TasLE 3.—Exeretion of Metabolites for All Subjects by Flights*

17 0H CS Epinephrine Nor-epinephrine
Flight# pinep!
pr T#* se P T s P T 8
nn 0.175 0, 061 0, 805 1,223 3.143 1,903
87% 18% 111% 927% 119% 37%
Doe eeeeeee 0,155 0.094 0, 506 2,998 0.386 | —1.128
57% 45% 62% 496% 9% | 338%
B.--------- 0.140 0.081 1.228} —0.111 1, 522 2,032
54% 34% 145% | -06% 39% 53%
4022 0,158 0.204 1.679 1, 807 1, 404 1,135
51% 88% 216% 133% 38% 29%
§.---------| 0.223 | —0.007 1, 566 0.904 0.334 | —0.004
99% —2% 273% 179% 9% -1%
6_--------- 0. 180 0,192 1.8885] 1.865 0, 624 1,678
64% 80% 262% 298% 15% 39%
Tansennneee 0.229 0.120 51.01 2.202 —0, 902 2,436
91% 49% 128% 495% =12% 76%
8..--------] 0.171 0.088 2.094 1,635 1,298 1,685
89% 26% 346% 560% 39% 36%
9.--------- 0.119 0.084 0.968 2. 288 1.179 2.336
36% 44% 175% 401% 32% 59%
10..------- 0.175 0, 288 2.031 1.044 1.949 1,686
95% 132% 314% 165% 62% 45%
0. 180 2.157 0.181
71% 349% 3%
0,211 1,652 2.852
84% 248% 96%
13_-.------ 0.244 1.645 1, 593
108% 127% 32%
14.-------- 0.207 0.274 1,977 2,306 0,825 2, 469
78% 130% 356% ANG 23% 57%
15.-------- 0.107 1.275 1.640 0.685 1,428 0.653
47% 111% 261% 128% 25% 16%
16..------- 0, 228 1.638 1,157
91% 349% 33%
17_-------- 0,348 0, 212 1,200 1.214 1,250 2.930
144% 109% 174% 165% 32% 2%
18_.------- 0.060 0, 253 1.723 1.769 0, 486 1.120
28% 94% 268% 308% 14% 44%
19_.------- 0, 202 1, 683 0, 713
74% 372% 20%
20.--------| * 0,284 1.075 1,358
130% 191% 34%
21.2... 0,182 0.110 0.848 1.892 1,981 1,428
61% 58% 198% 448% 39% 43%
22.2.2... 0, 283 1.172 1.443
142% 225% 40%
0.174 0. 841 1.674
66% 68% 46%

See footnotes on following page.



was used. Secondly, it was not possible to treat
the subjects continuously with the drug, because
of the prohibition against flying solo while on
drug treatment; at least 24 hours were allowed
to pass from the time of the last capsule until
solo flight was undertaken. A sufficiently high
blood level may not have been attained for an
effect to be seen. (If continuous dosage had been
possible, it would have been necessary to design
the study with tranquilizer-treated and placebo-
treated groups of subjects, thus requiring many
more subjects than was technically feasible.)
Thirdly, a more potent drug could have been
used. Chlordiazepoxide was chosen because of
its relative freedom from side effects identifiable
by the subjects. The subjects and the instructor
were asked to give an opinion as to what species
of capsule they had been given. The students
were correct 37-58% of the time and the in-
structor was correct 40-67% of the time. The
student and instructor agreed 60-100% of the
time.

Stress was evident, however, both in the uri-
nary excretion of “stress metabolites” and in the
heart rates. The excretion of catecholamines and
17-OH CS was increased in the pre- and post-
flight specimens over the values in the early
morning and evening specimens. Demos, Hale,
and Williams‘ have published values for excre-
tion of these metabolites by Air Force pilots
flying a variety of missions and have compared

those values with control values obtained from
laboratory workers and administrative personnel.
The solo values in specimen +3 presented in
Table 1 compare with those published by Demos
et. al. for F—102 pilots, as shown in Table 8.

TaBie 8.—Comparison of Student Pilot Data (#3
Specimen) with Demos, ef. al. Data on F-102 Pilots
and Controls !

Students | F-102 Controls
17-08 CS__ 0.47 0.49 0.39
Epinephrine. 2.18 1.60 0.74
Nor-epinephrine_ 5.34 5.38 2.85

V. Conclusions.

This study demonstrates once again that civil-
ian private pilot training is an experience com-
parable in stressfulness to much of the most
hazardous flying done by military pilots. The
use of a mild tranquilizer during the training
of civilian pilots apparently has a negligible
effect in mitigating the stress. However, it
should be pointed out that the drug had no un-
favorable effect on the student’s performance that
was apparent to the instructor. In this respect,
chlordiazepoxide is similar in effect to meproba-
mate used in an earlier study”.

