Battle Casualties in Korea, Studies of the Surgical Research Team, Volume I

Studies of the Absorption and Metabolism of Glucose Following Injury*

Captain John M. Howard, MC, USAR

This phase of the study of the metabolic response to injury was part of a broad program of investigation carried out by the Surgical Research Team in Korea. These studies, made at a forward surgical hospital, were designed, first, to expand the studies of the metabolic response following injury, and second, to study the absorption of glucose from the gastrointestinal tract following various types of injuries, in an effort to gain further insight into practical methods of treating mass casualties.

Methods

Casualties with various degrees of injury were selected for glucose and insulin tolerance tests. Glucose tolerance tests were performed on 14 casualties and 6 healthy soldiers. Four of the casualties had only minor soft tissue wounds. These injuries, although multiple, did not prevent the soldiers` continued preoperative ambulation. Two of this group required only local anesthesia for débridement; two required general anesthesia(pentothal, nitrous oxide, oxygen, and ether). Ten casualties, who had suffered major injuries, were studied. All of these men required general anesthesia except one who required spinal and one burned patient who received no anesthesia. The soldiers were all young men, 18 to 30 years of age, who had been in good health prior to injury. They had been on combat duty for 10 to 40 days prior to injury. All studies were made during the first week following injury and when feasible were repeated one or more times.

Glucose tolerance tests consisted of the oral administration of 100gm. of glucose in a single dose. All subjects had fasted 12 hours since having eaten or having received intravenous fluid. Except for this 12-hourfast, most of the casualties had been on a full diet. Heparinized samplesof blood were drawn prior to the administration of glucose and at regular periods thereafter (Table 1). Glucose analysis was by the Somogyi method.

¹⁵ 

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*Previously published in Annals of Surgery 141: 321, 1955.

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Table 1. Glucose Tolerance Following Injury
 

Patient	Injury	Day Post-Injury	Blood Sugar-Milligrams Per 100 cc.
			Fasting	30 min.	45 min.	60 min.	90 min.	120. min.	180 min.	240 min.
Controls 1	Normal	---	82 mg./ 100 cc.	130 mg./ 100 cc.	126 mg./ 100 cc.	120 mg./ 100 cc.	101 mg./ 100 cc.	88 mg./ 100 cc.	80mg./ 100 cc.	81 mg./ 100 cc.
2	Normal	---	78	127	118	111	100	82	74	79
3	Normal	---	90	146	137	127	119	107	84	94
4	Normal	---	84	131	128	119	101	91	75	86
5	Normal	---	89	143	135	127	113	102	83	90
6	Normal	---	87	127	110	104	86	82	72	73
Average		---	85	134	126	118	105	92	78	84
Minor Injuries
1	Soft tissue	4	95	120	132	123	162	138	128	77
2	Soft tissue	3	93	153	182	174	152	150	121	142
3	Soft tissue	1	98	132	174	163	147	141	111	105
4	Soft tissue	1	97	147	170	161	147	133	121	112
		4	93	142	168	162	140	122	99	102
Average		3	95	139	165	145	150	143	116	110
Major Injuries
1	Perforation of lung	1	95	177	217	237	165	123	104	71
2	Burn	Day of Burn	163	227	247	284	314	189	175	146
		1	120	211	213	209	240	170	102	112
		4	95	144	140	135	128	112	103	96
3	Perforation of lung	1	109	150	145	154	139	136	139	105
		3	100	147	149	167	162	146	128	121
4	Retroperitoneal hematoma	1	107	259	293	---	---	---	---	---
5	Traumatic amputation	2	111	165	163	166	173	161	180	159
6	Perforation of lung	2	156	205	209	204	209	176	217	195
7	Extensive soft tissue injuries	2	130	249	292	296	271	202	166	147
8	Perforation of chest	4	119	189	203	219	213	196	180	159
9	Perforation of stomach and kidney	6	111	161	174	151	136	115	110	118
10	Extensive wounds of abdomen and kidneys	4	114	133	143	161	---	---	---	---
		6	91	104	128	143	---	---	---	---
Average*		3	110	184	196	202	195	157	137	130

*Patients No. 4 and No. 10 excluded.

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Insulin tolerance tests were performed on three healthy soldiers, four casualties with minor injuries and six casualties with severe injuries. Prior to the insulin tolerance test the patients were prepared by fasting as before. Crystalline insulin, 0.1 unit per kilogram of body weight, was given intravenously and the blood glucose concentration was followed at regular intervals for a period of 2 hours. (Table 2).

Results

The glucose tolerance of the unwounded, noncombat soldier appeared normal (Table 1). The fasting blood glucose concentration in the six control subjects averaged 85 mg. per 100 cc. with a range of 78 to 90 mg. per 100 cc. Following the ingestion of glucose, the blood glucose concentration rose to an average peak of 134 mg. per 100 cc., 30 minutes after ingestion. It then fell to its fasting level, or less, within 3 hours.

Following minor injury, the fasting blood glucose concentration averaged95 mg. per 100 cc. when studied on the first to the fourth day after injury. Following the ingestion of glucose, the blood sugar concentration rose to an average peak of 165 mg. 45 minutes after ingestion (Table 1).

