803

ISOFLURANE - A NEW GENERAL

ANESTHETIC FOR THE 1980s*
ELIZABETH A. M. FROST, M.D.
Professor of Anesthesiology
Albert Einstein College of Medicine of Yeshiva University
Bronx, New York

ISOFLURANE (Forane compound 469), synthesized in 1965 by Terrell,

was developed after its isomer, enflurane, another halogenated anesthet-
ic agent.

PHYSICOCHEMICAL PROPERTIES
The molecular weight of isoflurane is the same as that of enflurane
(184.5) and slightly less than halothane (197.4). The boiling point
(48.50C) is closer to that of halothane (50.20C) than of enflurane
(56.50C). The vapor pressure at 220C, which is the critical factor in
determining precentage administered through the vaporizer, is 261.9 mm.
Hg, which approximates that of halothane (265.5 mm. Hg). Isoflurane
and enflurane maintain stability in the presence of soda lime and ultravio-
let light and do not require additional preservatives. Halothane, on the
other hand, must be stored in dark bottles and decomposes on contact with
soda lime. The minimal flammable concentration in 70% N20/30% 02 is
7% with isoflurane as compared with enflurane (5.8%) and halothane
(4.8%).1
The minimum alveolar concentration of isoflurane, at which 50% of
patients do not move on skin incision, decreases with age and the addition
of nitrous oxide. Under age 30, the minimum alveolar concentration for
isoflurane in 100% 02 is 1.28% and with 70% N20 it falls to 0.56%.2
Percentages for patients over 55 are 1.05% and 0.37%. Thus isoflurane
falls between enflurane and halothane (which is greatest) in potency.
Animal studies have indicated no change in minimum alveolar concentra-
tion with duration of anesthesia3 although concentration does decrease by
5.3% with each 1°C fall in temperature.4 In pregnant sheep, minimum
* Presented at a meeting of the Section on Anesthesiology of the New York Academy of Medicine
January 6, 1982.
Address for reprint requests: Albert Einstein College of Medicine, 1300 Morris Park Avenue,
Bronx, N.Y. 10461

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804 E. A. M. FROST

alveolar concentration is decreased by 40%,5 which may indicate that

administration of "ordinary" concentrations of isoflurane to parturients
may produce anesthesia more rapidly and to a deeper level. Alcohol
ingestion increases the minimum alveolar concentration of isoflurane by
about 25%, which makes alcoholic patients more difficult to anesthetize.
Drugs which stimulate central neurotransmitters (e.g., ephedrine and
amphetamines) also increase this,7 which may explain the apparent greater
potency of isoflurane over enflurane despite the similarity of their lipid
solubility. Enflurane has a central nervous system stimulant effect not
possessed by isoflurane, which may antagonize its anesthetic action.

UPTAKE AND DISTRIBUTION

Isoflurane has a low blood and tissue solubility, second only to that of
nitrous oxide. Thus induction is rapid, although the pungent smell may
induce breath holding. The alveolar (or arterial) partial pressure reaches
50% of inspired concentration in 4 to 8 minutes and 60% in 15 minutes.'
Fifty percent equilibration of isoflurane with brain, liver, and heart is
reached in 5 to 15 minutes, with muscle in two hours and with fat in
seven hours.8
The low solubility of isoflurane allows flexibility in altering anesthetic
depth as clinical requirements change. Recovery from isoflurane is rapid.
The average interval from discontinuation of anesthesia to opening of the
eyes is about 91/2 minutes and to answering questions is 12'/2 minutes
(Isoflurane New Drug Application, p. 54). Comparable figures for halo-
thane are 11½/2 and 15 minutes. An increase in duration of anesthesia from
one to three hours significantly prolongs the time for recovery but time
increases beyond three hours do not further delay awakening. (Isoflurane
New Drug Application, pp. 626-27).

