(Received for publication January 1, 1947) other conditions, a change in the L/P ratio is

Transcription

1 TRAUMATIC SHOCK. XV. CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK IN THE DOG' By ARNOLD M. SELIGMAN, HOWARD A. FRANK, BENJAMIN ALEXANDER AND JACOB FINE (From the Surgicl nd Medicl Reserch Deprtments, Beth Isrel Hospitl, Boston, nd the Deprtments of Surgery nd Medicine, Hrvrd Medicl School, Boston) (Received for publiction Jnury 1, 197) Trumtic shock my be regrded s process of rpid biologicdisintegrtion resulting from progressive tissue noxi consequent to peripherl circultory filure. This concept explins the recent groth of interest in the intermediry metbolic derngements in shock, hich hve been found to be severe, involving mny enzyme systems concerned ith protein nd crbohydrte metbolism. Since the liver is mster orgn in this respect, it deserves close scrutiny. Tht this orgn should suffer t lest s severely s ny orgn in shock is suggested by the shrp reduction in volume nd velocity of flo through the portl system (1, 2) nd by the observed reduction of liver excretory functions erly in shock (3). Moreover, the recent demonstrtion tht crosscircultion of the dog in hemorrhgic shock from donor dog vi the liver is cpble of preventing the onset of irreversibility to trnsfusion () nd of curing such irreversibility hen estblished (5) indictes tht liver dmge plys primry role in the shock phenomenon. It is, therefore, nturl tht reltionship should be sought beteen metbolic derngements in lrge prt normlly under liver control nd the progressive deteriortion chrcteristic of the lte stges of the shock syndrome hen therpy is no longer effective. The metbolism of pyruvic nd lctic cids nd glucose shos bnormlities in shock (6, 7). In shock the rise in blood pyruvic cid nd the simultneous nd usully disproportiontely greter rise in lctic cid, producing n increse in the lctic to pyruvic cid rtio, re due to noxi. Even though chnges in blood concentrtion of these metbolites re not specific mnifesttions of trumtic shock, since they occur lso in fever, folloing vigorous exercise, epinephrin injection, nd in other conditions, chnge in the L/P rtio is considered evidence of n bnorml crbohydrte metbolism s, for exmple, in thimine deficiency (8). It s considered necessry to explore the possible reltionship beteen-spontneous nd induced shifts in the blood concentrtion of these substnces nd the progressive deteriortion in hemorrhgic shock leding to the development of irreversibility to trnsfusion. This communiction reports the results obtined from study of tolernce curves of glucose, lctic nd pyruvic cids dministered intrvenously in vrious stges of hemorrhgic shock, both before nd fter trnsfusion. METHOD Irreversible hemorrhgic shock s produced in morphinized dogs by technic described elsehere (). The injection of compounds s folloed by rteril blood smpling every 15 minutes for 1 hour therefter. Tolernce curves ere obtined before hemorrhge, during hemorrhgic shock t constnt blood pressure of 3 mm. Hg, nd fter trnsfusion of ll shed blood. Pyruvic cid2 (Merck) s given s the sodium slt (neutrlized to phenolphthlein) in doses of.5 to 1 grm for ech tolernce test. Lctic cid (Merck, 85 per cent pure) s given s the sodium slt (neutrlized to phenolphthlein) in 1-grm doses. Blood pyruvic cid s determined by the method of Bueding nd Wortis (9), blood lctic cid by the method of Brker nd Summerson (1), totl mino cid nitrogen by the colorimetric method of Frme, Russell, nd Wilhelmi (11). Blood glucose s determined by the method of Folin (12). RESULTS 1. Blood levels of lctic, pyruvic, mino cids in hemorrhgic shock nd totl A. In dogs (M-22, 23, 27, 28) there s progressive rise in blood concentrtion of ll 3 cids before therpeutic trnsfusion. The rise in lctic cid s steeper thn tht in pyruvic cid 1 The ork described in this pper s done under contrct, recommended by the Committee on Medicl Reserch, beteen the Office of Scientific Reserch nd 2The pyruvic cid s distilled ithin 1 Development nd Hrvrd University. the time of injection. 536 eek prior to

