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Behavioral toxicity of anesthetic gases.

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Behavioral Toxicity of Anesthetic Gases
Bruce D. Synder, MD, Robert
S. Thomas,
P h D , and Zsuzsanna Gyorky, BA
Operating room personnel were studied for evidence of acute reversible or chronic cumulative cognitive dysfunction
s measured by psychometric testing. I n comparison with matched controls, no acute reversible deficits were noted in
3 relatively unpolluted operating room environment. There were only 2 marginally significant test differences
Jetween the control and operating room groups; however, control subjects did better than operating room personnel
m 16 of 18 tests at both the beginning and end of t h e work week. Analyses of the deficit patterns and correlations with
years of operating room exposure only weakly support the hypothesis that the test differences are due to toxic
Snyder BD, Thomas RS,Gyorky 2: Behavioral toxicity of anesthetic gases. Ann Neurol 3:67-7 1, 1978
4 series of studies have appeared suggesting that
inesthetic gases may produce toxic effects in continumsly exposed operating room personnel. T h e work of
3ruce and co-workers [2, 31, demonstrated that
,hort-term exposure to relatively low levels of
ialothane, enflurane and nitrous oxide produced
narked cognitive deficits among naive volunteers.
I e s e studies have generated questions regarding the
afety of current levels of exposure for operating
o o m personnel and their patients.
Our study surveys t h e performance of operating
oom personnel functioning under conditions of relaively low background pollution. Evidence was sought
or both short-term reversible and long-term cumulaive impairment in a variety of cognitive functions.
'he results bear on the establishment of safe
ireshold levels of exposure to these agents and on the
esign of equipment to maintain a safe operating room
7e measured background gas levels in the operating suites
nd in non-operating room areas at St. P a u l - h s e y Hospid and the Hospitals of the University of Minnesota. We
E n selected an experimental group of operating room
ersonnel from each hospital and a matched control group
'om the professional staff of the same hospitals working
itside the operating room.
Gas collections were made using a 150 cc metal canister
xmetically sealed with an all-metal gasket; these were
ipplied by Boehringer Laboratories, Wynnewood, PA, the
boratory performing the gas level determinations. Gas
mples were measured by a Varian chromatograph with
ermal and flame ionization systems. The standard deations of these systems for the concentration levels of
terest here are: nitrous oxide, f 1.9 parts per million;
dothane, 5 0.101 ppm. Gas level determinations and sites
'sampling are indicated in Table 1. Any toxic effect cannot
be directly related solely to the presence of either of these
gases, however, since other pollutants may have been present.
At St. Paul-Ramsey Hospital, waste gas removal is accomplished by a combination of air-conditioning (with six complete exchanges of operating room air per hour) and venting
of anesthesia machines at floor level. The University of
Minnesora Hospitals use similar air-conditioning systems,
but in addition, anesthesia machines exhaust directly outof-doors under a newly completed system. The &Ionditioning system has been in operation since 1954.
The experimental volunteer group was composed of 20
operating room staff members (student nurse anesthetists,
certified registered nurse anesthetists, and anesthesiologists). The control group consisted of 12 nurses
from the intensive care, coronary care, and kidney dialysis
units and 8 physicians from the departments of Neurology
and Pediatrics. The groups were matched for age, education,
years of working, complexity of tasks, and, so far as possible,
level of stress associated with occupation. We included no
subjects who were taking drugs, had a history of central
nervous system dysfunction, were ill, or had been o n night
shift the preceding week. Table 2 shows the median values
of these variables for the experimental and control groups.
A battery of tests was chosen to include well-established
gauges of mnemonic and other intellectual functions. These
included the following subtests of the Wechsler memory
scale [ 171: digits forward (DIG-FOR); digits backward
(DIG-BK); logical memory, both immediate (LOGMEM-I) and delayed recall after 25 minutes of other tests
(LOG MEM-D); and paired associates, both immediate
(PR-ASO-I) and delayed recall (PR-ASO-D). The Porteus
maze test (PORT) [ 131 and afour-choice visual reaction time
task with the dominant (RT-D) and nondominant (RT-N)
hands were also used [13,17]. In addition, some experimental tests that are especially sensitive to temporal and prefrontal dysfunction were used: the Thomas imagery battery,
both immediate (IMAG-I) and delayed recall (IMAG-D)
[16]; Make-a-Figure test (Mk-A-FIG) [4, 161; Word Arrangement (WD ARR) [4, 161; Homonyms (HOW [4, 161;
om the Departments of Neurology and Psychiatry. the University
Minnesota Medical School. St. Paul, MN.
