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Chapter 12

Chapter 12

Plasma Retention and Urinary Excretion of Dextran and Modified Fluid Gelatin in Combat Casualties*

First Lieutenant John P. Frawley, MSC, USAR
Major Curtis P. Artz, MC, USA

and

Captain John M. Howard, MC, USAR
with the technical assistance of
Corporal William Bohley
Private First Class Edward Hess

and

Corporal Charles Adams

Limitations in the availability of whole blood forward of the surgical hospital as well as the subsequent occurrence of homologous serum hepatitis following the administration of dried human plasma have repeatedly complicated the clinical management of the combat casualty. Following the successful use of dextran and modified fluid gelatin in experimental animals and in surgical patients,8 these materials were made available to forward medical units during the Korean conflict for evaluation of their effectiveness as resuscitative and supportive agents. Further evaluation was necessary since the fate and the limitations of use of these compounds in severely injured patients had not been sufficiently investigated. In addition, the potential usefulness of such information in managing casualties of future disasters was obvious.

Purpose

To substantiate the clinical observations on the effectiveness of dextran and gelatin in combat casualties,1, 2 certain metabolic studies were necessary. It was believed that measurement of the circulatory retention of the plasma expander would be the best index of the degree and longevity of circulatory support. Measurement of urinary excretion rates would offer an index of the method of elimination as might be affected by marked circulatory, renal10 and metabolic disturbances 


*Previously published in Surgery 37: 384, 1955.


167

accompanying massive trauma and hypotension. Of basic importance for the management of combat casualties was the relationship of effective circulatory support to evacuation time. During the period of this study (January-August 1953) the average evacuation time was approximately 3.5 hours, and these experiments were designed to evaluate the potential use of dextran and gelatin as the sole supportive agents during evacuation.

Materials and Methods

Of the several hundred patients who received dextran or gelatin, 16 of the seriously wounded dextran patients and 10 of the seriously wounded gelatin patients were selected for this study. The dextran used was a product of the Commercial Solvents Corp., Lot 250 R2, having an average molecular weight of 42,000,* the modified fluid gelatin was a product of the Knox Gelatine Company, Lot MFG #9, having an average molecular weight of 34,000.**

All patients studied were young, male, United Nations combat casualties with injuries from artillery, mortar, grenade, land mine, or small arms fire. Some appeared in extremis upon admission-with imperceptible pulse and blood pressure. In general, they represent the type of casualty that required immediate blood replacement and extensive surgical treatment. Table 1 demonstrates the wound distribution in the patients studied. 


*Molecular weight determination by Research Unit, Fort Totten, N. J.
**Molecular weight determination by University of Wisconsin.

Table 1. Distribution of Wounds in 26 Combat Casualties Used for Metabolic Studies of Dextran and Gelatin
 

Site of Primary Injury

Sites of Additional Injuries

Chest

Abdomen

Amputation

Compound Fracture

Major Artery

Massive Soft Tissue

Extremity Perforation

Chest

*(1)

0

0

1

0

1

1

Abdomen

0

(15)

2

8

3

9

8

Amputation

0

2

(5)

4

2

3

5

Compound fracture

1

8

4

(14)

2

8

11

Major artery

0

3

2

2

(4)

3

4

Massive soft tissue

1

9

3

8

3

(14)

14

Extremity perforation

1

8

5

11

4

14

(20)

*Figures in parenthesis indicate total sustaining specific wound.


168

An attempt was made to follow a strict protocol, but in the majority of instances deviation from the protocol was necessitated by the patient's condition. Nevertheless, the unanticipated complications, although destroying certain uniformity, were invaluable in determining the effectiveness and role of these expanders in the treatment of severely wounded.

