PROBLEMS IN AVIATION PERSONNEL:

Influence of a Tranquilizer on Temperature Regulation in Man

I, Introduction.

Current widespread use of the common tran-
quilizing agents has prompted considerable
research to clarify the dynamics of the psycho-
active drugs in modifying animal-behavior pat-
terns, ** psychomotor performance, 1 and the
course of certain mental illnesses.” In contrast
to this psychopharmacological approach, rela-
tively little attention has been given to the study
of such drugs as they affect physiological per-
formance." Prior investigations have demon-
strated that the temperature regulation of ani-
mals under the influence of chlorpromazine is
seriously impaired.’ Recent studies from this
laboratory have further shown that propiopro-
mazine is also effective in altering the thermal-
regulatory mechanisms of dogs exposed to either
hot or cold environments.’ It is the purpose of
the present study to elaborate more fully on the
alterations in human thermal balance that follow
administration of the propanediol derivative,
meprobamate.

Il. Experimental Design and Methods.

Thirty-six young men (Table 1) were equally
and randomly divided among three environ-
mental exposures [110°F (43.3°C), 50% RH;
80°F (267°C), 50% RH; 50°F(10.0°C), 50%
RH]. Within each environmental condition,
subjects were given either placebo or mepro-
bamate (800 mg) according to a randomized
schedule conforming with double-blind proced-
ure.* Table 2 outlines the experimental schedule.

‘Taste 1. Some characteristics of subjects (six subjects
in each group). Mean and range.

Age, Wt, Surface area,
Group yr kg sqm
g0° ¥, meprobamate 25 75.0 1.90
22-26 —60.5-83.7 —1.74-2.05
80° F, placebo 24 65.6 LIT
21-26  55.5-80.7 1.60-2.06
50° F, meprobamate 22 734 1.88
20-27  67.2-80,7 —1.80-1.98
50° F, placebo 22 21 1.89
20-28 650-818 1.80-2.00
110° F, meprobamate —_22 79.0 2.01
21-24 — 63.5-95.01.82-2.28
110° F, placebo 22 18 1.95
20-28 643-045 1.85-2.21

Subjects reported to the laboratory at 8:00
8:00 a.m. without breakfast. During preexperi-
mental preparations and for the course of the
exposure, subjects rested in a semireclining po-
sition on a plastic-meshed lounge chair. Each
run began at approximately 9:00 a.m. and ter-
minated at about 12:30 p.m.

Skin temperatures (17 points; coppercon-
stantan thermocouples) were monitored con-
tinuously and recorded on a Leeds-Northrup
Speedomax G recorder. Colonic temperatures

‘Tasre 2, Schedule of events.

Time,
min Event
0 First control measuments; chamber conditions
80°F, 50% RH

10 Second control measurements, first blood sample,
treatment (800 mg meprobamate or 800 mg glu-
cose with 200 ml water).

60 First drug control measurements.

70 Second drug control measurements, second blood
sample.

75 Rapid change of ambient temperature to either
110°F (43.3°0) or 50°F (10.0°C) or remain at 80°F
(267°C).

80 Experimental measurements every 10 minutes,
blood samples at 130 and 190 minutes.

190 Termination of exposure.

(T,) were measured with a YST thermistor
probe inserted 10 cm into the rectum and re-
corded on a Honeywell recorder.

Open-cireuit O2 consumption was determined
by means of the arrangement shown in Fig-
ure 1, Room air (25 J/m) was passed through
a plastic hood encasing the head of the subject.
Temperatures inside the hood were maintained
at chamber temperatures by appropriate heat-
exchange circuits. Outflow air was monitored
continuously for Oz concentration by a Beck-
man F-3 oxygen analyzer. O, consumption was
determined as the difference between O2 con-
tents of inflow and outflow air corrected for
total volume flow.