Address reprint requests to Dr Snyder,Department of Neurology,
St. Paul-Ramsey Hospital, St. Paul, M N 55101.
:cepted for publication July 1 5 , 1977.
@ 1978 by the American Neurological Association 67
Table I. Measured Gas Concentrations at Various
Sites In and Around Operating Rooms
Table 2. Sex, Age, h e 1 of Education, and Years
Worked in the Experimental and Control Groups
Gas Levels (ppm)
and Conditions
Uniilersity of Minnesota Hospitals
General medical ward
Anesthesia break room in OR
area, average weekday
Operating room corridor,
average weekday morning,
1.5 m above floor
Operating room: operation in
progress (0.8% halothane,
60% nitrous oxide, at 5
Urnin); sampled at level of
anesthesia cable
Operating room: operation in
progress (0.7% halothane,
60% nitrous oxide, at 5
L/min), vent to floor; sampled
at level of anesthesia table
St. Paul-Ranuey Hospital
Intensive care unit (medical)
Operating room corridor,
average weekday morning,
1.5 m above floor
Operating room (0.75%
halothane, 50% nitrous oxide,
at 4 L/min); sampled at level of
anesthesia machine, table
Same operation; sampled at
air-conditioning exhaust duct
Operating room (1% halothane,
60% nitrous oxide) at level of
anesthesia machine, table
and Elithorn mazes (ELITHORN) [I]. The ShipleyHartford vocabulary test (S-H voc) [I51 was included to
compare vocabularies of the experimental and control
groups since this measure is known to be highly resistant to
acquired cerebral dysfunction.
The Thomas imagery battery consists of lists of 15 highimagery noun-noun paired associates. T h e Make-a-Figure
test is a test of figural fluency; the Word Arrangement test
measures semantic fluency. Orientation Memory (OR
MEM) requires retention of the location of houses on a map;
Homonyms involves the retention of homonym pairs and
the recognition of their synonyms. Only immediate testing
was done for Orientation Memory and Homonyms.
T h e test battery emphasized mnemonic abilities, since
previous work [2,3, 101has indicated that these abilities are
particularly sensitive to toxic stress of various types. Prefrontal functions (fluency, mazes) were also emphasized as
another functional area sensitive to processes diffusely affecting the cerebral hemispheres [7, 81.
All subjects were administered the battery o n a Monday
morning, and again, using equivalent forms of the tests, on a
Friday afternoon. Half of each group started on Monday and
68 Annals of Neurology
Vol 3
No 1 January 1978
No. of subjects
Years worked
37 (22-59)
3 9 (22-61)
9 (16-25)
34 (1-34)
3 6 (1-37)
15 (12-27)
the other half on Friday; this procedure was adopted to
permit estimation of cumulative effects over a short period
and possible reversibility over a weekend. Each volunteer
was tested in a half-hour individual session followed by a
half-hour group session. This made for minimal interruption
of the subjects’ workday and most efficient use of the
psychometrician’s time.
The results are summarized in terms of hypotheses
Hypothesis I: Acute Reversible Effects
“The experimental group would do better on Monday
mornings than on Friday afternoons, while the control
group would show no difference between the scores
for these times of testing.”
