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A Study of Combat Stress in Korea, 1952

Medical Science Publication No. 4, Volume 1

A STUDY OF COMBAT STRESS IN KOREA, 1952:
PHYSIOLOGIC AND BIOCHEMICAL*

FRED ELMADJIAN, PH. D.
AND
STANLEY W. DAVIS, PH. D.

In late August 1952 a team, consisting of personnel from the Army, Navy and Operations Research Office, went to the Far East to study the physiologic, psychologic and psychiatric aspects of combat stress of infantrymen. The preliminary report has already been made (1). This is a presentation of the physiologic and biochemical data compiled and analyzed since that preliminary report, with emphasis on the adrenal cortical function and steroid metabolism. The data include urinary, 17-ketosteroids, Porter-Silber chromogens, sodium, potassium, urea and uric acid.

Subjects

Two principal groups of men in combat were studied: (1) A group of men designated as "Able Co.," who experienced an acute combat situation in which they were the lead company in an unsuccessful attempt to regain a hill position. Data to be presented from this group include a pre-combat (A) sample obtained some 2 hours after they were briefed for the attack; another sample (B) some 17 hours after they were returned to the rear (this group includes only five men who were in the original group), and a 4-day (C) and 22-day (D) follow-up after the principal engagement. (2) The second and smaller group consisted of men who experienced a prolonged and sustained action defending the hill position after it was taken, against enemy counterattacks for 5 days. No precombat (A) data were obtained from this group, which was designated as "George Co." However, data will be presented on (B) some 15 hours after they were relieved and some 10 days (C) after the defensive action.

These data are compared with a group of controls, men who were stationed immediately behind the main line of resistance in blocking position. Data of a group of psychiatric casualties will also be presented.


*Presented 19 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C.


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A second aspect of the data to be reported includes a small sample of each group, who were selected at random, to whom ACTH was given to test adrenal cortical reserve or responsiveness. Previous to testing the men in the combat area, a group of men in Japan (Camp Omiya) were given the ACTH in a test-retest situation to determine reproducibility in the same individual of the adrenal reserve of capacity.

Methods

Samples (not including the ACTH test) represent collections over a mean time of about 3 hours. Except for (B) samples of both Able and George Co., the majority of samples represented before-noon urines. Those receiving ACTH were injected with 2 cc. of Wilson's Gel preparation in the afternoon and collections were made over approximately a 15-hour period; the last voiding being the following morning about 5 to 6 a. m. See details for collecting period in tables 1, 2 and 3.

The method for extraction of 17-ketosteroids was that described by Pincus (2). The urine was hydrolyzed and extracted with ether and prepared to the point of Girard separation in Korea. The extracts in test tubes were flown to the United States and steroid analyses were completed at the Worcester Laboratories. The Butanol extraction for Porter-Silber chromogens and preparation of the samples for analysis were completed in Korea and sent in test tubes to Dr. Peter Forsham at the Metabolic Institute at the University of California Hospital, for the conduction of the Porter-Silber reaction. The method used was a modification of the Reddy method (3). Methods used for electrolytes, urea and uric acid have been previously described (1).

Results

Control and Combat Data

In table 1 and in figure 1, we present the mean 17-ketosteroid output values as mg. per hour in the various control and combat groups. In table 1 group (c) Able Co. A minus officers has been set up separately for two reasons: (1) officers contributed urines to the precombat (A) series but not to the subsequent ones, and (2) the officers exhibited, as a group, an extremely high output level of 17-ketosteroids (17-KS). The average (A) output value for the 5 officers was 1.07±0.187 mg. per hour, whereas the corresponding value for the 15 enlisted men was 0.56±0.06 mg. per hour. It is deduced that either these officers at any rate were a group of "high" 17-KS excretors (4) or that emotional tension attributable to battle anticipation led to especial activation of the pituitary-adrenal system during the pre-combat period.


30

FIGURE 1. Urinary 17-ketosteroid excretion. From left to right the first (A) represents the mean value of the controls; the first column under the second (A) represents the mean of the enlisted men in Able before combat and the second column under the second (A) represents the mean of the commissioned and noncommissioned officers. The third (A) represents the mean of all (enlisted and officers) of men in Able A (see text).