REFERENCES

1. Demos, Grorce T., Henry B, Hate, and Epear W.
WruaMs. “Anticipation Stress and Flight Stress in
F-102 Pilots,” SAM-TR-68-128, November, 1968.

2. Metron, Cartron B., Jr. “Physiological Recordings
from Pilots Operating an Aircraft Simulator,” FAA
OAM Report AM 64-18, September, 1964.

3. Metron, C. E. and Marrene Wicks. “In-flight
Physiological Monitoring of Student Pilots,” FAA
OAM Report AM 67-15, August 1967.


Preflight examinations consisted of determina-
tions of oral temperature (to reveal any unsus-
pected fever), blood pressure, and resting heart
rate. Each subject filled out a questionnaire
about the amount and quality of sleep the night
before, his current subjective feelings, and his

physical complaints. Post-flight examinations
consisted of determination of blood pressure and
the completion of another questionnaire concern-
ing his feelings about the flight, his physical
state, and his opinion about whether or not there
was an effect of the capsule. The instructor also

Tasiz 1.—Catecholamine and Steroid Excretion for All Subjects

Specimen 1 Specimen 2 Specimen 3 Specimen 4
pe | Te | s* P T 8 P T 8 P T 8

7 OH C8 ennenee 0.25 | 0.24] 0.24] 0.42/ 0.43] 0.42} 0.44] 0.42| 0.47] 0.33] 0.29) 0.35
mg./100 mg.

Creatinine_....|::0.10 |40.10 |+0.10 |+0.15 |40.18 |4+0.11 ]40.15 40.18 |40.15 | 0.18 | 0.11 | +£0.13
Epinephrine 0.66] 0.71] 0.67} 1.50| 1.59] 1.34] 211] 228] 2.18] 0.95] 1.06| 1.08

{100 mg.
SSreatinine...-|£0.60 |£0.10 [£0.10 |£0.11 |£0.13 [£0.11 |0.15 |40.17 [£0.15 |40.86 [40.10 | +0.86
Nor-epinepbrine..| 3.98 | 3.90 | 3.85] 4.39| 4.27] 4.65| 5.08| 5.28) 5.34/ 4.50] 4.93| 4.69

(100 mg.
SGreatinine. £0.27 |£0,27./40,18 |+0.19 |+0.19 |10.24 |40.26 |+0.28 |+0.29 [40.22 £0.18 | +0.26

*P—placebo  T=tranquilizer © S—solo (no treatment) Values are + SEM

filled out a questionnaire pertaining to the flight
and was asked to record his opinion of whether
or not the student showed any effect of the
medication.

Til.

Urine chemistry: Three variables indicative of
stress are shown in Table 1. These data show
that treatments cannot be differentiated on the
basis of the excreted metabolites. There is a
distinct increase, however, in the mean values
for the variables in the pre- and post-flight speci-
mens. . The absolute and percentage changes in
metabolite excretion from the (presumably)
basal values in the #1 specimen to the (presum-
ably) stressed values in the #8 specimen are
shown in Table 2. These data show that the
excretion of all the metabolites was increased in
the post-flight specimen, but that the increases
were about equal for the different treatments,
with slightly greater increases in the solo flight
specimens.

Results.

TaBLE 2. Absolute and Relative Differences for
Metabolite Excretion in the #1 and #3 Specimens

Placebo Tran- Solo
quilizer
17 OH CS. -- 0.19 0.18 0.23
mg./100 mg. Creatinine. +76% +75% +96%
Epinephrine--_ 1.45 1.57 1.51
pg./100 mg. Creatinine. +220%  +221%  +225%
Nor-epinephrine-- - ___ 1.10 1.38 1.49
pg-/100 mg. Creatinine, +28% 435% +39%

The results by flights for the three metabolites
are summarized in Table 3. If the assumption
is made that an increase in the amounts excreted
reflects the amount of stress, then Table 3 can
itself be summarized to show which treatment
was*‘associated with greatest stress on each dual
flight (Table 4). This tabulation reveals that
placebo and tranquilizer were equal in potency.


