The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene.

UNLABELLED: The differences in potencies of optical isomers of anesthetics support the hypothesis that anesthetics act by specific receptor interactions. Diastereoisomerism and geometrical isomerism offer further tests of this hypothesis but have not been explored. They are the subject of this report. We quantified the nonimmobilizing and convulsant properties of the cis and trans diastereomers of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane). Although the lipophilicity of the diastereomers predicts complete anesthesia at the partial pressures applied, neither diastereomer had anesthetic activity alone, and the cis form may have a small (10%) capacity to antagonize anesthesia, as defined by additive effects on the MAC (the minimum alveolar concentration required to suppress movement to a noxious stimulus in 50% of rats) of desflurane. Both diastereomers produced convulsions, the cis form being nearly twice as potent as the trans form: convulsant 50% effective dose (mean +/- SD) was 0.039 +/- 0.009 atmospheres (atm) for the purified cis and 0.064 +/- 0.009 atm for the purified trans isomer. The MAC value for cis-1,2-dichloroethylene equaled 0.0071 +/- 0.0006 atm, and MAC for trans-1,2-dichloroethylene equaled 0.0183 +/- 0.0031 atm. In qualitative accord with the Meyer-Overton hypothesis, the greater cis potency was associated with a greater lipophilicity. However, the product of MAC x solubility differed between the cis and trans isomers by 40%-50%. We conclude that neither the cis nor trans isomers of 2N have anesthetic properties, but isomerism does influence 2N's convulsant properties and the anesthetic properties of dichloroethylene. These isomeric effects may be as useful in defining receptor-anesthetic interactions as those found with optical isomers. IMPLICATIONS: Cis-trans isomerism can influence the convulsant properties of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) and the anesthetic properties of dichloroethylene. Such isomeric effects may be as useful as those found with optical isomers in defining receptor-anesthetic interactions.

Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties.

UNLABELLED: The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82+/-0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. IMPLICATIONS: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.

Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis.

UNLABELLED: The Meyer-Overton hypothesis predicts that the potency of conventional inhaled anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) x the olive oil/gas partition coefficient equals a constant of approximately 1.82 +/- 0.56 atm (mean +/- SD), whereas MAC x the octanol/gas partition coefficient equals a constant of approximately 2.55 +/- 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC x the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 +/- 0.072 atm) is one-tenth that found for conventional anesthetics, whereas the product for MAC x the octanol/gas partition coefficient (1.72 +/- 1.19) is similar to that for conventional anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC x olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 +/- 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC x the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. IMPLICATIONS: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity--i.e., a greater polarity.

Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms.

UNLABELLED: Some inhaled compounds cause convulsions. To better appreciate the physical basis for this property, we correlated the partial pressures that produced convulsions in rats with the lipophilicity (nonpolarity) and hydrophilicity (polarity) of 45 compounds: 3 n-alkanes, 18 n-haloalkanes, 3 halogenated aromatic compounds, 3 cycloalkanes and 3 halocycloalkanes, 13 halogenated ethers, and 2 noble gases (He and Ne). In most cases, convulsions were quantified by averaging the alveolar partial pressures just below the pressures that caused and slightly higher pressures that did cause clonic convulsions (ED50). The ED50 did not correlate with hydrophilicity (the saline/gas partition coefficient), nor was there an obvious correlation with molecular structure. For 80% of compounds (36 of 45), the ED50 correlated closely (r2 = 0.99) with lipophilicity (the olive oil/gas partition coefficient). Perhaps because they block the effect of GABA on GABA(A) receptors, five compounds were more potent than would be predicted from their lipophilicity. Conversely, four compounds may have been less potent than would be predicted because they (like conventional inhaled anesthetics) enhance the effect of GABA on GABA(A) receptors. IMPLICATIONS: Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. One correlates with lipophilicity (nonpolarity), and the other correlates with an action on GABA(A) receptors.

Rat strain minimally influences anesthetic and convulsant requirements of inhaled compounds in rats.