In general, the procedure employed was as follows: Upon admission, all patients received immediate resuscitation and operation was initiated only after blood volume replacement. Support of the circulation with whole blood continued during the operative procedure. Immediately after operation a plasma volume determination was performed (T-1824), and the infusion of the plasma expander started. The time of the infusion varied, in accordance with the patient's condition. If possible, 1,000 ml. was administered within 3 hours, as the standard dose. However, some patients received as much as 3,000 ml. and the infusion time was as long as 14 hours per 1,000 ml. in one patient. The average infusion times per unit (500 ml.) of dextran and gelatin were 2.7 hours and 2.5 hours, respectively. The immediate postoperative period was selected for these studies, since major hemorrhagic loss of the plasma expander could not be controlled prior to this time. Nevertheless, many of the patients were still hypotensive and in serious condition at the time of the study.

During the entire period of infusion and for the length of the study, urine was collected from an indwelling catheter. Aliquots for chemical analysis were taken immediately after the infusion and if the volume was sufficient to permit accurate sampling, at 3-, 6-, 12-, 24-, 48-, and 72-hour intervals. Samples were collected from a few patients for periods up to 7 days for each expander. Heparinized blood samples were drawn simultaneously, and additional plasma volume determinations performed, if feasible, immediately post-infusion and at 6-, 24-, and 72-hour intervals thereafter. Intermediate plasma volumes were estimated by interpolation.

Chemical analyses were performed at the forward surgical hospital. Samples that were not analyzed immediately were stored in the frozen state until analysis was feasible. Plasma and urinary dextran levels were determined by the method of Bloom,3 with only minor modification in technic necessitated by the situation. The procedure, in brief, consisted of alkaline hydrolysis of any protein, precipitation and isolation of macromolecular saccharides, and colorimetric determination of these saccharides with concentrated sulfuric acid and anthrone.

Gelatin determinations in plasma and urine were performed by the measurement of hydroxyproline resulting from acid hydrolysis of the


169

sample, by the method of Neuman and Logan.11 The method uses p-dimethylamino benzaldehyde for color development. The use of known quantities of gelatin for standards enabled conversion of hydroxyproline levels to gelatin levels. Plasma volume determinations were by a T-1824 dilution procedure, basically that of Gregersen,7 using three interval measurements to assure complete mixing. Occasionally, mixing appeared incomplete after the third sampling. Such determinations were discarded and values estimated by interpolation or clinical judgment.

Results

The data obtained from the 16 patients receiving dextran and the 10 receiving gelatin are reported on the scattergraphs shown in Figures 1 through 4. Figures 1 and 2 show the rate of disappearance from the plasma and Figures 3 and 4 show the cumulative urinary excretion for dextran and gelatin respectively. The scatter of the individual points is indicative of the variation. As Figures 1 and 2 demonstrate, both expanders remained in the circulation for approximately the same period of time.

FIGURE 1. Percentage of infused dextran in plasma of 16 combat casualties.


170

FIGURE 2. Percentage of infused gelatin in plasma of 10 combat casualties.

FIGURE 3. Cumulative percentage of dextran excreted in the urine of 16 combat casualties.


171

FIGURE 4. Cumulative percentage of gelatin excreted in the urine of 10 combat casualties.

Six hours after complete infusion an average of only 21 per cent and 23 per cent of dextran and gelatin, respectively, remained. Twelve hours post-infusion an average of only 15 per cent remained for each expander. Subsequent levels fell logarithmically with time to less than 3 per cent at 72 hours post-infusion. This rapid disappearance from the plasma is clearly a function of urinary excretion as indicated by Figures 3 and 4. Six hours post-infusion, an average of 45 per cent and 60 per cent of the infused dextran and gelatin had been excreted in the urine. The amount recovered in the urine continued to reflect the plasma loss until at 72 hours, 58 per cent and 75 per cent had been excreted. It should be noted that the difference in the total quantities excreted need not reflect a true difference in excretion of macro-molecular weight compounds, since inherent differences in chemical methodology exist. The method employed for the dextran determinations will determine dextran and some of the polysaccharide intermediary metabolites thereof. However, the method employed for gelatin will detect not only the parent molecule but also the intermediary metabolites, even to the free amino acid stage. Thus, the additional amount of urinary gelatin may reflect the additional metabolic products detected by the chemical procedure. This same consideration should be applied to the interpretation of the different slopes of the linear portions of the urinary excretion curves-Figures


172

3 and 4. The steeper slope of the delayed gelatin excretion curve is probably a reflection of the additional metabolites detected by the chemical procedure.