‘At the times indicated in Table 2, 30 ml of
yenous blood was withdrawn and analyzed for
plasma meprobamate* and total catecholamine
levels by a modification of the method of Mer-



IV. Discussion.

The results of these experiments demonstrate
clearly that a single 800-mg dose of the tran-
quilizer meprobamate may impair the ability of
resting man to maintain thermal balance in hot
and, particularly, in cold environments, Whether
meprobamate interference with temperature
regulation extends to active or working man
undergoing environmental stresses remains to be
determined by further studies,

At present the mechansims by which mep-
robamate alters the ability of man to regulate
body temperature are unknown, Considering
other studies, meprobamate may, like chlorpro-
mazine and propiopromazine, exert direct effects
on the temperature-regulating centers and
consequently inhibit those normal responses to
thermal _ stresses; @.g., vasoconstriction, vaso-
dilation, shivering, and sweating.

The most profound disturbances in regula-
tion occurred during exposure to cold where the
reduction in heat production of the drug group
appears to be primary. This consideration is
based on the well-recognized muscle relaxant
properties of meprobamate.: It must be addi-
tionally considered, however, that the controls
exerted by the temperature-regulating centers
might be sufficiently disordered so that appro-
priate compensations could not occur (i.e, pe-
ripheral vasoconstriction) . It appears, there-
fore, that the disturbance in thermal regulation
generated by meprobamate is most pronounced
during cold exposure, while during heat ex-
posure the deviations from normal are smaller.
At neutral temperatures, meprobamate involve-
ment in thermal regulation is not evident.
These results are supported by the fact that
plasma catecholamines increase markedly in
the cold, while the changes in this stress index
are minimal with heat or neutral exposures.
That the responses we have measured are the
result, of variable tranquilization is discounted
by the fact that plasma meprobamate levels are
comparable from group to group at each of the
time intervals examined. This must mean that
the disrupting properties of the drug are un-
masked only when the demands for thermal
regulation are high.

One observation from our studies deserves
special mention although no definite explana-
tion for it can be offffered at present. During

heat exposure, T, of the drug group is main-
tained higher than that of the placebo group,
in spite of the fact that in both groups T,, heat
production, and body-heat content were simi-
lar. As possible explanations of this point, it is
suggested, although no supporting data can be
offered, that sweating may not have been uni-
form between the two groups or that there may
be differences in the size of the “core” between
groups. Studies are continuing to pursue this
point and to investigate more thoroughly the
mechanisms of meprobamate action in the regu-
lation of body temperature.

REFERENCES

1. Berorr, F. M.: The chemistry and-mode of action of
transquilizing drugs. Ann. New York Acad. Sci.
67 :685-700, 1957.

2. Drttt, V. A.: Pharmacology in Medicine. New York,
McGraw-Hill Book Company, Ine, 1958, p. 331,

8. Hicons, E, A. Tamprerzo, P. F., Apams, T., and
Hormss, D. D.: Effects of a tranquilizer on body
temperature. Proc. Soc. Heptl. Biol. Med. 115 :1017-
1019, 1964.

4. Horrman, A. J., and Lvawia, B. J.: An improved
colorimetric method for the determination of mepro-
bamate in biological fuids. J. Am. Pharm. Assoc.,
Sci. Bd. 48 :740-742, 1959,

5. Horrmay, R. A., and Zarrow, M. X.: Hypothermia
in the rat, hamster, ground squirrel and pigeon, Am.
J. Physiol. 198 :547-552, 1958,

6. Horraan, R. A., and Zarrow, M. X.: Hypothermia
R. W., and Ravoronrs, A.: Experimental studies of
behavioral effects of meprobamate on normal sub-
Jects. Ann, New York Acad. Sci. 67 :701-711, 1957.

7. Menus, R. J.: A semiautomatic method for deter-
mination of catecholamines. Anal. Chem, 6:272-282,
1963,

8. Mou, Y., Turmex, L., Grantiras, H., and Forrma,
J.: Observations on the antihypertensive and sedative
effects of mebutamate, meprobamate and reserpine,
Canad. Med. Assoc. J. 89 :980-982, 1963,

9. Ostnrer, W. A.: Treatment of anxiety states with
meprobamate, Ann. New York Acad. Sei. 67 :766-771,
1957.

10. Pretrven, C. C.: Rropurze, A. J., Sarr, R, P,, JEn-
NEY, E. H., and WittiaMs, H. L.: Comparative study
of the effect of meprobamate on the conditioned
response, on strychnine and pentylenetetrazol thresh-
olds, on the normal electroencephalogram, and on
Dolysynaptic reflexes. Ann, New York Acad. Sci.
67 :784_745, 1957,

