Methyl-tert-butyl ether (MTBE): integration of rat and mouse carcinogenicity data with mode of action and human and rodent bioassay dosimetry and toxicokinetics indicates MTBE is not a plausible human carcinogen.

Methyl-tert-butyl ether (MTBE) is a fuel oxygenate used in non-United States geographies. Multiple health reviews conclude that MTBE is not a human-relevant carcinogen, and this review provides updated mode of action (MOA), exposure, dosimetry and risk perspectives supporting those conclusions. MTBE is non-genotoxic and has large margins of exposure between blood concentrations at the overall rat 400 ppm inhalation NOAEL and blood concentrations in typical workplace or general population exposures. Non-cancer and threshold cancer hazard quotients range from a high of 0.046 for fuel-pump gasoline station attendants and are 100-1,000-fold lower for general population exposures. Cancer risks conservatively assuming genotoxicity for these same scenarios are all less than 1 × 10-6. The onset of MTBE nonlinear toxicokinetics (TK) in rats at inhalation exposures less than 3,000 ppm, a dose that is also not practically achievable in fuel-use scenarios, indicates that high-dose specific male rat kidney and testes (3,000 and 8,000 ppm) and female mouse liver tumors (8000 ppm) are not quantitatively relevant to humans. Mode of action analyses also indicate MTBE male rat kidney tumors, and lesser so female mouse liver tumors, are not qualitatively relevant to humans. Thus, an integrated analysis of the toxicology, exposure/dosimetry, TK, and MOA data indicates that MTBE presents minimal human cancer and non-cancer risks.

The urinary metabolic profile of diethylene glycol methyl ether and triethylene glycol methyl ether in Sprague-Dawley rats and the role of the metabolite methoxyacetic acid in their toxicity.

Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (~0.5% for TEGME and ~1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME.

Intravenous dexmedetomidine pre-medication reduces the required minimum alveolar concentration of sevoflurane for smooth tracheal extubation in anesthetized children: a randomized clinical trial.

BACKGROUND: It has been known that Dexmedetomidine pre-medication enhances the effects of volatile anesthetics, reduces the need of sevoflurane, and facilitates smooth extubation in anesthetized children. This present study was designed to determine the effects of different doses of intravenous dexmedetomidine pre-medication on minimum alveolar concentration of sevoflurane for smooth tracheal extubation (MACEX) in anesthetized children. METHODS: A total of seventy-five pediatric patients, aged 3-7 years, ASA physical status I and II, and undergoing tonsillectomy were randomized to receive intravenous saline (Group D0), dexmedetomidine 1 µg∙kg-1 (Group D1), or dexmedetomidine 2 µg∙kg-1 (Group D2) approximately 10 min before anesthesia start. Sevoflurane was used for anesthesia induction and anesthesia maintenance. At the end of surgery, the initial concentration of sevoflurane for smooth tracheal extubation was determined according to the modified Dixon's "up-and-down" method. The starting sevoflurane for the first patient was 1.5% in Group D0, 1.0% in Group D1, and 0.8% in Group D2, with subsequent 0.1% up or down in next patient based on whether smooth extubation had been achieved or not in current patient. The endotreacheal tube was removed after the predetermined concentration had been maintained constant for ten minutes. All responses ("smooth" or "not smooth") to tracheal extubation and respiratory complications were assessed. RESULTS: MACEX values of sevoflurane in Group D2 (0.51 ± 0.13%) was significantly lower than in Group D1 (0.83 ± 0.10%; P < 0.001), the latter being significantly lower than in Group D0 (1.40 ± 0.12%; P < 0.001). EC95 values of sevoflurane were 0.83%, 1.07%, and 1.73% in Group D2, Group D1, and Group D0, respectively. No patient in the current study had laryngospasm. CONCLUSION: Dexmedetomidine decreased the required MACEX values of sevoflurane to achieve smooth extubation in a dose-dependent manner. Intravenous dexmedetomidine 1 µg∙kg-1 and 2 µg∙kg-1 pre-medication decreased MACEX by 41% and 64%, respectively. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR): ChiCTR-IOD-17011601 , date of registration: 09 Jun 2017, retrospectively registered.

The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting.