Addition of the cumulative excretion and plasma retention at any period of time reveals a significant quantity of either dextran or gelatin unaccounted for by these studies. Six hours post-infusion, this "unaccounted-for" fraction averaged 34 per cent for dextran and 17 per cent for gelatin. Loss through hemorrhage, into extravascular space, by metabolism,5 storage, and by other excretory pathways6 may all be factors contributing to this unaccounted-for fraction. This difference in the quantity of unaccountable dextran and gelatin may reflect the difference in specificity of the analytical methods.

The cases heretofore reported have been studied following operation after hemorrhage was controlled. Of additional importance in evaluating the practicality of an expander in the treatment of mass casualties was information regarding circulatory retention prior to surgical therapy. Therefore, a series of 10 casualties were administered dextran at a forward aid station and the plasma concentration measured between 1 and 4 hours later, upon arrival of the patient at a surgical hospital. These patients had no definitive treatment before arrival at the surgical hospital, only routine nonsurgical measures being employed to control hemorrhage.

Upon admission to the surgical hospital, the blood pressure was determined, and a blood sample drawn for chemical analysis. Blood volume determinations were impossible since hemorrhage was not adequately controlled and blood transfusions were needed almost immediately. For the purpose of calculating the percentage of the expander remaining in the circulation, it was necessary to make an estimation of plasma volume based upon clinical judgment, weight of the patients, and knowledge obtained from hundreds of T-1824 plasma volume determinations on other patients. The values used ranged from 2,200 to 2,500 ml., depending upon these conditions.

Table 2 shows the degree of hypotension upon admission to the surgical hospital and the approximate percentage of dextran remaining in the plasma at this time. It was observed that all 10 patients arrived without serious hypotension although many were seriously wounded and required multiple whole blood transfusions before and during operation. It was also observed that from 23 to 42 per cent of the plasma expander remained in the plasma, depending in general upon the time required for evacuation. The rate of disappearance from the circulation appears somewhat greater than in postoperative patients. This difference, however, appears small enough to be explainable by the existing hemorrhage.


173

Table 2. Plasma Retention of Dextran During Evacuation of Combat Casualties
 

Time of Evacuation (Hours)

Units of Dextran Administered

Blood Pressure at End of Evacuation

Approximate Per Cent of Plasma Dextran at End of Evacuation

1

1

128/50

41

1

2

100/68

40

1.5

1

110/50

30

1.5

1.6

160/80

42

1.5

2

90/70

27

1.5

2

110/58

25

2

1

120/68

32

2

2

 

32

3.5

2

150/80

23

4

1

120/80

80

Discussion

Previous investigators have demonstrated the relationship between circulatory retention and molecular size of dextran and gelatin.4, 9 Therefore, any interpretation of the results of this study must take consideration of these facts. Because of the low molecular weight of both the dextran and gelatin used in this study, prolonged retention could not be anticipated. However, in order to decide if the disappearance rate was faster in the seriously wounded, it is necessary to compare results with a study in normal individuals given expanders with the same molecular distribution. Although such a study is not, to our knowledge, available for dextran, it is available for gelatin. Rousselot,12 using the same lot of gelatin as employed in our other studies, found that the plasma retention of 10 normal humans averaged 35 per cent 6 hours post-infusion and 12 per cent 24 hours post-infusion. Since their infusion time was only 20 minutes as compared with our 2.5 hours per unit (a lag of approximately 4 hours for 2 units), our retention figures of 23 per cent at 6 hours and 9 per cent at 24 hours are quite comparable. We, therefore, feel that the circulatory retention of gelatin in seriously wounded combat casualties is not significantly different from that found in the normal.

