Battle Casualties in Korea, Studies of the Surgical Research Team, Volume I
Hepatic Function Following Wounding and Resuscitation With Plasma Expanders*
First Lieutenant Russel Scott, Jr., MC, USAR
Captain John M. Howard, MC, USAR
Introduction
During the recent Korean conflict, dextran and modified gelatin became available for field testing and use by the Surgical Research Team of the United States Army. This evaluation was undertaken by the Armed Forces because the plasma expanders could be produced in mass quantities at low cost, could be stockpiled, would not transmit the virus of hepatitis, and could be stored or carried in the field for long periods of time. They would, therefore, be of great value in the treatment of the battle casualty forward of blood bank facilities. The battle casualty had certain aspects of injury not usually found in civilian trauma, namely, exposure to the elements, delay in treatment, and often injuries of greater magnitude. Although dextran and modified gelatin had been given previously to many animals and people, it was deemed advisable to extend the scope of the study to the battle casualty.
This report represents a small fraction of a broad study on the clinical use of dextran and gelatin in support of the battle casualty.1-3
In addition to the evaluation of the plasma expanders themselves, this study throws light on the interpretation of the hepatic function of the battle casualty resuscitated with stored blood. In a previous communication,9 a study of hepatic function was described in which whole blood, 15 to 20 days of age, was used as the resuscitating agent. Many of the data on hepatic function which were collected in that study were difficult to interpret because the changes in the tests of hepatic function could have been on the basis of the hemolysis of the 15- to 20-day-old bank blood given during resuscitation.
Methods and Material
During the summer and fall of 1952, nine patients were selected for a study of hepatic function following resuscitation with dextran
*Previously published in Annals of Surgery 141: 357, 1955.
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(Commercial Solvent, 6 per cent) and modified gelatin (Knox, 3 per cent). In general, they were casualties who had received light to moderate injuries and in whom it was anticipated that the plasma expander required for therapy would not exceed 1,500 ml. Several, however, received more than 1,500 ml. A comparable group of 10 patients was selected for study and resuscitation with bank blood 15 to 20 days of age.
The casualties were treated in the forward area where tetanus toxoid and penicillin were administered. In some instances, plasma, albumin, dextran, or gelatin was given in the forward area. The casualties reached the Surgical Hospital 3 to 6 hours after being wounded. Study was begun on admission to the hospital and continued until the casualty was evacuated several days later.
The determinations consisted of plasma bilirubin concentration, bromsulphalein retention, urobilinogen excretion in the urine, cephalin flocculation and thymol turbidity. The methods for all determinations have been previouslydescribed.9
Results
Bilirubin
The plasma bilirubin concentration in 15 control subjects averaged 0.3mg. per 100 cc. and never exceeded 0.7 mg. per 100 cc.
Following resuscitation with one of the plasma expanders, the peak concentration was reached about 24 hours after operation, and averaged 0.8 mg. per 100cc. The highest bilirubin concentration observed was 1.8 mg. per 100 cc. (Table 1). After the second day no abnormal values were encountered.
Among the casualties resuscitated with bank blood a prompt rise in plasma bilirubin was noted which reached its maximum concentration 6 hours after operation and averaged 2.0 mg. per 100 cc. (Table 2). By the second postoperative day the average concentration was still 1.0 mg. per 100 cc. Table 3 summarizes the changes observed in the two groups.
Among the 10 casualties resuscitated with blood, 7 were noted to have an abnormal plasma bilirubin concentration after the second postoperative day. In contradistinction, none of the casualties resuscitated with plasma expanders had an abnormal elevation after the second postoperative day.
Bromsulphalein Retention
Among the casualties resuscitated with a plasma expander, the maximum bromsulphalein retention on the first postoperative day was 10 per cent, the average retention being 5 per cent, 45 minutes
Table 1.
Plasma Bilirubin Concentration During and Following Resuscitation With Plasma Expanders
Table 2.
