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.

Effects of acupuncture on the oxygenation of cerebral tissue.

Monitoring of regional cerebral oxygen saturation (r. cereb. O2 satn.) was carried out continuously in 12 healthy subjects (mean age 35.2 +/- 4.4 years; range 26-41 years; 4 women, 8 men), prior to, during and following acupuncture. Measurements were obtained with the INVOS 3100 cerebral oximeter (Somanetics Corp., Troy, USA). In addition new robotic transcranial Doppler sonography (TCD) probes enabling three-dimensional imaging of the middle cerebral artery by the use of multi-scan techniques were used simultaneously. The results showed small increases in r. cereb. O2 satn. mean values (69.9% before, 70.3% during and 70.2% after acupuncture) and a significant (p < 0.01; ANOVA, Tukey test) increase in mean bloodflow velocity during acupuncture measured simultaneously at different depths within the right middle cerebral artery. There are reports in the literature about the effects of acupuncture on the oxygenation of cerebral tissue in a study with animals. An increase in the cerebral oxygen saturation could be registered with the help of microelectrodes in the cortex. This is parallel evidence to the present results with near infrared spectroscopy and transcranial Doppler sonography. Quantifiable changes in the physiological effects of acupuncture may contribute to improved acceptance of this unconventional complementary medical procedure.

Compound A: solubility in saline and olive oil; destruction by blood.

Compound A is a degradation product of sevoflurane. Knowledge of the solubility of Compound A, CH2F-O-C(=CF2)(CF3), in blood and other solvents would aid in the definition of its kinetics. Accordingly, we determined solvent/gas partition coefficients of Compound A for saline (0.166 +/- 0.002 [mean +/- SD; n = 4]) and olive oil (20.1 +/- 1.1 [n = 4]). Measurement of solubility in blood was confounded by degradation of Compound A in blood and blood components. If a mixture of 99.3% saline and 0.7% oil provides the solubility equivalent to that possessed by blood (as it does for the parent compound, sevoflurane), then blood solubility and solubility in plasma, albumin, red blood cells, or pure hemoglobin is approximately 0.31. The order of Compound A degradation was human plasma = rat blood > whole human blood >5% human serum albumin = washed human red blood cells (hematocrit 50%) = 5% pure hemoglobin. Presuming a solvent/gas partition coefficient of 0.31, respective approximate times for 50% degradation equaled 2.7, 2.8, 4.6, 9.9, 11.0, and 12 min. The accuracy of these approximations was limited by the need to estimate, rather than determine, the solubility of Compound A in such solvents. Pasteurization (heating to 60 degrees C for 12 h) or pretreatment with N-ethylmaleimide (a compound that reversibly binds to sulfhydryl groups) decreased the degradation rate in plasma. These results suggest that degradation arises, at least in part, from reaction of Compound A with proteins in blood, possibly from covalent reaction of Compound A with protein and/or from an enzymatically mediated reaction. The products of degradation, the binding sites, and the clinical implications of such binding and degradation remain to be determined.

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.

Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis.

Neither lipophilicity nor vapor pressure of larger n-alkanes appear to correlate with their anesthetizing partial pressures in inspired gas. Such results suggest that the Meyer-Overton hypothesis and Ferguson's rule may not apply to these compounds. An alternative explanation might be that a large difference in inspired-to-arterial partial pressure exists, i.e., that the inspired partial pressure misrepresents the effective partial pressure. To test this explanation, we investigated the kinetics of five consecutive even-numbered n-alkanes (C2H6 to C10H22) in rats. The ratio of end-tidal-to-inspired (PA/PI), arterial-to-end-tidal (Pa/PA), and arterial-to-inspired (Pa/PI) partial pressures decreased with increasing carbon chain length, consistent with our separate finding that blood solubility increased. Using Pa/PI and the minimum inspired concentration (MIC) obtained previously, we calculated the true effective potency, minimum alveolar anesthetic concentration (MAC); of these n-alkanes as (Pa/PI)(MIC). This markedly improved, but did not perfectly correct, the correlation of MAC with lipid solubility (the Meyer-Overton hypothesis) and vapor pressure (Ferguson's rule). A coefficient of variation of 76.7% was found for the product of MAC and the olive oil/gas partition coefficient. More importantly, the correlation of the logarithm of MAC and oil solubility had a slope of -0.724 (i.e., deviated from -1.0), whereas the slope for eight conventional anesthetics was -1.046 (approached-1.0). These data imply that olive oil does not adequately mimic the nature of the anesthetic site of action of n-alkanes.

Anesthesia by n-alkanes not consistent with the Meyer-Overton hypothesis: determinations of the solubilities of alkanes in saline and various lipids.

