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ANESTHETIC PHARMACOLOGY

Solubility of Volatile Anesthetics in Bovine White Matter, Cortical Gray Matter, Thalamus, Hippocampus, and Hypothalamic Area

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Address correspondence to Edmond I Eger, MD, Box 0464, University of California, San Francisco, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu.

	Abstract

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Although known for whole brain, values are lacking for solubilities of modern volatile anesthetics in specific brain regions. Some regions should differ from others (e.g., gray matter versus white matter) because they differ in lipid content and because potent inhaled anesthetics are lipophilic. In the present report, we examined this issue in bovine brain, finding that white matter/gas partition coefficients are 1.6 (desflurane) to 2.4 (halothane) times larger than gray matter/gas partition coefficients, with values for isoflurane and sevoflurane lying between these at 1.9. Values for thalamus/gas, hypothalamic area/gas, and hippocampal/gas partition coefficients lie between those for gray and white matter. These data may be useful in defining the parts of the brain involved with return to consciousness during recovery from anesthesia.

	Introduction

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The elimination of anesthetic determines rapidity of awakening after anesthesia, and thus is more rapid with less soluble compounds. For example, elimination (defined by the descent of F_A/F_A0 where F_A is the alveolar concentration and F_A0 is the alveolar concentration at the end of anesthesia) of desflurane is more rapid than elimination of sevoflurane (1,2) or isoflurane (3) and the difference is consistent with a more rapid recovery (as defined by response to command, orientation, or return of judgment-cognition) after anesthesia with desflurane than with sevoflurane (1,4,5) or isoflurane (6,7), and more rapid after sevoflurane than after isoflurane (8,9).

Response to command first occurs after anesthesia with each of these drugs at a smaller end-tidal concentration than MAC_awake (the steady-state alveolar [end-tidal] concentration at which 50% of subjects respond appropriately to command). For desflurane, sevoflurane, and isoflurane, MAC_awake equals approximately a third of MAC (10,11). Because the anesthetic partial pressure in the brain lags behind that in the lungs during washout, in the period of anesthetic elimination after 2 h at 1.25 MAC, response to command occurs at alveolar concentrations considerably less than a third of MAC: 0.126 MAC desflurane, 0.141 MAC sevoflurane, and 0.166 MAC isoflurane. Part or all of the discrepancy may be attributable to the delay imposed by the need to eliminate anesthetic from the brain. Such elimination is a function of blood flow to the brain, the solubility of anesthetic in the brain, and, possibly, to intertissue diffusion from an inactive site of higher solubility (for example, white matter) to a site involved in anesthetic action (for example, cortical gray matter or nuclei).

In the present study, we tested whether solubility differences among anesthetics for whole brain exist proportionately for gray and white matter. The difference is of interest because of the possibility (indicated in the preceding paragraph) that white matter kinetics influence gray matter kinetics by intertissue diffusion, as suggested by the work of Cohen et al. (12,13). Except for halothane (14), data are absent concerning differences in solubility for gray versus white matter, particularly for more modern volatile anesthetics, and no report supplies data for solubilities in areas of brain such as the thalamus, hypothalamic area, and hippocampus, areas that may control consciousness, memory, and awakening. The present report provides such data.

	Methods

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Anesthetics were obtained from various sources: halothane was purchased from Halocarbon Laboratories (River Edge, NJ); desflurane and isoflurane were donated by Baxter Healthcare Corp. (New Providence, NJ); and sevoflurane was purchased from Abbott Laboratories (Abbott Park, IL). All anesthetics were >99% pure, as specified by the manufacturers.

The methods for determination of solubilities followed those previously reported (14–17). Cortical gray and white matter, thalamus, hypothalamic area, and hippocampus were dissected from fresh bovine brains (human brains were not available to us). The animals were approximately 18 mo of age. Care was taken to minimize contamination of gray with white matter and vice versa. Specific tissues (white, gray, etc.) from 5–8 brains were combined (pooled) and separately frozen until partition coefficients were determined. A precisely known amount of saline 0.9% (approximately half of the tissue volume) was added to the dissected pieces of each tissue in a calibrated cylinder, and the specific weight of the mixture and the tissue volume were calculated by volume displacement. The tissue-saline mixture was homogenized, and for each tissue approximately 10 mL was placed in each of 8 50-mL glass syringes capped with a stopcock. Thirty milliliters of either a mixture of isoflurane 0.464% and halothane 0.505%, or sevoflurane 1.35% and desflurane 3.82% was added to each syringe (4 syringes for each tissue and each gas mixture). For equilibration, the syringes were placed on a rotator in a water bath at 37°C for 2 h. Then, anesthetic concentrations (C) in the gas phase were analyzed using gas chromatography. After this analysis, the syringes were emptied until only 6 mL of the tissue-saline mixture was left. The syringes were weighed to calculate the exact volume from the known density of the mixture. Air was added to a total volume of 42 mL. The syringes were incubated again at 37°C for 2 h, and a second analysis of the concentration (C') gas phase was performed. The experiment for gray and white matter was repeated on another occasion.

The tissue/gas partition coefficient _T was calculated as:

where C and C' are the anesthetic concentrations in the syringe for the first and the second analysis, respectively; Vt is the volume of tissue and V_S is the volume of saline in the second analysis; V_G is the gas volume of the second analysis, and _S is the saline/gas partition coefficient. The saline/gas partition coefficient was determined independently (18–20).