Plasma Bilirubin Concentration During and Following Resuscitation With Bank Blood
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after the intravenous injection of 5 mg. per kg. of body weight. The retention in a group of 10 controls was less than 7 per cent in 45 minutes (average, 5 per cent).
Among the casualties resuscitated with blood the maximum retention on the first postoperative day was 21 per cent, and the average retention was 13 per cent (Table 4).
Cephalin Flocculation Reaction
Five of seven casualties resuscitated with plasma expanders demonstrated abnormal flocculation (greater than 1-plus in 24 hours) (Table 5). Four of the seven casualties reached 3-plus or greater. The return to normal was prompt (average, 2.5 days).
All of the 10 casualties resuscitated with bank blood demonstrated an abnormal flocculation reaction and 8 of the 10 casualties demon-
Table 3. Comparison of Plasma Bilirubin Concentration of Patients Following Resuscitation With Bank Blood and Plasma Expanders(Average of All Patients)
| Groups | Time Postoperative | ||||
Hours Postoperative | |||||
Immediately Postoperative | 6 | 12 | 24 | 48 | |
|
Bank Blood Group |
*1.5 |
2.0 |
1.8 |
1.3 |
1.0 |
|
Expander Group |
0.7 |
0.5 |
0.6 |
0.8 |
0.4 |
*Total plasma bilirubin concentration in mg. per 100 cc.
Table 4. Bromsulphalein Retention* Following Resuscitation With Plasma Expanders and Bank Blood
Patient Receiving Plasma Expander | B | C | D | E | F | Average |
|
Per cent BSP Retention* First Postoperative Day |
1 |
1 |
10 |
8 |
6 |
5 |
|
Patients Receiving Bank Blood |
#5 |
#6 |
#7 |
#9 |
#37 |
Average |
|
Per cent BSP Retention* First Postoperative Day |
16 |
12 |
5 |
21 |
12 |
13 |
*Per cent of dye retained 45 minutes after the intravenous injection of bromsulphalein (5 mg. per kg. of body weight).
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Table 5. Cephalin Flocculation Following Resuscitation With Plasma Expanders (24-hour Reading)*
|
| Hours Postoperative | Days Postoperative | |||||||||
0 | 12 | 24 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
B | ± | ± | ± | ± | ± | -- | ± | ± | ± | ± | ± |
C | 2+ | ± | 2+ | 2+ | 3+ | ± | ± | ± | ± | ± | ± |
D | 1+ | -- | 3+ | 2+ | 3+ | 4+ | -- | -- | -- | -- | -- |
E | 4+ | -- | 4+ | 4+ | 3+ | -- | -- | -- | -- | -- | 0 |
F | 2+ | -- | 3+ | 3+ | 1+ | -- | 1+ | ± | -- | ± | ± |
G | 1+ | -- | 0 | 0 | 0 | -- | -- | -- | -- | -- | -- |
J | -- | -- | 2+ | 2+ | ± | -- | -- | -- | -- | -- | -- |
*Normal Reactions
0 - No flocculation
± - Questionable flocculation
1+ - Slight flocculation
Abnormal Reactions
2+ - Moderate flocculation
3+ - Moderate to marked flocculation
4+ - Marked flocculation
strated a flocculation of 3-plus or greater (Table 6). As an average, the abnormal flocculation persisted about twice as long
(5 days) when the casualty was resuscitated with bank blood (Table7).
Urinary Urobilinogen Excretion
Control studies on the 24-hour urinary excretion of 10 healthy soldiers demonstrated that the maximum excretion never exceeded 4 mg. and was usually less than 2 mg.
