The Influence of Diet on Response toHemorrhagic Shock

WILLIAM R. DRUCKER, M.D., PATRICIA L. HOWARD, M.S., SUE MCCOY, PH.D.

Prior nutrition is known to influence tolerance to hypovolemicshock. This study was undertaken to determine the influence ofdietary composition on the response of animals subjected tohypovolemic shock. Particular attention was directed to the roleof high and low protein diet content with a proportionate changein carbohydrate content to yield isocaloric diets. Rats were placedon one of three diets and were subsequently subjected to shockeither by 1) hemorrhage to a pre-determined mean arterial bloodpressure, or by 2) hemorrhage of a pre-determined volume ofblood based on per cent of body weight. Serial measurementswere made of blood pressure, blood volume removed, survivaltime, hematocrit, blood glucose, pH and blood gases. The resultsindicate that a high protein diet does not prolong tolerance torecurrent blood loss but there is a greatly reduced tolerance tohemorrhagic shock in rats whose body weight was maintained ona low protein/high carbohydrate diet. The latter animals alsoexhibited impaired refill of plasma volume and a paradoxical,continuing hyperglycemic response during hypovolemia. Thisstudy suggests that although an abundant supply of blood glucoseis available as an energy source, glucose uptake in the peripheraltissues is inhibited during hypovolemia by unknown mechanismsand thus homeostasis is curtailed. The protein content of the dietmay be a critical factor in carbohydrate use during shock.

PRIOR NUTRITION is known to influence tolerance tohypovolemic shock. In 1942, Elman7 found that ani-

mals fed a high protein diet consisting of horse meatsurvived longer when subjected to repeated hemorrhagethan dogs fed a normal or non-protein diet. In Pareira'sstudy17 starved rats in tourniquet-induced shock exhi-bited a mortality rate that correlated with the degree ofpre-shock weight loss. Strawitz'9 concluded that severelyfasted rats with depleted hepatic glycogen were less tol-erant to hemorrhagic shock than well nourished rats and

Presented at the Annual Meeting of the Southern Surgical Associa-tion, December 9-11, 1974, Boca Raton, Florida.

This work was supported in part by the U.S. Public Health ServiceGrant #GM21075.

Reprint requests to: Dr. William R. Drucker, Office of the DeanUniversity of Virginia, School of Medicine, Charlottesville, Virginia22901.

From the Department of Surgery,University of Virginia School of Medicine,

Charlottesville, Virginia

frequently developed hypoglycemia before they died.Our previous studies of this problem demonstrate thatinfusion of a bolus of hypertonic glucose, afterhypovolemia had reached the stage of physiological de-compensation, would extend survival time beyond that ofcontrol animals.16

In preparing experimental diets to study the influenceof protein on response to stress there has been a ten-dency to regard carbohydrates simply as a supplemen-tary component to provide calories. The wisdom of main-taining a positive protein balance before and after surgeryhas been debated extensively while the possible disad-vantage of providing the bulk of calories as carbohydratehas been largely ignored. Yet, kwashiorkor in children isprecisely such a clinical condition in which a high intakeof carbohydrate is associated with a deficiency of pro-tein, but with a caloric intake that is adequate to maintainor even increase body weight.2 This study was underta-ken to determine the influence of dietary composition onthe response of animals subjected to the acute stress ofhypovolemic shock with particular attention directed tothe role of high and low protein content in which a pro-portionate change in carbohydrate content gave anisocaloric diet.

Methods

Growing male Sprague-Dawley rats were placed onone of three diets (Table 1). The Charles River OriginalFormula Diet was used as the Control (C) diet. It con-tained a mixture of grains, soy bean, and corn as thesource of carbohydrate, analyzed as N-free extract. Dueto a relatively high content of water (13%), the quantityof nutrient per 100 g of diet was less than that in the test

698

RESPONSE TO HEMORRHAGIC SHOCKVol. 181 * No. 5

TABLE 1. Diet Composition

TestHigh Low

Control Protein Protein

kcal/100 g 341 412 412(calculated)Composition %Protein 26.5 55.0 3.5Carbohydrate 43.0 30.0 81.5Fat 7.0 8.0 8.0Other* 23.5 7.0 7.0

100. 100Io10.0Io.O

*Minerals, vitamins, fiber, and moisture

diets. The high and low protein test diets (HP and LP)*were prepared according to the Hegsted and Changmethod. 13 The variation in protein content was compen-sated for by a proportionate change in carbohydrate con-tent which yielded equal caloric values for both test diets.In order to pellet the HP and LP diets the carbohydratewas provided as cornstrarch (15%) and sucrose. All threediets contained vitamin supplements and the animalswere allowed ad lib. access to their respective diets.