2 CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK ith resulting 2- to -fold elevtion of the lctic/pyruvic cid rtio. Figures 1 nd 2 give the dt for dogs M-23 nd M-27, hich re typicl. B. In the sme dogs fter therpeutic trnsfusion, hich s ineffective for survivl, the lctic cid level fell proportiontely more thn the pyruvic cid level, ith return of the L/P rtio to ner norml. The mino cid level did not chnge. In dog M-27, observed for 5 hours fter trnsfusion, secondry rise in lctic nd mino cid occurred fter the blood pressure hd gin fllen belo 6 mm. Hg. 537 ride solution s performed in 3 norml dogs (M-15, 38, 39). The lctic nd pyruvic cid levels rose promptly in ll 3 dogs nd the L/P rtio rose in 2 dogs. The lctic cid concentrtion leveled off fter one hour in 2 dogs, but continued to rise in the third dog (M-38), hich ent into shock during the injection (2 hours) nd died 15 minutes fter discontinunce of the intrvenous drip. In 2 of 3 dogs, elevtion of the blood glucose level s folloed by fll to belo the initil concentrtion during the second nd third hours. The third dog (M-15) mintined n elevted blood glucose level throughout the experiment hich lsted 3 hours. All dogs shoed systolic blood pressure levels of bout 2 mm. Hg during the epinephrin drip. Dog M-15 survived; dog M-39 (Figure 3), hose systolic blood pressure s 1 mm. Hg fter discontinunce of the injection, died 12 hours lter. 2. Lctic nd pyruvic cid blood levels folloing epinephrin injection in norml dogs A continuous intrvenous injection of epinephrin hydrochloride (3 mgm. per kgm. per min.) in volume of 2 to ml. of.85 per cent sodium chlo CC. n V) :. -j z so CL. -J 3 9 5: X. 1- $ Z x FIG. 1.

3 538 A. M. SELIGMAN, H. A. FRANK, B. ALEXANDER, AND J. FINE - IL 9 -j 1 12 co - - U-J t 1 ;, z i 6. Us N X I N FIG. 2. The chnges in blood lctic nd pyruvic cids in these experiments ere not unlike those observed during vigorous exercise (8), but of loer order of mgnitude thn s observed in hemorrhgic shock. Comment: The chnges in blood lctic nd pyruvic cids in shock, therefore, re not referble entirely to epinephrin secretion or to the blood pressure level. 3. Blood levels of lctic nd pyruvic cids in hemorrhgic shock in drenlectomi ed dogs To determine the reltionship of the blood levels of these cids in shock to totl drenl secretion, unilterl drenlectomy s folloed in 2 eeks by removl (under locl nesthesi) of the second drenl. Immeditely therefter hemorrhgic shock s induced. Poor tolernce to hemorrhge nd poor response to trnsfusion ere observed. In 5 dogs (M-36, 37,, 1, 2) so studied (Figure, M-36) though the blood glucose fell, prompt rises in lctic nd pyruvic cid nd in the L/P rtio similr to those noted bove (Section 1) ere observed. The lctic nd pyruvic cid levels remined elevted fter trnsfusion. Comment: These chnges in shock, therefore, cnnot be ttributed to epinephrin or corticl hormone secretion. It lso ppers tht they ber no reltionship to the level of blood glucose.. In vitro experiments To determine to ht extent the observed shifts in lctic nd pyruvic cids my reflect intrvsculr chnges prt from those due to the ctivity of tissues other thn blood, in vitro experiments ere mde s follos: 65 mgm. of glucose ere dded to 26 ml. of sterile rteril heprinized blood drn under oil, ith resulting rise in glucose concentrtion from 7 mgm. per cent to 33 mgm. per cent. The blood s kept t 37.5 C. under oil for 2 hours nd smpled t 2-minute intervls. It took on the color of venous blood during the period of observtion. The glucose concentrtion remined unchnged but the L/P

4 CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK 539 FULLuWING ADDITION OF Z W GLUCOSE W 6.~~~~~~ ~~~~~~z Co GLUCOSE L W -i s i ) AMINO ACID NITROGEN.2 C to. 2 2 X 2 FIG. 3. rtio rose slightly, though significntly, in 2 hours, in prt t lest becuse of fll in the pyruvic cid, phenomenon not observed in shock. The em _) W X, 2 FIG. 5. chnges in lctic cid, pyruvic cid, nd mino cid concentrtion re shon in Figure 5. One hundred fifteen mgm. pyruvic cid neutrlized ith NOH s dded to 3 ml. rteril heprinized blood drn under oil nd kept t 37.5 C. The pyruvic cid concentrtion rose from.8 mgm. to 32 mgm. per cent immeditely folloing the ddition of pyruvic cid nd dropped to 3 mgm. per cent in 1.5 hours. There s concomitnt rise in lctic cid, presumbly derived Co i UV -I co I- I-. z. 9 i l. -j 2 z i 9. FIG.. FIG. 6.