UNLABELLED: We assessed the effect of rat strain on susceptibility to anesthesia and convulsions produced by inhaled compounds. We determined the minimum alveolar anesthetic concentration (MAC) of desflurane and nitrous oxide, and the convulsive 50% effective dose (ED50) of 1,2-dichlorohexafluorocyclobutane, flurothyl, and difluoromethyl-1-chlorotetrafluoroethyl ether in five strains (three inbred [Long Evans, Sprague-Dawley, and Wistar] and two outbred [Fischer and Brown Norway]). Strain had slight effects on anesthetic potency, the strains with the highest MAC values (Long Evans and Brown Norway) having values < or =28% greater than the strains with the lowest values (Sprague Dawley and Wistar). MAC for nitrous oxide correlated directly with MAC for desflurane as a function of strain. MAC for either desflurane or nitrous oxide correlated inversely with the convulsive ED50 of 1,2-dichlorohexafluorocyclobutane, but correlated poorly (and directly) with the convulsive ED50 of the remaining compounds. Convulsivity varied little as a function of strain (greatest difference 21%) and did not vary consistently as a function of strain. No consistent difference was seen between inbred versus outbred strains. IMPLICATIONS: Rat strain has a minimal effect on the potency of inhaled anesthetics or the convulsant activity of inhaled compounds. It seems that the sites acted on by inhaled compounds to produce anesthesia and convulsions are conserved across common rat strains.

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

UNLABELLED: 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.

Circuit absorption of halothane, isoflurane, and sevoflurane.

UNLABELLED: Uptake of inhaled anesthetics may be measured as the amount of anesthetic infused to maintain a constant alveolar concentration of anesthetic. This method assumes that the patient absorbs all of the infused anesthetic, and that none is lost to circuit components. Using a standard anesthetic circuit with a 3-L rebreathing bag simulating the lungs, and simulating metabolism by input of carbon dioxide, we tested this assumption for halothane, isoflurane, and sevoflurane. Our results suggest that after washin of anesthetic sufficient to eliminate a material difference between inspired and end-tidal anesthetic, washin to other parts of the circuit (probably the ventilator) and absorbent (soda lime) continued to remove anesthetic for up to 15 min. From 30 min to 180 min of anesthetic administration, circuit components absorbed trivial amounts of isoflurane (12 +/- 13 mL vapor at 1.5 minimum alveolar anesthetic concentration, slightly more sevoflurane (39 +/- 15 mL), and still more halothane (64 +/- 9 mL). During this time, absorbent degraded sevoflurane (321 +/- 31 mL absorbed by circuit components and degraded by soda lime). The amount degraded increased with increasing input of carbon dioxide (e.g., the 321 +/- 31 mL increased to 508 +/- 48 mL when carbon dioxide input increased from 250 mL/min to 500 mL/min). Measurement of anesthetic uptake as a function of the amount of anesthetic infused must account for these findings. IMPLICATIONS: Systems that deliver inhaled anesthetics may also remove the anesthetic. Initially, anesthetics may diffuse into delivery components and the interstices of material used to absorb carbon dioxide. Later, absorbents may degrade some anesthetics (e.g., sevoflurane). Such losses may compromise measurements of anesthetic uptake.

Changing from isoflurane to desflurane toward the end of anesthesia does not accelerate recovery in humans.