When mg. per hour pre-combat values (c) are compared with post-combat values (d) for Able Co., a not quite significantly higher value is obtained for the latter period. In contrast the post-combat values (f) for George Co. are significantly lower than both the Korean control (a) and the post-combat (d) Able Co. values. There are no other statistically significant differences between the various sets of data. It is notable, however, that the psychiatric battle casualties (h) exhibit the lowest mg. per hour output, indicating no stimulation, but rather a damping of the 17-KS output.

The Na/K ratios are depicted in figure 2. We note that in the control group we have fairly good agreement between A and A' (test-retest at 1-week interval), somewhere around three as a value. However, in observing the data on Able Co. we find that A of Able has a relatively low ratio, indicating some degree of adrenal cortical activity with respect to electrolytes and, furthermore, that it is still low in B. However, in C value we find that the value comes back towards normal, in fact a little above normal, and that this continues in D. With regard to George Co. we find that the ratio is high on the


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Table 1. Urinary 17-ketosteroids of Combat Infantrymen in Korea, 1952

Group studied

Date

Time sampled

Number

17-KS

(a) Korean controls

26, 27 Oct

9:00 a. m.-12:30 p. m.

24

0.64±0.04

(b) Able Co. A

13 Oct

3:00 p. m.-5:30 p. m.

20

0.69±0.08

(c) Able Co. A minus officers.

13 Oct

3:00 p.m.-5:30 p.m.

15

0.56±0.06

(d) Able Co. B

15 Oct

12:30 p. m.-4:00 p. m.

20

0.93±0.19

(e) Able Co. C

19 Oct

6:00 a. m.-1:00 p. m.

20

0.64±0.08

(f) George Co. B

21 Oct

1:30 a. m.-6:00 a. m.

10

0.46±0.04

(g) George Co. C

30, 31 Oct

11:00 a. m.-5:00 a. m.

12

0.52±0.03

(h) Psychiatric casualties.

10, 14 Oct

(3) 2:00 a. m.-5:00 a. m.

(2) 7:00 a. m.-3:00 p. m.

5

0. 43±0.06


Significances


(c, d)
(a, f)
(d, f)

          t
          1. 85
          3. 16
          2. 43

P
<0.1
<0.01
<0.05


    >0. 05
    ----------
    >0. 02

FIGURE 2. Urinary sodium potassium (molar) ratio. Numbers at the base of the open columns indicate the number of determinations included in each group.


32

average, indicating hypoadrenal activity. Then, some 9 to 10 days later we find that the value has returned back towards normal. The psychiatric group shows a low Na/K ratio, indicating some degree of adrenal cortical activity, in fact the same degree of activity as that of Able A or B, but with a very low 17-KS.

FIGURE 3. Urine urea nitrogen excretion. Figures at base of open columns indicate number of determinations included in each group.

Figure 3 shows the urea nitrogen in terms of mg. per hour. We note that in the Korean controls A and A' we have fairly decent agreement, namely, within 400 to 500 mg. urea nitrogen per hour. In A of Able there is an increase; this increase is only of marginal significance. In B we have a real increase in the urea nitrogen, indicating a significant protein catabolism (almost doubling the urea nitrogen output above that of the normal controls). In C we see this return of urea nitrogen back towards its normal value and in D a rather slight increase, but not significant. In the case of the chronic stress situation we find that rather than a nitrogen catabolism, the value is in the normal range, and in the post-stress the C value increases somewhat though not significantly. The psychiatric group shows a decreased urea output. This value is quite low and significantly lower than the controls. It should be pointed out that in the B of Able, the increased urea nitrogen excretion is reflected in the blood with a very significantly high urea value; almost 20 mg. per 100 cc. urea nitrogen in the blood.


33

Figure 4 contains 17-KS values of those individuals of Able on whom we have both B and C values. We note that there are from B to C some decreases and some increases in 17-KS. We also note that the decreases are predominant. The data contributing to the large S. E. also are evident in B of Able. We will see what relationship these values of Able B have to the other indices, such as Na/K, urea and uric acid.