All but one of five patients resuscitated with a plasma expander demonstrated abnormal quantities of urobilinogen in the urine. The average excretion on the day of maximal excretion in a given casualty was 40 mg. per 24 hours. There was no characteristic pattern relative to the time of onset or duration of the increased excretion of urobilinogen in the urine (Table 8). This increase in the excretion of urobilinogen is qualitatively comparable to that seen in casualties resuscitated with blood.9
Discussion
A review of the literature fails to demonstrate evidence that dextran or modified gelatin is deleterious to hepatic function in the experimental animal or man, injured or uninjured.5-8 11
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In this study, comparable groups of casualties were selected for resuscitation with bank blood, and with plasma expanders. By comparison, the hepatic function tests deviated more from the normal in the group resuscitated with blood. This observation is not the final answer but can be used as a stepping stone to more definitive study. In addition to an evaluation of the plasma expander itself, these data throw light on the etiology of some of the abnormalities noted in the hepatic function tests following resuscitation with bank blood.
Table 6. Cephalin Flocculation Following Resuscitation With Bank Blood (24-Hour Reading)*
|
| Hours Postoperative | Days Postoperative | |||||||||
0 | 12 | 24 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
1 | -- | 3+ | -- | 3+ | 1+ | ± | 2+ | 1+ | 1+ | -- | -- |
5 | -- | 3+ | -- | 3+ | 2+ | -- | 2+ | 2+ | 1+ | 2+ | -- |
6 | -- | 3+ | -- | 3+ | 3+ | -- | 2+ | 2+ | 1+ | 1+ | -- |
7 | 3+ | -- | 3+ | 4+ | 2+ | 2+ | 2+ | 1+ | 3+ | -- | -- |
8 | 2+ | 3+ | -- | 3+ | -- | 3+ | 1+ | 1+ | 1+ | -- | -- |
9 | -- | 3+ | -- | 4+ | 3+ | 4+ | -- | -- | -- | -- | -- |
25 | 2+ | -- | 3+ | 2+ | 1+ | 3+ | 1+ | 1+ | 1+ | 0 | 0 |
33 | 3+ | 2+ | 2+ | 3+ | -- | 2+ | 2+ | -- | -- | 2+ | 1+ |
36 | 3+ | 2+ | 1+ | 1+ | -- | 1+ | -- | 1+ | 1+ | 1+ | -- |
37 | ± | 2+ | 2+ | ± | 1+ | ± | -- | ± | 2+ | -- | ± |
*Normal Reactions
0 - No flocculation
± - Questionable flocculation
1+ - Slight flocculation
Abnormal Reactions
2+ - Moderate flocculation
3+ - Moderate to marked flocculation
4+ - Marked flocculation
Table 7. Comparison of Cephalin Flocculation Study of Patients Resuscitated With Bank Blood and With Plasma Expanders
|
| Blood Group | Expanders Group |
|
Number of patients in each group |
10 |
7 |
|
Per cent of patients demonstrating abnormal flocculates |
100 |
70 |
|
Per cent of patients attaining a 3-plus reaction |
80 |
57 |
|
Number of days abnormal reaction persisted (Average) |
5 |
2.5 |
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Table 8. Urinary Urobilinogen Excretion Following Resuscitation With Plasma Expanders (Milligrams per 24 Hours)
|
| Days Post-injury | |||||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
B | 4 | 78 | --- | --- | 2 | 0.3 | 0.6 | 0.5 | --- | --- |
C | 1 | 2 | 3 | 0.4 | 0.7 | 0 | 0 | 0.3 | 0.2 | --- |
D | 2 | 6 | 4 | 9 | 3 | 8 | 8 | --- | --- | --- |
E | --- | --- | --- | --- | 93 | 64 | 19 | 32 | 13 | 2 |
F | 0.9 | 12 | 8 | --- | 14 | 8 | 2 | 9 | 11 | 2 |
By coincidence, the selection of patients was such that the group resuscitated with blood was probably slightly less severely wounded than the group resuscitated with plasma expanders; one index of the severity being the volume of intravenous therapy required to support the blood volume of a casualty. The group resuscitated with plasma expanders required an average of 2,400 ml. of intravenous therapy. The probability exists that the volume of plasma expander required to support a given casualty is larger than the volume of blood required. We are, at least, able to say that the group resuscitated with blood did not require more therapy than the expander group.