5 5 A. M. SELIGMAN, H. A. FRANK, B. ALEXANDER, AND J. FINE from the dded pyruvte through the ction of the red cells, Figure 6. Comment: These observtions indicte tht decline in blood oxygen content per se does not ccount for ny substntil frction of the rise in the blood lctic cid in shock. 5. Glucose tolernce curves in hemorrhgic shock Seven dogs (M-16, 29, 3, 33, 3, 7, 8), in hich irreversible hemorrhgic shock s produced, ere given 1 grm per kgm. of glucose intrvenously before hemorrhge, gin during shock, nd gin folloing trnsfusion. Glucose, lctic nd pyruvic cid levels in rteril blood ere determined t 15-minute intervls fter ech injection. The disppernce of injected glucose from the blood in norml dogs required more thn 1 hour. The disppernce rte during hemorrhgic shock s prolonged, but folloing trnsfusion it s ner norml, hether the subsequent decline in blood pressure s precipitous or grdul. Comment: The lctic nd pyruvic cid levels chrcteristic of shock ppered not to be influenced by the injection of glucose (Figure 7). 6. Lctic cid tolernce curves in hemorrhgic shock Sodium lctte, injected into norml dogs, incresed the blood lctic cid concentrtion from 1 to 3 mgm. per cent t the pek of the rise. The lctte s usully, but not lys, completely clered. In one experiment the rteril blood ph s loered from 7. to 7.2 (glss electrode). No significnt ltertion in blood pyruvic cid occurred. Folloing the injection of lctte in hemorrhgic shock (Figure 8, M-19), the resulting superimposed rise in the blood lctic cid level s no greter thn tht folloing the injection of lctte in the norml dog. The shocked niml s ble to cler the blood of injected lctte bout s ell s the norml dog. Folloing trnsfusion, injected lctte s clered from the blood t norml or greter thn b, FIG. 7.

