Br. J. Anaesth.
(1986), 58, 551-554
ALCOHOL INCREASES THE SOLUBILITY OF
ANAESTHETICS IN THE LIVER
A. FASSOULAKI AND E. I. EGER n
Alcoholism is associated with an increase in
anaesthetic requirement. Bert (1879) noted that an
alcoholic patient was not anaesthetized by 1.5
atmospheres of nitrous oxide, a partial pressure
well above the MAC value for this agent
(Hornbein et al., 1982). Cross-tolerance exists
between ethanol and barbiturates (Kalant,
Khanna and Marshman, 1970), and alcoholism
increases the MAC of halothane in humans (Han,
1969) and mice (Johnstone, Kulp and Smith,
1975). Similarly, Koblin and colleagues (1980)
found that mice tolerant to alcohol were also
tolerant to nitrous oxide. The mechanism for this
tolerance is not clear.
This increase in anaesthetic requirement might
of itself seem sufficient to explain the clinical
impression that increased concentrations of inhaled
anaesthetics are needed to anaesthetize the
alcoholic patient. However, we considered the
possibility that another cause might exist. Ingestion
of alcohol influences lipid metabolism and trans-
port, and alcoholism results in hepatic steatosis
(Lieber, Spritz and De Carli, 1966). Since volatile
anaesthetics are lipophilic, the transport of fat in
the blood and the accumulation of fat in the liver
might significantly increase solubility in both
tissues. The result would be an increase in
anaesthetic uptake. Therefore, we tested the
possibility that the solubility of anaesthetic agents
in the liver and blood would be increased by acute
or chronic ingestion of ethanol.
MATERIALS AND METHODS
Specific pathogen-free female Sprague-Dawley Single injection of ethanol
rats weighing 175-225 g were housed individually,
fed standard rat chow and allowed free access to two groups. The experimental group (« = 9) was
AHGYRO FASSOULAJU,* M.D.; EDMOND I. EGER II, M.D.;
Department of Anesthesia, University of California, 1386
HSE, San Francisco, California 94143, U.S.A.
•Present address: 57-59 Raftopoulou Street, Athens 405/1, and two of the rats died. The control group (n = 8)
Greece.
Correspondence to E.I.E.
SUMMARY
LiverI gas partition coefficients for isoflurane,
enflurane, halothane and methoxyf/urane in-
creased two-fold in rats killed 16 h after a single
injection of 15% ethanol 7 g kg-1. In contrast
bloodjgas and brain/gas partition coefficients
did not change. Chronic (21 days) ingestion of
ethanol increased liverj gas partition coefficients
four-fold, although this increase was largely
attributable to nutritional changes rather than to
a direct effect of ethanol. Only minimal changes
(usually not more than 15%) occurred in
blood/gas and brain/gas partition coefficients.
On account of this effect of ethanol on
anaesthetic solubility in the liver, the ingestion of
ethanol may modestly increase uptake of anaes-
thetic during the induction of anaesthesia.
water until the start of the investigation. They
were exposed to a light cycle of 12 h light and 12 h
dark. All animals were killed (carbon dioxide
inhalation) between 6 a.m. and 11 a.m.
Aliquots (approximately 2 ml) of blood, liver
and brain (the whole brain) were taken for the
determination of tissue/gas partition coefficients
for enflurane, isoflurane, halothane and methoxy-
fluraneat37 °C. Blood samples were anticoagulated
with EDTA. The method used for determining
partition coefficients has been described previously
(Fassoulaki and Eger, 1986).
Seventeen rats were weighed and divided into
given ethanol 7 g kg~J subcutaneously as a 15%
solution in normal saline ("acute ethanol" rats).
This dose produced a profound state of narcosis,
was injected with the same volume of physiological
saline per kilogram body weight as that given to
552
the experimental group ("acute control" rats).
After the injections were made, food was withheld
from both groups. Rats were killed 16 h after
