RBE in individuals. Further studies are required to quantify the distribution of RBE in a larger cohort and assess the effect of other potential factors. CLINICAL TRIAL REGISTRATION: ChiCTR-ONC-13003291.

Assessment of the performance of the Marsh model in effect site mode for target controlled infusion of propofol during the maintenance phase of general anaesthesia in an unselected population of neurosurgical patients.

BACKGROUND: Propofol target-controlled infusion (TCI) in effect site mode has become popular since it became commercially available. OBJECTIVE: We have performed a study to assess the pharmacokinetic performance of the Marsh model in effect site mode in an unselected group of patients during neurosurgery during the maintenance phase of anaesthesia. DESIGN: Fifty American Society of Anesthesiologists (ASA) physical status classes 1 to 3 adults underwent elective neurosurgery receiving propofol TCI using the Marsh model in effect site mode. Propofol dose titration and level of patient monitoring was determined by the attending anaesthesiologist. Arterial blood was sampled at regular intervals during the maintenance phase of anaesthesia and measured plasma propofol concentrations were compared with those estimated using TCI. SETTING: Large tertiary referral centre in Birmingham, UK, with a specialist neuroanaesthesia service. PATIENTS: Fifty ASA status I to III adult patients undergoing elective neurosurgery. MAIN OUTCOME MEASURES: Performance of Marsh model as assessed by median performance error (bias) and median absolute performance error (imprecision). RESULTS: Performance of the Marsh model showed a positive bias (median performance error) of 27.6%, and imprecision (median absolute performance error) of 29.4%. Analysis of pooled data demonstrated greatest bias in the early phase (15 to 30 min) of anaesthesia (mean prediction error of 51.6%). Analysis of covariates demonstrated that obesity (BMI >30 kg m(-2)) contributed around half of the bias detected (mean prediction error 47 vs. 23%, P < 0.001). Patients with advanced age and significant comorbidity (ASA physical status class >2) actually demonstrated significantly lower prediction errors. CONCLUSION: Pharmacokinetic analysis suggests that the performance of the Marsh model in effect site mode is poor in this broad patient population. The greatest bias demonstrated occurred in the early maintenance phase of anaesthesia. Of the covariates analysed, obesity contributed most significantly to an increased bias. Despite overall poor performance of the Marsh model, attending anaesthesiologists modified targeted propofol concentrations only 0.3 times per hour on average, using remifentanil dose modification nine times more frequently, with good surgical conditions in all patients.

[Assessment of factors leading to postanesthetic shivering in patients undergoing laparoscopic colectomy with total intravenous anesthesia using remifentanil].

BACKGROUND: It has been reported that postanesthetic shivering is associated with general anesthesia using remifentanil infusion. The aim of this retrospective study was to evaluate the factors leading to postanesthetic shivering. METHODS: The patient populations include patients who had undergone laparoscopic colectomy under total intravenous anesthesia with propofol, remifentanil infusion and fentanyl bolus administration. Preoperative clinical variables of interest included age, sex, height, weight, and body surface area. Intraoperative variables of interest included the duration of anesthesia and surgery, pharyngeal temperature at the beginning and the end of the surgery, predicted plasma and effect site concentration of fentanyl at the extubation and mean infusion rate of remifentanil. RESULTS: The authors identified 53 patients and 9 of them had shown shivering. In shivering group, the duration of anesthesia and surgery was significantly longer, and the predicted plasma and effect site fentanyl concentrations in extubated period were significantly lower. There was no significant difference in either background or core temperature. CONCLUSIONS: These data suggest that fentanyl concentration may be important for avoiding postanesthetic shivering and the duration of surgery may be a predictor for postanesthetic shivering.

Assessment of the cough reflex after propofol anaesthesia for colonoscopy.