TasLe 3.—Continued

17 0H CS Epinephrine Nor-epinophrine
Flight
Pe TH st P T s P T 8
Py an 0.222 1, 546 0,646
92% 302% 16%
B_..... 0.215 | 0.325 1,562] 2.179 1.493 | 0.840
95% | 152% 157% | 670% 40% 30%
26... 0,293 2.157 2.813
145% 380% 17%
Pl 0.150 1, 089 1.864
52% 132% 44%
rr 0.240 1.826 1.758
89% 300% 52%
29... 0.168 | 0.224 0.984 | 2.197 1.062] 1,656
63% | 113% 181% | 332% 80% 34%
30-.-- 0.182| 0.190 2.092 | 1,568 2,623 | 2,459
60% 79% 290% | 250% 39% 92%
31. 0.262 | 0.106 1.478 | 0.581 2.545 | —1,931
136% 38% 35% 32% 76% | 29%

*The top number in each rank represents the absolute difference between the #1 and #3 specimens. The percentages
represent the relative change. Positive numbers mean that the amount in the #3 specimen was increased over the resting
value in the #1 specimen; negative numbers mean that there was a decrease in the amount excreted in the # 3 specimen.

**P=Placebo  T—Tranquilizer  S—Solo (no treatment)

Taste 4, Summary of Data in Table 3

Flight # 17 OH CS | Epinephrine Nor-
epinephrine
P* TTM* T
P T P
P P T
T P T
P P P
T T T
P T P
P T T
T T T
T P T
T T T
T P P
P P T
T T P
P T P
T T P
T T T
T P P
P T P
P>9/19 P>7/19 P>9/19
T> 10/19 T>12/19 T>10/19

*P=Placebo

T=Tranquilizer

Heart rate: The average heart rates over the
entire syllabus are about the same for both the
treatment and no-treatment flights. However,
the previously-observed increases in heart rates
from the beginning of training to solo and again
at the end of the syllabus* are evident also in
this study (Table 5). The average heart rate
on flight 10, just prior to solo, is higher for the
placebo group than for the tranquilizer group
but the large variance renders the difference in-
significant.

Table 6 is a comparison of heart rates during
maneuvers traditionally held to be among. the
most stressful for students. There is scarcely any
difference in the averages for the tranquilizer and
placebo groups, except for short-field landings
which show the placebo group to be about one
standard deviation greater than the tranquilizer
group. The values obtained on solo flights are
consistently higher than those obtained on dual
flights, as previously found in another study.

Table 7 shows resting heart rates for all sub-
jects by treatment prior to flights. It is evident
from these figures that there is no difference for
the three treatments.


AM 69-12

THE USE OF A TRANQUILIZER (CHLORDIAZEPOXIDE)
IN FLIGHT TRAINING

C. E. Melton, Jr.
Marlene Hoffmann

R. H. Delafield
Approved by Released by
é
J. Rosert Diniz, M.D. P. V. Sreern, M.D.
Cuter, Crvm AEROMEDICAL Feprrat Arr Surgeon
Insrrrute
July 1969

Department of Transportation

FEDERAL AVIATION ADMINISTRATION
Office of Aviation Medicine



Tawue 5.—Heart Rate Averages by Flights

‘Tranquilizer Placebo Solo (No Treatment)
Flight #
Heart Rate Heart Rate Heart Rate
N Mean sD N Mean sD N Mean sD
5 89.98 16.34 6 86.45 11,34
6 91.34 13.71 5 18.13
5 104, 54 20.34 6 12,75
6 94.98 12,74 5 28.77
5 96. 61 27.10 6 10.98
6 101,87 13,43 5 24.31
5 104, 82 19.68 3 8.04
6 99.00 10.11 5 18,55
3 119.31 23.55 5 12,51
6 101,49 12.76 4 26.72
it 108,19 16,91
iL 111, 62 15, 54
10 111, 28 13.66
5 105.04 21.52 6 98.33 6.90
6 95.0! 677 5 101.75 18.03
iL 102.79 12,59
5 108. 86 16.08 3 93.83 8.39
4 88.73. 3.94 4 104.95 26. 56
8 107.11 20.00
8 105. 26 11.39
2 89.41 6.19 2 119,97 14,49
7 94.78 16.12
8 95.36 10. 20
9 95.74 11.85
4 92,46 18,21 2 91.04 35.55
8 99.12 11.93
9 100, 00 16.51
9 103. 46 18.57
5 110. 57 22,67 3 112.90 17,52
4 103. 22 9, 83. 4 104, 26 10. 81
- 5 115.02 20.27 5 106, 41 10.72
Avg. 100.65 Avg. 102.36 Avg. 102.89
Taste 6. Heart Rates During Selected Events Tasz 7. Resting Heart Rates
Solo (No Subject No. | Tranquilizer| Placebo Solo (No
Event Tranquilizer Placebo Treatment Treatment)
101417 102418 107416 81 78 81
106413 106+ 15 116415 80 81 78
107 106 105
103415 103411 116422 95 95 99
92 98 103
94415 109413 118418 87 92 90
- x x 119418 97 95 94
78 83. 82
landings-.-- 10947 102000 |------------ 83 84 83
99 97 93
101 98 98
9143 9243 9143