6 CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK 51 1 LACTIC IRREEVERSIBLE ACID TOLERACE sod IMrS/com HEMORRHAGIC TE STS SHOCK I ' o 11"I 12 C') (no. 6 -i I 9 * 8~ 6h Y LACTATE C) U /SLOOD PRESSURE 2 ra -9 2 I LACTATE L LACTATE do 82 2 to A I e-p IVP I FIG. 8. '.IL S P.X norml rte. In one experiment (Figure 8, M-19) the expected fll in blood lctic cid level s so rpid s to msk completely the increse due to injected lctte, even though trnsfusion s ineffective nd s folloed by rpid decline in blood pressure. Comment: Since injected lctte is clered from the blood in hemorrhgic shock t norml rte even hen the niml is dying fter n ineffective trnsfusion, the deteriortion of the orgnism in shock cnnot be ccounted for by the filure of enzyme systems to ctbolize this crbohydrte intermedite. The foregoing dt lso suggest tht n increse in the rte of lctic cid production is not the sole determinnt of the level chieved. An ltertion in the equilibrium beteen lctte nd pyruvte or other crbohydrte intermedites my exist nd be due in prt to impirment of volume nd velocity of blood flo rther thn to dmge to enzyme systems. 7. Lctic cid tolernce in cidosis To lern hether the concentrtions of lctic nd pyruvic cids re determined by cidosis previling in shock, 1-grm doses of neutrlized lctic cid ere injected intrvenously into norml dogs before nd fter the production of cidosis by intrvenous hydrochloric cid. In one dog (M-53, Figure 9) the lctic cid tolernce curve folloing the injection of 1 grm of lctte s the sme before nd 1 minutes fter the injection of 25 ml. of 1 per cent solution of hydrochloric cid. In nother dog (M-52), 1 grm of lctte rised the rteril ph from 7. to 7.6. In the course of 3 minutes, 25 ml. of.1 N HC1 ere then injected. During the injection the blood pressure dropped to 7 mm. Hg, then to 3 mm. Hg nd the rteril blood ph dropped to 7.2, but the blood lctic cid rose only 1 mgm. per cent. Deth occurred fe minutes lter. In this experiment

7 . *. P S,. s 1 ~~~~~~~~~~3 52 A. M. SELIGMAN, H. A. FRANK, B. ALEXANDER, AND J. FINE 8. Pyruvic cid tolernce in norml dogs LACTIC ACID TOLERANCE TEST Folloing the injection of pyruvic cid (.5 to LIJ BEFORE AFTER INTRAVENOUSLY.1 grm per kgm. dog) neutrlized to phenolph- INJECTED HYDROCOLORIC ACID C') O MOMS/NON thlein, the return to the bsl vlue occurred ithin 5 minutes in 13 of 17 norml dogs. The 12 I originl level s not reched in this time in dogs. The increse folloing the injection of 3 so pyruvte vried from to 1. mgm. per cent. -J Concomitnt lctic cid determintions shoed 6 25cc 1% HYDROCHLORIC ACID very slight rises or no effect, but drops in lctic LACTATE LACTATE cid of 5 to 1 mgm. per cent belo the strting.h level ere noted in nerly ech cse t the end o PH 7. of 5 minutes (Figure 11). In 6 of 9 dogs the Gtt mino / > cid it nitrogen s lso depressed 2 or more LACTIC ACID mgm. per cent 5 minutes fter the injection of 1< R DF~zejpyruviccid in 6 of 9 dogs. PYRUVIC ACID 2 Q 9. Pyruvic cid tolernce in hemorrhgic shock. 2~cured. by trnsfusion In of 7 dogs cured of hemorrhgic shock by trnsfusion, the pyruvic cid tolernce curves ere FIG. 9. the sme before nd fter trnsfusion s in the norcidosis more severe in degree thn occurs in h-5 hemorrhgic shock did not produce so gret n LACTIC ACID* TOLERANCE elevtion of the blood lctic cid level s is found AFTER INJECTION O HYDROCHLORIC ACID in shock. In third dog (M-51, Figure 1) repeted in- 12 (3OMONS/KGM) jections of 1 N hydrochloric cid cused stedy fll in the CO2 combining poer of the blood nd f s y BLOOD PRESSURE in rteril blood ph. At the sme time there s stedy rise in blood lctic cid, hile pyruvic cid 8 Z go -I chnged very little. Though the L/P rtio rose, co it remined ithin norml limits. During this. *N HYDROCHLORIC ACID\ time the injection of.5 grm of lctte produced N norml tolernce curve (superimposed on the W stedily rising blood lctic cid level) similr to LACTATE 15 tht observed in hemorrhgic shock (Figure 8). The dog developed circultory collpse nd died PH hen cidosis becme severe. 7. Comment: It ppers tht the dog in cidosis, I 6 metbolizes lctic cid s ell s the norml or 'o.) shocked niml. The rise in the blood levels of c 2 Pl GE pyruvte nd lctte (see Figures 9 nd 1), fol- G = 2 loing the production of severe grde of cidosis; rp$ is not of the mgnitude observed in hemorrhgic.. shock. The chnges in these cids seen in hemor- O 23R rhgic shock re not determined by the concurrent cidosis. FIG. 1.