BACKGROUND: Dysfunction of the cough reflex as a result of the lingering effects of anaesthetics may lead to aspiration pneumonia or retained secretions after general anaesthesia. It is unknown whether low concentrations of propofol alter the cough reflex in the early period after anaesthesia. The objective of this study was to investigate the effect of low concentrations of propofol on the cough reflex sensitivity as assessed by the cough reflex threshold to an inhaled irritant. METHODS: Fifteen, ASA I-II, non-smoking patients undergoing elective colonoscopy were studied. Anaesthesia was induced and maintained with a blood target-controlled propofol infusion. Cough reflex threshold was measured with citric acid. Increasing concentrations of nebulized citric acid (2.5, 5, 10, 20, 40, 80, 160, 320, and 640 mg ml(-1)) were delivered during inspiration until a cough was evoked. The citric acid concentration eliciting one cough (C1) was defined as the cough reflex threshold. C1 was log transformed for statistical analysis (Log C1). Log C1 was measured before anaesthesia and during the recovery period with estimated decreasing propofol concentrations of 1.2, 0.9, 0.6, and 0.3 microg ml(-1). RESULTS: Log C1 (median; interquartile range) measured with propofol concentrations of 1.2, 0.9, 0.6, 0.3, and 0 microg ml(-1) were 1.9 (0.6), 1.9 (1.0), 1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml(-1) (NS), respectively. However, light sedation was observed with propofol concentrations of 1.2 and 0.9 microg ml(-1). CONCLUSION: This study indicates that residual sedation after propofol anaesthesia for colonoscopy does not adversely affect the cough reflex.

Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane-anesthetized cats.

OBJECTIVE: To determine the hemodynamic effects of lidocaine (administered IV to achieve 6 plasma concentrations) in isoflurane-anesthetized cats. ANIMALS: 6 cats. PROCEDURE: Cats were anesthetized with isoflurane in oxygen (end-tidal isoflurane concentration set at 1.25 times the predetermined individual minimum alveolar concentration). Lidocaine was administered IV to each cat to achieve target pseudo-steady-state plasma concentrations of 0, 3, 5, 7 9, and 11 microg/mL, and isoflurane concentration was reduced to an equipotent concentration. At each plasma lidocaine concentration, cardiovascular and blood gas variables; PCV; and plasma total protein, lactate, lidocaine, and monoethylglycinexylidide concentrations were measured in cats before and during noxious stimulation. Derived variables were calculated. RESULTS: n isoflurane-anesthetized cats, heart rate, cardiac index, stroke index, right ventricular stroke work index, plasma total protein concentration, mixed-venous PO2 and hemoglobin oxygen saturation, arterial and mixed-venous bicarbonate concentrations, and oxygen delivery were significantly lower during lidocaine administration, compared with values determined without lidocaine administration. Mean arterial pressure, central venous pressure, pulmonary artery pressure, systemic and pulmonary vascular resistance indices, PCV, arterial and mixed-venous hemoglobin concentrations, plasma lactate concentration, arterial oxygen concentration, and oxygen extraction ratio were significantly higher during administration of lidocaine, compared with values determined without lidocaine administration. Noxious stimulation did not significantly affect most variables. CONCLUSIONS AND CLINICAL RELEVANCE: In isoflurane-anesthetized cats, although IV administration of lidocaine significantly decreased inhalant requirements, it appeared to be associated with greater cardiovascular depression than an equipotent dose of isoflurane alone. Administration of lidocaine to reduce isoflurane requirements is not recommended in cats.

Closed-loop control of propofol anaesthesia using bispectral index: performance assessment in patients receiving computer-controlled propofol and manually controlled remifentanil infusions for minor surgery.

BACKGROUND: In a previous study we used the bispectral index (BIS) for automatic control of propofol anaesthesia, using a proportional-integral-differential control algorithm. As control was less than optimal in some patients, we revised the constants of the control algorithm. The aim of the current study was to measure the performance of the revised system in patients undergoing minor surgery under propofol and remifentanil anaesthesia. METHODS: Twenty adult patients scheduled for body surface surgery were enrolled. Anaesthesia was manually induced with target-controlled infusions (TCI) of propofol and remifentanil. After the start of surgery, when anaesthesia was clinically adequate, automatic control of the propofol TCI was commenced using the revised closed-loop system. For patients 11-20, effect-site steering was also incorporated into the closed-loop control algorithm. Adequacy of anaesthesia during closed-loop control was assessed clinically, and by calculating the median performance error (MDPE), the median absolute performance error (MDAPE) and the mean offset of the control variable. RESULTS: The system provided adequate operating conditions and stable cardiovascular values in all patients during closed-loop control. The mean MDPE and MDAPE were -0.42% and 5.63%, respectively. Mean offset of the BIS from setpoint was -0.2. No patients reported awareness or recall of intraoperative events. CONCLUSIONS: The system was able to provide clinically adequate anaesthesia in all patients, with better accuracy of control than in the previous study. There was a tendency for more accurate control in those patients in whom the control algorithm incorporated effect-site steering.

