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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.
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Abstract |
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Introduction |
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Response to command first occurs after anesthesia with each of these drugs at a smaller end-tidal concentration than MACawake (the steady-state alveolar [end-tidal] concentration at which 50% of subjects respond appropriately to command). For desflurane, sevoflurane, and isoflurane, MACawake 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.
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Methods |
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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:
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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 VS is the volume of saline in the second analysis; VG 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.
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Results |
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Discussion |
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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 MACawake. 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 MACawake 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 MACawake (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.
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Footnotes |
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EIE is a paid consultant to Baxter Healthcare Corp.
Accepted for publication September 8, 2004.
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