METABOLISM
Isoflurane is more stable than other volatile anesthetics in that it does
not break down on exposure to soda lime or ultraviolet light. It requires no
preservative and has a shelf life of at least five years.' In vivo metabolism
of isoflurane is extremely low. Only 0.17% of isoflurane taken up by the
body has been recovered as metabolites. This figure compares to 2 to 4%
for enflurane, 20% for halothane, and 50% for methoxyflurane. Isoflurane
also causes an extremely small increase in serum inorganic fluoride (1/10
of that seen with enflurane)9 and urinary organic fluoride'0 (from day

Bull. N.Y. Acad. Med.

 ISOFLURANE
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805

three to ten, about 1/6 to 1/10 of that observed after halothane).

Pretreatment of animals with such drugs as phenobarbital and pheny-
toin, which induce the enzymes responsible for metabolism of isoflurane,
have failed to demonstrate significant increase in microsomal defluorinase
activity, further attesting to the in vivo stability of the agent." The
absence of biodegradation is a desirable characteristic because toxicity
such as liver and kidney injury, mutogenicity, carcinogenicity, and terato-
genicity may result from the process or products of metabolism.

EFFECTS ON ORGAN SYSTEMS

Isoflurane has several effects on bodily functions, some of which are
predictable and others which are unique to the drug.
Respiratory system. Isoflurane depresses respiration in a dose-related
fashion to a slightly greater extent than occurs with halothane but consid-
erably less than that seen during enflurane anesthesia.'2 However, addition
of N20 (70%) or morphine (0.15 mg./kg.), which may be used to replace
isoflurane, significantly decrease the ventilatory depression seen with
isoflurane alone.'3"4 All inhaled agents depress the ventilatory response to
imposed increases in Paco2, which implies that the drive to overcome
resistance to respiration is impaired and thus the danger of hypoxia
occuring is enhanced. Apnea occurs at concentrations above 2 minimum
alveolar concentration. The ventilatory response to decreased Pa02 is
also depressed by halogenated anesthetic agents. This depression is evi-
dent at 0.1% minimum alveolar concentration and no ventilatory response
is seen at 1. 1%.' Thiopental also depresses the response to hypoxia but to
a lesser extent.
Ventilatory depression is accompanied by both general metabolic de-
pression and decreased functional requirements.' Whole body oxygen
consumption is reduced from 250 ml./min. to 150 ml./min. at 2% mini-
mum alveolar concentration. Relatively, the greatest decrease in oxygen
consumption occurs in the myocardium.'7 Respiratory depression is offset
by assisting ventilation and by surgical stimulation, which increases venti-
lation by 40% at clinical levels of anesthesia.'4
The effects of isoflurane on pulmonary mechanics are similar to those
of other general anesthetics. Functional residual capacity and lung compli-
ance decrease slightly at 1% but not at 2%. Chest wall compliance does
not change. Pulmonary resistance increases to about 140% of the awake
value. This increase has also been reported with other general anesthet-

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806 E. A. M. FROST

ics.18 Thus, isoflurane is as suitable as other agents for anesthetizing

patients with chronic obstructive pulmonary disease.
Postoperative respiratory complications with isoflurane are few. In a
large study, 3.4% developed postoperative atelectasis, 0.6% were diag-
nosed as having some degree of pneumonic infiltration, and aspiration or
pneumothorax occurred in 1.3%. Complications were related to age,
duration of anesthesia, pre-existing disease, and surgical site. (Isoflurane
New Drug Application, p. 3018).
Cardiovascular system. Isoflurane concentrations which provide surgi-
cal anesthesia cause little or no depression of myocardial function, cardiac
output, or tissue perfusion.16 No change was seen in the acceleration
imparted to the body by the ejection of blood from the heart (ballistocar-
diogram wave) with up to 1.9% minimum alveolar concentration isoflur-
ane as compared to at least a 50% decrease from the awake state observed
with both halothane and enflurane.16 A further indication of the minimal
myocardial depression caused by isoflurane is the absence of an increase
in right atrial pressure up to 1.4% and only a slight increase at 1.9%. 6
All other inhalation agents increase right atrial pressure, indicating greater
depression of myocardial function. The cardiac anesthetic index, which is
the ratio of the anesthetic concentration in the heart at minimum alveolar
concentration, is significantly longer for isoflurane than for other haloge-
nated anesthetics. However, circulatory depression becomes progressively
more evident at concentrations above 2.5%.19
Although stroke volume is decreased by about 20% at 2% minimum
alveolar concentration, cardiac output is kept constant by a small compen-
satory increase in heart rate.16 Isoflurane may also have mild beta recep-
tor-stimulating properties which may also support myocardial function.16
Despite the maintenance of cardiac output and myocardial function,
arterial blood pressure decreases in a dose-related fashion due to decrease
in total peripheral resistance.'6 Increased peripheral flow to all tissues,
especially muscle, increases, which again may be due to a peripheral
beta sympathetic effect on blood vessels caused by interference with the c-
AMP system.20 Minimal changes in base excess from the awake state
suggest that there is overall adequacy of tissue perfusion during isoflurane
anesthesia. 16
Administration of 1 to 2% minimum alveolar concentration does not
significantly change pulmonary arterial blood pressure, wedge pressure, or
vascular resistance. Stability of the pulmonary circulation is maintained