8 CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK 53 (Fl 5 M-%2 REVERS1BL IIJZ - -J co iblood PRESSUR PYRUVATE PYR UVATE.PYRUVATE 22Z(.2 < o X z~~~~~~~ I 2 3 H( DuJRS FIG ml or preshock stge, lthough the preinjection levels of bloods pyruvte ere higher during the shock stte thn before shock s instituted. In the remining 3 dogs the lst point of the tolernce curves during shock before nd fter trnsfusion ere slightly higher thn the preinjection level (Figure 11). The mximum rise in pyruvic cid during shock s in some instnces slightly higher thn in. the norml. In some experiments evidence of lctic cid production from injected pyruvte during shock s suggested by the rpid rises in lctic cid levels -immeditely fter the injection of pyruvte. Subsequent depressions in mino cid levels ere observed. The usul rise in the L/P rtio during shock nd its return tord norml folloing trnsfusion s in no y ltered by'pyruvte injections. Comment: Elevtion of the pyruvic cid level in shock is not due to inbility of the orgnism to cler the blood of pyruvic cid. The significnce of the drop in mino cid nitrogen folloing pyruvte injection ill be discussed in subsequent publiction. 1. Pyruvic cid tolernce in hemorrhgic shock not remedible by trnsfusion Similr results ere obtined in 3 of 9 dogs in hemorrhgic shock hich did not respond to trnsfusion (M-9, Figure 12). In 5 dogs, someht poorer clernce occurred during shock thn in the norml or in the post-trnsfusion stge. One dog (M-21) shoed very poor clernce before nd fter trnsfusion s compred to the norml. Although this dog received tice the usul dose of pyruvte, 2 others hich received the double dose shoed only slightly poorer clernce in the shock stge thn in the norml. The injection of pyruvte in these doses s folloed in some cses by drops in blood pressure. One norml dog not included in the series ent

9 5 In (~~~ A. M. SELIGMAN, H. A. FRANK, B. ALEXANDER, AND J. FINE srn~vn so ie en = go HEMORRHAM SHOCK PYRUVIC ACID Z 6 TOLERANCE TE -6, MOMS/Kom -J 3 BLOOD PRESSURI so/ CBO >'6 - s PYRUVAE/. _J 2 into shock for considerble time folloing the injection of double dose. Figure 12 shos tht the rise of lctic cid, during shock nd the fll folloing trnsfusion re not ltered by the injection of pyruvic cid. Depression of the mino cid level s noted mong these dogs s ell s in the previous group (cf. Figure 11 ith Figures 1 nd 2). Comment: It is concluded tht non-toxic doses of pyruvte re clered by the dog in shock someht less ell thn in-the norml before trnsfu-' sion nd bout s ell s norml fter trnsfusion, hether reversible or irreversible to trnsfusion. These results suggest tht the slightly- decresed clernce in the pre-trnsfusion stges is due to decresed blood flo, prticulrly through the liver, rther thn to ny specific dmge to the enzyme systems involved, for if dmge to enzyme systems ere responsible for defective clernce, one ould not expect so prompt recovery of clernce function folloing trnsfusion, nd one Fc 3 G. 12. ould expect disprity beteen the results in irreversible nd reversible shock. DISCUSSION It hs been demonstrted in trumtized rts (13) tht the ccumultion in the blood of lctic cid, inorgnic phosphte, nd phosphopyruvic cid occurs simultneously ith progressive exhustion of energy reservoirs in tissues (1), prticulrly in liver nd brin. A correltion hs been sid to exist beteen survivl nd the mgnitude of the originl rise in the blood level of these intermediry metbolites s ell s in the speed of their return to norml vlues (13). If the blood concentrtions of these metbolites reflect the extent of the biochemicl lesion in the tissues, study of their behvior in response to therpeutic trnsfusion in hemorrhgic shock in dogs might provide key to the nture of the irreversible lesion nd t the sme time demonstrte hether they re essentil components of the lethl process or. I