Pilot StudiesIn order to provide rats with similar body weights at

the time of experimental hemorrhage, a pilot study wasconducted to determine the time required for rats on eachdiet to reach a given range of body weight. Rats wereweighed every 3 days and those on HP and C diets gainedsteadily from their initial weight while the rats on LP dietlost weight for 7 to 10 days but subsequently maintained aconstant weight for at least 3 weeks.From this preliminary study it was determined that large

rats (350-375 g) should be fed LP diets to reach a finalweight of about 340 g by the time of the shock study andthat small rats (initially 225 g) should be fed HP and Cdiets in order to reach a similar final weight within thesame time span (3.5 to 7 weeks).

Since growth curves are not linear with time, a pilotstudy was made to compare the growth curves of 7 rats,from both the HP and C diet groups, which started withidentical weights (Fig. 1).Four rats were maintained on the LP diet for 9 weeks

to determine the stability of body weight with prolongedconsumption of this experimental diet (Fig. 1).

Shock ModelsSix hours before hemorrhage, food was removed from

the rat's cage. Anesthesia was administered 90 minutespreceding hemorrhage by an intraperitoneal injection ofNembutal (5 mg/100 g body weight). Tracheal intubationwas not performed. The rectal temperature was main-tained within the range of 37-39 C by the intermittentexternal application of heat. One common iliac arterywas cannulated and connected to a mercury manometer;the contralateral artery was cannulated and connected toa reservoir. Each cannula included a stopcock for remov-ing blood samples. One hundred units of heparin per 100g of body weight was given intravenously and the can-nulae were filled with a solution of heparin in saline (1000u/ml) following withdrawal at each blood sample. Thirtyminutes before hemorrhage and again immediately priorto hemorrhage blood samples were taken to obtain pre-shock values of hematocrit, pH, Pco,, and Po, and bloodglucose. Determination of hematocrit was made in dupli-cate by the micromethod; ofpH, Pco, and Po. with a Radio-meter Blood Gas Analyser*; and of glucose levels byBoehringer Mannheim glucose oxidase assay.**Hypovolemic shock was produced by two

methods-Model I: hemorrhage to a pre-determinedmean arterial blood pressure (MABP) (modified Wiggersmodel) and Model II: hemorrhage to a pre-determinedvolume of blood based on percent of body weight. Inboth models blood samples were taken at 30 minute in-tervals for analyses.

In Model I, 13 rats fed HP diet and 16 rats fed LP diet

*Obtained from General Biochemicals, Laboratory Park, ChagrinFalls, Ohio.

350H

MEANBODYWEIGHT(grams)

C.

300 H

*The London Company, Cleveland, Ohio.**Boehringer Mannheim Corp., New York, New York.

80_O L.P.

601-DIET V

(grams/AOg1) 40h-I

2501-

200

20

High Control LowProtein Protein

40

TIME (days) Protein 22Carbohydrate *Fat

FIG. 1 Effect of dietary protein/carbohydrate on growth. LP-low protein; HP-high protein; C-control diet.

0 10 20 30

699

Ann. Surg. * May 1975DRUCKER, HOWARD AND MCCOY

TABLE 2. Pre-shock Values

High LowProtein Control Proteinn = 20 n = 22 n = 19

MABP(mm Hg) 85.6+15.0 82.0+17.7 54.8±7.4

hct 49.0+1.9 47.6+2.2 41.5±3.1blood glucose

mg/100 141.0±12.9 130.6±12.2 139.6±13.2pH 7.390+.024 7.420±.040 7.407±.023

80.3±+6.3 79.3±10.0 80.1±6.2(mm Hg)

Pco2(mm Hg) 38.1±4.0 34.4±3.5 32.5±4.6

* values = standard error

Mean art

2.0k_

BLOODVOLUMELOSS

(% body wt.)1.0

OL

13

,t P<.o01

0 10

wr.;u, Il%% X,..."..