Bull. N.Y. Acad. Med.

 ISOFLURANE
ISOFLURANE
807
807

during both spontaneous and controlled ventilation. The only exception

appears to be in the effect of isoflurane on the pulmonary vasoconstrictive
response to hypoxia.22 Unlike halothane, both isoflurane and nitrous oxide
diminish this vasoconstrictive response, i.e., PaO2 is lower during isoflur-
ane administration if there is a coexistent hypoxic lung segment. If there is
no respiratory disease, there is no evidence of a decrease in PaO2 during
spontaneous respiration.
An important difference between isoflurane and halothane is the greater
stability of myocardial rhythm after exogenous administration of epineph-
rine which is seen with the former agent. Whereas during halothane
anesthesia 2.1 pug./kg. epinephrine produces ventricular extrasystoles,
under isoflurane this dose is increased to 6.7 ,ig./kg.23 Deepening anes-
thesia and increasing Paco2 further increases the dose of epinephrine that
causes arrhythmias for both agents.2:3 The relative stability of heart rhythm
is also seen when other vasoactive drugs such as metaraminol phenyleph-
rine or ouabain are injected.24 The mechanism for the difference in effect
between halothane and isoflurane has been attributed to the effect of the
agents on impulse transit through the heart. Whereas halothane slows the
conduction of impulses through the cardiac conduction system and de-
presses conduction within the atrioventricular node which tends to facili-
tate the re-entry of sinus impulses, isoflurane does not.25
A similar stability of the circulatory system is also seen in older patients
(> 60 years).21 Profound hypothermia (< 20°C) can be tolerated without
the development of ventricular extrasystoles in dogs.26 Animal experi-
ments suggest a greater protective effect with isoflurane during progres-
sive blood loss, perhaps due to decreased sympathetic response producing
lower serum catecholamine and lactate levels and higher pH, base excess,
and mixed venous P02.27
Clinical observations suggest that isoflurane has no adverse effect in
combination with the usual premedications and can also be given safely in
the presence of therapeutic levels of beta-adrenergic blockade.28 No clini-
cally significant changes in serum electrolytes occur, but blood glucose
levels rise by about 60 mg./dl. after one hour.29 Plasma levels of growth
and thyroid hormone also increase. Cortisol is higher, an effect seen more
after surgical incision than during isoflurane alone. A slight increase in the
Bohr shift has been described, which means that if pH is decreased in the
presence of isoflurane, oxygen dissociates more readily from
hemoglobin.30
Postoperative circulatory complications are very low following isoflur-