BACKGROUND: In an attempt to combine the advantage of the lower solubilities of new inhaled anesthetics with the lesser cost of older anesthetics, some clinicians substitute the former for the latter toward the end of anesthesia. The authors tried to determine whether substituting desflurane for isoflurane in the last 30 min of a 120-min anesthetic would accelerate recovery. METHODS: Five volunteers were anesthetized three times for 2 h using a fresh gas inflow of 2 l/min: 1.25 minimum alveolar concentration (MAC) desflurane, 1.25 MAC isoflurane, and 1.25 MAC isoflurane for 90 min followed by 30 min of desflurane concentrations sufficient to achieve a total of 1.25 MAC equivalent ("crossover"). Recovery from anesthesia was assessed by the time to respond to commands, by orientation, and by tests of cognitive function. RESULTS: Compared with isoflurane, the crossover technique did not accelerate early or late recovery (P > 0.05). Recovery from isoflurane or the crossover anesthetic was significantly longer than after desflurane (P < 0.05). Times to response to commands for isoflurane, the crossover anesthetic, and desflurane were 23 +/- 5 min (mean +/- SD), 21 +/- 5 min, and 11 +/- 1 min, respectively, and to orientation the times were 27 +/- 7 min, 25 +/- 5 min, and 13 +/- 2 min, respectively. Cognitive test performance returned to reference values 15-30 min sooner after desflurane than after isoflurane or the crossover anesthetic. Isoflurane cognitive test performance did not differ from that with the crossover anesthetic at any time. CONCLUSIONS: Substituting desflurane for isoflurane during the latter part of anesthesia does not improve recovery, in part because partial rebreathing through a semiclosed circuit limits elimination of isoflurane during the crossover period. Although higher fresh gas flow during the crossover period would speed isoflurane elimination, the amount of desflurane used and, therefore, the cost would increase.

The effect of anesthetic duration on kinetic and recovery characteristics of desflurane versus sevoflurane, and on the kinetic characteristics of compound A, in volunteers.

UNLABELLED: This study documents the differences in kinetics of 2 h (n = 7) and 4 h (n = 9) of 1.25 minimum alveolar anesthetic concentration (MAC) of desflurane (9.0%) versus (on a separate occasion) sevoflurane (3.0%), both administered in a fresh gas inflow of 2 L/min. These data are extensions of our previous 8-h (n = 7) studies of these anesthetics. By 10 min of anesthetic administration, average inspired (F(I)) and end-tidal concentration (F(A)) (F(I)/F(A); the inverse of the more commonly used F(A)/F(I)) decreased to less than 1.15 for both anesthetics, with the difference from 1.0 nearly twice as great for sevoflurane as for desflurane. During all sevoflurane administrations, F(A)/F(I) for Compound A [CH2F-O-C(=CF2) (CF3); a vinyl ether resulting from the degradation of sevoflurane by Baralyme] equaled approximately 0.8, and the average inspired concentration equaled approximately 40 ppm. Compound A is of interest because at approximately 150 ppm-h, it can induce biochemical and histological evidence of glomerular and tubular injury in rats and humans. During elimination, F(A)/F(A0) for Compound A (F(A0) is the last end-tidal concentration during anesthetic administration) decreased abruptly to 0 after 2 h and 4 h of anesthesia and to approximately 0.1 (F(A) approximately 3 ppm) after 8 h of anesthesia. In contrast, F(A)/F(A0) for desflurane and sevoflurane decreased in a conventional, multiexponential manner, the decrease being increasingly delayed with increasing duration of anesthetic administration. F(A)/F(A0) for sevoflurane exceeded that for desflurane for any given duration of anesthesia, and objective and subjective measures indicated a faster recovery with desflurane. Times (mean +/- SD) to initial response to command (2 h 10.9 +/- 1.2 vs 17.8 +/- 5.1 min, 4 h 11.3 +/- 2.1 vs 20.8 +/- 4.8 min, 8 h 14 +/- 4 vs 28 +/- 8 min) and orientation (2 h 12.7 +/- 1.6 vs 21.2 +/- 4.6 min, 4 h 14.8 +/- 3.1 vs 25.3 +/- 6.5 min, 8 h 19 +/- 4 vs 33 +/- 9 min) were shorter with desflurane. Recovery as defined by the digit symbol substitution test, P-deletion test, and Trieger test results was more rapid with desflurane. The incidence of vomiting was greater with sevoflurane after 8 h of anesthesia but not after shorter durations. We conclude that for each anesthetic duration, F(I) more closely approximates F(A) with desflurane during anesthetic administration, F(A)/F(A0) decreases more rapidly after anesthesia with desflurane, and objective measures indicate more rapid recovery with desflurane. Finally, it seems that after 2-h and 4-h administrations, all Compound A taken up is bound within the body. IMPLICATIONS: Regardless of the duration of anesthesia, elimination is faster and recovery is quicker for the inhaled anesthetic desflurane than for the inhaled anesthetic sevoflurane. The toxic degradation product of sevoflurane, Compound A, seems to bind irreversibly to proteins in the body.