It should be pointed out that the observed alterations in the hepatic function tests are influenced by a combination of factors, some of which are probably independent of the state of hepatic function itself. The infusion of large quantities of red cells, many of which are nonviable, would presumably influence the plasma bilirubin concentration, the bromsulphalein retention and the production of urobilinogen. The factor of hemolysis has been largely eliminated with the injection of substances free of hemoglobin. Hematomas, of course, cannot be eliminated as a source of hemoglobin pigment.
Analysis of the data revealed that six casualties received a plasma substitute but no whole blood. Of this group, three were shown to have a normal plasma bilirubin concentration throughout the immediate postoperative phase and convalescence (Table 1). Of the three patients resuscitated solely with plasma expanders, who demonstrated an elevated plasma bilirubin concentration during the first 24 hours, one returned to normal by the sixth hour after surgery (Patient C), one the second day (Patient G) and the third (Patient A) was evacuated without subsequent determination. The plasma bilirubin concentration did not rise above 1.8 mg. per 100 cc. in any patient resuscitated solely with a plasma expander. Of particular
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interest is Patient E who received 3,400 ml. of dextran and 3,000 ml. of fresh blood following which the plasma bilirubin concentration remained normal. Similarly, Patient K received 2,500 ml. of dextran in addition to a small amount of blood and his plasma bilirubin concentration was normal on the 2 days it was determined.
These results are in marked contrast with the group of patients resuscitated solely with bank blood (Table 2). If the patients are comparable, one can only conclude that a significant portion of the elevation in plasma concentration of bilirubin was on the basis of the free hemoglobin given during resuscitation or following hemolysis of the stored blood.
Four patients resuscitated with plasma expanders alone had a normal bromsulphalein retention on the first day after injury. Two patients had, in addition to the plasma expander, received whole blood and both had elevated bromsulphalein retention on the first day after injury (Table 4).
In a previous communication,9 it was suggested that part of the bromsulphalein retention could be on the basis of competition between bromsulphalein and the hemoglobin pigments for metabolism or excretion by the reticuloendothelial system or liver. The observation that patients resuscitated with agents not containing hemoglobin had a normal bromsulphalein retention would be in support of this contention. It should, however, be pointed out that the two casualties who received plasma expander and blood were more severely wounded and were the only casualties who suffered shock. The occurrence of shock may well have contributed to the abnormal retention on the first postoperative day. In the previous communication, the positive correlation between shock and bromsulphalein retention was also demonstrated.9 Previous authors have studied liver function after injury or elective surgery.4,10 Bromsulphalein retention, as marked or more marked than the changes observed in the battle casualty resuscitated with plasma expanders, was reported.
An abnormal cephalin flocculation reaction was regularly observed after injury and resuscitation with stored blood.9 It was suggested in the previous report that the early elevation during the first or second day after injury did not represent hepatic damage but was on the basis of metabolism or shifts in albumin or globulin. It was observed also that stored blood itself produced a 3- to 4-plus cephalin flocculation reaction.9 In the casualty resuscitated with dextran, it is also likely that these early changes represent shifts in the various protein fractions. The complete normality or the prompt return of the cephalin flocculation to normal in the casualty who had received only plasma expander is notable. In the casualty resuscitated
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with bank blood this abnormality lasted an average of 5 days. The group of casualties resuscitated with dextran alone did not demonstrate an abnormal cephalin flocculation past the second postoperative day.
Patients resuscitated with whole blood often excreted large quantities of urobilinogen in the urine.9 Since the patients resuscitated with dextran and gelatin excreted less urobilinogen than these previously studied, yet excreted an abnormal amount, it might be suggested that pigment from hematomas, perhaps superimposed on a reduced hepatic function, accounted for these changes.
Conclusion
From this study, no evidence was obtained that dextran or modified gelatin was deleterious to hepatic function. Following resuscitation with the plasma expanders, the alteration in the panel of hepatic function studies was less marked than when the casualties were resuscitated with stored, citrated blood. This observation does not lead to the conclusion that a plasma expander is superior to whole blood. The most likely implication would be that the casualty resuscitated with plasma expander does not receive pigment containing compounds that produce alterations in the standard hepatic function tests which simulate hepatic insufficiency.