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80
A. M.
E..A M
FROST
RS

ane anesthesia (4%). An identical incidence was seen after halothane but
the patients in this latter group were younger, healthier preoperatively, and
underwent a shorter anesthetic exposure (Isoflurane New Drug Applica-
tion, p. 515).
Specific indications for the use of isoflurane might include patients with
coronary artery disease or congestive cardiac failure when the decrease in
myocardial oxygen requirement induced by isoflurane and the stability of
right and left atrial pressures and cardiac rhythm are advantageous.
However, the tachycardia and decrease in peripheral resistance induced
may be hazardous to the patient with aortic stenosis.
Neuromuscular effects. Not only can isoflurane produce sufficient
relaxation for most surgical procedures, it is at least twice as effective as
halothane in enhancing the effect of muscle relaxants.31 Using d-tubocur-
arine, the dose of relaxant required to produce a 50% decrease in twitch
height (i.e., the ED50) during 1.25% minimum alveolar concentration
isoflurane was found to be 1.7 mg./m2; the comparison dose at 1.25%
halothane was 5.6 mg./m2 .32 The ability of a muscle to sustain contraction
in response to tetanic stimulation is also decreased in a dose-related
fashion.33
The enhancement of relaxant effect reduces possible complications
induced by such relexants as histamine release, hypotension, tachycardia,
increased myocardial consumption, and postoperative respiratory depres-
sion. Speculation that isoflurane would be useful for patients with myas-
thenia gravis has yet to be tested. Similarly, as metabolism and elimina-
tion of muscle relaxants requires adequate hepatic and renal function,
isoflurane may be the agent of choice in patients with compromise of
these systems.
Central nervous system effects. At subanesthetic concentrations of
isoflurane, electroencephalographic frequency increases from 8 to 12 Hz
(alpha) to greater than 15 Hz. Voltage is also increased. As the isoflurane
concentration reaches minimum alveolar concentration, maximum elec-
troencephalographic amplitude increases to an average of 140-150 micro-
volts. A lower frequency develops. Further deepening of anesthesia sup-
presses the low amplitude waves with 12-14 Hz frequency. Burst
suppression appears at 1.5% minimum alveolar concentration, and an
isoelectric line develops at 2% .31 In contradistinction to the isomer enflur-
ane, isoflurane does not cause seizure activity in man. Epileptic patterns
cannot be evoked by increasing depth, lowering Pac02 or by auditory or
visual stimuli.34 The ability to produce electroencephalographic silence at
Bull. N.Y. Acad. Med.
 ISOFLURANE
ISOFLURANE
809

surgical concentrations suggests a cerebral protective effect of isoflurane

which has been confirmed in animal studies.'3
As might be expected, isoflurane causes a transient central nervous
system depression immediately after anesthesia but there appear to be no
long-term effects.36 No retrograde amnesia occurs even after a six-hour
anesthetic procedure,7 although there may be memory impairment for
acoustically or visually presented items for up to two hours. Isoflurane
causes significantly less adverse general symptoms such as nausea or
weakness than are reported after exposure to halothane.38
Cerebral blood flow and intracranial pressure do not increase from
awake levels at 0.6-1.1% but double at 1.6% minimum alveolar concen-
tration.39 These increases may be prevented by hyperventilation.40 Thus,
at levels that produce neurosurgical anesthesia there appear to be no
significant changes in intracranial dynamics. We also found that at up to
1.5%,vascular response to CO2 and autoregulation are well maintained.
However, after creation of a small cryogenic lesion in dogs, higher
increases in intracranial pressure and edema are associated with isoflurane
and the other halogenated anesthetics than with barbiturates.4'
Hepatic effects. In healthy volunteers isoflurane and enflurane do not
alter. bromsulphalein retention, although halothane significantly impairs
this aspect of liver function for up to seven days after administration.42
Other indices of hepatic integrity, such as serum LDH and SGOT, are
also maintained intact but do increase slightly with surgery.3' Periopera-
tive factors such as preexisting liver disease, shock, congestive heart
failure, upper abdominal surgery, or viral infection may all alter hepatic
function and, theoretically, response to anesthetic administration. Howev-
er, patient studies support the safety of isoflurane with regard to liver
function. Bromsulphalein levels may increase slightly on the second
postoperative day but quickly return to normal.42 Postoperative enzyme
values do not correlate with duration of anesthesia and have been shown
to relate inversely to the level found before anesthesia. Repeated adminis-
tration of isoflurane has also failed to produce hepatic dysfunction (Iso-
flurane New Drug Application, p. 86).
Animal studies have shown that hypoxia in the presence of isoflurane
does not increase liver injury43 and that prolonged exposure to subanes-
thetic concentrations produces neither degenerative hepatic lesions nor a
failure to thrive.44 Liver methionine synthetase activity, important for the
synthesis of DNA and red blood cell formation, is decreased by N20 but
remains intact in the presence of isoflurane.45