In figure 5 we have a scatter diagram of the Na/K ratio against the 17-KS of Able Co. B, indicated by the dots with the circles around them and the X, indicating the George Co. B group. The correlation coefficient of the Able group was -0.6, but was not significant. However, we note that the extreme values in Able Co., those who had a low 17-KS, are those who have a high Na/K ratio and the converse, the low Na/K ratio individuals, are those who have a high 17-KS. We note that in the George Co. (the X's) they are scattered along the low 17-KS and high Na/K ratio area.

Figure 6 shows the urea nitrogen mg. per hour against 17-KS in mg. per hour. We have a very good correlation of +0.74 and a significance of <0.01. Here again we note that the data of George Co. B are clustered around the low 17-KS and low urea areas.

FIGURE 4. 17-ketosteroid changes of individuals of Able Co. on whom both B (17 hours after battle) and C (4-day followup) were obtained.


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FIGURE 5. Relationship of the Na/K ratio with 17-ketosteroid excretion of both Able Co. B and George Co. B.

We have in figure 7 the same picture as that with the urea when uric acid is plotted against 17-KS. The r here is +0.54, with a significance of <0.01. In general, we see from these data that Able Co. B shows increased adrenal cortical activity in the indices examined between 17-KS and Na/K with catabolism as shown by the urea and uric acid output. The catabolism is evident also with higher creatinine values. This is not apparent in the chronic group, namely, George B, where we have no increase in 17-KS; the nitrogen metabolism is of normal range. In the psychiatric group we find that there is a low 17-KS, but, unlike George B, a low 17-KS with some degree of electrolyte activity.

ACTH Tests

In table 2 are the 17-KS data on the group of seven soldiers stationed at a rehabilitation center in Japan (Camp Omiya), and subjected to an initial (A) and a repeat (B) ACTH test with urine


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FIGURE 6. Scatter diagram of urinary urea nitrogen excretion and the 17-ketosteroids of both Able Co. B and George Co. B.

FIGURE 7. Relationship between urinary uric acid excretion and 17-ketosteroids of both Able Co. B and George Co. B.


36

collected from the 15 hours following ACTH administration. No pre-injection samples were determined. Whether the data are calculated as mg. 17-KS per hour or per 100 mg. creatinine, remarkably high and significant correlations between the data of the two tests are had, indicating that with the ACTH used the 17-KS response is remarkably uniform and highly characteristic for each individual.

Table 2. Reproducibility of ACTH Test-September 16-24, 4 days between A and B*

17-KS, mg./hr.

17-KS mg./100 mg. Creat.

 

A

B

A

B

M 7856

0. 52

0. 57

0. 69

0. 70

R 5249

. 21

. 16

. 38

. 67

W 9926

. 62

. 51

. 90

------------------------------

J 1789

. 73

. 73

1. 14

1. 11

M 2878

. 24

. 35

. 55

. 51

M 7056

. 23

. 29

. 30

. 40

P 9139

. 06

. 15

. 10

. 26

r=0.95

r=0.94

*Time of each collection represented urine collected from 3 p. m. to 7 a. m. thus including overnight sample. ACTH given about 3 p. m.

FIGURE 8. 17-ketosteroid excretion mg./100 mg. creatinine before and after ACTH. Number at the base of open bars indicates the number of individuals tested.


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Table 3 and figure 8 present the mean data of 17-KS for various subjects in the ACTH test. It should be noted, first of all, that the Korean controls exhibited no increase of 17-KS excretion following ACTH administration. Since the pre-injection urine collections were made between approximately 9:00 a. m. and 12:30 p. m., and the post-injection collection for the following 15 hours which included a period of sleep, this apparent lack of stimulation may in fact involve sufficient stimulation to restore toward the morning level the known decline in 17-KS output values occurring in the afternoon and during sleep (5).

