Zexu Fang

Carbon Monoxide Production from Degradation of Desflurane, Enflurane, Isoflurane, Halothane, and Sevoflurane by Soda Lime and Baralyme@

Anecdotal reports suggest that soda lime and Baralyme Registered Trademark brand absorbent can degrade inhaled anesthetics to carbon monoxide (CO).We examined the factors that govern CO production and found that these include: 1) The anesthetic used: for a given minimum alveolar anesthetic concentration (MAC)-multiple, the magnitude of CO production (greatest to least) is desflurane >or=to enflurane > isoflurane much greater than halothane = sevoflurane. 2) The absorbent dryness: completely dry soda lime produces much more CO than absorbent with just 1.4% water content, and soda lime containing 4.8% or more water (standard soda lime contains 15% water) generates no CO. In contrast, both completely dry Baralyme Registered Trademark and Baralyme Registered Trademark with 1.6% water produce high concentrations of CO, and Baralyme Registered Trademark containing 4.7% water produces concentrations equaling those produced by soda lime containing 1.4% water. Baralyme Registered Trademark containing 9.7% or more water and standard Baralyme Registered Trademark (13% water) do not generate CO. 3) The type of absorbent: at a given water content, Baralyme Registered Trademark produces more CO than does soda lime. 4) The temperature: an increased temperature increases CO production. 5) The anesthetic concentration: more CO is produced from higher anesthetic concentrations. These results suggest that CO generation can be avoided for all anesthetics by using soda lime with 4.8% (or more) water or Baralyme Registered Trademark with 9.7% (or more) water, and by using inflow rates of less than 2-3 L/min. Such inflow rates are low enough to ensure that the absorbent does not dry out. (Anesth Analg 1995;80:1187-93)

Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products.

Background Desflurane and sevoflurane permit speedier changes in anesthetic partial pressures than do older halogenated anesthetics. The authors determined the kinetic characteristics of desflurane and sevoflurane and those of compound A [CH2 F-O-C(= CF2)(CF3)], a nephrotoxic degradation product of sevoflurane. Methods Volunteers received 1.25 minimum alveolar concentration of desflurane or sevoflurane, each administered for 8 h in a fresh gas inflow of 2 l/min. Inspired (FI) and end-tidal (FA) concentrations of anesthetic and compound A were measured during administration, and FA relative to FAO (the last end-tidal concentration during administration) during elimination. The indices of recovery were also measured. Results The ratio FI /FA rapidly approached 1.0, with values greater for sevoflurane (desflurane 1.06 +/- 0.01 vs. sevoflurane 1.11 +/- 0.02, mean +/- SD). The ratio FA /FI for compound A was approximately 0.8. The FA /FAO ratio decreased slightly more rapidly with desflurane than with sevoflurane, and objective measures indicated faster recovery with desflurane: The initial response to command (14 +/- 4 min vs. 28 +/- 8 min [means +/- SD]) and orientation (19 +/- 4 vs. 33 +/- 9 min) was quicker, and recovery was faster as defined by results of the Digit Symbol Substitution, P-deletion, and Trieger tests. Desflurane produced less vomiting (1 [0.5, 3]; median [quartiles] episodes) than did sevoflurane (5 [2.5, 7.5] episodes). The FA /FAO ratio for compound A decreased within 5 min to a constant value of 0.1. Conclusions These anesthetics have kinetics consistent with their solubilities. Sevofluranes greater biodegradation probably increases F sub I /FA differences during anesthetic administration and decreases FA /FAO differences during elimination. The FA for compound A differs from FI by 20% (FA /FI = 0.8) because of substantial degradation. Recovery from anesthesia proceeds nearly twice as fast with desflurane than with sevoflurane. Differences in ventilation, or alveolar or tissue elimination, do not completely explain the slower recovery with sevoflurane.

Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics)

We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. Implications: It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect. (Anesth Analg 1998;87:419-24)

Anesthetic potencies of n-alkanols: Results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics

The mechanism by which n-alkanols produce anesthesia and the characteristics relevant to those mechanisms (e.g., lipid solubilities versus potencies) remain unknown. Accordingly, we determined potencies (minimum alveolar anesthetic concentration [MAC]) and solubilities of normal methanol, ethanol, butanol, hexanol, and octanol. We also determined the additivity of these alkanols with a conventional anesthetic (desflurane) and the additivity of methanol with butanol. Finally, we determined whether alkanol metabolism influences alkanol potencies. MAC for methanol, ethanol, butanol, hexanol, and octanol (0.00200, 0.000989, 0.000133, 0.0000214, and 0.00000117 atm, respectively) increased with an increasing solubility in olive oil (olive oil/gas partition coefficients 48.6, 108, 1,650, 11,600, and 93,500, respectively) and octanol (octanol/gas partition coefficients 163, 1,150, 22,900, 135,000, and 4,140,000) to give a product of MAC x solubility for olive oil approximately 10 times less (values of 0.10-0.25) than that expected from the Meyer-Overton hypothesis (compared with conventional inhaled anesthetics). There was less deviation for octanol, but the results were more variable. Inhibition of methanol and butanol metabolism by 4-methylpyrazole did not alter MAC. Methanol, ethanol, butanol, hexanol, and octanol had approximately additive anesthetic effects with desflurane, with some small but statistically significant deviations both above and below additivity. In the presence of 0.5 MAC of desflurane, we needed to add 0.4-0.6 MAC of each alkanol to inhibit the movement of 50% of the rats in response to noxious stimulation. Similarly, the effects of methanol and butanol were additive (with each other). The saline/gas partition coefficient for each alkanol was high (3700, 2650, 1400, 900, and 709 for methanol through octanol), which indicates high polarity. We conclude that the potent anesthetic effects of normal alkanols may result from an affinity to both polar and nonpolar phases. Our finding of additivity of alkanols with each other is consistent with a common mechanism of action. Similarly, the finding of additivity or slight deviations from additivity for alkanols with desflurane is consistent with mechanisms of action that have much in common. (Anesth Analg 1997;84:1042-8)

Specific gravities of desflurane, enflurane, halothane, isoflurane, and sevoflurane

We determined the specific gravities of presently available volatile anesthetics in order to supply a consistent quantitative basis for calibration standards. Using four 50-mL volumetric flasks, we obtained the following values at 20°C: desflurane 1.4651 ± 0.0004 g/mL (mean ± SD); enflurane 1.5230 ± 0.0003 g/mL; halothane 1.8680 ± 0.0007 g/mL; isoflurane 1.5019 ± 0.0006 g/mL; and sevoflurane 1.5203 ± 0.0008 g/mL. Measurements made at 0°C, 10°C, 20°C, and 25°C (not for desflurane at 25°C) revealed a decrease in specific gravity of 0.00250 ± 0.00014 g/mL for each degree of increase in temperature. These data bear on the issue of cost for anesthetics that are stored as liquids, but used as gases.

Maturation Decreases Ethanol Minimum Alveolar Anesthetic Concentration (mac) More than Desflurane Mac in Rats

The potency of conventional inhaled anesthetics increases with increasing age:the 50% effective dose (minimum alveolar anesthetic concentration [MAC]) for anesthesia in the neonatal animal or human exceeds MAC in the young adult by approximately 30% to 60%. We tested whether this relationship also applies to the alkanols, using ethanol as a representative alkanol. We found that the MAC of ethanol in neonatal rats was 1.86 times (86% greater than) the MAC for adult rats, based on ethanol partial pressures determined from brain specimens. In contrast, the MAC of desflurane in neonatal rats was 1.19 times (19% greater than) the MAC for adult rats, less than one-fourth the 86% found for ethanol. These differences must be explained by any unitary theory of narcosis. Alternatively, the mechanistic basis for alkanol versus conventional inhaled anesthetics may differ in part or whole. (Anesth Analg 1997;84:852-8)

Convulsant activity of nonanesthetic gas combinations

Most nonanesthetics (inhaled compounds that neither cause anesthesia when given alone nor decrease the partial pressure of a known inhaled anesthetic required to produce anesthesia) and transitional compounds (inhaled compounds that are less potent than would be predicted by the Meyer-Overton hypothesis) cause convulsions. A possible exception is the perfluoroalkane series of nonanesthetics. The present study tested whether perfluoroalkanes do provide an exception. Further, we tested whether the convulsant effects of nonanesthetic and transitional compounds were additive. The nonanesthetic perfluoropropane caused convulsions at 7.5 +/- 0.7 atm (mean +/- SD). Convulsions also were produced by perfluorocyclobutane (0.976 +/- 0.002 atm), 1,2-dichlorotetrafluoroethane (0.358 +/- 0.011 atm), 2,3-dichlorooctafluorobutane (0.085 +/- 0.007 atm), 1,2-dichlorohexafluorocyclobutane (0.055 +/- 0.007 atm), and flurothyl (0.00156 +/- 0.00039 atm). Of these, 1,2-dichlorotetrafluoroethane is a transitional compound, the remainder being nonanesthetics. The combination of flurothyl plus 1,2-dichlorohexafluorocyclobutane gave evidence of antagonism (a 17% +/- 21% deviation from additivity; P < 0.05), whereas the combination of 1,2-dichlorotetrafluoroethane plus 2,3-dichlorooctafluorobutane gave evidence of synergy (a -13% +/- 8% deviation from additivity; P < 0.05). The combinations of perfluoropropane plus perfluorocyclobutane (-4% +/- 15%), and perfluoropropane plus 1,2-dichlorohexafluorocyclobutane (-1% +/- 26%) did not produce results that deviated significantly from additivity. We conclude that pairs of these compounds either produce convulsions in an additive manner, a finding consistent with (but not proving) a common mode of action; or deviate modestly from additivity, a finding suggesting that at least a portion of the mechanistic basis for convulsions might differ, particularly for flurothyl plus other nonanesthetics, or for the combination of nonanesthetics and transitional compounds. (Anesth Analg 1997;84:634-40)