One of the basic limitations to the use of dextran and gelatin for the maintenance of blood volume is their temporary retention. Figures 1 and 2 clearly emphasize this consideration. However, the circulatory retention of both dextran and gelatin was of sufficient duration to permit circulatory support during an evacuation period of


174

several hours. It should be emphasized that the retention studies herein reported are based on rather slow drip infusions-averaging 2.5 hours per 500 ml. Since the infusion of plasma expanders in practice often took place almost continuously during evacuation, the immediate post-infusion retention (approximately 40 per cent) was an index of the degree of expansion upon the arrival of the casualty at the surgical hospital. Successful management of the patient during evacuation was, therefore, possible despite the temporary volume expansion. More prolonged expansion would be desirable for situations involving greater delay before the administration of whole blood and undoubtedly could be furnished by larger molecular fractions.4, 9 However, the expansion obtained from 42,000 molecular weight dextran and 34,000 molecular weight gelatin was satisfactory for the short evacuation time in Korea.

Conclusion

Plasma retention and urinary excretion of dextran (average molecule size-42,000) and modified fluid gelatin (average molecule size-34,000) have been followed in a total of 26 seriously wounded combat casualties. No significant difference in plasma retention was observed between the two expanders. The retention of both was of short duration, 21 per cent or 23 per cent being retained in the plasma 6 hours post-infusion. This rate did not appear to be significantly different than that in normal humans receiving the same molecular weight fraction (gelatin). The rapid loss of the expander from the plasma was reflected by a rapid urinary excretion. Nevertheless, both expanders, when administered slowly, maintained a circulating concentration capable of sufficient volume expansion to support many casualties for several hours before blood administration.

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 Observations on the Use of Dextran and Modified Fluid Gelatin in Combat Casualties. Surgery 37: 612, 1955. (Chapter 14, this volume.)

3. Bloom, W. L., and Wilcox, M. L.: Determination of Dextran in Blood and Urine. Proc. Soc. Exper. Biol. & Med. 76: 3, 1951.

4. Bull, J. P., et al.: Dextran as a Plasma Substitute. Lancet 1:134, 1949.

5. Gray, I., Siiter, P. K., and Pulaski, E. J.: Metabolism of Plasma Substitutes. 1. Dextran. Proc. Soc. Exper. Biol. & Med. 77: 626, 1951.

6. Gray, I.: Metabolism of Plasma Expanders Studied with Carbon-14 Labeled Dextran. Am. J. Physiol. 174: 462, 1953.


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7. Gregersen, M. I.: A Practical Method for the Determination of Blood Volume with the Dye T-1824. J. Lab. and Clin. Med. 29: 1266, 1944.

8. Gropper, A. L., Raisz, L. G., and Amspacher, W. H.: Plasma Expanders. Surg. Gynec. & Obst. 95: 521, 1952.

9. Hoffman, W. S., and Kozoll, D. D.: The Fate of Intravenously Injected Gelatine in Human Subjects. J. Clin. Invest. 25: 575, 1946

10. Howard, J. M., Frawley, J. P., Artz, C. P., and Sako, Y.: The Fate of Dextran and Modified Fluid Gelatin in Casualties with Renal Insufficiency. Surg. Gynec. & Obst. 100: 207, 1955. (Chapter 13, this volume.)

11. Newman, R. E., and Logan, M. A.: The Determination of Hydroxyproline. J. Biol. Chem. 184: 299, 1952.

12. Rousselot, L. M., and Metcalf, W.: Progress Report III: Gelatine (MFG-7). D. A. Contract No. DA-49-007-MD-199, Nov., 1952.

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