Table 3 shows that the control group did better on 7
of the 18 tests Monday and better on the other 11tests
on Friday. Considering the 5 tests for which the differences were significant, the control group performed better on Monday for 2 tests and better on
Friday for 3. Overall, these results suggest no consistent advantage for the control group for either time of
the week, as hypothesized. Similarly, the experimental group did better on 7 of the 18 tests Monday and
better on the other 11 tests Friday (Table 3). Of the 4
tests for which the differences were significant, the
experimental group did better on Monday for 1test and
better on Friday for 3 tests. Control and experimental
groups had differences in the same direction for 12
tests and in opposite directions for 6 tests. These
results fail to support the hypothesis that a week’s
exposure to trace anesthetic gases in the operating
room produces marked degradation of higher cortical
functions. They also fail to support the related
hypothesis that a weekend away from the operating
room is sufficient to reverse any acute deterioration of
these functions that might have taken place.
Table 3 . Within-Group Differences between Friday and Monday Test PerfmmanceJ
by Wilcoxon Matched Pairs Signed-Ranks Test
Experimental Group (N
Verbal memory
Nonverbal memory
Verbal fluency
Figure fluency
Planning and judgment
Reaction time
Symbolic reasoning
= 20)
Control Group (N = 20)
Direction of
Level of
Direction of
Result a
Level of
0.02 < p
p < 0.01
< 0.05
p < 0.01
p < 0.01
p < 0.01
0.02 < p < 0.05
p < 0.01
0.02 < p < 0.05
p < 0.01
’A plus sign indicates that better scores on the specified test were obtained on Monday; minus indicates Friday performance was superior.
bAIl values based on two-tailed tests of significance.
See text for explanation of tests.
Hypothesis 11: Chronic Cumulative Toxicity
“The control group would do better than the experimental group on both Monday mornings and Friday
There were no significant differences between the
experimental and the control group on Friday and
only 2 marginally significant differences on Monday.
A sign test, however, suggests a strong trend toward
better performance by the control group on both
Monday and Friday afternoons. The control group did
better on 16 of the 18 tests each day. The probability
of such a finding (i.e., 16 of 18 in one direction)
occurring by chance alone is only 0.0007. Before such
a finding is accepted as evidence of subtle deteriorauon in the experimental group, however, it is necessary to consider alternative explanations.
While the experimental and control groups were
well matched for age and years of education (the experimental group actually averaged 2.7 5 more years of
education), they were, of necessity, of somewhat different occupation. It is possible under such circumstances that the groups could differ enough along
some intellectual dimensions to produce the observed
superiority in the control group. To evaluate this possibility, we reviewed the results of the Shipley‘I
Hartford vocabulary test. Since vocabulary normally
is the least sensitive measure of organic cerebral dysfunction, differences here should be smaller than
other differences if the controlgroup’s advantage is, in
fact, due to organic deterioration in the experimental
group. For both days, vocabulary differences are
among the smaller variations as judged by the value of
the Mann-Whitney U, with smaller U’s implying
greater differences. Nevertheless, about one-third of
the other test differences are even smaller than that of
Shipley-Hartford vocabulary. The fact that variations
in vocabulary tend to be smaller than other differences
weakly supports the hypothesis of deterioration in the
experimental group.
Another check on the significance of the control
group’s advantage was to correlate scores in the experimental group with their years of exposure in the
operating room. In order to rule out the possibility of
interactions among age, education, and years of exposure concealing (or producing) significant correlations
between test scores and years of exposure, these correlations were calculated with the effects of age and
education partialed out. Since Monday-Friday differences were minimal, the Monday and Friday scores
were summed to produce the partial correlations in
Snyder, Thomas, and Gyorky: Toxicity of Anesthetic Gases 69
Table 4 . Partial Correlation Coefficients in Experimental Group between Years of Exposure
and Test Scores a
Verbal memory
Nonverbal memory
Verbal Fluency
Figure fluency
Planning and judgment
Reaction time
Symbolic reasoning
”Age and years of education are controlled; Monday and Friday
scores are combined.
”p < 0.05.
Table 4. Only Orientation Memory shows a significant
correlation with years of exposure. With 18 tests, 1
significant correlation could easily be due to chance.
Again, however, a mild (not significant) trend is indicated in that 11 of the 18 tests are negatively correlated with years of exposure, and the 3 correlations of
numerically greatest absolute magnitude all have
negative correlations; all 3 are recent memory tests.