Effects of inhaled nonimmobilizer, proconvulsant compounds on desflurane minimum alveolar anesthetic concentration in rats.

Anesthetics depress the central nervous system, whereas nonimmobilizers (previously called nonanesthetics) and transitional compounds having the same physical properties (e.g., solubility in lipid) do not produce anesthesia (nonimmobilizers) or are less potent anesthetics than might be predicted from their lipophilicity (transitional compounds). Potential explanations for the absent or decreased anesthetic effect of nonimmobilizer and transitional compounds include the theories that the nonimmobilizers are devoid of anesthetic effect and that transitional compounds have a decreased capacity to produce anesthesia; that the effects of these compounds are not apparent because the concentrations examined are too low; or that anesthesia, or lack thereof, results from a balance between depression and excitation (all nonimmobilizer and transitional compounds produce convulsions). To examine these issues further, we tested the effect of various multiples of the convulsive 50% effective dose (ED50) of three nonimmobilizers and one transitional compound on the minimum alveolar anesthetic concentration (MAC) of desflurane in rats. The nonimmobilizer 2,3-dichlorooctafluorobutane (NI-1), from 0.7 to 1.1 times its convulsive ED50, increased the MAC of desflurane by 14%-27%, but at 1.6 times its convulsive ED50 caused no change in MAC; the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (NI-2) did not change MAC at concentrations up to its convulsant ED50, but it increased MAC by 25% and 36% at 1.3 and 1.7 times its convulsant ED50, respectively. The nonimmobilizer flurothyl (NI-3) decreased the MAC of desflurane by 20% +/- 6% (mean +/- SD) at 0.5 times its convulsant ED50, but it caused no change at higher partial pressures (up to 7.8 times its convulsant ED50), and the transitional compound CF3 CCl2-O-CF2 Cl (T-1) significantly decreased MAC by 16% +/- 7% at 0.8 times its convulsant ED50, but the 6%-8% decreases in MAC at 0.4 and 1.6 times its convulsant ED (50) were not significant. Thus, neither nonimmobilizer nor transitional compounds produced a consistent dose-related effect on the MAC of desflurane, and any changes were small. These results suggest that the excitation produced by transitional compounds or nonimmobilizers does not explain their limited ability or inability to produce anesthesia. The data are consistent with a decreased anesthetic efficacy of transitional compounds and the lack of efficacy of nonimmobilizers. Implications: Inhaled compounds that do not cause anesthesia (nonimmobilizers) are used to test theories of anesthetic action. Their use presumes that a trivial explanation, such as cancelling stimulatory and depressant effects, does not explain the absence of anesthesia. The present results argue against such an explanation. (Anesth Analg 1997;85:1149-53)

Maturation decreases ethanol minimum alveolar anesthetic concentration in mice as previously demonstrated in rats : There is no species difference

The potency of conventional inhaled anesthetics increases with maturation:the 50% effective dose (minimum alveolar anesthetic concentration [MAC]) for conventional inhaled anesthetics in the neonatal rat or human exceeds MAC in the young adult. This increase also applies to ethanol in rats tested using MAC as the measure of anesthesia. However, the converse appears to be true for studies in mice assessed with the righting reflex; that is, adult mice are six times more resistant than neonates to the effects of ethanol. These disparate findings imply that maturation in rats and mice may produce opposing changes in the quantity or sensitivity of one or more receptors that mediate the actions of anesthetics that lead to the anesthetic state. Such a finding would be important for two reasons. First, both rodents are widely used in studies of anesthetic effects, and, thus, a species-dependent divergence in anesthetic effects has immediate experimental implications. Second, confirmation of such a species difference would supply an opportunity to test which receptors might be crucial to anesthetic mechanisms. Accordingly, we investigated whether maturation decreased ethanol potency in mice, using MAC as the measure of anesthesia. Applying standard techniques, we tested MAC for ethanol in 15 CF-1 mice aged 10 days (6-8.5 g) and in 13 mice aged 77-84 days (34-39 g). MAC decreased with maturation, and the decrease was indistinguishable from that found in our previous studies of rats. (Anesth Analg 1997;85:160-3)