Donald D. Koblin

Polyhalogenated and perfluorinated compounds that disobey the meyer-overton hypothesis

Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.

What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs ?

The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% ± 0.24% (mean ± standard deviation) and 7.71% ± 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) × solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (−1.04 ± 0.07) for lecithin, but a slope differing from unity for benzene (−0.82 ± 0.05) and olive oil (−0.87 ± 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.

Hypothesis: Inhaled Anesthetics Produce Immobility and Amnesia by Different Mechanisms at Different Sites

Recent evidence supplies new insights regarding the two universal effects of inhaled anesthetics: 1) immobility in response to a noxious stimulus and 2) amnesia. We hypothesize that these two effects result from actions at separate molecular and anatomic sites and that they are produced by different mechanisms. We propose that inhaled anesthetics cause immobility in response to noxious stimuli by an action in the spinal cord at an interface between polar and nonpolar regions. Such a site might be an interfacial region adjacent to membranes or proteins. In contrast, we propose that production of amnesia occurs at a supraspinal site and occurs in a nonpolar environment. An example of such a nonpolar site could be the interior of a phospholipid bilayer or a hydrophobic pocket within a protein.

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)

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

Sevoflurane (CH2 F-O-CH[CF3]2) reacts with carbon dioxide absorbents to produce Compound A (CH2 F-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. (Anesth Analg 1997;85:1154-63)

FLUORIDE METABOLITES AFTER PROLONGED EXPOSURE OF VOLUNTEERS AND PATIENTS TO DESFLURANE

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

The Effect of Anesthetic Duration on Kinetic and Recovery Characteristics of Desflurane Versus Sevoflurane, and on the Kinetic Characteristics of Compound A, in Volunteers

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 (FA) (FI/FA; the inverse of the more commonly used FA/FI) 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, FA/FI for Compound A [CH2 F-O-C(=CF2) (CF3); a vinyl ether resulting from the degradation of sevoflurane by Baralyme[registered sign]] 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, FA/FA0 for Compound A (FA0 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 (FA approximately 3 ppm) after 8 h of anesthesia. In contrast, FA/FA0 for desflurane and sevoflurane decreased in a conventional, multiexponential manner, the decrease being increasingly delayed with increasing duration of anesthetic administration. FA/FA0 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, FI more closely approximates FA with desflurane during anesthetic administration, FA/FA0 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. (Anesth Analg 1998;86:414-21)

Humans Anesthetized with Sevoflurane or Isoflurane Have Similar Arrhythmic Response to Epinephrine

BackgroundAnesthetics can alter the dose of exogenously administered epinephrine that causes cardiac arrhythmias. The purpose of this study was to test the hypothesis that in humans anesthetized with sevoflurane, the arrhythmic response to epinephrine is not different from the response in humans anesthetized with isoflurane. MethodsWe determined the arrhythmogenicity of submucosally administered epinephrine in 40 ASA physical status 1 or 2 patients who were to undergo transsphenoidal surgery. Patients were assigned randomly to be given 1.0–1.3 minimum alveolar concentration sevoflurane or isoflurane. A surgeon, blinded to the anesthetic and the concentration of epinephrine, injected into the nasal submucosa epinephrine 10, 13.3, or 20 μg/ml in saline of volume sufficient for surgical need. We defined a “positive” response as three or more premature ventricular contractions within 5 min after initiation of injection. Responses between anesthetic groups within each dose range of epinephrine were compared by chi-squared analysis. ResultsNo patient given either anesthetic developed premature ventricular contractions with doses of epinephrine less than 5 μg/kg. At larger doses of epinephrine (5–9.9 and 10–14.9 μg/kg), the frequency of arrhythmias did not differ between patients given sevoflurane and patients given isoflurane. Patients anesthetized with 1.2 minimum alveolar concentration sevoflurane had blood pressure similar to and heart rate less than those of patients anesthetized with similar concentrations of isoflurane. Blood pressure and heart rate were increased similarly in both groups after laryngoscopy and tracheal intubation and after epinephrine injection. ConclusionsSevoflurane and isoflurane do not differ in their sensitization of the human myocardium to the arrhythmogenic effect of exogenously administered epinephrine.

Nitrous oxide inactivates methionine synthetase in human liver.

Activity of methionine synthetase was measured in liver biopsies of seven patients who had received 50% to 70% nitrous oxide supplemented by a combination of a narcotic and/or barbiturate with or without a volatile anesthetic, and from seven patients who were anesthetized without nitrous oxide (control group). Methionine synthetase activity (±SE) averaged 219 ± 28 nmol of methionine per hour per gram of liver in patients given nitrous oxide, and 414 29 in control patients. Inactivation of methionine synthetase progressively increased as the product of the concentration of nitrous oxide and the exposure time increased. These results in humans are similar to those in animals and suggest that inactivation of methionine synthetase may play a role in the development of the pathologic effects seen in patients and medical personnel after exposure to nitrous oxide.

Inactivation of Methionine Synthetase by Nitrous Oxide in Mice

To characterize the nitrous oxide-induced inhibition of the enzyme, methionine synthetase, we measured enzyme inactivation as a function of nitrous oxide concentration and exposure time. Mice exposed to 0.8 atm nitrous oxide exhibited more than a 50 per cent decrease in liver methionine synthetase activity within 30 min, and activity dropped to 5–25 per cent of the original value after a 4-hour exposure. Although 4-hour exposures to low nitrous oxide partial pressures (less than 0.05 atm) did not significantly alter methionine synthetase activity, higher concentrations of nitrous oxide caused a progressive inhibition over this time period. Continuous exposure to trace levels of nitrous oxide (approximately 1100 ppm) for eight to 22 days produced a small but significant reduction in liver and brain methionine synthetase activity. Methionine synthetase activity returned to control levels two to four days following inactivation. Other anesthetics (xenon, halothane, isoflurane, enflurane) did not produce inactivation.