Patient Summaries
Patient B (Fig. 1), age 21, height 6 feet, weight 155 pounds, was wounded at 11:00 A. M., 31 October 1952, by a land mine which resulted in a traumatic amputation of the left foot and multiple penetrating wounds of the right leg. Intravenous therapy was not given in the forward area. On admission to the Surgical Hospital at 3:00 P. M., his blood pressure was 135/68, pulse rate 108 per minute. He was not in shock but it was believed that the blood volume deficiency existed and this was treated with 1,000 ml. of dextran in the preoperative ward. During operation he had a limited débridement of the right leg and amputation of the left foot. Throughout the period of resuscitation and surgery he did not require more than the original 1,000 ml. of dextran given in the preoperative ward. His subsequent course was uneventful.
Discussion. This patient represents a lightly wounded casualty who was resuscitated solely with dextran. Except for a minimal elevation in urine urobilinogen excretion on the second postoperative day, the panel of liver function studies remained normal.
Patient C (Fig. 2), age 21, height 6 feet, weight 175 pounds, was wounded at 10:00 A. M., 3 November 1952, by mortar shell fragments, resulting in a traumatic amputation of the left foot. In the aid station he received 500 ml. of plasma. On admission to the hospital at 11:15 A. M., his blood pressure was 115/70, pulse rate 80 per minute. He was pale but warm and exhibited good peripheral venous filling. During the preoperative and operative periods he received 1,500 ml. of modified gelatin. There was no period of hypotension.
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Surgery consisted of surgical amputation of the left foot. The course in the hospital through the succeeding days was uncomplicated.
Discussion. This patient also represents a casualty with light wounds who was resuscitated solely with a plasma expander. In this patient the only abnormality was a transient rise in plasma bilirubin concentration at the sixth hour after operation and a moderate rise in the cephalin flocculation reaction for the first 2 days after surgery.
Patient D (Fig. 3), age 22, height 6 feet, weight 174 pounds, was wounded at 12:15 P. M., 15 November 1952, by a land mine which inflicted multiple penetrating wounds of all extremities. In the aid station he received 1,000 ml. of modified gelatin. On admission to the hospital his blood pressure was 112/70, pulse rate 112 per minute; his skin was pale. He appeared to be in a state of incipient shock. In the preoperative ward gelatin was continued until a total of 2,000 ml. had been given. Bank blood was then started and a total of 2,000 ml. was given. Surgery consisted of extensive débridement of all extremities. During the operation, the patient received an additional 500 ml. of gelatin. Throughout the 8 days in the Surgical Hospital he spiked a daily oral temperature of 103° but was without an obvious site of infection.
Discussion. This patient represents a casualty who required blood in addition to dextran. The need for blood in addition to dextran is probably good evi-
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dence that he was more severely injured than the two preceding casualties. It should be noted that because of more severe injury or because of the administration of bank blood, the liver function studies became abnormal.
Patient E (Fig. 4), age 22, height 6 feet, weight 173 pounds, was wounded at 11:30 A. M., 12 August 1952, by mortar shell fragments. His wounds consisted of about 50 penetrating wounds of the extremities. He received 100 ml. of concentrated albumin at the aid station and arrived at the Surgical Hospital at 12:30 P. M. (1 hour after injury) with a blood pressure of 120/78. He was warm and dry, but his skin was pale. Because he appeared to be in incipient shock, he was given 800 ml. of dextran in the preoperative ward. With the induction of spinal anesthesia, the blood pressure fell from 120/60 to 70/40 and the pulse rate rose to 155. During the 2-hour operation the 50 penetrating wounds of the extremities were débrided and part of the left foot was amputated. At the end of the operation the blood pressure was 110/50, pulse rate 152 per minute. A total of 3,400 ml. of fresh blood was given. Aside from a continuous ooze of a serous fluid through the dressing there was no untoward complication. On the second to the fourth day the patient spiked an oral temperature of 104°. After the fourth day the oral temperature fell to 99°.The etiology of the fever was not apparent. His subsequent course was uneventful.