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E. A. M. FROST

Renal action. As do all anesthetics, isoflurane decreases renal blood

flow, glomerular filtration rate, and urinary flow.46 Serum potassium
levels increase about 25% although other electrolytes are unchanged.42
The minimal metabolism and rapid elimination of isoflurane suggest little
impairment of renal function which has been confirmed by volunteer,
patient, and animal studies.1 Rat experiments have indicated that metabo-
lism of isoflurane (i.e., no increase in serum liver enzyme) is not altered
even during renal failure.47
Obstetrics. Isoflurane causes a dose-related depression of uterine muscle
contractions which is about 50% at 1.5% minimum alveolar concentra-
tion. Although isoflurane analgesia probably does not increase blood loss
at term delivery, anesthesia increases hemorrhage during therapeutic abor-
tion.49 Experiments in ewes have shown that at 1 to 1.5% minimum
alveolar concentration, uterine blood flow, fetal base excess, and fetal
oxygenation all remain at awake levels despite a dose-related decrease in
maternal systemic arterial blood pressure and cardiac output. At 2%, all
the variables decrease.5
In a study comparing analgetic concentrations of isoflurane with 40%
N20, no differences were detected in indices of fetal well being. However,
isoflurane analgesia developed more slowly during the first 10 minutes.5O
The additional oxygen which is delivered with isoflurane may be advanta-
geous in some situations.
Genetic and immune studies. Mutagenicity and carcinogenicity of
chemicals may be due to alteration in DNA or chromosomal proteins. The
limited metabolism of isoflurane minimizes the potential for interaction
with DNA, and the low solubility and rapid elimination lessen the time of
exposure of the immune system.
The Ames test for mutagenicity measures the conversion of bacteria
from histidine-dependent to histidine-independent organisms which occur
when the bacteria are exposed to a suspected mutagen. It is a widely
accepted test which identifies 90% of carcinogenic compounds and gives
false positive results in only 10 to 15% of cases. Using this test, no
mutagenic potential for isoflurane or its metabolites have been identified.5'
Similarly, results from the sister chromatid exchange test (another test of
mutagenicity) showed no evidence of adverse action with isoflurane.52
Teratogenicity studies in animals with prolonged isoflurane exposure
during gestation have shown no differences in fetal viability or congenital
anomalies over controls.'
A pilot study had suggested that mice exposed to isoflurane for ex-

Bull. N.Y. Acad. Med.

 ISOFLURANE 811

tended periods had a higher incidence of liver tumors.53 A subsequent,

better controlled study eliminating all contaminants did not confirm this
finding.54 Effects of isoflurane in immune defences are undetermined,
although liquid isoflurane is bactericidal55 and, at 0.2% minimum alveolar
concentration, replication of measles virus in vitro is inhibited by 50%.