Human health risk assessment of inhalation exposures generally includes a high-to-low concentration extrapolation. Although this is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high concentration levels. In the presence of saturable kinetic processes of the parent compound or metabolites, disproportionate increases in internal blood or tissue concentration relative to the external concentration administered may occur resulting in nonlinear kinetics. The present paper critically reviews human health risk assessment of inhalation exposure. More specific, it emphasizes the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in humans. For two selected chemicals, i.e. methyl tert-butyl ether and 1,2-dichloroethane, PBTK-modelling was used, for illustrative purposes, to follow the extrapolation and conversion steps as performed in existing risk assessments for these chemicals. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose is important. Without this, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.

The effects of intravenous lignocaine on depth of anaesthesia and intraoperative haemodynamics during open radical prostatectomy.

BACKGROUND: Lignocaine is a local anaesthetic agent, which is also commonly used as a perioperative analgesic adjunct to accelerate rehabilitation and enhance recovery after surgery. Lignocaine's systemic effects on intraoperative haemodynamics and volatile anaesthetic requirements are not well explored. Therefore, we evaluated the effects of intravenous lignocaine on intraoperative volatile agent requirements and haemodynamics in patients undergoing major abdominal surgery. METHODS: We performed an analysis of 76 participants who underwent elective open radical retropubic prostatectomy. Patients received lignocaine (1.5 mg/kg loading dose) followed by an infusion (1.5 mg/kg/h) for the duration of surgery, or saline at an equivalent rate. The aims of the study were to evaluate the end-tidal sevoflurane concentration required to maintain a bispectral index of between 40 and 60. Measurements included intraoperative blood pressure, heart rate, and the volume of intravenous fluids and dosage of vasoactive medications administered. RESULTS: The average end-tidal sevoflurane concentration was lower in the Lignocaine group compared to saline [1.49% (SD: 0.32) vs. 1.89% (SD: 0.29); 95% CI 0.26-0.5, p < 0.001]. In the Lignocaine group, the average mean arterial pressure was 80.3 mmHg (SD: 4.9) compared to 85.1 mmHg (SD: 5.4) in the Saline group (95% CI 2.4-7.1, p < 0.001). Systolic blood pressure was also lower in the Lignocaine group: 121.7 mmHg (SD: 6.1) vs. 128.0 mmHg (SD: 6.4) in the Saline group; 95% CI 3.5-9.2, p < 0.001, as was the mean heart rate [Lignocaine group: 74.9 beats/min (SD: 1.8) vs. 81.5 beats/min (SD: 1.7) in the Saline group, 95% CI 4.1-9.1, p < 0.001]. Maintenance fluid requirements were higher in the Lignocaine group: 3281.1 mL (SD: 1094.6) vs. 2552.6 mL (SD: 1173.5) in the Saline group, 95% CI 206-1251, p = 0.007. There were no differences in the use of vasoactive drugs. CONCLUSIONS: Intravenous lignocaine reduces volatile anaesthetic requirements and lowers blood pressure and heart rate in patients undergoing open radical prostatectomy.

miRNAs may regulate GABAergic transmission associated genes in aged rats with anesthetics-induced recognition and working memory dysfunction.

BACKGROUND: Isoflurane and sevoflurane are widely used anesthetics in surgery and administration of these anesthetics could lead to postoperative cognitive dysfunction (POCD). However, the mechanisms remain unclear. METHODS: Aged Wistar rats were exposed to isoflurane and sevoflurane for 2 or 4h. Recognition memory and spatial working memory were measured using Novel object recognition (NOR) and Y-maze test, respectively. Apoptotic cells were detected by TUNEL staining. miRNA expression was measured by Real-time PCR while protein expression was measured by Western blot. Dual-Luciferase reporter assay was used to establish the direct relationship between miRNAs and Gabra5 and gephyrin gene expression. RESULTS: Exposure to isoflurane and sevoflurane for 2 or 4h significantly decreased the NOR index in the NOR test and spontaneous alternations in arm entries in the Y-maze test in aged rats. TUNEL staining showed that isoflurane and sevoflurane administration significantly induced apoptosis in the mPFC and hippocampus. The protein level of α5 GABAA receptor (α5GABAAR), gephyrin, and dystrophin were significantly increased, whereas the expression of miR-30a, miR-31, miR-190a, and miR-190b was significantly decreased in the hippocampus and mPFC in aged rats exposed to isoflurane and sevoflurane compared to control rats. The protein levels of α5GABAAR, gephyrin, and dystrophin protein in the hippocampus and the mPFC significantly correlated with NOR index and spontaneous alternations. Dual-Luciferase reporter assay showed that miR-30a and miR-190a/b mimics significantly inhibited Gabra5 and gephyrin gene expression, respectively. CONCLUSION: There might be a miRNAs-GABAergic transmission pathway which may be involved in the pathophysiological alteration in anesthetics-induced POCD.