11, Taytor, R. B., and Fancry, M. J.: Effect of reserpine
on body temperature regulation of the rat. J. Phar.
‘macol. and Exp. Ther, 188-200-207, 1962,

2. Une, L, and Murer, J. G, (eds).: Drugs and
Behavior. New York, John Wiley and Sons, Inc.,
1960.

67-3067


al T '
o 9, 4 tt a Q tetiesamte -
g y . (80005)
: Wal) ;
: AyAdadiga34 & % |
pam eRe EM Mag ogadtt232
3-100} 4 gor 4
q 4
1 1 1 1 1 1 1 1 1 1 1 1 1 J 1 1
rq T T T T T T T T D T T T T T T T T
+05 4 + ast 4
3 re 4 & re
. eh i
8 — s+ 4 est 4
‘ a
| controt EXPOSURE (80°F, 26.7°C) TP controt EXPOSURE (80°F, 26.7°C)
L 4 1 4 1 1 4 1 1 L A L L 1 1 1 1 J
10% 60 80 100 120 140 160 180 2 10 * 60 80 100 120 140 160 180 200

TIME IM MINUTES

Fiovne 3. Changes in mean skin temperature, rectal temperature,
exposure to 80°F (26.7°C) are shown as a function of time.

‘The 10-minute control value is taken as a baseline and all other values are shown as

Meprobamate (800 mg) or placebo was given immediately following the 10-minute

error of six men.
change from this point.
reading.

C. Ewposure to a hot environment [110°F
(43.3°C), 60% RH). During the first 25 min-
utes of exposure to heat, T, of both groups in-
creased approximately 4°C (7.2°F) and remained
at that level for the duration of the exposure
(Figure 4A). Drug and placebo groups re-
sponded similarly (P = 0.48). Following the
initial decline during the preexposure period, T,
of both groups increased during heat exposure
in a nearly linear fashion (Figures 4B). At end
exposure, the drug group T, increased 0.42°C
(0.8°F), while placebo group T, increased only

body-heat content, and heat production during
Each point represents the mean and standard

037°C (07°F). During the entire period of
exposure, T, of the drug group was consistently
and significantly higher than that of the placebo
group (P = 0.05). TBHC of both groups in-
creased by approximately 1.25 keal/kg at the
time exposure was terminated (Figure 4C).
The difference between groups was not signifi-
cant (P = 0.61). Both groups maintained heat

production relatively constant over the course
of heat exposure (Figures 4D). No drug in-
volvement in this parameter was evident
(P = 0.16).



Fieure 1. Open-cireuit system for measurement of oxy-
gen consumption. Inner hood temperatures were
maintained to correspond with ambient by the heat-
exchange circuits shown.

rills? Throughout the study, visual observation
of the subjects was maintained by closed-circuit
television. All instrumentation was located out-
side the chamber.

Mean weighted skin temperautres (T,) were
computed from weighted values for individual
skin points; average body temperatures were
determined from skin and rectal temperatures
(0.7 T, + 08 T.). Total body-heat content
(TBHC) was calculated according to the ex-
pression (TBHC = average body temperature,
°C X 0.88 X body weight, kg). Heat produc-
tion was computed from oxygen-consumption
data,

Differences between placebo and drug groups
under each condition were determined by analysis
of variance over both preexposure and exposure
periods.

II. Results.

A. Meprobamate concentrations in plasma.
Concentration of meprobamate in plasma dur-
ing each of the environmental exposures is
shown in Figure 2, Peak levels (10.0 to 10.5
»g/ml) were attained 2 hours after oral ad-
ministration of the drug (800 mg) and were
maintained for the duration of the exposure.
No differences between exposure groups were
detected in plasma levels of the drug. Within

the 1-hour period prior to exposure, drug levels
among the three groups ranged between 7.1
and 8.7 yg/ml; the differences were not signifi-

cant.
" T T T T T
conraos erowne
wh 4
+
BL J
i
deb | © trate 4
H 2 of ate
is = wh mee, 4
ab 4
i 1 L 1 L L
i} E w w a rT a)

Ficure 2. Plasma meprobamate levels during the con-
trol period and subsequent exposure to three
environmental conditions. Each point represents the
mean and standard error of six men.