In any event, in contrast to the control subjects, the men of Able Co. tested show increases of 17-KS output following ACTH both in the post-combat (B) period and 10 days later (C). The George Co. subjects, on the other hand, demonstrate a decline of 17-KS output following ACTH (which is particularly obvious in the mg. per hour data) during the B period, but 10 days later during ACTH an output increase occurs. The psychiatric casualties demonstrate a significant increase of 17-KS per 100 mg. creatinine in the post-combat period.

Figure 9 contains the Na/K ratio before and after ACTH. We find that on A and A' on eight individuals we have fairly good agreement in adrenal sensitivity as noted by the Na/K ratio. We find that in B of Able the adrenal responds to the ACTH even though the presamples already indicate some degree of adrenal activity. In D sample (C samples were lost) we find that the Na/K ratio is high,

FIGURE 9. Urinary sodium/potassium (molar) ratio before and after ACTH. Number at the base of the open column represents the number of individuals included.


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Table 3. 17-Ketosteroid/Creatinine Excretion Before and After ACTH

 


No.

A

B

C

Before

After

Before

After

Before

After

Korean controls

8

0. 85±0. 05

0. 79±0. 09

----------

----------

---------

----------

Able Co

4

----------

----------

0. 72±0. 09

1. 60±0. 61

0. 68±0. 20

0. 96±0. 07

George Co

4

----------

----------

0. 53±0. 07

0. 43±0. 06

0. 60±0. 06

0. 80±0. 11

Psychiatric casualties

5

----------

----------

0. 76±0. 13

1. 48±0. 13

----------

----------

17-Ketosteroid Excretion Before and After ACTH

 


No.

A

B

C

Before

After

Before

After

Before

After

Korean controls

8

0. 64±0. 05

0. 44±0. 07

----------

----------

----------

----------

Able Co

4

----------

----------

0. 71±0. 11

0. 87±0. 30

0. 49±0. 17

0. 62±0. 21

George Co

4

----------

----------

0. 43±0. 06

0. 27±0. 05

0. 53±0. 04

0. 61±0. 06

Psychiatric casualties

5

----------

----------

0. 43±0. 06

0. 72±0. 32

----------

----------

Note. All after ACTH included night sample: before ACTH of George Co. B represented collection 1:30 a. m.-5 a. m. ACTH was given at 3 p. m. of same day and collection was concluded next morning at about 6 a. m. Psychiatric casualties after ACTH samples did not represent overnight sample but were collected during waking hours.


39

that it is back to normal in the pre-ACTH samples, and is responsive to the ACTH by a reduction in the Na/K ratio. Now the interesting feature is that of George Co., where there is a hypoadrenal cortical activity as indicated by the Na/K ratio. There is, however, a response to the electrolytes after ACTH, though there was no such evidence in the 17-KS. (We will note next that the 17-KS are about the same as the P-S.) The values in C return to normal. In B of the psychiatric group we find that though the adrenals are active there is much more activity in terms of electrolytes after ACTH.

In figure 10 we have the P-S chromogens in terms of mg. per hour in three separate groups: (1) the Korean control, (2) George Co. B and C, and (3) the psychiatric group. Our Porter-Silber data were scattered because only a portion of the total samples extracted were analyzable. This in all probability is due to the high blank and other defects in this particular method used, as well as possible technical errors in preparation for analysis. (At present there is a method described by Nelson and Samuels which does not have this difficulty and the high blanks which make readings impossible have been obviated and this matter has been corrected.) We notice that in our Korean controls there are only a few determinations. The first block indicates the pre-ACTH group and is followed by the post-ACTH. In these particular data the post-ACTH group do not include any of the individuals in the pre-ACTH group. There is a clear increase as a result of ACTH injection. In B of George Co. we notice that there are some seven determinations for pre-ACTH and three for post-

FIGURE 10. Porter-Silber chromogens before and after ACTH (see text).