0 mm Hg 3

11

16 _'

Controlo

High protein diet 13 rats

Low protein diet 16 rats

p<.OOl

1 1 1 130

p<.05

60

were subjected to hemorrhage to 40 mm Hg in 10 min-utes. This MABP was then maintained by further bleed-ing or infusion (modified Wiggers model).5 The volume ofblood removed to maintain the MABP was recordedevery 5 minutes. Survival time was calculated from thebeginning of hemorrhage until death.

In Model II, 20 rats fed HP diet, 19 rats fed LP diet,and 22 rats fed C diet were initially bled a volume equal to0.8% of body weight which was the average volume ofblood lost to reach a MABP of 40 mm Hg in a preliminarygroup of control rats. At 30 minute intervals thereafteruntil death, a volume equal to 0.5% body weight was bledas an approximation of the continuing blood loss neces-sary to maintain a reduced MABP of 40 mm Hg by theWiggers model. Ten minutes were allowed for eachepisode of bleeding with a 20 minute recovery period.The MABP was recorded every 5 minutes. Every 30minutes blood samples were taken for hematocrit, pH,Pco,, Po., and glucose determinations. Survival time was

calculated from the beginning of the first hemorrhageuntil death.

Results

The effect of diet on the physiological and metabolicparameters listed in Table 2 was recorded as typicalbaseline data for rats subsequently subjected tohypovolemic shock. The preshock values for pH, Pco,,and Po, were similar in all rats regardless of diet. How-ever, the MABP and hematocrit were significantly lowerin rats fed a LP diet compared with those fed either a HPor C diet (P<0.001).For Model I, rats subjected to hemorrhagic shock by

the modified Wiggers method, the mean volume of bloodloss required to maintain a MABP of 40 mm Hg is illus-trated in Fig. 2. The P values indicate a significant differ-ence between the rats on HP and LP diets at each sampl-ing time. The mean survival times for rats fed a HP dietor a LP diet is recorded in Table 3. The hyperglycemicresponse was greater in animals fed a HP diet than in

those fed a LP diet (Fig. 3). In rats fed a LP diet the level

TIME (minutes)FIG. 2. Effect of diet on blood volume loss during shock. The P values

compare the volume loss for rats fed HP and LP diets at each samplingtime.

of blood glucose had declined by the time of death of theanimals to hypoglycemic levels, 26 mg/100 ml below thepreshock value.When rats were bled on the basis of body weight

(Model II), all animals regardless of diet demonstratedgood initial recovery of MABP, almost to preshock

I.-

Lu

'U

0=E

:)o- 0

-.0 Em0

i1

Model 1

maximal'

-40- change pre-terminal

+80r

+401

Model 2

DIET

High protein

Low P/High CHO

Control

maximal 'Nchange pre-

terminal

FIG. 3. Effect of diet on changes in hematocrit and blood glucose duringshock. Significance (two-tailed t test): For the maximum change in

hematocrit values in: Model I high protein vs. low protein P<0.001.

Model II control vs. low protein 0.05<P<0.10; high protein vs. low

protein 0.0O<P<0.02; high protein vs. control 0.6<P<0.7. For the

maximum recovery in pre-terminal hematocrit values in Model I high

protein vs. low protein 0. l0<P<0.20. Model II high protein vs. control

0.80<P<0.90; control vs. low protein 0.05<P<0.10; high protein vs.

low protein 0.025<P<0.05. For the maximum change in blood glucose

values in Model I high protein vs. low protein 0.02<P<0.025. Model II

high protein vs. control 0.001<P<0.005; control vs. low protein

P<o.001; high protein vs. low protein 0. l0<P<0.20. For maximum fall

in pre-terminal glucose levels in Model I low protein vs. high protein

0.025<P<0.05. Model II high protein vs. control P<0.001; control vs.

low protein P<0.001; high protein vs. low protein 0.025<P<0.05.

700

RESPONSE TO HEMORRHAGIC SHOCK 701TABLE 3. Survival Time

Diet Survival TimeModel I Model II

High Protein 55.1±+ 13.4 min 99.3 ±+15.0 min*Control 95.2+18.0 min

Low Protein 67.1±20.8 min 82.4+22.4 min

* ± values = standard errorSignificance (two-tailed t test):Model I: High protein vs. low protein = 0.05<P<0. 10Model II: High protein vs. control = 0.40<P<0.50; High protein vs. lowprotein = 0.005<P<0.01; Control vs. low protein = 0.025<P/<0.05

levels. However, survival after the third bleeding episodewas reduced in animals fed a LP diet compared with thatof rats fed HP or C diets. Total survival times from the firsthemorrhage until death are recorded in Table 3.