injection. All livers were removed and weighed.
Chronic ingestion of ethanol
Twenty rats were weighed and divided into two
groups. The following diets were given instead of
rat chow and water. The experimental group
(n = 9) was given a mixture of 7 % ethanol plus
15% sucrose in Ringer's lactate ("chronic
ethanol" rats). To this mixture were added 0.22 %
ethyl linoleate and a vitamin mixture (per litre:
vitamin A 3 mg, vitamin D 10 ug, vitamin C 200
mg, vitamin 1^ 10 mg, vitamin Bs 10 mg, niacin-
amide 100 mg, vitamin B, 5 mg, vitamin B12 5 |ig
and panthenol 20 mg). The control group (n = 11)
was given an identical mixture, except that ethanol
was omitted and the concentration of sucrose was
increased to 20% ("chronic control" rats).
Initially, the two groups were "pair fed"; that is,
the volume consumed by a chronic ethanol rat was
then given (without ethanol) to its peer chronic
control the next day. However, two of the chronic
control rats died after 13 and 15 days (respectively)
of this diet, and the volume given to all chronic
control rats was increased by 20 ml per day
thereafter.
After 21-22 days of this diet, the diet was
discontinued and rats were given water but no food
for 16 h. Then rats were killed and weighed;
aliquots of blood, brain and liver were taken for
determination of tissue/gas partition coefficients.
In addition the liver was weighed.
A separate group of female Sprague-Dawley
rats of similar weight who had been fed standard
rat chow up to the time of killing and who had not
received ethanol provided a separate control group
TABLE I. Liver/gas partition coefficients (mean ± SEM) in rats after a single injection of, or chronic treatment
with, ethanol. a = Number of determinations
Group Isoflurane
Fed rats 2.60±0.10
Acute ethanol 6.37 ±1.02
Acute control 3.41 ±0.20
Chronic ethanol 11.69±2.21
Chronic control 8.14±1.45
(i = 9)
BRITISH JOURNAL OF ANAESTHESIA
("fed rats"). They were allowed unrestricted
access to water. The rats were purchased at the
same time and from the same vendor as the
experimental rats.
Statistics
To determine whether alcohol acutely influenced
solubility, we compared the results for the acute
control v. acute ethanol groups using t tests.
Similarly, tests were made for the chronic control
v. chronic ethanol groups. Comparison of the
values for the acute ethanol group with those
obtained from the chronic ethanol group tested
whether acute administration differed from
chronic administration in its effect on solubility.
As a final control comparison, we tested the data
for all groups against the data obtained from the
fed rats. We accepted P < 0.05 as representing
statistical significance.
RESULTS
Liver/gas partition coefficients were higher in the
acute ethanol group than in the acute control
group (table I) (P < 0.025). Both groups had
liver/gas partition coefficients that were higher
than those obtained in fed rats (P < 0.025) except
when halothane and methoxyflurane were com-
pared for acute control v. fed values (ns).
Rats in the chronic ethanol group had liver/gas
partition coefficients that were markedly higher
than those for acute ethanol rats (P < 0.025).
However, this increase was not significantly
greater than that found in the chronic control rats
fed a similar diet without ethanol (table I). Both
groups of rats had higher liver/gas partition
coefficients than fed rats (P < 0.005).
Only small differences were found in the
Enflurane Halothane Methoxyflurane
2.84±0.13 5.64 ±0.07 29.41 ±0.90
6.96±1.19 13.69±2.53 65.20±9.20
3.80 ±0.32 6.83 ±0.75 35.77±3.06
13.45 ±2.20 26.51 ±4.40 123.96 ±20.34
(i = 9)
8.77±1.56 17.40±3.11 83.60± 15.38
ALCOHOL AND SOLUBILITY 553
TABLE II. Blood/gas partition coefficients (mean±.SEM) in rats after a single injection of, or chronic
treatment with, ethanol. n = Number of determinations