Fast, simple and cost-effective determination of thiopental in human plasma by a new HPLC technique.

BACKGROUND: Thiopental is an anaesthetic drug that is largely used in both short-term and long-term infusion. After long-term infusion of thiopental, non-linear and inter-individual-dependent pharmacokinetics occur because of the saturation and/or induction of the metabolism. Clinical monitoring is important so that therapeutic adjustments can be made in many of the different pharmacological treatments, especially when long-term infusion is required. We describe a new, rapid HPLC method for the determination of plasma thiopental. METHODS: Sample preparation involved precipitation of plasma proteins using a mixture of methanol, zinc sulfate and ethylene glycol, and containing the internal standard 5-ethyl-5-p-tolyl-barbituric acid. After adding trichloroacetic acid, the sample was centrifuged and the supernatant was injected into a C(18) reversed-phase column. The mobile phase used was water-methanol-acetonitrile (50:40:10, v/v). The eluent was monitored at 290 nm. RESULTS: The calibration curve was linear from 0.2 to 100 microg/mL. Precision, calculated as the coefficient of variation (%), was in the range of 3.62-0.70% for the within-day assay and 5.77-1.51% for the between-day assay. The absolute recoveries obtained from supplemented samples were never less than 100%. CONCLUSIONS: This technique shows good reliability and seems to be suitable for a very fast and simple therapeutic monitoring of plasma thiopental.

First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model.

BACKGROUND: The principal site for elimination of propofol is the liver. The clearance of propofol exceeds hepatic blood flow; therefore, extrahepatic clearance is thought to contribute to its elimination. This study examined the pulmonary kinetics of propofol using part of an indocyanine green (ICG) recirculatory model. METHODS: Ten sheep, immobilized in a hammock, received injections of propofol (4 mg/kg) and ICG (25 mg) via two semipermanent catheters in the right internal jugular vein. Arterial blood samples were obtained from the carotid artery. The ICG injection was given for measurement of intravascular recirculatory parameters and determination of differences in propofol and ICG concentration-time profiles. No other medication was given during the experiment, and the sheep were not intubated. The arterial concentration-time curves of ICG were analyzed with a recirculatory model. The pulmonary uptake and elimination of propofol was analyzed with the central part of that model extended with a pulmonary tissue compartment allowing elimination from that compartment. RESULTS: During the experiment, cardiac output was 3.90+/-0.72 l/min (mean +/- SD). The blood volume in heart and lungs, measured with ICG, was 0.66+/-0.07 l. A pulmonary tissue compartment of 0.47+/-0.16 l was found for propofol. The pulmonary first-pass elimination of propofol was 1.14+/-0.23 l/min. Thirty percent of the dose was eliminated during the first pass through the lungs. CONCLUSIONS: Recirculatory modeling of ICG allows modeling of the first-pass pulmonary kinetics of propofol concurrently. Propofol undergoes extensive uptake and first-pass elimination in the lungs.

In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat.

PURPOSE: The relative contribution of the intestinal mucosa, liver and lung to the in vivo disposition of propofol in the rat was investigated. METHODS: Propofol (4.9-5.1 mg.kg-1) was administered to groups of rats (n = 4) via the intra-arterial, intravenous, hepatic portal venous and oral routes. The AUC's of propofol were estimated and the fractions of the administered dose escaping first pass metabolism by the gut wall (fG), liver (fH) and lung (fL) were calculated. In addition, transport experiments were carried out using Caco-2 cell monolayers to rule out the possibility that intestinal permeability is limiting the oral absorption of propofol. RESULTS: Values for fG, fH and fL were the following: 0.21 +/- 0.07, 0.61 +/- 0.13, and 0.82 +/- 0.09, respectively. The apparent permeability coefficient of propofol across Caco-2 cell monolayers was 24.2 +/- 0.3 x 10(-6) cm.sec-1, which is similar to the apparent permeability coefficient obtained for propranolol (30.7 +/- 1.7 x 10(-6) cm.sec-1), a compound known to easily cross the intestinal epithelial membranes. The formation of propofol glucuronide, a major metabolite of propofol, could not be demonstrated during the flux experiments across the Caco-2 cell monolayers. CONCLUSIONS: The intestinal mucosa is the main site of first pass metabolism following oral administration of propofol in the rat. Intestinal metabolism could therefore also contribute to the systemic clearance of propofol.