Ventilatory effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) in swine.

UNLABELLED: Nonimmobilizers (inhaled compounds that do not suppress movement in response to a noxious stimulus) resemble anesthetics in their capacity to suppress memory, but unlike anesthetics, they can cause convulsions. Higher concentrations of nonimmobilizers may cause death, even with apparent suppression of convulsions by the concurrent administration of conventional inhaled anesthetics. We hypothesized that nonimmobilizers can depress ventilation and can cause death by adding to the depression of ventilation produced by conventional anesthetics. To test these hypotheses, we administered 1,2-dichlorohexafluorocyclobutane (2N) to four pigs anesthetized with desflurane. The addition of 2N decreased PaCO2 and tended to increase the slope of the ventilatory response to imposed increases in PETCO2. Limited results from study of two other nonimmobilizers (2,3-dichlorooctafluorobutane and perfluoropentane), in two pigs each, were consistent with the findings for 2N. However, experimental limitations (e.g., toxicity of 2,3-dichlorooctafluorobutane, and hypoxia from perfluoropentane) confound interpretation of these latter results. Our findings do not support our hypotheses--2N (and presumably all nonimmobilizers) seems to be a respiratory stimulant, not a depressant. IMPLICATIONS: A new class of inhaled compounds, nonimmobilizers, allow tests of how inhaled anesthetics act. Nonimmobilizers may act like anesthetics (e.g., impair learning) or may not (e.g., do not prevent movement in response to a noxious stimulus). The present work shows that, unlike anesthetics,nonimmobilizers do not depress breathing.

Enhanced choline acetyltransferase activity does not explain the action of inhaled convulsants.

Enhancement of choline acetyltransferase (ChAT) activity and increased intraneuronal acetylcholine (ACh) may explain the convulsant activity of some inhaled compounds. Enflurane, for example, enhances such activity. Accordingly, we measured choline acetyltransferase (ChAT) activity in rat cortical synaptosomes in the presence of two inhaled convulsants, flurothyl (CF3CH2OCH2CF3) and 1,2-dichlorohexafluorocyclobutane at partial pressures below and greatly exceeding those which produce convulsions in vivo. Neither agent changed the kinetic parameters, maximum velocity (vmax) or Michaelis constant (Km). The vmax for controls in the flurothyl series was 016 (0.06) nmol mg-1 min-1 and the Km was 0.23 (0.11) mmol litre-1. For the 1,2-dichlorohexafluorocyclobutane series of experiments the results for the controls were vmax 0.23 (0.10) nmol mg-1 min-1 and Km 0.20 (0.08) mmol litre-1. Modification of ChAT activity did not contribute to the excitatory effects of these agents.

Acute hypovolemia may cause segmental wall motion abnormalities in the absence of myocardial ischemia.

UNLABELLED: New segmental wall motion abnormalities (SWMA) detected by echocardiography are considered sensitive and specific markers of myocardial ischemia. However, we have observed new SWMA during pacing-induced reductions in left ventricular filling, which resolved immediately with cessation of the atrial pacing and simultaneous restoration of filling. Therefore, we designed this study to determine whether acute reduction in filling can induce new SWMA in the absence of ischemia. Institution of cardiopulmonary bypass was used as a clinical model of acute reduction in filling, and a beat-by-beat analysis of left ventricular contraction, filling, blood pressures, and electrocardiogram was performed when the drainage of blood to the cardiopulmonary bypass machine rapidly emptied the heart. Acute reduction in filling induced new SWMA in 4 of 38 study patients. All 4 patients had preexisting abnormalities of left ventricular contraction, but translocation of these preexisting SWMA did not explain the new SWMA, nor did myocardial ischemia. We conclude that acute reduction in left ventricular filling can cause new SWMA in the absence of ischemia. This finding limits the usefulness of new SWMA as a marker of ischemia in the presence of acute reduction in filling, such as that secondary to severe hypovolemia. IMPLICATIONS: This study documented that acute reduction in cardiac filling can be associated with new systolic wall motion abnormalities detected by transesophageal echocardiography in the absence of documented myocardial ischemia. These findings indicate that segmental wall motion may not be a valid marker for ischemia in the setting of acute hypovolemia.