B. Exposure to a neutral environment [80°F
(26.7°C), 50% RH]. No alterations in thermal
balance were detected in either drug or placebo
groups, indicating that meprobamate does not
intefere with temperature regulation of rest-
ing man in a neutral environment (Figure 3).
For purposes of uniformity, all values are re-
ported as changes from the 10-minute control
readings.

During the 75-minute preexposure period, T,
fell about 0.5°C (0.9°F) in both groups (Fig-
ure 8A), This level was maintained throughout
the 80°F exposure, and the differences between
groups were not significant (P = 0.41), The
gradual decline in T, through the preexposure
period was characteristic of all subjects studied.
T, also declined during the preexposure period
to a level about 0.25°C (04°F) lower than
the 10-minute values. This level was also
maintained during the period of neutral expo-
sure. No differences were attributed to the
drug (P = 0.41). Changes in TBHC are shown
in Figure 3C. A small reduction in TBHC
(0.25 kcal/kg) was observed during the pre-
exposure period in both groups, but no further
change was exhibited during neutral exposure.
Again, no drug effects were noted (P = 0.84).
Heat production (Figures 3D) was similar in
both drug and placebo groups (P = 0.21), with
no major changes detectable over the course of
the exposure.


T T T T T T T T
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5-9 goof 4
PrN +
z-s0 3 i Te.
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g \
q 2 re © PLACEBO
4 {EPROBAMATE
(800 mg)
1 1 i 1 1 1 1 1 1 i 1 i J 1
T on fe
oF
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z F+wr wW 4
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é 5 its AN an
5 FH L . / 4
: z fa ttrt
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4 a9 LT conrnoe EXPOSURE (SPF, 10.0°C) te 4 PF conrron | exposure csi*r, 10.0%)
inf

14 4 tt dt at |p 1 1 1
io % 60 80 100 120 140 160 180 200 10” 60 80 100 120 140 160 180 200
TIME IN MINUTES

Ficure 5. Changes in mean temperature, rectal temperature, body-heat content, ‘and heat production are shown
‘as a function of time during exposure to 50°F (10°C). Each point represents the mean and standard error of
six men. The 10-minute control value is taken as paseline and all other values are shown as change from this
point. Meprobamate (800 mg) or placebo was given immediately following the 10-minute readings. Ambient
temperature was changed from 80°F (26.7°C) to 50°F (10°C) at 75 minutes.

E. Catecholamine levels in plasma. No differ- ” T T T T T T
ences in plasma catecholamine levels were de- me conte xrowne 4
tected between drug and placebo groups at any ‘ [
point in the study. To demonstrate the en- = Hér 4
vironmental effects on sympathomedullary funee | serra) —
tions, these data were combined within conditions. Pr oe . on 71
Changes in plasma catecholamine levels for the Saul 4
three exposures are shown in Figure 6. During 3
the preexposure periods, no significant changes du 4
were observed for any group. Increases in cate- i
cholamine concentration during both neutral and 0 x La 10 (10 a0

heat exposures were slight put not significant.

The greatest change in plasma catecholamine suse 6. Changes in plasma total catecholamines shown

as a function of time. Values for placebo and

levels occurred during cold exposure, where sig” rug groups are combined with environmental condt-
nificance (P<0.03) increases of about 50% were tions, Points represent means and standard error
detected. of 12 men.