An Unusual Complication With the Administration of a Volatile Anesthetic Agent for Status Asthmaticus in the Pediatric Intensive Care Unit: Case Report and Review of the Literature.

In severe cases of status asthmaticus, when conventional therapies fail, volatile anesthetic agents remain a therapeutic option. When delivered outside of the operating room setting, specialized delivery techniques are needed to ensure the safe and effective use of volatile anesthetic agents. We present a 16-year-old adolescent with status asthmaticus who required the therapeutic administration of the volatile anesthetic agent, sevoflurane, in the pediatric intensive care unit (PICU). Although initially effective in reducing bronchospasm, progressive hypercarbia developed due to defective functioning of the carbon dioxide absorber of the anesthesia machine. This failure occurred as the soda lime compartment filled with water accumulated from circuit humidification and continuous albuterol therapy. The role of volatile anesthetic agents in the treatment of status asthmaticus in the PICU is discussed, options for delivery outside of the operating room presented, and potential problems with delivery reviewed.

Pharmacokinetics of ketamine and norketamine enantiomers after racemic or S-ketamine IV bolus administration in dogs during sevoflurane anaesthesia.

The aims of this study were to measure plasma levels of R- and S-ketamine and their major metabolites R- and S-norketamine following single intravenous bolus administration of racemic or S-ketamine in sevoflurane anaesthetised dogs and to calculate the relevant pharmacokinetic profiles. Six adult healthy beagle dogs were used in the study. An intravenous bolus of 4mg/kg racemic ketamine (RS-KET) or 2mg/kg S-ketamine (S-KET) was administered, with a three-weeks washout period between treatments. Venous blood samples were collected at fixed times until 900min and R- and S-ketamine as well as R- and S-norketamine plasma levels determined by liquid chromatography coupled with tandem mass spectrometry. Cardiovascular parameters were recorded during the anaesthesia until 240min. All dogs recovered well from anaesthesia. No statistical differences between groups were detected in any cardiovascular parameter. The pharmacokinetics of S-ketamine did not differ when injected intravenously alone or as part of the racemic mixture in dogs anaesthetised with sevoflurane. Following racemic ketamine, the area under the curve of R-norketamine was statistically higher than the one of S-norketamine.

Monitoring the end-tidal concentration of sevoflurane for preventing awareness during anesthesia (MEETS-PANDA): A prospective clinical trial.

OBJECTIVE: It was hypothesized that monitoring end-tidal sevoflurane (ETS) during endoscopic surgery could reduce the incidence of intraoperative awareness in patients undergoing general anesthesia. Herein, the incidence of intraoperative awareness and other correlative factors was recorded and compared. METHODS: Two thousand five hundred ASA I-III patients aged 18-80 years who underwent general anesthesia were randomly divided into 2 groups (n = 1250): routine care group (R) and ETS concentration group (E). ETS concentration was monitored in group E and maintained at a sevoflurane minimum alveolar concentration (MAC) of 0.7-1.3; group R was monitored using routine care, and the sevoflurane was maintained. Patients were assessed for intraoperative awareness with a questionnaire on their explicit memory 24-48 h after surgery. RESULTS: A total of 2532 patients were selected, and 86 patients were excluded. As for the groups, 1219 patients were assigned to group E, and 1227 patients were assigned to group R. As for intraoperative awareness, group E had 2 patients, and group R had 14. Compared with group R, the incidence of intraoperative awareness in group E was significantly lower (p = 0.003); the time-averaged ETS concentration and sevoflurane dosage were lower in group E (p < 0.05); and no significant changes were found in tracheal extubation time, intravenous general anesthetic dosage, or postoperative complication incidence in either group (p > 0.05). The incidence of intraoperative awareness was higher in women than men in group R (p < 0.05). CONCLUSION: Using ETS-guided anesthesia and maintaining the sevoflurane concentration (0.7-1.3 MAC) can decrease the incidence of patient awareness during endoscopic surgery.