Dehydration of Baralyme increases compound A resulting from sevoflurane degradation in a standard anesthetic circuit used to anesthetize swine.

UNLABELLED: In a model anesthetic circuit, dehydration of Baralyme brand carbon dioxide absorbent increases degradation of sevoflurane to CF2=C(CF3)OCH2F, a nephrotoxic vinyl ether called Compound A. In the present study, we quantified this increase using "conditioned" Baralyme in a circle absorbent system to deliver sevoflurane anesthesia to swine. Mimicking continuing oxygen delivery for 2 days after completion of an anesthetic, we directed a conditioning fresh gas flow of 5 L/min retrograde through fresh absorbent in situ in a standard absorbent system for 40 h. The conditioned absorbent was subsequently used (without mixing of the granules) in a standard anesthetic circuit to deliver sevoflurane to swine weighing 78 +/- 2 kg. The initial inflow rate of fresh gas flow was set at 10 L/min with the vaporizer at 8% to achieve the target end-tidal concentration of 3.0%-3.2% sevoflurane in approximately 20 min. The flow was later decreased to 2 L/min, and the vaporizer concentration was decreased to sustain the 3.0%-3.2% value for a total of 2 h (three pigs) or 4 h (eight pigs). Inspired Compound A increased over the first 30 +/- 60 min to a peak concentration of 357 +/- 49 ppm (mean +/- SD), slowly decreasing thereafter to 74 +/- 6 ppm at 4 h. The average concentration over 2 h was 208 +/- 25 ppm, and the average concentration over 4 h was 153 +/- 19 ppm. Pigs were killed 1 or 4 days after anesthesia. The kidneys from pigs anesthetized for both 2 h and 4 h showed mild inflammation but little or no tubular necrosis. These results suggest that dehydration of Baralyme may produce concentrations of Compound A that would have nephrotoxic effects in humans in a shorter time than would be the case with normally hydrated Baralyme. IMPLICATIONS: The vapor known as Compound A can injure the kidney. Dehydration of Baralyme, a standard absorbent of carbon dioxide in inhaled anesthetic delivery systems, can cause a 5- to 10-fold increase in Compound A concentrations produced from the inhaled anesthetic, sevoflurane, given at anesthetizing concentrations in a conventional anesthetic system.

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

UNLABELLED: 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 CF3CCl2-O-CF2Cl (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 ED50 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.

Dose-related biochemical markers of renal injury after sevoflurane versus desflurane anesthesia in volunteers.