In contrast to Model I animals, rats fed a LP diet andsubjected to shock by hemorrhage to a pre-determinedvolume (Model II) exhibited a greater hyperglycemic re-sponse than did rats fed HP or C diets. In addition, theblood glucose level remained elevated and was signifi-cantly higher in the pre-terminal sample in the rats fed aLP diet. While the blood glucose concentration of therats fed HP diet was lower than that of the rats fed LPdiet, it was higher than rats fed C diet (Fig. 3).

Fig. 3 also illustrates that during shock the hematocritfell the least in animals fed a LP diet regardless of theshock model employed.There was a progressive fall in pH throughout the

course of shock produced by either model, associatedwith a fall in Pco, and a rise in arterial Po,. No significantdifference in these values was observed among the ratsregardless of diet or shock model employed.

DiscussionThe results of this study indicate that a low protein/

high carbohydrate diet will significantly impair thehomeostatic capacity of rats to withstand repeatedepisodes of blood loss. The following discussion willeliminate several possible causes for this effect in eachshock model and explain why the most likely cause isaltered carbohydrate metabolism.

Diet and StressIt is unlikely that chronic caloric depletion exerted a

significant influence in this study since the animals fedthe low protein/high carbohydrate diet maintained a sta-ble body weight for 3.5 to 7 weeks. The initial weight losswas only 6% of the mean starting weight; however, thelow protein content of the diet undoubtedly had a criticaleffect on total body metabolism as reflected in thehypotension and anemia (Table 1) recorded in these ani-mals prior to hemorrhage.17,20

The significant decrease in survival time for animalsfed a LP diet when subjected to recurrent hemorrhage(Model II) is consistent with an extensive literature indi-cating the detrimental influence of protein depletion ontolerance to stress.8'18'10 Frequently, however, the lowprotein intake is associated with low caloric intake sothat it is difficult to ascertain whether the impaired toler-ance to stress reflects only protein deficiency or bothprotein and caloric deficiency. In this study care wastaken to provide caloric intake adequate to maintain bodyweight (Table 1).

In contrast to the results of Elman7 with dogs subjectedto shock similar to Model II, in this study those animalsfed a HP diet did not exhibit a longer survival time thanrats fed a control (C) diet (Table 3). The greater rate ofweight gain in rats fed HP diets than rats fed C dietsdoes, however, suggest a significant influence of the dieton body metabolism (Fig. 1). The fact that HP and C ratswere selected for study at a time when their body weightswere within a similar range may have obviated an intrin-sic benefit of a high protein intake suggested by thegreater rate of weight gain in those rats fed a HP diet. It isinteresting that some studies indicate that a HP diet mayactually exert a detrimental influence after stress.4 Nosuch effect was apparent using Model II in this study;rather, the animals fed a HP diet responded as well orbetter than those on C diets and significantly better thananimals fed a LP diet (Table 3).

HypotensionThe hypotension found in the rats fed a LP diet may

reflect a decrease in blood volume.17 The severehypotension in turn was probably responsible for thesmall volume of blood loss required to reduce the pre-shock mean arterial blood pressure from 54 mm Hg to thepre-determined arbitrarily selected level of 40 mm Hgupon hemorrhage by the modified Wiggers model (ModelI) (Fig. 2). In contrast, a significantly greater volumeloss, indicative of a higher preshock MABP and a moreeffective homeostatic mechanism, is required to achieveand maintain the low level of blood pressure of40 mm Hgin the rats fed the HP diet than is required in those fed theLP diet.

In view of the marked differences in blood loss be-tween rats fed HP and LP diets in Model I, it is notsurprising that the mean survival time for the protein-deficient rats was longer than for the rats fed a HP diet.But the blood volume loss was so consistently and sig-nificantly greater for rats fed a HP diet that it was neces-sary to employ a different shock model for another com-parison of survival times (Model II).