10 CARBOHYDRATE METABOLISM IN HEMORRHAGIC SHOCK merely concurrent phenomen of secondry importnce. Russell et l (7) concluded tht since eviscerted (liverless) rts do not sho elevtions in the L/P rtio comprble to those in non-eviscerted rts or eviscerted shocked rts, peripherl noxi rther thn liver filure is lrgely responsible for the increse in the L/P rtio. Dogs in hemorrhgic shock sho progressive increse in lctte nd fll in glucose in the venous s compred to the rteril blood, suggesting n incresed conversion of glucose to lctte cused by the noxi of peripherl vsculr filure (15). Our experiments re consistent ith these conclusions. They indicte further tht the ctul level of blood lctte chieved is controlled by fctor other thn the mere rte of production of lctic cid. The rise in the L/P rtio in hemorrhgic shock results from the predominnce of nerobic over erobic crbohydrte metbolism, especilly in muscle (16), in the presence of peripherl circultory filure. In this sitution energy is derived lrgely from glycolysis, hose end product is lctic cid. This is much less efficient thn erobic oxidtion since 8 to 1 times s much substrte is required to yield the sme mount of energy (17). In spite of the rise in lctic nd pyruvic cids nd the increse in the L/P rtio in shock, dditionl lods of these cids nd of glucose re metbolized lmost s ell s in the norml stte," regrdless of the severity of the shock stte or the response to trnsfusion. The return of the L/P rtio to norml folloing trnsfusion indictes return to erobic metbolism of crbohydrte. Since this is the cse hether or not the trnsfusion is therpeuticlly effective, it ppers tht even temporry improvement of blood flo is cpble of restoring the norml rte of crbohydrte brekdon but is not cpble of restoring the integrity of the fctor responsible for mintennce of norml function of the peripherl vsculr system. It follos tht the distortion in crbohydrte metbolism, s reflected by the blood chnges studied, is probbly not primry fctor in peripherl vsculr filure. If it ere otherise, deth from ordinrily ftl shock ould not be prevented by liver perfusion, during hich the distortion of We do not ssume tht the disppernce of these metbolites from the blood in shock is necessrily chieved by the mechnism previling in the norml stte. 55 crbohydrte metbolism is of the sme kind nd mgnitude s is seen in shocked dogs not perfused or perfused vi nother route (). To be sure, our blood nlyticl dt my not disclose persisting metbolic bnormlities in certin vitl tissues, hose function, therefore, continues to be dversely ffected; for exmple, the brin stem my suffer from the decrese in oxygen supply (1) in spite of the pprently norml enzymtic behvior suggested by the blood findings. But there is no evidence to indicte tht in the circumstnces of our experiments ny orgn prt from the liver is of criticl importnce ith respect to the collpse of the peripherl vsculr system in shock, since such orgns, including the brin, respond ell to trnsfusion fter exposure to degree of hypotension nd hypoxi hich the liver cnnot tolerte. Since the liver hs been shon to be the criticl orgn ith respect to the integrity of the peripherl vsculr system in shock, the dmge it suffers involves t lest nother ctegory thn tht of crbohydrte oxidtion. SUMMARY 1. Morphinized dogs bled into shock shoed rpid elevtion of blood lctic cid, pyruvic cid, mino cid nitrogen, nd the lctic/pyruvic cid rtio 2. A rpid return tord norml of blood lctic nd pyruvic cids nd the lctic/pyruvic cid rtio folloed trnsfusion, hether or not the trnsfusion s curtive. 3. The blood mino cid nitrogen remined elevted folloing trnsfusion.. A continuous drip of epinephrin produced elevtions in blood glucose, but much smller elevtions in blood lctic nd pyruvic cids nd in the lctic/pyruvic cid rtios thn occur in hemorrhgic shock. 5. In drenlectomized dogs, hose tolernce to hemorrhge s poor, the blood levels of lctic nd pyruvic cid nd the lctic/pyruvic cid rtio incresed even though the blood glucose level fell. 6. Arteril blood under oil kept t body temperture shoed slight increse in lctic cid nd the lctic/pyruvic cid rtio. 7. The disppernce of injected glucose from the blood s poor or nil during hemorrhgic shock. Folloing trnsfusion (even in irreversible shock) this clernce s norml.