Discussion. This casualty is similar to Patient D in that both required blood
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In addition to plasma expander. Patient D received stored blood while Patient E received fresh blood, several hours old. It should be noted that both had an elevated bromsulphalein retention on the first postoperative day. Patient D had an early transient rise in plasma bilirubin concentration; Patient E did not. This elevation might have resulted from the nonviable red cells contained in stored blood. Patient E did, however, have a rather marked elevation in urine urobilinogen excretion. The excretion of abnormal amounts of urobilinogen in the urine by patients resuscitated with expanders was fairly constant. The increased excretion may be reflection of hematoma formation with subsequent hemolysis. Urobilinogen excretion in the urine was usually elevated in patients resuscitated with blood.9
Patient F (Fig. 5), age 21, a white male, was wounded at 5:00 A. M. by artillery shell fragments which inflicted about 50 penetrating wounds of all 4 extremities, the neck and the face. No intravenous therapy was given in the forward area and the patient was admitted to the Surgical Hospital at 8:30 A. M. On admission he was considered to be in good condition, with a blood pressure of 120/80. In the preoperative ward 1,000 ml. of dextran was given by fast drip. At operation he was found to have a fracture of the mandible and of one metatarsal bone. Operation consisted of débridement of the 50 penetrating wounds. By the completion of operation he had received a total of 2,000 ml.
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of dextran. He was returned to the ward and his subsequent course was uncomplicated.
Discussion. This patient represents a casualty resuscitated solely with a plasma expander. The only abnormality observed after the first postoperative day was the excretion of abnormal quantities of urobilinogen in the urine.
References
1. Amspacher, W. H., and Curreri, A. R.: Use of Dextran in Control of Shock Resulting from War Wounds. Arch. Surg. 66: 730,1953.
2. Artz, C. P., Howard, J. M., and Frawley, J. P.: Clinical Experience with the Use of the Plasma Expanders. A Study in Korea. (To be published.)
3. Frawley, J. P., Artz, C. P., and Howard, J. M.: Plasma Retention and Urinary Excretion of Dextran and Modified Fluid Gelatin in Combat Casualties. A Study in Korea. (In press.)
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4. Geller, W., and Tagnon, H. J.: Liver Dysfunction Following Abdominal Operations, the Significance of Postoperative Hyperbilirubinemia. Arch. Int. Med. 86: 908, 1950.
5. Goldenberg, M., Crane, R. D., and Popper, H.: Effect of Intravenous Administration of Dextran, a Macromolecular Carbohydrate, in Animals. Am. J. Clin. Path. 17: 939, 1947.
6. Nelson, A. A., and Lusky, L. M.: Pathological Changes in Rabbits from Repeated Intravenous Injections of Periston or Dextran. Proc. Soc. Exper. Biol. & Med. 76: 765-766, 1951.
7. Popper, H., Volk, B. W., Meyer, K. A., Kozoll, D. D., and Steigmann, F.: Evaluation of Gelatin and Pectin Solutions as Substitutes for Plasma in the Treatment of Shock. Arch. Surg. 50: 34, 1945.
8. Reinhold, J. G., von Frijtag Drabbe, C. A. J., Newton, M., and Thomas, J.: Effects of Dextran and of Polyvinylpyrrolidone Administration on Liver Function in Man. Arch. Surg. 65: 706, 1952.
9. Scott, R., Jr., Howard, J. M., and Olney, J. M.: Hepatic Function of the Battle Casualty. A final report to the Army Medical Service Graduate School, 1954. (To be published.)
10. Tagnon, H. J., Robbins, G. F., and Nichols, M. P.: The Effect of Surgical Operation on the Bromsulphalein Retention Test. New Eng. J. Med. 238: 556, 1948.
11. Thorsen, G.: Dextran as a Plasma Substitute. Lancet.1:132, 1949.