CONCLUSION
Isoflurane is a nonflammable, stable halogenated anesthetic agent. It
has low blood and tissue solubility and permits rapid induction and
recovery. Metabolism is minimal. Cardiovascular stability is well main-
tained and muscle relaxation is good. Organ toxicity is absent or extreme-
ly low. Its few disadvantages include the pungent smell, respiratory
depression, increased uterine relaxation, and decreased cerebrovascular
resistance. The cost, although higher than that of enflurane and halothane,
remains a relatively small part of the entire anesthetic experience.
REFERE NCES
1. Eger, E. I., II: Isoflurane A Compendi- thetic requirement (MAC). Anesthesi-
um and Reference. Ohio Medical Prod- ology 29:1153-58, 1968.
ucts, 1981. 8. Holaday, D. A., Fiserova-Bergerova,
2. Stevens, W. C., Dolan, W. M., Gib- V., Latto, I. P., et al.: Resistance of
bons, R. T., et al.: Minimum alveolar isoflurane to biotransformation in man.
concentrations (MAC) of isoflurane Anesthesiology 43:325-32, 1975.
with and without nitrous oxide in pa- 9. Dobkin, A. B., Kin, D., Choi, J. K.,
tients of various ages. Anesthesiology and Levy, A. A.: Blood serum fluoride
42:197-200, 1975. levels with enflurane (Ethrane) and iso-
3. Koblin, D. D., Eger, E. I., II, Johnson, flurane (Forane) anaesthesia during and
B.H., et al.: Are convulsant gases also following major abdominal surgery.
anesthetics? Anesthesiology 53:S47, Can. Anaesth. Soc. J. 20:494-98, 1973.
1980. 10. Mazze, R. I., Cousins, M. J., and Barr,
4. Vitez, T. S., White, P. F., Eger, E. I., G. A.: Renal effects and metabolism of
II: Effects of hypothermia on halothane isoflurane in man. Anesthesiology
MAC and isoflurane MAC in the rat. 40:536-42, 1974.
Anesthesiology 41:80-81, 1974. 11. Caughey, G. H., Rice, S. A., Kosek, J.
5. Palahniuk, R. J., Shnider, S. M., and C., and Mazze, R. I.: Effect of pheny-
Eger, E. I., II: Pregnancy decreases the toin (DPH) treatment on methoxyflur-
requirement for inhaled anesthetic ane metabolism in rats. J. Pharmacol.
agents. Anesthesiology 41:82-83, 1974. Exp. Ther. 2/0:180-85, 1979.
6. Johnstone, R. E., Kulp, R. A., and 12. Calverley, R. K., Smith, N. T., Prys-
Smith, T. C.: Effects of acute and Roberts, C., et al.: Cardiovascular ef-
chronic ethanol administration on iso- fects of enflurane anesthesia during con-
flurane requirement in mice. Anesth. trolled ventilation in man. Anesth.
Analg. 54:277-81, 1975. Analg. 57:619-28, 1978.
7. Miller, R. D., Way, W. L., and Eger, 13. Eger, E. I., II, Dolan, W. M., Stevens,
E. I., II: The effects of alpha-methyl- W. C., et al.: Surgical stimulation an-
dopa, reserpine, guanethidine, and tagonizes the respiratory depression
iproniazid on minimum alveolar anes- produced by Forane. Anesthesiology