UNLABELLED: Sevoflurane (CH2F-O-CH[CF3]2) reacts with carbon dioxide absorbents to produce Compound A (CH2F-O-C[=CF2][CF3]). Because of concern about the potential nephrotoxicity of Compound A, the United States package label (but not that of several other countries) for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more. We previously demonstrated in humans that a 2-L/min flow rate delivery of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane for 8 h can injure glomeruli (i.e., produce albuminuria) and proximal tubules (i.e., produce glucosuria and urinary excretion of alpha-glutathione-S-transferase [alpha-GST]). The present report extends this investigation to fasting volunteers given 4 h (n = 9) or 2 h (n = 7) of 1.25 MAC sevoflurane versus desflurane at 2 L/min via a standard circle absorber anesthetic system (all subjects given both anesthetics). Markers of renal injury (urinary creatinine, albumin, glucose, alpha-GST, and blood urea nitrogen) did not reveal significant injury after anesthesia with desflurane. Sevoflurane degradation with a 2-L/min fresh gas inflow rate produced average inspired concentrations of Compound A of 40 +/- 4 ppm (mean +/- SD, 8-h exposure [data from previous study]), 42 +/- 2 ppm (4 h), and 40 +/- 5 ppm (2 h). Relative to desflurane, sevoflurane given for 4 h caused statistically significant transient injury to glomeruli (slightly increased urinary albumin and serum creatinine) and to proximal tubules (increased urinary alpha-GST). Other measures of injury did not differ significantly between anesthetics. Neither anesthetic given for 2 h at 1.25 MAC produced injury. We conclude that 1.25 MAC sevoflurane plus Compound A produces dose-related glomerular and tubular injury with a threshold between 80 and 168 ppm/h of exposure to Compound A. This threshold for renal injury in normal humans approximates that found previously in normal rats. IMPLICATIONS: Human (and rat) kidneys are injured by a reactive compound (Compound A) produced by degradation of the clinical inhaled anesthetic, sevoflurane. Injury increases with increasing duration of exposure to a given concentration of Compound A. The response to Compound A has several implications, as discussed in the article.

Quantitative differences in the production and toxicity of CF2=BrCl versus CH2F-O-C(=CF2)(CF3) (compound A): the safety of halothane does not indicate the safety of sevoflurane.

UNLABELLED: Carbon dioxide absorbents degrade both halothane and sevoflurane to toxic unsaturated compounds (CF2=CBrCl and CH2F-O-C[=CF2][CF3] [i.e., Compound A], respectively). Given the long history of safe administration of halothane, comparable toxicities of these degradation products would imply a similar safety of sevoflurane. We therefore examined CF2=CBrCl in the context of four issues relevant to previous studies of the toxicity of Compound A: 1) reactivity of the degradation product in vitro; 2) rate of its production in vitro; 3) its in vivo toxicity; 4) importance of the beta-lyase pathway to the toxicity in vivo. We found the following. 1) CF2=CBrCl is less reactive than Compound A, degrading in human serum albumin at one-fifth the rate of Compound A. 2) Over a 3-h period of "anesthesia," a standard circle system containing Baralyme (Allied Healthcare Products, Inc., St. Louis, MO) produces 30 times as much Compound A from a minimum alveolar anesthetic concentration (MAC) concentration of sevoflurane as CF2=CBrCl from a MAC concentration of halothane; with soda lime, the difference is 60-fold. Correcting for differences in uptake of halothane versus sevoflurane decreases the differences to 20-40 times. 3) For a 3-h administration to rats, the partial pressure of Compound A causing minimal renal injury or necrosis of half the affected tubule cells exceeds the partial pressure of CF2=CBrCl causing minimal injury or necrosis of half the affected tubule cells by a factor of approximately 4-6. Thus, the ratio of production (Item 2 above) to the partial pressure causing injury with CF2=CBrCl is approximately a quarter of that ratio for Compound A. 4) Compounds that block the beta-lyase pathway either do not change (acivicin) or decrease (aminooxyacetic acid; AOAA) renal injury from CF2=CBrCl in rats, whereas these compounds increase (acivicin) or do not change (AOAA) injury from Compound A. We conclude that the safety of halothane cannot be used to support the safety of sevoflurane. IMPLICATIONS: Carbon dioxide absorbents degrade halothane and sevoflurane to unsaturated compounds nephrotoxic to rats. Relative to sevoflurane's degradation product, halothane's degradation product has less toxicity relative to production, less reactivity, and a different mechanism of injury. The clinical absence of halothane nephrotoxicity does not necessarily indicate a similar absence for sevoflurane.

Baralyme dehydration increases and soda lime dehydration decreases the concentration of compound A resulting from sevoflurane degradation in a standard anesthetic circuit.