40

ACTH. In the post-ACTH data the three are included in the pre-ACTH. We note that the adrenal is non-responsive as measured by the P-S reaction. However, in C we note that there is a response to the ACTH after 9 to 10 days, and the four individual determinations are included in the pre-ACTH. In the psychiatric group the two pre-ACTH are not the same individuals as in the post-ACTH. We note here that two features stand out: (1) There is in control samples a greater increase in the post-ACTH in the P-S than there was in the 17-KS, and (2) the adrenal non-reactivity observed in B of George Co. in the 17-KS is confirmed with the P-S reaction. However, in the psychiatric group there is a difference-we have an increased reactivity to 17-KS after ACTH, but we do not have such a phenomenon in the P-S reaction. The data in this group are admittedly small in number and rather scattered, but we feel that these data are at least internally consistent and indicate a differential steroid excretion.

In figure 11 we have a scatter of all ACTH determinations (samples obtained in Korea as well as in Japan), where the Na/K ratio is plotted against the 17-KS mg. per 100 mg. of creatinine. We observe here a correlation between the Na/K ratio and the 17-KS in terms of 100 mg. creatinine, of -0.60 and this is significant to better than 0.001.

FIGURE 11. Relation of urinary Na/K ratio with 17-ketosteroids mg./100 mg. creatinine of all post-ACTH samples of all groups studied in Korea as well as Japan.


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In figure 12 we have all the 17-KS determinations on which we have P-S. The scatter diagram represents P-S mg. per hour against 17-KS mg. per hour. We note two features in these data: (1) From about 0.3 mg. of the 17-KS per hour excretion to about 0.7 mg., we find the distribution of these points such that a small increase in 17-KS is related to a greater increase in the P-S. However, we note that after this critical point of somewhere between 0.7 and 0.8 mg. per hour, the 17-KS continue to increase but the P-S titer decreases. We feel that some fundamental aspect of steroid metabolism is revealing itself here with respect to stress.

FIGURE 12. The relation of the 17-ketosteroid and Porter-Silber chromogens determined on same samples.

In figure 13 we plotted those samples which we considered as controls. They represent the Korean controls and C of George Co., and the ACTH in both these groups. We note that in this chart the solid dot represents all pre-ACTH points and the circled dot indicates post-ACTH test samples. We notice here that the distribution of the points between 0.3 mg. and 0.7 mg. is in large portion if not practically all represented by control value, in which case we have small 17-KS increases with very large P-S increases (fig. 12). Figure 14 depicts all samples which are considered as after-combat samples. We note here that the 17-KS values are high when compared with P-S.


42

FIGURE 13. The distribution of samples considered as controls on which both 17-ketosteroids and Porter-Silber chromogens were obtained.

FIGURE 14. Scatter of the combat samples on which both 17-ketosteroids and Porter-Silber values were obtained.

Discussion

In the comparison of an acute stress against that of a chronic stress situation, a large number of indices indicate that the biochemical


43

status, or say biochemical profile, of a chronic battle situation is quite different from that of the acute. Where, in the acute state there is an indication of increased steroid output with increased protein catabolism, we find that in the chronic state (as far as the steroid measures are concerned) there is a dulling of the adrenal cortical function and no protein catabolism. However, it should be clear from the electrolyte data observed in the chronic stress situation after ACTH that the adrenal is not completely non-responsive; it is non-responsive as far as 17-KS and P-S are concerned, but it does respond to ACTH where some hormone apparently related to the electrolyte function is stimulated. It may be inferred that whatever hormone is being stimulated after ACTH (acting on the electrolytes) in the chronic group, these hormones are not the compounds detectable in 17-KS titer or in the P-S titer. In the pre-ACTH psychiatric group we see that 17-KS and the P-S indicate a lower adrenal cortical function level, but with some degree of electrolyte action present. Furthermore, when ACTH is given in the psychiatric group, there is a marked 17-KS response, but the P-S is not very great, as a matter of fact it is clearly less than normal. The electrolyte response is very sharp. The lowest electrolyte ratios are observed in the psychiatric group. Reviewing the data, then, each particular group, namely, the controls, the acute group, the chronic group and the psychiatric group, has a different "biochemical profile" and can be differentiated one from the other (table 4).

Table 4. Summary

Control data

Acute

Chronic

Psychiatric

Urine

17-KS

 

0.64 mg./hr

 

(+)

 

(-)

 

(-)

P. S. Chrom

0.51 mg./hr

(+)

(-)

(-)

Na/K (molar)

3.0

(-)

(+)

(-)

Urea

450 mg. urea N/hr

(+)

n . . .