Vol. 58, No. 9, December 1982

 812 E. A. M. FROST
36:544-49, 1972.
14. France, C. J., Plumer, M. H., Eger, E.
I., II, and Wahrenbrock, E. A.: Ventila-
tory effects of isoflurane (Forane) or ha-
lothane when combined with morphine,
nitrous oxide and surgery. Br. J. An-
aesth. 46:117-20, 1974.
15. Fourcade, H. E., Stevens, W. C., Lar-
son, C. P., et al.: The ventilatory effects
of Forane, a new inhaled anesthetic. An-
esthesiology 35:26-31, 1971.
16. Stevens, W. C., Cromwell, T. H., Hal-
sey, M. J., et al.: The cardiovascular
effects of a new inhalation anesthetic,
Forane, in human volunteers at constant
arterial carbon dioxide tension. Anesthe-
siology 35:8-16, 1971.
17. Theye, R. A. and Michenfelder, J. D.:
Whole-body and organ V02 changes
with enflurane, isoflurane, and haloth-
ane. Br. J. Anaesth. 47:813-16, 1975.
18. Rehder, K., Mallow, J. E., Fibuch, E.
E., et al.: Effects of isoflurane anesthe-
sia and muscle paralysis on respiratory
mechanics in normal man. Anesthesiol-
ogy 41:477-85, 1974.
19. Wolfson, B., Hetrick, W. D., Lake, C.
L., and Siker, E. S.:. Anesthetic indices
- further data. Anesthesiology 48:187-
90, 1978.
20. Sprague, D. H., Yang, J. C., and Ngai,
S. H.: Effects of isoflurane and haloth-
ane on contractility and the cyclic 3', 5'-
adenosine monophosphate system in the
rat aorta. Anesthesiology 40:162-67,
1974.
21. Tarnow, J., Bruckner, J. B., Eberlein,
H. J., et al.: Haemodynamics and myo-
cardial oxygen consumption during iso-
flurane (Forane) anaesthesia in geriatric
patients. Br. J. Anaesth 48:669-75,
1976.
22. Mathers, J., Benumof, F. J., and Wah-
renbrock, E. A.: General anesthetics
and regional hypoxic pulmonary vaso-
constriction. Anesthesiology 46:111-14,
1977.
23. Joas, T. A. and Stevens, W. C.: Com-
parison of the arrhythmic doses of epin-
ephrine during Forane, halothane and
fluroxene anesthesia in dogs. Anesthesi-
ology 35:48-53, 1971.
24. Tucker, W. K., Rackstein, A. D., and
Munson, E. S.: Comparison of arrhyth-
mic doses of adrenaline, metaraminal,
ephedrine and phenylephrine during iso-
flurane anaesthesia in dogs. Br. J. An-
aesth. 46:392-96, 1974.
25. Blitt, C. D., Raessler, K.L., Wight-
man, M. A., et al.: Atrioventricular
conduction in dogs during anesthesia
with isoflurane. Anesthesiology 50:210-
12, 1979.
26. Sato, S., Vanini, V., Sands, M. P., et
al.: The use of Forane anesthesia for
surface-induced deep hypothermia.
Ann. Thorac. Surg. 20:299-307, 1975.
27. Theye, R. A., Perry, L. P., and Bri-
zica, S. M.: Influence of anesthetic
agent on response to hemorrhagic
hypotension. Anesthesiology 40:32-40,
1974.
28. Philbin, D. M. and Lowenstein, E.:
Hemodynamic consequences of the
combination of isoflurane anesthesia (1
MAC) and beta-adrenergic blockade in
the dog. Anesthesiology 42 :567-73,
1975.
29. Oyama, T., Latto, P., and Holaday, D.
A.: Effect of isoflurane anaesthesia and
surgery on carbohydrate metabolism and
plasma cortisol levels in man. Can. An-
aesth. Soc. J. 22:696-702, 1975.
30. Waltemath, C. L.: The effect of Forane
on hemoglobin function in vitro. Anes-
thesiology 37:454-56, 1972.
31. Homi, J., Konchigeri, H. N., Ecken-
hoff, J. E., and Linde, H. W.: A new
anesthetic agent - Foraneg. Preliminary
observations in man. Anesth. Analg.
51:439-47, 1972.
32. Miller, R. D., Way, W. L., and Dolan,
W. M.: Comparative neuromuscular ef-
fect of pancuronium, gallamine and suc-
cinylcholine during Forane and halo-
thane anesthesia in man. Anesthesiology
35:509-14, 1971.
33. Miller, R. D., Eger, E. I., II, and Way,
W. L.: Comparative neuromuscular ef-
fects of Forane and halothane alone and
in combination with d-tubocurarine in
man. Anesthesiology 35:38-42, 1971.
34. Eger, E. I., II, Stevens, W. C., and
Cromwell, T. H.: The electroenceph-
alogram in man anesthetized with For-
ane. Anesthesiology 35:504-08, 1971.
Bull. N.Y. Acad. Med.
 ISOFLURANE 813