Group Isoflurane Enflurane Halothane Methoxyflurane

Fed rats 1.78 ±0.05 2.57 ±0.07 4.76±0.14 25.02 ±1.42

in = 10) in = 10) (n = 10) (n = 10)
Acute ethanol 1.85 ±0.06 2.57 ±0.07 4.64±0.16 25.30±1.85
(n = 7) (" = 7) (n = 6) (n = 7)
Acute control 1.76±0.08 2.51 ±0.07 4.67±0.18 25.26 ±1.04
(n = 7) (n = 8) (n = 8) (n = 8)
Chronic ethanol 1.65±0.10 2.25±0.11 4.30±0.27 23.66 ±1.80
(n = 9) (n = 9) (n = 9) (n = 9)
Chronic control 1.78±0.05 2.54±0.08 4.60±0.17 26.01 ±1.24
(n = 9) in = 9) (n = 9) (n = 9)

partition coefficients for blood or brain in any solubility in the liver. We believe these results
comparisons among the various groups (tables II reflect a change in the lipid content of the liver
and III). The blood/gas partition coefficient for rather than a change induced by dehydration.
enflurane in the chronic ethanol rats was lower Dehydration was a consideration, because rats
(P < 0.05) than the blood/gas values for the blood injected with ethanol ate nothing and drank little
from fed rats, from acute ethanol rats or from or nothing for 16 h. However, dehydration also
chronic control rats. The brain/gas partition would have increased the protein and lipid
coefficients for all anaesthetics for the chronic concentrations in blood and brain, and yet no
ethanol rats were 11-25 % (P < 0.05) higher than changes in anaesthetic solubility in blood and brain
the coefficients for fed rats. A similar trend was were found in rats injected with ethanol.
found in the chronic control v. fed rats (a The increase in anaesthetic solubility in the liver
significant difference was found for only the is consistent with an increased mobilization of fat
enflurane and halothane comparisons). from fat stores (Scheig and Isselbacher, 1965;
All chronically treated rats lost weight. Weight Lieber, Spritz and De Carli, 1966). However, the
loss tended to be greater in chronic ethanol rats argument that mobilization is increased has been
(71.0±4.82g v. 58.2±5.6g) than in chronic disputed (Brodie et al., 1961; Mallov, 1961).
control rats. Livers of chronic ethanol rats weighed Alternatively, acute administration of ethanol may
less (6.67 ±0.17 g, mean±SEM) than livers from decrease the metabolism of fatty acids by the liver.
acute ethanol rats (7.38 ±0.18 g). Also consistent with our thesis is the fact that
chronic ingestion of ethanol was associated with a
four-fold increase in the liver/gas partition
DISCUSSION
coefficient. Such an increase could be explained by
Consistent with our thesis is the fact that the acute a large hepatic accumulation of fat, as occurs in
administration of ethanol increased anaesthetic humans and rats. This fat is not the same as that
TABLE III. Brain/gas partition coefficients (mean±SEM) in rats after a single injection of, or chronic
treatment with, ethanol. n = Number of determinations

Group Isoflurane Enflurane Halothane Methoxyflurane

Fed rats 2.04 ±0.04 2.31 ±0.08 4.51±0.11 24.35 ±1.07

(n = 11) (» = 11) (i=H) (n = 11)
Acute ethanol 2.05±0.16 2.30 ±0.30 4.58±0.27 22.70±1.21