Operating room staffs are perpetually exposed to low
background levels of escaped anesthetic gases.
Among surveys of gas levels in operating rooms in the
United States, depending upon the quahty of airconditioning and scavenging equipment, values of up
to 85 ppm of halothane and 7,000 ppm of nitrous
oxide have been reported [3, 91. Of concern is
whether the efficiency and performance of surgical
personnel are being impaired by this exposure, and if
so,whether such impairment is short-term and reversible or whether there may be a chronic cumulative
Previous studies have demonstrated that anesthetic
agents can cause behavioral deficits without altering
the level of consciousness or producing obvious intoxication. Subjects in experimental situations have
70 Annals of Neurology Vol 3 No 1 January 1978
been able to function and to complete psychometric
tests while under the influence of low levels of anesthesia [2,3,10,121. These studies have been primarily
concerned with the short-term effects of anesthetic
exposure, and no study of w h c h we are aware has
addressed the problem of chronic intoxication in man.
Rats exposed to 10ppm of halothane from conception
to 60 days of age demonstrated lasting impairment in
memory function, though similar exposure of adult
rats (> 60 days of age) produced no detectable deficits.
Tissue samples from the cortex of rats exposed to
halothane during early development showed “electron
microscopic evidence of neuronal degeneration . . .
[with] permanent failure of formation of the synaptic
web and postsynaptic membrane density in 30 per
cent of the postsynaptic membranes” [14].
Two recent studies [2,3] have investigated the performance of subjects following relatively short-term
exposure to anesthetic gases. A total of 90 subjects
were exposed to one of four different conditions: (1)
nitrous oxide, 500 ppm [3]; (2) nitrous oxide, 500
ppm, and halothane, 15 ppm [3]; (3) nitrous oxide,
500 ppm, and enflurane, 15 ppm [21; and (4) room air
[2, 31. Exposure time was four hours, and subjects
were tested immediately afterward. Groups 1,2, and 3
showed significant decrements on a variety of tests,
ranging from an audiovisual task to subtests of the
Wechsler memory scale. It is notable that the concentrations of gases used are similar to background gas
concentrations detected in functioning operating
rooms 16, 111. Measurable levels of halothane have
been demonstrated in the venous blood and expired
air of operating room nurses and anesthetists [5].
The present study attempted to establish whether
operating room personnel presently working in institutions with good-quality scavenging and airconditioning equipment and with proved low background levels of gases demonstrated any behavioral
deficit. The nurses and anesthesiologists tested had
worked in a variety of hospitals; and older staff members had probably been previously exposed to much
higher background gas levels. For example, the
operating suites of St. Paul-Ramsey Hospital had no
air-conditioning equipment prior to 1965; as one
anesthesiologist put it, “We opened the windows.”
Our test results therefore were analyzed for evidence of both relatively short-term intoxication and
chronic, irreversible intoxication.
We found no evidence for acute reversible intoxication of operating room staff in our study. Subtle and
inconclusive evidence of deterioration was found in
the more chronically exposed group, however. Although no indwidual test result indicated a clearly
significant level of chronic cumulative toxicity, a
strong trend toward superiority of the matched control group was seen. Inspection of the pattern of dif-
ferences and correlation of test scores with years of
exposure, however, only weakly supported the
hypothesis that this trend in fact was based on deterioration of the exposed group. The greatest differences and the highest correlations with years of exposure
were seen on tests of recent memory.
Data from other investigators indicate that relatively high background levels of anesthetic gases can
produce short-term deficits in exposed individuals.
Our study could not eliminate the possibility that, in
addition, individuals perpetually exposed to lower
background levels may manifest subtle but irreversible deficits.
Supported by Grant 801D114 from the Medical Education and
Research Foundation,St. Paul, MN.
The authors wish to express their gratitude to Dr G. Thomas Wier
for his encouragement and willing help. We are additionally grateful
to those members of the Departments of Anesthesia, Pediatrics,
Neurology, and Nursing at both hospitals who conuibuted their
time in these studies. Dr F. H. Van Bergen reviewed the manuscript.
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