35. Newberg, L. A. and Michenfelder, J. E., et al.: Inactivitation of methionine

J. D.: Cerebral Protection by isoflurane synthetase (MS) by nitrous oxide. Anes-
during hypoxemia or ischemia. Anesthe- thesiology 53:S49, 1980.
siology, In press. 46. Mazze, R. I., Cousins, M. J., and Barr,
36. Adam, N.: Effects of general anesthesia G. A.: Renal effects and metabolism of
on memory functions in man. J. Comp. isoflurane in man. Anesthesiology
Physiol. Psychol. 83:294-305, 1973. 40:536-40, 1974.
37. Bahlman, S. H., Eger, E. I., II, and 47. Rice, S. A., Sievenpiper, T. S., and
Cromwell, T. H.: Anesthetics and am- Mazze, R. I.: In vitro anesthetic defluor-
nesia. Anesthesiology 36:191, 1972. ination and in vivo liver function in Fi-
38. Davison, L. A., Steinhelber, J. C., scher 344 rats with chronic renal failure.
Eger, E.I., II, et al.: Psychological ef- Anesthesiology 53:S253, 1980.
fects of halothane and isoflurane anes- 48. Munson, E. S., and Embro, W. J.: En-
thesia. Anesthesiology 43:313-24, flurane, isoflurane and halothane and
1975. isolated human uterine muscle. Anesthe-
39. Murphy, F. L., Jr., Kennel, E. M., siology 46:11-14, 1977.
Johnston, R. E., et al.: The effects of 49. Dolan, W. M., Eger, E. I., II, and
enflurane, isoflurane and haiothane on Margolis, A. J.: Forane increases bleed-
cerebral blood flow and metabolism in ing in therapeutic suction abortion. An-
man. Annual Meeting Amer. Soc. esthesiology 36:96-97, 1972.
Anes., 1974, pp. 61-2. 50. Hicks, J. S., Shnider, S. M., and Co-
40. Adams, R. W., Cucchiara, R. F., Gron- hen, H.: Isoflurane (Forane) analgesia in
vert, G. A., et al.: Isoflurane and cer- obstetrics. Annual Meeting Amer. Soc.
brospinal fluid pressure in neurosurgical Anes., 1975, pp. 99-100.
patients. Anesthesiology 54:97-99, 51. Waskell, L.: A study of the mutageni-
1981. city of anesthetics and their metabolites.
41. Smith, A. L. and Marque, J. J.: Anes- Mutat. Res. 57:141-53, 1978.
thetics and cerebral edema. Anesthesi- 52. White, A. E., Takehisa, S., Eger, E. I.,
ology 45:64-72, 1976. II, et al.: Sister chromatid exchanges
42. Stevens, W. C., Eger, E. I., II, Joas, T. induced by inhaled anesthetics. Anesthe-
A., et al.: Comparative toxicity of iso- siology 50:426-40, 1979.
flurane, halothane, fluroxene and diethyl 53. Corbett, T. H.: Cancer and congenital
ether in human volunteers. Can. An- anomalies associated with anesthetics.
aesth. Soc. J. 20:357-68, 1973. Ann. N. Y. Acad. Sci. 271:58-66, 1976.
43. Harper, M. H., Johnson, B. H., Col- 54. Eger, E. I., II, White, A. E., Brown, C.
lins, P., and Eger, E. I., II: Hepatic L., et al.: A test of the carcinogenicity
injury following halothane, enflurane of enflurane, isoflurane, halothane, me-
and isoflurane anesthesia in rats. Anes- thoxyflurane, and nitrous oxide in mice.
thesiology 53:S242, 1980. Anesth. Analg. 57:678-94, 1978.
44. Stevens, W. C., Eger, E. I., II, White, 55. Johnson, B. H. and Eger, E. I., II:
A., et al.: Comparative toxicities of en- Bactericidal effects of anesthetics. An-
flurane, fluroxene and nitrous oxide at esth. Analg. 58:136-38, 1979.
subanaesthetic concentrations in labora- 56. Knight, P. R., Nahrwold, M. L., Co-
tory animals. Can. Anaesth. Soc. J. hen, P. J., and Gayner, J. A.: Alteration
24:479-89, 1977. of virus growth by halogenated anesthe-
45. Koblin, D. D., Watson, J. E., Deady, tics. Anesthesiology 51:S253, 1979.

Vol. 58, No. 9, December 1982