Because deviations from the Meyer-Overton rule may provide insights into the attributes of the anesthetic site of action, we characterized the solubility of the n-alkanes in various hydrophobic solvents (n-tetradecane, olive oil, n-octanol, and lecithin) as well as saline using variations on standard techniques. Increasing alkane chain length correlated with a decrease in solubility in saline and an increase in solubility in the hydrophobic solvents. The product of solubility in the hydrophobic solvents x the partial pressure (in atmospheres) required to produce anesthesia (i.e., the Meyer-Overton rule) did not produce a constant for any one of these solvents. The means and standard deviations for the products were: tetradecane, 65 +/- 103; olive oil, 33 +/- 63; n-octanol, 64 +/- 129; and lecithin, 16 +/- 26. Thus, our data suggest that the n-alkanes (especially those longer than n-heptane) do not follow the Meyer-Overton rule.

The neuromuscular effects of desflurane, alone and combined with pancuronium or succinylcholine in humans.

The neuromuscular effects of desflurane administered alone were studied in ten healthy human volunteers aged 20-27 yr. Also, the dose-response relationships of pancuronium and succinylcholine in surgical patients during anesthesia with desflurane (n = 13) were compared to those during isoflurane anesthesia (n = 14). In the volunteers, we measured the mechanical response of the adductor pollicis muscle to stimulation of the ulnar nerve in a train-of-four (TOF) sequence at 2 Hz and at tetanic frequencies of 50, 100, and 200 Hz, each administered for 5 s. Amplitudes of the first response (T1) in each TOF sequence and the ratios of the fourth TOF response (T4) to the first were similar at 3, 6, and 9% desflurane and decreased significantly only at 12% (P less than 0.05). Desflurane concentrations of 3-12% caused tetanic fade (greater than 10% decrement in amplitude) at 50, 100, and 200 Hz. The addition of N2O and the duration of anesthetic exposure did not alter desflurane's neuromuscular effects. The only neuromuscular variable influenced by CO2 was T1 amplitude, which decreased as arterial CO2 tension (PaCO2) increased. The doses of pancuronium that depressed T1 amplitude by 50% (ED50) were similar during anesthesia with 1.25 MAC desflurane, 10.5 +/- 2.8 micrograms/kg (mean +/- SD) and 1.25 MAC isoflurane, 12.3 +/- 5.0 micrograms/kg. The ED50 doses of succinylcholine were similar during anesthesia with desflurane 132 +/- 76 micrograms/kg and isoflurane 123 +/- 36 micrograms/kg. We conclude that desflurane significantly depresses neuromuscular function and augments the action of pancuronium and succinylcholine to a degree similar to that of isoflurane.

Is chronic ethanol consumption associated with tolerance to intrathecal lidocaine in the rat?

Intoxication with alcohols can produce anesthesia. In contrast, chronic ethanol consumption can produce tolerance to inhaled and other general anesthetics. We tested whether ongoing consumption decreased, and whether withdrawal from such consumption increased, the intrathecal dose of lidocaine that induces sensory and motor blockade in female Sprague-Dawley rats. Sensory blockade was assessed using the tail-flick test, and motor blockade by the animal's inability to move its hind limbs. Rats were tested before commencing ethanol intake; during ethanol ingestion (9 days after beginning ingestion); and on the 15th day of ingestion, 14 h after withdrawing ethanol from their diet. Pair-fed control rats were tested at the same intervals. Ongoing administration of ethanol decreased the dose of lidocaine required to produce sensory blockade, but this difference was not significant relative to the control group (i.e., the difference was significant within group but not across groups). Withdrawal of ethanol increased the dose requirements for sensory and motor blockade by 80% and 53% (P less than 0.01 and P less than 0.0001) and decreased the duration of the motor blockade (P less than 0.01). Dose requirements producing sensory block differed between alcoholic and control groups (P less than 0.0001). These results suggest that chronic ethanol intake produces tolerance to the local anesthetic effects of lidocaine. Whether this change results from a change in kinetics or in sensitivity is not known, but the latter would seem more likely, because duration of blockade was minimally affected or unaffected.

Partition coefficients of I-653 in human blood, saline, and olive oil.

The purpose of this study was to determine partition coefficients for a new, inhaled anesthetic, I-653. Blood samples were taken from 11 patients scheduled for elective surgery who were ASA physical status I-III and ranged in age from 25 to 76 yr. At 37 degrees C, we found a blood/gas partition coefficient of 0.424 +/- 0.024 (mean +/- SD); a saline/gas partition coefficient of 0.225 +/- 0.002; and an oil/gas partition coefficient of 18.7 +/- 1.1. These values indicate that I-653 will have a minimum alveolar concentration (MAC) required for anesthesia that is four to five times that of isoflurane and that I-653 will produce a rapid induction of and recovery from anesthesia.

Partition coefficients for sevoflurane in human blood, saline, and olive oil.

The purpose of this study was to determine partition coefficients for a new, rapid-acting inhaled anesthetic, sevoflurane. Blood samples were taken from 19 ASA physical status I-III patients ranging in age from 21 to 77 yr who were scheduled for elective surgery. At 37 degrees C, we found a blood/gas partition coefficient of 0.686 +/- 0.047 (mean +/- SD), a saline/gas partition coefficient of 0.370 +/- 0.016; and an oil/gas partition coefficient of 47.2 +/- 2.7. These values are consistent with the clinical observation that sevoflurane is a potent inhaled anesthetic that produces a rapid induction of and recovery from anesthesia.

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 gran 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.