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.

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) x 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.

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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.

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.

Present package labeling for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more when delivering anesthesia with sevoflurane. This recommendation resulted from a concern about the potential nephrotoxicity of a degradation product of sevoflurane, "Compound A," produced by the action of carbon dioxide absorbents on sevoflurane. To assess the adequacy of this recommendation, we compared the nephrotoxicity of 8 h of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane (n = 10) versus desflurane (n = 9) in fluid-restricted (i.e., nothing by mouth overnight) volunteers when the anesthetic was given in a standard circle absorber anesthetic system at 2 L/min. Subjects were tested for markers of renal injury (urinary albumin, glucose, alpha-glutathione-S-transferase [GST], and pi-GST; and serum creatinine and blood urea nitrogen [BUN]) before and 1, 2, 3, and/or 5-7 days after anesthesia. Desflurane did not produce renal injury. Rebreathing of sevoflurane produced average inspired concentrations of Compound A of 41 +/- 3 ppm (mean +/- SD). Sevoflurane was associated with transient injury to: 1) the glomerulus, as revealed by postanesthetic albuminuria; 2) the proximal tubule, as revealed by postanesthetic glucosuria and increased urinary alpha-GST; and 3) the distal tubule, as revealed by postanesthetic increased urinary pi-GST. These effects varied greatly (e.g., on postanesthesia Day 3, the 24-h albumin excretion was < 0.03 g (normal) for one volunteer; 0.03-1 g for five others; 1-2 g for two others; 2.1 g for one volunteer; and 4.4 g for another volunteer). Neither anesthetic affected serum creatinine or BUN, nor changed the ability of the kidney to concentrate urine in response to vasopressin, 5 U/70 kg subcutaneously (i.e., these measures failed to reveal the injury produced). In addition, sevoflurane, but not desflurane, caused small postanesthetic increases in serum alanine aminotransferase (ALT), suggesting mild, transient hepatic injury.

This paper compares the conductance induced by bath-applied acetyl-choline (ACh) and by the same transmitter released from nerve terminals at Electrophorus electroplaques. For the former case, dose-response relations are characterized by the maximal agonist-induced conductance, rgamma (130 mmho/cm2), and by the concentration which induces half this conductance; this concentration is termed Kapp and equals 50 micron at -85 mV. For the latter case, neurally evoked postsynaptic currents (PSCs) are characterized by the peak conductance during strongly facilitated release, gPSC, and by the rate constant for decay, alpha. Since gPSC roughly equals rgamma, it is concluded that the PSC activates nearly all available receptor channels. These and other data agree with recent estimates that during the growth phase of the quantal response, (a) the ACh concentration is at least several hundred micromolar; and (b) most nearby channels are activated. However both alpha and Kapp increase during depolarization, at a rate of about e-fold per 86 mV. These observations on voltage sensitivity suggest that a suprathreshold synaptic event is rapidly terminated because the action potential abruptly releases ACh molecules from receptors.

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.