AM 66-14

PROBLEMS IN AVIATION PERSONNEL:

Influence of a Tranquilizer on Temperature Regulation in Man

P, F. Iampietro
V. Fiorica
J. R. Dille
E. A. Higgins
G. Funkhouser
R. Moses

Approved by Released by

J. Rosert Ditie, M.D. P. V. Srecet, M.D.

Crier, Crvu. AEROMEDICAL Feperat Arr SURGEON
InstITuTe

May 1966

FEDERAL AVIATION AGENCY
Office of Aviation Medicine



al T T T T T T T a! T T T T T T T
a) ’ o herrosauare
e +20 2+ oe (800 mg)
5 +0) g + 02+
5+ ub = ob
z Oo ee. 4 §-o
= Lah 44
q L 1 1 1 1 1 1 1 1
Cc T T T T T T T T D T T T T T T T T
+ 15 4
+t 7
2 tM é
S cS
3 ? 0 nei sad
, +05 &
g 3-05 4
ios :
i 4 4
q = 05 T conreor | exrowteaitenasty 1 conrece | exrosune wrote, anatey
1 4 1 L L 1 L L 1 L 4 1 1 L 1 L 1 1
10 YO 80 100 120 140 160180 200 10% eo 80 100120140160 180 Z00

TIME IN MINUTES

Ficvre 4, Changes in mean skin temperature, rectal tem

shown as a function of time during exposure to 110°F (43.3°C),
‘ute control value is taken as a
Meprobamate (800 mg) or
Ambient temperature was changed from 80°F (26.7°C) to 110°F (43.3°C) at 75 minutes.

error of six men. The 10-min|

change from this point.

readings.

D. Exposure to a cold environment [0°RF
(10.0°C), 50% RH}. During exposure to cold,
T, for both groups declined progressively (Fig-
ure 5A). Although Ts of the drug grop was
lower by 1.25°C: (2.25°F) than that of the
Placebo group at. end exposure, no statistical
significance was attached to the difference
(P = 0.18). Overall falls in T, were 80°C
(14.4°F) and 6.75°C (12.2°F) for the drug and
placebo groups, respectively. T, of both groups
increased during the first hour of cold exposure,
then decreased over the remainder of the ex-
posure (Figures 5B). T, of the drug group was
consistently lower during the exposure than
that of the placebo group. These differences
were significant (P = 0.001). At end exposure

perature, body-heat content, and heat production are

Each point represents the Mean and standard
baseline, and all other values are shown as
placebo was given immediately following the 10-minute

T, of the drug group was 0.3C (0.5°F) lower
than that of the placebo group. Throughout
the exposure period, the drug group maintained
a lower TBHC than did the placebo group
(P = 0.05). At the termination of exposure,
TBHC decreased about 1.6 keal/kg for the
Placebo group and 2.1 keal/kg for the drug
group (Figures 5C). Heat production from
shivering reached peak levels after 20 minutes
of exposure in both groups (Figure 5D). There-
after, these levels were maintained for the dura-
tion of the exposure. Heat production of. the
placebo group increaséd approximately 1.0 kcal/
kg/hr, while heat: production of the drug group
increased only 0.6 keal/kg/hr. The group dif-
ferences approached significance (P 0.06).




FOREWORD

The population concerned with the conduct of civil-aviation matters,
like the population in general, resorts to the use of many types of drugs
to counteract illness, pain, and fatigue and to enhance mental well-being.
Tt is well recognized that many of these commonly available drugs may
have untoward side effects. Since a primary demand on those personnel
engaged in many civil-aviation duties is aviation safety, it is imperative
that the job efficiency of those personnel is in no way compromised, An
unrecognized side effect of any of the generally used drugs could well
furnish that compromise. ‘It becomes critical, therefore, to recognize the
physiological effects that drugs have, especially in the working environment.

The present study was conducted to furnish information on the physi-
ological responses of ‘men under the influence of a commonly used tran-
quilizer. The results. of this investigation indicate that the ability of men
to regulate body temperature is impaired by this drug when ambient tempera-
tures increase or decrease from the normal comfortable working environment.
How additional physical or mental activity further affects the regulatory
impairment described remains unknown and should be the object of further
study.



ACKNOWLEDGMENTS

The authors thank Drs. T. Adams and C.
Brake and Messrs. D. Mayer and D. de Steiguer
for their advice and assistance.

Qualified requestors may obtain Aviation Mi
Center. The general public may
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U.S. Dept. of Commerce, Springfield, Va. 22151