UNLABELLED: Soda lime and Baralyme brand carbon dioxide absorbents degrade sevoflurane to CF2 = C(CF3)OCH2F, a potentially nephrotoxic vinyl ether called Compound A. Dehydration of these absorbents increases both the degradation of sevoflurane to Compound A and the degradation of Compound A. The balance between sevoflurane degradation and Compound A degradation determines the concentration of Compound A issuing from the absorbent (the net production of Compound A). We studied the effect of dehydration on the net production of Compound A in a simulated anesthetic circuit. Mimicking continuing oxygen delivery for 1, 2, or 3 days after completion of an anesthetic, we directed a "conditioning" fresh gas flow of 5 L/min or 10 L/min retrograde through fresh absorbent in situ in a standard absorbent system for 16, 40, and/or 64 h. The conditioned absorbent was subsequently used (without mixing of the granules) in a standard anesthetic circuit in which a 3-L rebreathing bag substituted for the lung. Metabolism was mimicked by introducing 250 mL/min carbon dioxide into the "lung," and the lung was ventilated with a minute ventilation of 10 L/ min. At the same time, we introduced sevoflurane in a fresh gas inflow of 2 L/min at a concentration sufficient to produce an inspired concentration of 3.2%. Because of increased sevoflurane destruction by the absorbent, progressively longer periods of conditioning (dehydration) and/or higher inflow rates increased the delivered (vaporizer) concentration of sevoflurane required to sustain a 3.2% concentration. Dehydration of Baralyme increased the inspired concentration of Compound A by up to sevenfold, whereas dehydration of soda lime markedly decreased the inspired concentration of Compound A. IMPLICATIONS: Economical delivery of modern inhaled anesthetics requires rebreathing of exhaled gases after removal of carbon dioxide. However, carbon dioxide absorbents (Baralyme/soda lime) may degrade anesthetics to toxic substances. Baralyme dehydration increases, and soda lime dehydration decreases, degradation of the inhaled anesthetic sevoflurane to the toxic substance, Compound A.

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 [CH2F-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 (F(I)) and end-tidal (F(A)) concentrations of anesthetic and compound A were measured during administration, and F(A) relative to F(A0) (the last end-tidal concentration during administration) during elimination. The indices of recovery were also measured. RESULTS: The ratio F(I)/F(A) rapidly approached 1.0, with values greater for sevoflurane (desflurane 1.06 +/- 0.01 vs. sevoflurane 1.11 +/- 0.02, mean +/- SD). The ratio F(A)/F(I) for compound A was approximately 0.8. The F(A)/F(A0) 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 F(A)/F(A0) ratio for compound A decreased within 5 min to a constant value of 0.1. CONCLUSIONS: These anesthetics have kinetics consistent with their solubilities. Sevoflurane's greater biodegradation probably increases F(I)/F(A) differences during anesthetic administration and decreases F(A)/F(A0) differences during elimination. The F(A) for compound A differs from F(I) by 20% (F(A)/F(I) = 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.

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.

Minimum alveolar anesthetic concentration values for the enantiomers of isoflurane differ minimally.

Results of in vivo and in vitro studies of the anesthetic potencies of the enantiomers (optical isomers) of isoflurane provide various results ranging from no difference to differences of nearly two fold. A finding of a difference in anesthetic requirement in the whole animal has particular relevance to theories of anesthetic mechanisms of action because it suggests that anesthesia may result from a specific anesthetic-receptor interaction. This led to our decision to redetermine the minimum alveolar anesthetic concentration (MAC) of (+)-S and (-)-R enantiomers of isoflurane in 12 Sprague-Dawley rats (six per group). The (+)-S enantiomer gave a MAC of 0.0144 +/- 0.0012 atm (i.e., 1.44% +/- 0.12% at 1 atm pressure; mean +/- SD) and the (-)-R enantiomer gave a MAC of 0.0169 +/- 0.0020 atm. Although the 17% greater value for the (-)-R enantiomer is qualitatively consistent with previous results the difference is not significant (P = 0.06), and the absolute difference is smaller than that found by a previous study. However, given the small sample size, our power to define a small significant difference is limited. Regardless of statistical significance, our results do not confirm the conclusion that interaction with a specific receptor is important to the mechanism of action of inhaled anesthetics.