(-)

Uric acid

30 mg./hr

(+)

n . . .

n . . .

ACTH

17-KS

 

(+)

 

(+ +)

 

(-)

 

(+ +)

P. S. Chrom

(+ +)

(-)

(-)

(-)

Na/K

(-)

(-)

(-)

(- -)

As far as the consequences to individuals having these various profiles are concerned: (1) The acute stress pattern is in favor of the individual, especially with respect to the possibility of an added insult to the organism such as a physical wound. The organism here has its


44

adrenals quite responsive. The glands are alert, and in case of any physical injury, the organism can very readily handle the result of physical wounds, such as loss of blood, etc. (2) In the chronic stress situation this is not the case. The individual's general physiologic condition indicates that with an added stress, such as a physical wound, the gland may be unable to handle its role in protecting the organism. The adrenal seems to be non-responsive, especially with regard to C 21 compounds. These are the compounds (F type) which are very important in resistance and adaptation to stress.

In the psychiatric group we find that there is a low 17-KS output and a low P-S in the pre-ACTH, but in the post-ACTH values there is a marked response of 17-KS. This marked increase in 17-KS, with the more or less feeble P-S reaction, encourages us to make the following inference: Either the compounds in this particular group are not C 21 in their origin, but C 19, or the C 21 compounds are rapidly converted to C 19. The C 19 in general are mostly androgenic in character and do not have a protective effect in a stress situation. Furthermore, since the steroid excretion is low in the psychiatric group even though the individuals showed marked emotional display and apparent stress, the pituitary possibly has been blocked and is unable to secrete normal amounts of ACTH. We may make the inference that in all probability increased adrenalin secretion could be responsible for this blockage. Thorn has shown that a continued infusion of the adrenalin does cause a blockage of the pituitary-adrenal axis. Adrenalin metabolism in conjunction with adrenal steroid metabolism is an area of study which should be investigated thoroughly, especially with respect to psychiatric breakdown.

As plausible as these points seem, the final proof of these various statements will depend on the chromatography of 17-KS, where the individual steroids will be separated out and quantitatively analyzed. We are getting to know to a great extent what the precursor of each compound (17-KS) in the urine is, and in this way can give a quantitative estimate of the various steroids presumed to be secreted by the adrenal glands.

A Final Speculation. From the data the following hypothesis may be offered. The adrenal gland on the first impulse, that is, in the first stages of stress, produces compound F (C 21) in large amounts. (It does produce some C 19 as well.) However, as the stress continues, we find that either the organism ceases to produce C 21 type of compound and produces in majority C 19, or that C 21 compounds are converted to C 19 more rapidly. These phenomena could have purposive explanations. (1) Since C 21 compounds (such as "F") are catabolic, it is clear that if the catabolism continued over a long period of time the organism would lose considerable nitrogen and deteriorate into a meta-


45

bolic disturbance simulating overdosage of "F." However, with the switch from C 21 to C 19 types (and these compounds are anabolic in their general metabolic effect) we find here a feed-back mechanism, where the excess protein catabolism is now counteracted by the steroids of the C 19 type which are anabolic, whereby the organism now is better able to protect itself. (2) If "F" were produced in excess over a long period of time, it would block the pituitary. The testing of this hypothesis will depend in great measure on the chromatographic results which should be completed within 6 months.

References

1. A Study of Combat Stress In Korea, 1952. Preliminary Report. Technical Memorandum ORO-T-41 (FEC).

2. Pincus, G.: The Analysis of Human Urines for Steroid Substances. J. Clin. Endocrinol. 5: 291,1945.

3. Reddy, W. J., Jenkins, D., and Thorn, G. W.: Estimation of 17-hydroxycorticoids In Urine. Metabolism 1: 511, 1952.

4. Pincus, G., Romanoff, L. P., and Carlo, J.: (Unpublished.)

5. Pincus, G.: A Diurnal Rhythm in The Excretion of Urinary Ketosteroids by Young Men. J. Clin. Endocrinol. 3:195,1943.