During the first week after major trauma, 14 glucose tolerance studies were performed on 10 soldiers (Table 1). The fasting blood sugar concentration averaged 110 mg. per 100 cc. Following the ingestion of glucose, the blood concentration rose to reach a maximum of 202 mg. (average) at 60 minutes. The curve often failed to demonstrate a sharp peak but tended to rise and remain high. Four hours after ingestion, the concentration had not yet subsided to the fasting level (Table 1).

The insulin tolerance studies demonstrated a similar relationship between the degree of abnormality and the degree of injury.

The three control subjects demonstrated an average fasting blood sugar concentration of 82 mg. per 100 cc. (Table 2). Following the intravenous injection of insulin, the blood glucose concentration fell to a low of 40 mg. (average) after 30 minutes. It then returned to the pretreatment level within 2 hours. Following minor injuries, patients were slightly less sensitive to insulin. Four such patients had an average fasting blood sugar of 94 mg. per 100 cc. which fell to 56 mg. 30 minutes after the injection of insulin. Six severely injured casualties were studied during the first5 days after injury. Including two repeat tests, the average fasting glucose concentration was 113 mg. per 100 cc. The concentration fell to 78 mg.(average) after 30 minutes and then returned toward normal but had not, in any instance, quite reached the pretreatment level 120 minutes after the start of the study.

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Table 2. Insulin Tolerance Following Injury
 

Patient	Injury	Day Post-injury	Blood Sugar-Milligrams per 100 cc.
			Fasting	20 min.	30 min.	40 min.	60 min.	120 min.
Control	---	---	82	50	36	44	78	83
Control	---	---	79	57	39	47	75	87
Control	---	---	89	52	46	57	85	84
Control-Average	---	---	83	53	40	49	79	85
Minor Injuries   1
	Soft tissue	2	89	62	55	58	86	87
2	Soft tissue	3	93	67	52	55	96	94
3	Soft tissue	1	98	69	62	61	87	94
4	Soft tissue	1	101	78	61	67	92	96
		4	88	61	51	56	82	85
Average		2	94	67	56	59	89	89
Major Injuries   1
	Perforation of iliac artery. Fractured pelvis.	1	130	62	62	68	82	112
2	Perforation of colon	2 5	126 93	104 79	91 59	94 54	103 81	113 90
3	Extensive injuries of extremities	2	115	98	91	91	106	110
4	Perforation of femoral artery	2	101	68	64	62	81	94
5	Massive wounds of abdomen and extremities	5	112	89	82	83	88	92
6	Perforation of lung and axillary artery	2 5	115 114	98 103	88 97	97 98	102 100	108 104
Average		3	113	87	78	82	93	103

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FIGURE1.
Glucose Tolerance vs. Degree of Injury
Glucose tolerance decreased as the severity of injury increased.

Discussion

As reported in Chapter 2, Volume II, the absorption of water (deuterium oxide) from the gastrointestinal tract is somewhat impaired following injury, and results in prolonged equilibration time following oral ingestion.⁶ The absorption of glucose may also be impaired but no such defect is demonstrated by this study of the blood levels following ingestion. Instead, the blood glucose concentration rises rapidly, and high concentrations are reached, even following wounds of the gastrointestinal tract per se. Any defect in absorption is, therefore, hidden and insufficient to prevent increases in plasma concentration.

The diabetic-type defect in the glucose tolerance curve appears to be more marked following severe injuries than following minor injuries (Figs.1, 2). It gradually subsides as convalescence progresses^{5, 13}(Fig. 3).

Similarly the refractoriness to insulin appears to be directly related to the severity of injury (Fig. 4). As convalescence progresses, the insulin tolerance also returns toward normal (Fig. 5). Infection (empyema) was associated with a continued resistance to insulin (Fig. 6).

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FIGURE2.
Glucose Tolerance Curve
Demonstrating three glucose tolerance curves obtained
simultaneously in three patients with various degrees of injury.

The mechanism of the intolerance to glucose and decreased sensitivity to insulin is not fully known. Starvation will produce such a picture^2,4 but starvation was negligible in some of these patients. Pancreatic ischemia, with resultant insulin deficiency, would hardly lead to insulin resistance. Impairment of hepatic function, demonstrated in some of these casualties as well as in many others,¹⁴ would not be expected to reproduce this picture, although it does produce a decreased sensitivity to insulin.

An increase in circulating epinephrine might contribute to this metabolicpicture¹⁶ although the duration of the epinephrine response following injury is unknown.