Feasibility of Anesthesia Maintenance With Sevoflurane During Cardiopulmonary Bypass: A Pilot Pharmacokinetics Study.

OBJECTIVE: Adequate maintenance of hypnosis during anesthesia throughout surgery using sevoflurane alone was investigated. In addition, sevoflurane pharmacokinetics during cardiopulmonary bypass were analyzed. DESIGN: This was a pilot pharmacokinetic study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 10 patients aged between 18 and 75 years who underwent elective mitral valve surgery. INTERVENTIONS: The end-tidal and sevoflurane plasma concentrations were measured throughout cardiac surgery procedures involving cardiopulmonary bypass. The sevoflurane plasma concentration was measured using gas chromatography. In addition, the ratio between sevoflurane alveolar concentration and inspired concentration over time (FA/FI) was analyzed to describe wash-in and wash-out curves. MEASUREMENTS AND MAIN RESULTS: Hypnosis was maintained adequately throughout surgery using sevoflurane alone. The bispectral index was maintained between 40 and 60 during cardiopulmonary bypass. The end-tidal sevoflurane was significantly different before and during cardiopulmonary bypass (1.86%±0.54% v 1.30%±0.58%, respectively; p<0.001). However, the sevoflurane plasma concentration was not significantly different before and after cardiopulmonary bypass start-up (40.55 µg/mL [76.62-125.33] before cardiopulmonary bypass and 36.24 µg/mL [56.49-81-42] during cardiopulmonary bypass). This mismatch possibly can be explained by changes that occured after cardiopulmonary bypass start-up, such as reductions of body temperature (36.33°C±0.46°C v 32.98°C±2.38°C, respectively; p<0.001) and hematocrit (35.62%±3.98% v 25.5%±3.08%, respectively; p<0.001). The sevoflurane alveolar concentration varied according to sevoflurane plasma concentration and bispectral index values. No adverse events regarding sevoflurane administration during cardiopulmonary bypass were observed. CONCLUSIONS: Sevoflurane end-tidal values were reliable indicators of adequate anesthesia during all cardiac surgery procedures involving cardiopulmonary bypass.

The effect of fresh gas flow rate and type of anesthesia machine on time to reach target sevoflurane concentration.

BACKGROUND: Anesthesia machines have been developed by the application of new technology for rapid and easier control of anesthetic concentration. In this study, we used a test lung to investigate whether the time taken to reach the target sevoflurane concentration varies with the rate of fresh gas flow (FGF) and type of anesthesia machine (AM). METHODS: We measured the times taken to reach the target sevoflurane concentration (2 minimum alveolar concentration = 4%) at variable rates of FGF (0.5, 1, or 3 L/min) and different types of AM (Primus®, Perseus®, and Zeus® [Zeus®-F; Zeus® fresh gas mode, Zeus®-A; Zeus® auto-mode]). Concomitant ventilation was supplied using 100% O2. The AMs were connected to a test lung. A sevoflurane vaporizer setting of 6% was used in Primus®, Perseus®, and Zeus®-F; a target end-tidal setting of 4% was used in Zeus®-A (from a vaporizer setting of 0%). The time taken to reach the target concentration was measured in every group. RESULTS: When the same AM was used (Primus®, Perseus®, or Zeus®-F), the times to target concentration shortened as the FGF rate increased (P < 0.05). Conversely, when the same FGF rate was used, but with different AMs, the time to target concentration was shortest in Perseus®, followed by Primus®, and finally by Zeus®-F (P < 0.05). With regards to both modes of Zeus®, at FGF rates of 0.5 and 1 L/min, the time to target concentration was shorter in Zeus®-A than in Zeus®-F; however, the time was longer in Zeus®-A than in Zeus®-F at FGF rate of 3 L/min (P < 0.05). CONCLUSION: Shorter times taken to reach the target concentration were associated with high FGF rates, smaller internal volume of the AM, proximity of the fresh gas inlets to patients, absence of a decoupling system, and use of blower-driven ventilators in AM.

Effect of fentanyl and lidocaine on the end-tidal sevoflurane concentration preventing motor movement in dogs.

OBJECTIVE To determine effects of fentanyl, lidocaine, and a fentanyl-lidocaine combination on the minimum alveolar concentration of sevoflurane preventing motor movement (MACNM) in dogs. ANIMALS 6 adult Beagles. PROCEDURES Dogs were anesthetized with sevoflurane in oxygen 3 times (1-week intervals). Baseline MACNM (MACNM-B) was determined starting 45 minutes after induction of anesthesia. Dogs then received 1 of 3 treatments IV: fentanyl (loading dose, 15 µg/kg; constant rate infusion [CRI], 6 µg/kg/h), lidocaine (loading dose, 2 mg/kg; CRI, 6 mg/kg/h), and the fentanyl-lidocaine combination at the same doses. Determination of treatment MACNM (MACNM-T) was initiated 90 minutes after start of the CRI. Venous blood samples were collected at the time of each treatment MACNM measurement for determination of plasma concentrations of fentanyl and lidocaine. RESULTS Mean ± SEM overall MACNM-B for the 3 treatments was 2.70 ± 0.27 vol%. The MACNM decreased from MACNM-B to MACNM-T by 39%, 21%, and 55% for fentanyl, lidocaine, and the fentanyl-lidocaine combination, respectively. This decrease differed significantly among treatments. Plasma fentanyl concentration was 3.25 and 2.94 ng/mL for fentanyl and the fentanyl-lidocaine combination, respectively. Plasma lidocaine concentration was 2,570 and 2,417 ng/mL for lidocaine and the fentanyl-lidocaine combination, respectively. Plasma fentanyl and lidocaine concentrations did not differ significantly between fentanyl and the fentanyl-lidocaine combination or between lidocaine and the fentanyl-lidocaine combination. CONCLUSIONS AND CLINICAL RELEVANCE CRIs of fentanyl, lidocaine, and the fentanyl-lidocaine combination at the doses used were associated with clinically important and significant decreases in the MACNM of sevoflurane in dogs.

Metamizole (dipyrone) effects on sevoflurane requirements and postoperative hyperalgesia in rats.

Unlike non-steroidal anti-inflammatory drugs (NSAIDs), metamizole has poor anti-inflammatory effects; and is suitable for models where analgesia, but not anti-inflammatory effects, is desirable. Like opioids, these drugs produce perioperative analgesia while reducing anaesthetic requirements, but it remains unclear whether they may develop tolerance or hyperalgesia, and thus decrease in analgesic efficacy. The aim was to determine whether tolerance or hyperalgesia to metamizole occurred in rats, and whether the sevoflurane minimum alveolar concentration (MAC) was affected. In a randomized, prospective, controlled study, male Wistar rats ( n = 8 per group) were administered metamizole (300 mg/kg, day 4). Previously, the following treatments were provided: daily metamizole for four days (0-3), morphine (10 mg/kg; positive control, day 0 only) or saline (negative control). The main outcome measures were mechanical (MNT) and warm thermal (WNT) nociceptive quantitative sensory thresholds. The baseline sevoflurane MAC and the reduction produced by the treatments were also determined. The mean (SD) baseline MAC [2.4(0.2)%vol] was decreased by morphine and metamizole by 45(11)% and 33(7)% ( P = 0.000, both), respectively. Baseline MNT [35.4(4.5) g] and WNT [13.2(2.4) s] were decreased by morphine and metamizole: MNT reduction of 22(6)% ( P = 0.000) and 22(7)% ( P = 0.001), respectively and WNT reduction of 34(14)% ( P = 0.000) and 24(13)% ( P = 0.001). The baseline MAC on day 4 was neither modified by treatments nor the MAC reduction produced by metamizole (days 0 and 4; P > 0.05). In conclusion, repeated metamizole administration may produce hyperalgesia, although it may not modify its anaesthetic sparing effect. The clinical relevance of this effect in painful research models requiring prolonged analgesic therapy warrants further investigation.

Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study
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OBJECTIVE: This research studied the influence of different blood lipid components on the rate of alveolar-capillary uptake of sevoflurane. Method: 104 patients aged 20 - 50 years undergoing elective operations under general anesthesia were mechanically ventilated through endotracheal intubation after intravenous injections of midazolam, vecuronium, fentanyl, and etomidate. They inhaled 2% sevoflurane at an oxygen flow of 2 L/min, then the inspired concentrations (FI) and expired concentrations (FA of sevoflurane were recorded at 1, 3, 5, 7, 10, 15, 20, and 30 minutes. These cases were divided into a normal group and an abnormal group according to the lipid levels. Then, based on the lipid criteria, those cases with abnormal lipid levels were classified into a high-triglyceride (TG) and total-cholesterol (TC) group (group TG+TC) and a group with decreased high-density lipoprotein cholesterol (group HDL-C).The values of FA/FI and the times required to reach the titration value FA/FI = 0.8 were calculated were calculated for each group. RESULTS: Compared with the normal group, FA/FI decreased within 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was prolonged in the abnormal group (p < 0.05). The value of FA/FI decreased during 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was longer (p < 0.05) in the group TG+TC. CONCLUSIONS: The increased value of blood/gas partition coefficients (B/G) was caused by the increase in the concentrations of TG and TC in blood lipids.
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Determination and pharmacokinetics of chinensinaphthol methyl ether in rat urine by a sensitive and specific UFLC-ESI-MS/MS method.

A rapid, stable, and sensitive method based on ultra-fast liquid chromatography combined with electrospray ionization tandem mass spectrometry (UFLC-ESI-MS/MS) was established and optimized for quantification and pharmacokinetics analysis of chinensinaphthol methyl ether (CME) in rat urine. Samples were prepared by liquid phase extraction with ethyl acetate, and chromatographic separation was performed on an ACQUITY UPLC(®) BEH Phenyl column (2.1×50mm, 1.7µm). For gradient elution, we used a mobile phase consisting of water containing 0.1% formic acid and 5mmol/L ammonium formate and methanol with 0.1% formic acid. The quantification was executed under multiple reaction monitoring (MRM) in positive mode. The precursor/product transition (m/z) in the positive ion mode was [M+H](+)m/z=395.1→346.1. This method was validated by evaluating specificity, linearity, matrix effects, recovery, accuracy, precision, and stability, which were all shown to be reasonable and reliable. The lower limit of quantification (LOQ) was 0.5ng/mL, and the linear range was 0.5-100ng/mL. The method was successfully applied to quantify and analyze the pharmacokinetics of CME in rat urine. After oral administration of a single dose of CME (5.0mg/kg), the accumulated amount of CME excreted in urine was 162.3±54.1ng, and the terminal elimination half-life was 53.4±5.3h, indicating low CME excretion in urine and significant CME metabolism in vivo.

Effects of ketamine and lidocaine in combination on the sevoflurane minimum alveolar concentration in alpacas.

This study investigated the effects of ketamine and lidocaine in combination on the minimum alveolar concentration of sevoflurane (MACSEVO) in alpacas. Eight healthy, intact male, adult alpacas were studied on 2 separate occasions. Anesthesia was induced with SEVO, and baseline MAC (MACB) determination began 45 min after induction. After MACB determination, alpacas were randomly given either an intravenous (IV) loading dose (LD) and infusion of saline or a loading dose [ketamine = 0.5 mg/kg body weight (BW); lidocaine = 2 mg/kg BW] and an infusion of ketamine (25 µg/kg BW per minute) in combination with lidocaine (50 µg/kg BW per minute), and MACSEVO was re-determined (MACT). Quality of recovery, time-to-extubation, and time-to-standing, were also evaluated. Mean MACB was 1.88% ± 0.13% and 1.89% ± 0.14% for the saline and ketamine + lidocaine groups, respectively. Ketamine and lidocaine administration decreased (P < 0.05) MACB by 57% and mean MACT was 0.83% ± 0.10%. Saline administration did not change MACB. Time to determine MACB and MACT was not significantly different between the treatments. The quality of recovery, time-to-extubation, and time-to-standing, were not different between groups. The infusion of ketamine combined with lidocaine significantly decreased MACSEVO by 57% and did not adversely affect time-to-standing or quality of recovery.

La présente étude visait à examiner les effets d'une combinaison de kétamine et de lidocaïne sur la concentration alvéolaire minimale de sevoflurane (CAMSEVO) chez des alpagas. Huit alpagas mâles entiers et en santé ont été étudiés en deux occasions distinctes. L'anesthésie a été induite avec du SEVO, et la détermination de la CAM de base (CAMB) débutée 45 min après l'induction. Après détermination de la CAMB, les alpagas ont reçu par voie intraveineuse (IV), sur une base aléatoire, une dose de charge (DC) et une infusion de saline ou une dose de [kétamine = 0,5 mg/kg de poids corporel (PC); lidocaïne = 2 mg/kg PC] et une infusion de kétamine (25 µg/kg PC par minute) en combinaison avec de la lidocaïne (50 µg/kg PC par minute), et la CAMSEVO re-déterminée (CAMT). La qualité de la récupération, le temps pour extuber, et le temps pour se tenir debout ont également été évalués. La CAMB moyenne était de 1,88 % ± 0,13 % et de 1,89 % ± 0,14 % pour les groupes saline et kétamine + lidocaïne, respectivement. L'administration de kétamine et de lidocaïne entraîna une diminution (P < 0,05) de 57 % de CAMB et la CAMT moyenne était de 0,83 % ± 0,10 %. L'administration de saline n'a pas changé la CAMB. Le temps pour déterminer la CAMB et la CAMT n'était pas significativement différent entre les groupes de traitement. La qualité de la récupération, le temps pour extuber, et le temps pour se tenir debout n'étaient pas significativement différents entre les groupes. L'infusion de kétamine combinée à la lidocaïne a diminué significativement la CAMSEVO de 57 % et n'affecta pas négativement le temps pour se tenir debout ou la qualité de la récupération.(Traduit par Docteur Serge Messier).

Comparison of sevoflurane concentration for insertion of proseal laryngeal mask airway and tracheal intubation in children (correlation with BIS) / Comparação da concentração de sevoflurano para a inserção de ML proseal e intubação traqueal em crianças (correlação com BIS)

BACKGROUND: Sevoflurane is an inhalational agent of choice in paediatric anaesthesia. For management of airways in children a suitable alternative to ETT is a paediatric proseal laryngeal mask airway (benchmark second generation SAD). Various studies have shown that less sevoflurane concentration is required for LMA insertion in comparison to TI. BIS is a useful monitor of depth of anaesthesia. AIMS: To compare concentration of sevoflurane (end tidal and MAC value) required for proseal laryngeal mask airway insertion and tracheal intubation in correlation with BIS index. METHOD: The prospective randomised single blind study was done in children between 2 and 9 years of ASA I and II and they were randomly allocated to Group P (proseal laryngeal mask airway insertion) and Group TI (tracheal intubation). No sedative premedication was given. Induction was done with 8% sevoflurane and then predetermined concentration was maintained for 10 min. Airway was secured either by proseal laryngeal mask airway or endotracheal tube without using muscle relaxant. End tidal sevoflurane concentration, MAC, BIS, and other vital parameters were monitored every minute till insertion of an airway device. Insertion conditions were observed. Statistical analysis was done by ANOVA and Students t test. RESULTS: Difference between ETLMI (2.49 ± 0.44) and ETTI (2.81 ± 0.65) as well as MACLMI (1.67 ± 0.13) and MACTI (1.77 ± 0.43) was statistically very significant, while BISLMI (49.05 ± 10.76) and BISTI (41.25 ± 3.25) was significant. Insertion conditions were comparable in both the groups. CONCLUSION: We can conclude that in children airway can be secured safely with proseal laryngeal mask airway using less sevoflurane concentration in comparison to tracheal intubation and this was supported by BIS index.