IV. Discussion.

It is obvious from these data that the tran-
quilizer, chlordiazepoxide, had no observable
effect in alleviating the stress of flights, for there
was no apparent difference in urinary metabolite

excretion or heart rate values between placebo-
and tranquilizer-treated subjects. Several rea-
sons for this lack of effect can be envisioned.
First, the drug may not have been given in suf-
ficient amounts, though the usual 10-mg. dosage



Acknowledgment

The authors express their gratitude to Hoffman-LaRoche, Inc., of Nutley,
NJ. for their help and for the Librium (chlordiazepoxide~-HC1) and the
identical-appearing placebo capsules.

Qualified requesters may obtain Aviation Medical Reports from Defense Documentation
Center. The general public may purchase from Clearinghouse for Federal Scientific and
Technical Information, U.S. Dept. of Commerce, Springfield, Va. 22151.


THE USE OF A TRANQUILIZER (CHORDIAZEPOXIDE) IN FLIGHT
TRAINING

I. Introduction,

Studies on student pilots undergoing primary
flight training have led to the conclusion, based
primarily on their heart rates, that the human
stress incident to flight training is generally
equivalent to that experienced by astronauts or
pilots in actual combat. The stress is believed
to arise from the fear and anxiety felt by stu-
dents in the flight situation where there are many
unfamiliar elements and where the potential for
failure or embarrassment is great. These latter
considerations led to the idea that these “ten-
sions” could possibly be alleviated and thus be
evaluated by the use of a tranquilizer during the
course of student training.

IL. Methods.

Eleven male students, ranging in age from
81 to 46 were subjected to a conventional but
highly standardized flight syllabus at the Civil
Aeromedical Institute (CAMI). All of the sub-
jects had passed the FAA Private Pilot written
examination and each possessed a Class II or III
medical certificate. All flight training was given
in a Cessna 150 airplane by a certificated flight
instructor who, aside from casual knowledge of
the experiment, was otherwise unrelated to the
conduct of the experiment.

For each flight, the subjects were fitted with
stainless steel plate ECG electrodes positioned
on the lateral chest walls where they were se-
cured with an elastic strap. The skin was cleaned
with alcohol prior to attachment of the electrodes
and contact with the skin was effected through
conductive jelly.

The subjects were requested to collect urine
specimens after voiding at bedtime the night
before the flight. Specimen #1 consisted of any
voidings during the night plus the voiding upon
arising in the morning. Specimen +2 consisted
of a voiding just prior to flight, specimen #3
was the urine voided in flight and immediately

post-flight. Specimen #4 consisted of all the
urine voided until bedtime.

Prior to every dual flight, with the exception
of the flights that included solo, each student
received four capsules that contained 10 mg. of
chlordiazepoxide or a placebo. The first capsule
was taken at 4:00 PM the day prior to flight, the
second at bedtime, the third upon arising, and
the fourth 1 hour prior to flight. The contents
of the identical-appearing capsules were unknown
to the experimenters and the subjects. The code
was not broken until the conclusion of the study.
‘The syllabus consisted of 31 flights, with the first
solo flight specified on flight 11 and cross-country
flights similarly specified on flights 14, 15, 17,
19, 20, and 21. Just prior to each dual flight,
each student was examined by a physician who
determined the student’s fitness for flight.

The leads from the biosensors and from dual
microphones, one each for the student and in-
structor, were connected to appropriate ampli-
fiers, the outputs of which led to three channels
of an on-board instrumentation tape recorder.
The entire recording system was battery oper-
ated. Recordings were taken continuously
throughout every flight.

Data reduction was carried out in the labora-
tory at CAMI. The ECG was processed through
a cardiotachometer, rigged so that the R-wave
triggered a pulse output that was used to trip a
printing digital counter. Print-out, reset, and
paper advance functions were controlled by
motor-driven notched wheels that activated
microswitches every minute. Events were iden-
tified by the voice record that. was played back
over a speaker simultaneously with the ECG.
The ECG records were marked according to on-
going activity.

The urine specimens were acidified and frozen
until they were analyzed for epinephrine, nor-
epinephrine, 17-OH corticosteroids, and creati-
nine. All values were referred to 100 mg.
creatinine,