This aspect of carbohydrate metabolism following injury is closely related to the adrenal cortical response but is not due directly to adrenal corticalhypersecretion.^{1, 9, 10-12} There is no direct evidence to link this response in carbohydrate metabolism with the severe, uncontrolled "pseudo diabetes" described by Evans and Butterfield as a late complication of thermal burns.³ Burns, Engel and their co-workers,¹ in a detailed and thorough study, demonstrated that the continued

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FIGURE 3.
Glucose Tolerance vs. Stage of Convalescence
As convalescence progressed, the glucose tolerance curve returned toward normal.

administration of cortisone produced a sustained hyperglycemia. A single oral dose of 200 mg. of cortisone to normal subjects was followed 4 hours later by a significant elevation of the blood sugar and an impairment of glucose tolerance. Similarly, cortisone resulted in a slight decrease in sensitivity to insulin. Similar results were noted following administration of cortisone to normal subjects for 8 days. Again, reduced sensitivity to insulin was not prominent. As with the casualties in the present study, ill patients, who were given cortisone, demonstrated a more marked impairment of glucose tolerance and a greater resistance to insulin than did the normal subjects who received cortisone in acute or chronic experiments. This finding, in conjunction with previous studies which demonstrated the tremendous adrenal cortical response to combat stress⁸ and injury,⁷ partially explains the combination of glucose intolerance and insulin resistance.

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FIGURE4.
Insulin Tolerance vs. Degree of Injury
The maximal decrease in blood glucose concentration in the normal subjects was
52 per cent, minor-injury group was 40 percent, and major-injury group was 31 per cent.

Conclusions

As a manifestation of the metabolic response to injury, the oral glucose tolerance curve becomes diabetic in type and the insulin tolerance curve demonstrates a flattening in its pattern. Both the decreased glucose tolerance and the resistance to insulin appear proportional to the degree of injury. Both abnormalities diminish as convalescence progresses. One study suggests that the resistance to insulin persists for a longer period in the face of severe infection.

Following injuries of several types, the battle casualty was found to absorb an appreciable amount of glucose from the gastrointestinal tract as indicated by striking elevations in the blood sugar concentration. Under conditions of mass casualties many such patients may, as a compromise, have to receive water and solutions orally. Further quantitative studies are essential to determine the limitations of this form of therapy.

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FIGURE5.
Insulin Tolerance vs. Stage of Convalescence
On the second day after injury the decrease in the blood glucose concentration following
insulin was only 28 percent of the fasting concentration. On the fifth day,
the concentration decreased by 44 per cent.

FIGURE6.
Unlike the preceding patient, this casualty with an empyema and febrile
course did not demonstrate the return toward normal in insulin sensitivity.

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References

1. Burns, R. W., Engel, F. J., Viau, A., Scott, J. L., Jr., Hollingsworth, D. R., and Werk, E.: Studies on the Interdependent Effects of Stress and the Adrenal Cortex on Carbohydrate Metabolism in Man. J. Clin. Invest. 32: 781, 1953.

2. Conn, J. W.: Interpretation of the Glucose Tolerance Test. Am. J. Med. Sc. 199: 555, 1940.

3. Evans, E. I., and Butterfield, W. J. H.: The Stress Response in the Severely Burned. Ann. Surg. 134: 588, 1951.

4. Goldblatt, M. W., and Ellis, R. W. B.: The Metabolism of Carbohydrate after Starvation. Biochem. J. 26: 991, 1932.

5. Hayes, M. A., and Brandt, R. L.: Carbohydrate Metabolism in the Immediate Postoperative Period. Surgery 32: 819, 1952.

6. Howard, J. M.: Studies of the Absorption and Equilibration of Water (Deuterium Oxide) From the Gastrointestinal Tract Following Injury. A Study of Battle Casualties in Korea. Surg., Gynec. & Obst. 100:69, 1955 (Chapter 2 in Volume II of this series).

7. Howard, J. M., Olney, J. M., Jr., Frawley, J. P., Peterson, R. E., and Guerra, S. Adrenal Function in the Combat Casualty. In press.

8. Howard, J. M., Olney, J. M., Jr., Frawley, J. P., Peterson, R. E., Guerra, S., Smith, L. H., and Dibrell, W. H.: Studies of Adrenal Function in Combat and Wounded Soldiers. Ann. Surg. 141: 314, 1955(Chapter 4 of this volume).

9. Ingle, D. J.: Some Studies on the Role of the Adrenal Cortex in Organic Metabolism. Ann. New York Acad. Sc. 50: 576, 1949.

10. Ingle, D. J.: Parameters of Metabolic Problems. Rec. Prog. Hormone Res. 6: 159, 1951.

11. Ingle, D. J.: The Role of the Adrenal Cortex in Homeostasis. J. Endocrinol. 8: 23, l952.

12. Ingle, D. J.: Some Further Studies on the Relationship of Adrenal Cortical Hormones to Experimental Diabetes. Diabetes 1:345, 1952.

13. Sachar, L., Walker, W., and Whittico, J.: Carbohydrate Tolerance, Blood Ketone Levels and Nitrogen Balance after Human Trauma(Fractures). Arch. Surg., 60: 837, 1950.

14. Scott, R., Olney, J. M., Jr., and Howard, J. M.: Hepatic Function in the Battle Casualty. In press (Chapter 8, this volume).

15. Somogyi, M.: A New Reagent for the Determination of Sugars. J. Biol. Chem. 160: 61, 1945.

16. Stoner, H. B., Threlfall, C. J., and Green, H. N.: Studies on the Mechanism of Shock. Carbohydrate Metabolism in Nucleotide and Ischaemic Shock. Brit. J. of Exp. Path. 33: 131, 1952.