Acute control 2.10±0.04 2.36 ±0.07 4.79 ±0.11 23.40 ±0.95

d = 8) (n = 8) (i = 8) (n = 7)
Chronic ethanol 2.27±0.06 2.61±0.10 5.19±0.10 30.55 ±0.81
(i-9) (i = 9) (n-9) (i = 9)
Chronic control 2.22 ±0.08 2.58±0.08 5.23 ±0.13 28.69 ±2.05
(i = 9)
554
found in peripheral stores (Lieber and Spritz,
1965). Prolonged ingestion of ethanol produces a
fatty liver by increasing the synthesis of fatty acids
by the liver and by decreasing their oxidation
(Lieber, De Carli and Schmid, 1960; Reboucas
and Isselbacher, 1961). However, this increase did
not differ from that found in rats fed the same diet
but no ethanol. Thus the increase in solubility in
the rats fed ethanol cannot be attributed to ethanol
itself. The increase in solubility in both groups is
qualitatively the same as the increase associated
with starvation (Fassoulaki and Eger, 1986).
Malnutrition may explain the fatty livers and
increased solubility found in both of the chronically
treated groups.
Not consistent with our thesis, however, is the
fact that blood solubility did not increase after
acute or chronic administration of ethanol. Thus,
either fat mobilization is too small or the liver or
other organs clear the fat too rapidly to permit an
increase in blood lipid concentrations sufficient to
affect solubility. However, these data in rats may
not apply to humans. In humans, there is a strong
correlation between chronic alcohol consumption
and the concentrations of high- and low-density
lipoprotein cholesterol (Castelli et al., 1977). A
weaker correlation exists for alcohol ingestion and
plasma triglyceride concentration.
If our data apply to patients, acute ingestion of
ethanol should slightly increase uptake of inhaled
anaesthetics during induction of anaesthesia and
thus delay induction. However, alcohol would
contribute to the anaesthetic state, and thus
induction might be hastened. The chronic ingestion
of alcohol produces a four-fold increase in liver
solubility, and such an increase in solubility would
have a more profound effect on the initial uptake
of anaesthetic and, hence, on the induction
process. The delay in induction would be
compounded by the tolerance to anaesthesia
produced by chronic alcoholism.
ACKNLOWLEDGEMENT
Supported by a grant from the National Institute on Aging (AG
03104-03). Halothane (Fluothane) was donated by Ayerst
BRITISH JOURNAL OF ANAESTHESIA
Laboratories. Isoflurane (Aerrane) and enflurane (Alyrane)
were donated by Anaquest.
REFERENCES
Bert, P. (1879). Anesthesie par le protoxyde d'azote melange-
d'oxygene et employe sous pression. C. R. Acad. Sci. (Paris),
89, 132.
Brodie, B. B., Butler, W. M. jr, Homing, M. G., Maickel,
R. P., and Maling, H. M. (1961). Alcohol-induced trigly-
ceride disposition in liver through derangement of Cat
transport. Am. J. Clin. Nutr., 9, 432.
Castelli, W. P., Gordon, T., Hjortland, M. C , Kagan, A.,
Doyle J. T., Hames, C. G., Hulley, S. B., and Zuckel, W. J.
(1977). Alcohol and blood lipids. The cooperative lipoprotein
phenotyping study. Lancet, 2, 153.
Fassoulaki, A., and Eger, E. I. II (1986). Starvation increases
the solubility of volatile anaesthetics in rat liver. Br. J.
Anaesth., 58, 327.
Han, Y. H. (1969). Why do chronic alcoholics require more
anesthesia? Anesthtsiology, 30, 341.
Hornbein, T. F., Eger, E. I. u, Winter, P. M., Smith, G.,
Wetstone, D., and Smith, K. H. (1982). The minimum
alveolar concentration of nitrous oxide in man. Anesth.
Analg., 61, 553.
Johnstone, R. E., Kulp, R. A., and Smith, T. C. (1975). Effects
of acute and chronic ethanol administration on isoflurane
requirement in mice. Anesth. Analg., 54, 277.
Kalant, H., Khanna, J. M., and Marshman, J. (1970). Effect
of chronic intake of ethanol on pentobarbital metabolism. J.
Pharmacol. Exp. Ther., 175, 318.
Koblin, D. D., Deady, J. E., Dong, D. E., and Eger, E. I. II
(1980). Mice tolerant to nitrous oxide are also tolerant to
alcohol. J. Pharmacol. Exp. Ther., 213, 309.
Lieber, C. S., De Carli, L. M., and Schmid, R. (1960).
Stimulation of hepatic fatty acid synthesis in vivo and in vitro.
J. Clin. Invest., 39, 1007.
Spritz, N. (1965). Dietary, adipose tissue and newly
synthesized fatty acids in the pathogenesis of the fatty liver
produced by prolonged ethanol intake. Gastroenterology, 48,
500.
De Carli, L. M. (1966). Role of dietary, adipose and
endogenously synthesized fatty acids in the pathogenesis of
the alcoholic fatty liver. J. Clin. Invest., 45, 51.
Mallov, S. (1961). Effect of ethanol intoxication on plasma free
fatty acids in the rat. Q. J. Studies Alcohol, 22, 250.
Reboucas, G., and Isselbacher, K. J. (1961). Studies on the
pathogenesis of the ethanol-induced fatty liver. J. Clin.
Invest., 40, 1355.
Scheig, R., and Isselbacher, K. J. (1965). Pathogenesis of
ethanol-induced fatty liver: III. In vivo and in vitro effect of
ethanol on hepatic fatty acid metabolism in rat. J. Lipid Res.,
6, 269.