Anesthetic concentrations in the gas phase were analyzed by gas chromatography using a Gow Mac model 580 gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) equipped with a 15-foot long SF96 column at 60°C. A nitrogen carrier stream of 15 mL/min was directed through the column to the detector. A flame ionization detector at 110°C was supplied with hydrogen at 20 mL/min and with air at 200 mL/min. Samples were injected into a 0.5-mL gas sample loop. The chromatograph was calibrated with primary standards produced by injection of a liquid aliquot of the compound into a flask of known volume or by secondary (cylinder) standards that had been calibrated with primary standards.

Results were analyzed as mean ± sd values. We compared partition coefficients of the different brain tissues for a given anesthetic by a repeated-measures analysis of variance followed by a Student-Newman-Keuls post hoc test.

	Results

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Tissue/gas partition coefficients varied widely among anesthetics (Table 1) [(21)]. For each specific portion of the brain, solubilities were ranked desflurane < sevoflurane < isoflurane < halothane, with the solubility of each succeeding anesthetic being 1.5–2.5 times greater than that of the preceding anesthetic. Mean tissue/gas values for white matter exceeded those for gray matter (P < 0.01) by a factor of 1.6 (desflurane) to 2.4 (halothane). Mean tissue/gas values for the thalamus, hypothalamic area, and hippocampus were between those for gray and white matter. All tissue/gas partition coefficients for a specific anesthetic differed significantly, except for sevoflurane hippocampus versus thalamus, for halothane hippocampus versus thalamus, and for desflurane hippocampus versus gray matter. For white matter, 1 of 8 measurements for each anesthetic was discarded because the results deviated more than 3 standard deviations from the mean.

	Discussion

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As previously determined for halothane (14), we found that white matter/gas partition coefficients of modern volatile inhaled anesthetics significantly exceeded the partition coefficients for gray matter. These findings are consistent with the greater lipid content of white matter and the substantial fat/gas partition coefficients of all potent inhaled anesthetics. The data showing intermediate solubility values for thalamus, hypothalamic area, and hippocampus might be explained as the result of admixture of white matter with the largely gray matter of these areas.

The study by Larson et al. (14) compared bovine halothane partition coefficients with human values: 2.3 versus 2.3, respectively for whole blood; 4.8 versus 6.0 for whole brain; 4.2 versus 6.0 for liver; 3.5 versus 3.6 for kidney; and 7.0 versus 8.0 for muscle. Thus, although the data from the present study are for pooled samples from bovine brains, they provide values that probably approximate those for human brains. As would be expected, Larson et al. found that the average value for whole human brain lay between the values for gray (5.4) and white (8.3) matter. They found less of a difference between gray and white matter than did we (Table 1), possibly because of technical reasons (e.g., less separation of gray from white matter, or their use of an alinear infrared analyzer) or possibly because of our use of bovine rather than human tissue.

Other factors may also affect comparisons and the quantitative nature of the determinations made in the present study. We assumed that we accurately separated the body of the neuron (gray matter) from axons (white matter). This is a reasonable assumption for white matter, but some white matter might have contaminated our samples of gray, and we made no measurements (e.g., analysis of myelin protein content) that might have given us an estimate of the extent of contamination. We believe, however, that the extent was not great because the boundary of gray and white matter is distinct and because of the care with which we performed the dissections. Consistent with the importance of the accuracy of separation, our value for the easy-to-separate white matter (8.93 ± 0.53) approximates the value of 8.3 found by Larson et al. (14), whereas our value for the harder-to-separate gray matter (3.76 ± 0.18) is significantly less than, and perhaps more accurate than, their value of 5.4.

As suggested in the Introduction to this report, during anesthetic elimination (i.e., during a nonsteady-state condition) response to command occurs after each drug has reached a concentration smaller than MAC_awake. During anesthetic elimination, response to command occurs at an alveolar concentration equal to 0.126 MAC desflurane (1), 0.141 MAC sevoflurane (1), and 0.166 MAC isoflurane (22), values considerably less than the MAC_awake values (0.33 MAC) for these anesthetics. Part of the discrepancy is attributed to the delay imposed by the need to eliminate anesthetic from the brain; cerebral elimination must lag elimination from alveoli. Such a lag could not be explained by washout from gray matter because the time needed to achieve equilibration is too short. For example, 3 time constants for gray matter for sevoflurane (i.e., the time to a 95% equilibration) would equal approximately 7 minutes: but 7 minutes before awakening after a 2-hour anesthetic with 1.25 MAC sevoflurane, alveolar sevoflurane concentrations are still less than MAC_awake (1).

If elimination from the bulk of cortical gray matter does not completely explain awakening, perhaps elimination from a subset of that gray matter provides an explanation. Possibly, elimination must occur from gray matter adjacent to, and influenced (slowed) by, white matter. The white matter might influence the gray by intertissue diffusion (12,13). The present data may allow a computer simulation of this possibility.

	Footnotes

 
This study was not funded by Baxter Healthcare Corp., but Baxter Healthcare supplied the isoflurane and desflurane used in this study.

EIE is a paid consultant to Baxter Healthcare Corp.

Accepted for publication September 8, 2004.

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