11 5656CARBOHYDRATE. METABOLISM IN HEMORRHAGIC SHOCK 8. The clernce of injected lctte from the blood during shock s norml. The restortion of the elevted lctic cid level to norml by trnsfusion is such s to msk completely the expected increse in level from injected lctte. 9. Clernce of injected lctte in norml dogs s not ltered by cidosis induced by the intrvenous dministrtion of minerl cid. 1. In norml dogs the pyruvic cid level in the blood returned to norml ithin 5 minutes folloing the injection of pyruvte. 11. The elevted lctic/pyruvic cid rtio in shock s only temporrily ltered by injected pyruvte. 12. Dogs in irreversible hemorrhgic shock shoed disppernce rtes for injected pyruvte similr to the norml in the post-trnsfusion phse of shock but someht poorer in the hypotensive pre-trnsfusion phse of shock, hen doses of pyruvic cid tht ere not toxic ere used (under.1 grm per kgm.). CONCLUSIONS It is concluded tht hile hemorrhgic shock my interfere ith the functionl efficiency of the enzyme systems involved in crbohydrte metbolism,. the integrity of the enzyme systems involved in lctic nd pyruvic cid metbolism is not seriously dmged, becuse they sho rpid return to norml function folloing trnsfusion. The occsionlly loered tolernce to injected glucose nd pyruvic cid noted during the oligemic phse of hemorrhgic shock is due to deficient velocity nd volume of blood flo through tissues. The ccumultion of these metbolites in the blood results from the combined effects of poor blood flo nd n incresed rte of production in noxic tissues. The development of irreversibility to trnsfusion in hemorrhgic shock is not due to inbility of the liver to metbolize lctic nd pyruvic cids. Abnormlities in crbohydrte metbolism, so fr s they re reflected in the elevtions of lctic nd pyruvic cids, re not relted to the development of irreversibility to trnsfusion. Acknoledgment is due the folloing for technicl ssistnce: Miss Mrth Goldberg, Miss Gertrude Weinberger, Mrs. R. B. Griffin, Miss Dorothy Kufmn, Miss Gret Lndehr, nd Mr. Thoms W. Brnett. BIBLIOGRAPHY 1. Bllock, A., nd Levy, S. E., Effect of hemorrhge, intestinl trum nd histmine on prtition of the blood strem. Am. J. Physiol., 1937, 118, Wiggers, C. J., Opdyke, D. F., nd Johnson, J. R., Portl pressure grdients under experimentl conditions, including hemorrhgic shock. Am. J. Physiol., 196, 16, Goldberg, M., nd Fine, J., Unpublished observtions.. Frnk, H. A., Seligmn, A. M., nd Fine, Y., Trumtic shock. XIII. The prevention of irreversibility in hemorrhgic shock by vivi-perfusion of the liver. J. Clin. Invest., 196, 25, Seligmn, A. M., Frnk, H. A., nd Fine, J., Trumtic shock. XIV. The successful tretment of hemorrhgic shock irreversible to trnsfusion by vivi-perfusion of the liver. J. Clin. Invest., 197, 26, Engel, F. L., Winton, M. G., nd Long, C. N. H., Biochemicl studies on shock. I. The metbolism of mino cids nd crbohydrte during hemorrhgic shock in the rt. J. Exper. Med., 193, 77, Russell, J. A., Long, C. N. H., nd Engel, F. L., Biochemicl studies on shock. II. The role of the peripherl tissues in the metbolism of protein nd crbohydrte during hemorrhgic shock in the rt. J. