Salient features of enantioselective gas chromatography: the enantiomeric differentiation of chiral inhalation anesthetics as a representative methodological case in point.

The enantiomeric differentiation of the volatile chiral inhalation anesthetics enflurane, isoflurane, and desflurane by analytical and preparative gas chromatography on various modified cyclodextrins is described. Very large enantioseparation factors α are obtained on the chiral selector octakis(3-O-butanoyl-2,6-di-O-pentyl)-γ-cyclodextrin (Lipodex E). The gas-chromatographically observed enantioselectivities are corroborated by NMR-spectroscopy using Lipodex E as chiral solvating agent and by various sensor devices using Lipodex E as sensitive chiral coating layer. The assignment of the absolute configuration of desflurane is clarified. Methods are described for the determination of the enantiomeric distribution of chiral inhalation anesthetics during narcosis in clinical trials. The quantitation of enantiomers in a sample by the method of enantiomeric labeling is outlined. Reliable thermodynamic parameters of enantioselectivity are determined by using the retention-increment R' approach for the enantiomeric differentiation of various chiral halocarbon selectands on diluted cyclodextrin selectors.

Preparation of the Dräger Primus anesthetic machine for malignant hyperthermia-susceptible patients.

PURPOSE: Preparation of anesthesia machines for patients who are susceptible to malignant hyperthermia includes flushing the machine with vapour-free fresh gas to washout residual anesthetic agents. To establish guidelines for the preparation of the Dräger Primus machine, we compared the washout profiles for isoflurane and sevoflurane in the Dräger Primus and Ohmeda Excel 210 anesthesia machines. TECHNICAL FEATURES: The machines were primed with 1.5% isoflurane or 2.5% sevoflurane. Fresh gas flow (FGF) was set at 10 L.min(-1) during the early washout phase, and subsequently reduced to 3 L.min(-1) during the late washout phase. A Miran ambient air analyzer measured the anesthetic concentration every minute during washout until a concentration of 5 ppm was achieved in the inspiratory limb of the circle circuit. We found that at a FGF of 10 L.min(-1), maximum washout times for isoflurane and sevoflurane in the Primus, 70 and 74 min, respectively, were approximately tenfold greater than for isoflurane in the Excel 210 (7.0 min). Increasing the FGF to 18 L.min(-1) decreased the washout time for isoflurane in the Primus, only moderately, to 52 min. We observed a threefold increase in anesthetic concentration in the Primus during the late washout phase. CONCLUSION: We conclude that the Primus must be flushed for at least 70 min to decrease the anesthetic concentration to 5 ppm when using a FGF of 10 L.min(-1). We recommend maintaining a FGF of 10 L.min(-1) for the duration of anesthesia in order to prevent the rebound increase in anesthetic concentration in the FGF.

Silica zeolite scavenging of exhaled isoflurane: a preliminary report.

PURPOSE: We evaluate the effectiveness of a silica zeolite (Deltazite) hydrophobic molecular sieve adsorbent, in removing exhaled isoflurane. METHODS: In three experiments, a simulated anesthesia mannequin was ventilated using 1% isoflurane in nitrous oxide and oxygen (1:1 ratio) at a gas flow of 3 L x min-1. Airway pressures, end-tidal carbon dioxide [ETCO2], inspired and end-tidal isoflurane were measured. The scavenging line was connected to a canister containing 750 g of the silica zeolite. Concentrations of isoflurane entering and exiting the canister were measured, as well as the pressure gradient across the canister and gas flow through the canister. In phase 1 (n = 3), the mannequin was ventilated for 6.5 hr, followed by phase 2 where a test lung replaced the simulator. The time (phase 1 plus phase 2) until isoflurane 'breakthrough' (> 0.02%) was noted. RESULTS: The average canister weight increase was 68 g, however 92 g of isoflurane were used. The isoflurane concentration exiting the canister remained undetectable throughout phase 1 in each experiment. The pressure gradient across the canister averaged 0.13 cm H2O and did not increase throughout phase 1. The time to 'breakthrough' (phase 1 plus phase 2) was 8.0 hr, 8.8 hr and 9.0 hr. CONCLUSIONS: Silica zeolite was effective at completely removing 1% isoflurane from exhaled gases for periods of eight hours. The technology shows promise in removing isoflurane emitted from anesthesia machine scavenging systems.

A follow-up study on occupational exposure to inhaled anaesthetics in Eastern European surgeons and circulating nurses.

OBJECTIVE: Although no dose-response relationship exists for the health risks associated with the occupational exposure to inhaled anaesthetics, public health authorities recommend threshold values. The aim of the present study was to assess whether and to what extent these threshold values are exceeded in surgeons and circulating nurses of an Eastern European university hospital, before and after measures had been taken to reduce occupational exposure. METHODS: At nine workplaces, occupational exposure to nitrous oxide and the volatile anaesthetic used (halothane or isoflurane) was measured within the breathing zones of surgeons and circulating nurses by means of photoacoustic infrared spectrometry. The measurements were carried out in 1996 and were repeated in 1997 after the installation of active scavenging devices at five workplaces, and an air-conditioning system at one workplace. RESULTS: Occupational exposure to nitrous oxide and halothane or isoflurane was lower in 1997 compared with that of 1996. In 1996, 89% of the nitrous oxide values were above the European threshold value of 100 ppm, whereas in 1997 approximately 50% were above this limit. In 1996 the majority of the measurements for the volatile anaesthetics were already below 5 ppm halothane and 10 ppm isoflurane and the number of measurements exceeding these limits was further reduced in 1997. CONCLUSION: The measures taken were effective in reducing waste gas exposure. Nevertheless, further efforts are necessary, especially for nitrous oxide, to reach Western European standards and to minimise possible health risks. These efforts comprise the installation of (active) scavenging devices, air-conditioning systems and new anaesthesia machines at all workplaces, the use of low-flow anaesthesia, the replacement of inhaled anaesthetics by intravenous anaesthetics and an appropriate working technique.

Headspace gas chromatography-mass spectrometry analysis of isoflurane enantiomers in blood samples after anesthesia with the racemic mixture.

Several in vivo and in vitro studies on the stereoselective potency of isoflurane enantiomers suggest beneficial effects of the (+)-(S)-enantiomer. In order to detect possible differences in the pharmacokinetics of isoflurane enantiomers, a clinical study of 41 patients undergoing general anesthesia maintained with racemic isoflurane was performed. The isoflurane enantiomers were analyzed in blood samples drawn before induction, at cessation (day 0), and up to eight days after isoflurane anesthesia (day 1-8). A multipurpose sampler (Gerstel MPS) was used for the headspace gas chromatography-mass spectrometry (GC/MS) analysis, and it was combined with a cold injection system (Gerstel CIS 3) for coldtrapping, enrichment, and focusing of the analyte. The enantiomer separation was achieved by using a capillary column coated with octakis(3-O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E) dissolved in the polysiloxane PS 255. Detection was done in the selected ion monitoring mode with ions m/z 117 and m/z 149. An enrichment of (+)-(S)-isoflurane in all blood samples drawn after anesthesia was found. The highest enantiomer bias, up to 52-54% (+)-(S)-isoflurane as compared to 50% for the racemate, was observed on day 2 for most of the patients. Furthermore, quantification of isoflurane in blood samples of five patients was done by enantiomer labeling, employing enantiomerically pure (+)-(S)-isoflurane as internal standard. The isoflurane concentration decreased rapidly from 383 nmol/ml to 0.6 nmol/ml (mean values) eight days after anesthesia. The present study shows differences in the pharmacokinetics of isoflurane enantiomers in man. However, it is not possible to distinguish between enantioselective distribution and enantioselective metabolism, if any.

Preparative enantiomer separation of the inhalation anesthetics enflurane, isoflurane and desflurane by gas chromatography on a derivatized gamma-cyclodextrin stationary phase.

The preparative enantiomeric separation of the inhalation anesthetics enflurane (1) and isoflurane (2) in very high chemical (> 99.5%) and enantiomeric excess (ee > 99%) by gas chromatography (GC) on octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-cyclodextrin (4), dissolved in the apolar polysiloxane SE-54 and coated on Chromosorb P AW DMCS, is described. Up to 1 g of each enantiomer of 1-2 can been obtained per diem. The enantiomers of the highly volatile desflurane (3) can also be separated, albeit with diminished ee. The enantiomeric excess of 1-3 was checked by analytical GC on 4 and the absolute configuration of 2 and 3 has been determined via anomalous X-ray diffraction.

Approach to the thermodynamics of enantiomer separation by gas chromatography. Enantioselectivity between the chiral inhalation anesthetics enflurane, isoflurane and desflurane and a diluted gamma-cyclodextrin derivative.

The thermodynamics of enantioselectivity, -delta D,L(delta G), -delta D,L(delta H), delta D,L(delta S) and Tiso, have been determined by gas chromatography employing the concept of the retention increment R' for the inhalation anesthetics enflurane (1), isoflurane (2) and desflurane (3) and the selector octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-cyclodextrin (4) in the polysiloxane SE-54. It is shown that the separation factor alpha is concentration-dependent. Therefore, the separation factor alpha should not be employed as a criterion for enantioselectivity in diluted systems. The -delta DL(delta G) data for 1 and 4 are corroborated by 1H NMR spectroscopic measurements.

Inhalational anesthetics stereochemistry: optical resolution of halothane, enflurane, and isoflurane.

Halothane (I), enflurane (II), and isoflurane (III), which are among the most important inhalation anesthetics, are currently administered as racemic mixtures. The pure enantiomers have not been described, and no analytical method for resolving the commercially available racemic mixtures has been reported. Complete optical resolution of (+/-)-I and (+/-)-III on per-n-pentylated alpha-cyclodextrin (Lipodex A) and of (+/-)-II and (+/-)-III on octakis(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin capillary columns has been achieved, making rapid and convenient determination of enantiomeric ratios in samples of all three of these anesthetics possible.