In Model II it is unlikely that a reduced blood volumewas entirely responsible for the decreased tolerance toshock in the rats fed a LP diet since reduction in blood

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DRUCKER, HOWARD AND McCOY

volume with protein deficiency is proportional to reduc-tion in body weight17 and the animals in this study werebled on the basis of their body weight. The recovery ofMABP of all animals after their initial hemorrhage regard-less of diet was particularly surprising for those deficientin protein in view of their low pre-shock MABP. Thissuggests that factors in addition to blood volume andcardiovascular performance are involved in decreasedtolerance to repeated blood loss. There is an increasedworkload placed on the cardiovascular system by a re-duction in red blood cell mass, but the reduction inhematocrit must be marked before a significant influenceon tolerance to acute hemorrhagic shock is evidenced.5

It is probable that low protein diet results in a reduc-tion of plasma oncotic pressure through inadequate pro-tein synthesis.2' Such reduction in oncotic pressurewould account for the significantly impaired refill ofplasma from interstitial spaces during hypovolemia as

evidenced by the lesser fall in hematocrit with eithershock model (0.001<P<0.025) for rats fed the LP diet.While the blood loss in the modified Wiggers model(Model I) may have been insufficient to induce a drop inhematocrit, the blood volume removed on a basis ofbodyweight (Model II) was certainly adequate, as evidencedby the marked fall in hematocrit that occurred with thismodel, for rats fed HP and C diets (Fig. 3). It is nowrecognized that capillary-interstitial fluid exchange dur-ing shock is a more complex process than the Starling-Bayliss hypothesis and depends, probably to a consider-able extent, on energy use.15

Carbohydrate MetabolismThe hyperglycemia that occurs during shock (Model II)

might be expected to exert an osmotic effect, pullinginterstitial fluid into the circulation. That it did not do soin the LP rats, indicates the severity of impairment of themechanism responsible for refill of plasma from intersti-tial fluid. Failure to observe a significant hyperglycemicresponse in LP rats in Model I probably reflects the smallblood loss in these animals since rats fed an identical dietmanifested a marked rise of blood glucose level whensubjected to a greater blood loss (Model II).The striking finding in this study is the magnitude of

the hyperglycemic response to shock in the LP rats inModel II with the high level of blood glucose persistingduring the terminal phase of shock in these animals. Ahigh carbohydrate intake is known to expand the hepaticstores of glycogen.2.20 Due to the action of epinephrine,liberated as an integral part of the homeostatic responseto hypovolemic shock, there is rapid catabolism of thelarge hepatic glycogen stores. This could account for thegreater rise of blood glucose level than that found in the Cor HP rats during the early phase of shock. Ordinarily,however, the level of blood glucose declines progress-

ively with continuing shock and this fall in blood glucose

level correlates with the onset of physiological deteriora-tion (5,19). In fact, some degree of prolonged tolerance topersisting shock can be achieved by the infusion of abolus of glucose at the time homeostatic mechanismsbegin to fail.'6 The fall in blood glucose level after theinitial hyperglycemic response has been ascribed to de-pletion of hepatic glycogen while the peripheral tissuescontinue to take up glucose.3 In dogs peripheral uptake isaccelerated during shock and the increased rate of re-moval of glucose from the blood occurs so long ashypovolemia persists.6 Presumably, the need of hypoxiccells for additional glucose to support their energymetabolism is sufficient to overcome the inhibition ofcellular uptake expected in view of the high blood levelsof epinephrine and cortisol. The role of insulin, however,as a determinant of peripheral uptake of glucose duringshock remains to be clarified.The high level of blood glucose observed at the time of

death in rats fed a high carbohydrate/low protein dietmight reflect hepatic output of glucose from the largestores of glycogen which continues to exceed peripheraluptake. But previous studies suggest that tolerance forhypovolemia persists until hepatic glycogen is depletedand the level of blood glucose declines.'6"19 While manyfactors undoubtedly contribute to loss of tolerance toshock our hypothesis is that a key requirement forhomeostasis is the continued supply of energy. If this istrue it would be difficult to explain the significantly de-creased survival time of the LP rats when their pre-terminal level of blood glucose was significantly highercompared with rats fed C and HP diets.