JUSTIFICATIVA: Sevoflurano é um agente inalatório de escolha em anestesia pediátrica. Para o manejo de vias aéreas em crianças, uma opção adequada para o TET é uma MLP pediátrica (referência de segunda geração SAD). Vários estudos mostraram que uma menor concentração do sevoflurano é necessária para a inserção da ML em comparação com a IT. O BIS é um monitor útil da profundidade da anestesia. OBJETIVOS: Comparar a concentração de sevoflurano (valores no fim da expiração e da CAM) necessária para a inserção de MLP e intubação traqueal em correlação com o BIS. MÉTODO: Estudo prospectivo, randômico e cego conduzido com crianças entre 2-9 anos, estado físico ASA I-II, randomicamente alocados nos grupos P (inserção de MLP) e IT (intubação traqueal). Pré-medicação sedativa não foi administrada. A indução foi feita com sevoflurano a 8% e, em seguida, a concentração predeterminada foi mantida durante 10 minutos. A via aérea foi garantida por MLP ou tubo endotraqueal, sem o uso de relaxante muscular. A concentração de sevoflurano no fim da expiração, CAM, BIS e outros parâmetros vitais foram monitorados a cada minuto até a inserção do dispositivo respiratório. As condições de inserção foram observadas. A análise estatística foi feita com o teste t de Student e Anova. RESULTADOS: As diferenças entre TEIML (2,49 ± 0,44) e TEIT (2,81 ± 0,65), bem como CAMIML (1,67 ± 0,13) e CAMIT (1,77 ± 0,43), foram estatisticamente muito significativas; enquanto BISIML (49,05 ± 10,76) e BISIT (41,25 ± 3,25) foram significativos. As condições de inserção foram comparáveis em ambos os grupos. CONCLUSÃO: Podermos concluir que a MLP em comparação com a intubação traqueal pode ser segura para a via aérea de crianças com o uso de menos concentração de sevoflurano, o que foi confirmado pelo BIS.

Comparison of sevoflurane concentration for insertion of proseal laryngeal mask airway and tracheal intubation in children (correlation with BIS).

BACKGROUND: Sevoflurane is an inhalational agent of choice in paediatric anaesthesia. For management of airways in children a suitable alternative to ETT is a paediatric proseal laryngeal mask airway (benchmark second generation SAD). Various studies have shown that less sevoflurane concentration is required for LMA insertion in comparison to TI. BIS is a useful monitor of depth of anaesthesia. AIMS: To compare concentration of sevoflurane (end tidal and MAC value) required for proseal laryngeal mask airway insertion and tracheal intubation in correlation with BIS index. METHOD: The prospective randomised single blind study was done in children between 2 and 9 years of ASA I and II and they were randomly allocated to Group P (proseal laryngeal mask airway insertion) and Group TI (tracheal intubation). No sedative premedication was given. Induction was done with 8% sevoflurane and then predetermined concentration was maintained for 10 min. Airway was secured either by proseal laryngeal mask airway or endotracheal tube without using muscle relaxant. End tidal sevoflurane concentration, MAC, BIS, and other vital parameters were monitored every minute till insertion of an airway device. Insertion conditions were observed. Statistical analysis was done by ANOVA and Students t test. RESULTS: Difference between ETLMI (2.49 ± 0.44) and ETTI (2.81 ± 0.65) as well as MACLMI (1.67 ± 0.13) and MACTI (1.77 ± 0.43) was statistically very significant, while BISLMI (49.05 ± 10.76) and BISTI (41.25 ± 3.25) was significant. Insertion conditions were comparable in both the groups. CONCLUSION: We can conclude that in children airway can be secured safely with proseal laryngeal mask airway using less sevoflurane concentration in comparison to tracheal intubation and this was supported by BIS index.

Systematic analysis of the polyphenol metabolome using the Phenol-Explorer database.

SCOPE: The Phenol-Explorer web database details 383 polyphenol metabolites identified in human and animal biofluids from 221 publications. Here, we exploit these data to characterize and visualize the polyphenol metabolome, the set of all metabolites derived from phenolic food components. METHODS AND RESULTS: Qualitative and quantitative data on 383 polyphenol metabolites as described in 424 human and animal intervention studies were systematically analyzed. Of these metabolites, 301 were identified without prior enzymatic hydrolysis of biofluids, and included glucuronide and sulfate esters, glycosides, aglycones, and O-methyl ethers. Around one-third of these compounds are also known as food constituents and corresponded to polyphenols absorbed without further metabolism. Many ring-cleavage metabolites formed by gut microbiota were noted, mostly derived from hydroxycinnamates, flavanols, and flavonols. Median maximum plasma concentrations (C(max)) of all human metabolites were 0.09 and 0.32 µM when consumed from foods or dietary supplements, respectively. Median time to reach maximum plasma concentration in humans (T(max)) was 2.18 h. CONCLUSION: These data show the complexity of the polyphenol metabolome and the need to take into account biotransformations to understand in vivo bioactivities and the role of dietary polyphenols in health and disease.