Several studies of kwashiorkor suggest a possible in-terpretation of the paradoxical finding of hyperglycemiain the pre-terminal blood samples in Model II (starvationin the midst of plenty). Using labeled glucose, Gillmandemonstrated a decreased rate of removal of blood glu-cose in the presence of dietary protein insufficiency and ahigh carbohydrate intake in humans.9 Many studies indi-cate a deficiency of insulin effect but it has not beenclearly established whether the impairment relates to in-sulin synthesis, release, or peripheral action."'2"24Whatever the precise mechanism may be, the consensusis that a low protein/high carbohydrate diet impairsperipheral uptake of glucose. """, 2 Undoubtedly, someuptake occurs and this is reflected in the results of studieswith Model I in which the blood glucose levels fell tohypoglycemic levels during shock. But in this model, theblood loss may have been too small to stimulate an ap-preciable release of hepatic glycogen. Clearly, studies ofhepatic output and peripheral uptake of glucose duringshock are necessary to account for the terminalhyperglycemia.Thus the hypothesis is advanced that although an

abundant supply of blood glucose is available as an

energy source during shock, uptake of glucose by

702 Ann. Surg. * May 1975

RESPONSE TO HEMORRHAGIC SHOCK

peripheral tissues is inhibited and thus homeostasis iscurtailed in animals maintained on an antecedent highcarbohydrate diet with a low protein content. While themechanisms involved and the hypothesis itself requirefurther study, the results indicate that some minimumamount of protein is required for adequate carbohydratemetabolism. This requirement becomes particularly ob-vious under the conditions of stress such as hemorrhagicshock when energy use is apparently increased.

AcknowledgmentThe authors are indebted to Kathy Cushman, Pat Simpson, and

Connie Maitland for their help in preparation of the manuscript and toCarol Schuit, M.A., for her patient editorial assistance.

References1. Ausman, L. M., Hayes, K. C., and Hegsted, D. M.: Protein

Deficiency and Carbohydrate Tolerance of the Infant SquirrelMonkey (Saimiri sciureus). J. Nutr., 102:1519, 1972.

2. Baig, H. A. and Edozien, J. C.: Carbohydrate Metabolism inKwashiorkor. Lancet, ii:662, 1965.

3. Beatty, C. H.: The Effect of Hemorrhage on the Lactate/PyruvateRatio and Aterial-Venous Differences in Glucose and Lactate.Am. J. Physiol., 143:579, 1945.

4. Cabak, V., Dickerson, J. W. T., and Widdowson, E. M.: Responseof Young Rats to Deprivation of Protein or of Calories. Br. J.Nutr., 17:601, 1963.

5. Drucker, W. R., Holden, W. D., Kingsbury, B., et al.: MetabolicAspects of Hemorrhagic Shock II. Metabolic Studies on theNeed for Erythrocytes in the Treatment of Hypovolemia due toHemorrhage. J. Trauma, 2:567, 1962.

6. Drucker, W. R., Maitland, C. L., Craig, W. D., et al.: Effect ofReduced Peripheral Blood Flow on Glucose Uptake. Clin. Res.,22:648A, 1974.

7. Elman, R.: Acute Protein Deficiency (Hypoproteinemia) in Surgi-cal Shock. JAMA, 120:1176, 1942.

8. Fisher, J., Grun, J., Shapiro, R., and Ashley, J.: Protein Reserves:

Evidence for Their Utilization under Nutritional and DiseaseStress Conditions. J. Nutr., 83:165, 1964.

9. Gillman J., Gillman, T., Scraggs, J., et al.: Some Aspects of theMetabolism of Kwashiorkor and of Normal Infants as Deter-mined by the Utilization of I-14C Sodium Acetate, 2-14C Pyruvateand Uniformly-Labelled 14C Glucose. S. Afr. J. Med. Sci., 26:31,1961.

10. Goldschmidt, S., Vars, H. M., and Ravdin, I. S.: The Influence ofFoodstuffs upon the Susceptibility of the Liver to Injury byChloroform, and the Probable Mechanism of Their Action. J.Clin. Invest. 18:289, 1939.

11. Hadden, D. R.: Glucose, Free Fatty Acid, and Insulin. Inter-relations in Kwashiorkor and Marasmus. Lancet ii:589, 1967.

12. Heard, C. R. C., and Henry, P.A. J.: The Insulinogenic Responseto Intravenous Glucose in Dogs Fed Diets of Different ProteinValue. J. Endocrinol., 45:375, 1969.

13. Hegsted, D. M., and Chang. Y.: Protein Utilization in GrowingRats. J. Nutr., 85:159, 1965.

14. MacDonald, I.: Some Effects of Carbohydrate in ExperimentalLow-Protein Diets. J. Physiol., 160:306, 1962.

15. Mellander, S., and Lewis, D. H.: Effect of Hemorrhagic Shock on

the Reactivity of Resistance and Capacitance Vessels and on

Capillary Filtration Transfer in Cat Skeletal Muscle, Circ. Res.,13:105, 1963.

16. Moffat, J. G., King, J. A. C., and Drucker, W. R.: Tolerance toProlonged Hypovolemic Shock: Effect of Infusion of an EnergySubstrate. Surg. Forum, 19:5, 1968.

17. Pareira, M. D., Sicher, N., and Lang, S.: Blood Volume, SerumProtein, and Hematocrit Changes in Abnormal NutritionalStates. Arch. Surg., 77:191, 1958.

18. Serkes, K. D., Lang, S., and Pareira, M. D.: Response of AcutelyStarved and Chronically Undernourished Rats to Saline TherapyFollowing Tourniquet Shock. Proc. Soc. Exp. Biol. Med.,103:12, 1960.

19. Strawitz, J. G., Hift, H., Ehrhardt, A., and Cline, D. W.: Irreversi-ble Hemorrhagic Shock in Rats: Changes in Blood Glucose andLiver Glycogen. Amer. J. Physiol., 200:261, 1961.

20. Svoboda, D., Grady, H., and Higginson, J.: The Effects of ChronicProtein Deficiency in Rats. Lab. Invest., 15:731, 1966.

21. Whipple, C. H., Hopper, C. W., and Robscheift-Robbins, F. S.:Blood Regeneration Following Simple Anemia. Am. J. Physiol.,53:151, 1920.

DISCUSSIONDR. STANLEY DUDRICK (Houston, Texas): About three or four dec-ades ago in the- Harrison Department of Surgical Research at theUniversity of Pennsylvania, Drs. Ravdin, Parkins, Vars and Rhoadswere interested in studying the effect of hypoproteinemia and its as-

sociated decreased tolerance to shock both in dogs that were plas-mapheresed and in rates that were hypoalbuminemic after having beenfed protein-free diets for several weeks. I recall they tried to correlateprimarily the degree of hypoproteinemia with the rapidity with whichthe animal might go into hypovolemic shock, and these were among theearlier such studies that Dr. Drucker mentioned, together with those ofElman and many other teams throughout the country at that time.

Dr. Drucker has described a phenomenon here that I think perhapseven he didn't expect exactly, the fact that his animals did maintain thesame weight while he was feeding some of them isocalorically highcarbohydrate, low protein, rather than high protein low carbohydrate,certainly bespeaks some subtle change in the body composition of theseanimals. I suspect that there was probably a decrease in total bodyprotein, and an increase on body fat and water.

It would be interesting-and he may already have these data to someextent-to know what the body composition of these animals might be,not only in the serum, but also in the tissue. I'm sure there's some

protein-related mechanism that allows a vast difference in the degreeresponse to injury. You probably have all experienced, in the im-mediate posttrauma period, the tremendous difficulty in maintainingserum albumin concentration and normal oncotic pressure, despite thefact that large amounts-perhaps 150 gm of albumin per day, and

perhaps another 150 gm of amino acids-are given by vein in variousforms of total intravenous therapy.So something happens, particularly under conditions of shock and

trauma, that interferes greatly with protein metabolism. I hope that hiswork and others' might some time elucidate some of the mechanisms.

Dr. Drucker, I was wondering if you have any means by which you

can determine how much of the rise and persistence of thehyperglycemia might be due just to the increased carbohydrate load,and how much might be due to some form of impaired glucosemetabolism.

Also, I was wondering if you did do any serum albumin measure-

ments, and whether you might have actually studied the liver itselfhistologically, or histochemically, to determine or to correlate any

change in the animal, together with the increased susceptibility to shock.particularly in your low-protein, high-carbohydrate animals.

DR. JONATHAN E. RHOADS (Philadelphia, Pennsylvania): I rise to

congratulate Drs. Drucker, McCoy and Howard on what I think is a

very elegant study. The study that Dr. Stanley Dudrick referred to thatwe did was quite a crude study. We were anxious to get an effect, so we

did plasmapheresis on dogs, and kept them on an almost protein-freediet until their proteins came down about to edema levels. We then put

them through a shock procedure which was similar to the second one

that Dr. Drucker described. When we had bled them enough times so

that their blood pressure stayed under 60 mm Hg for 30 minutes, we

considered this the end point.On that basis, the normal animals required an average loss of 4.5% of

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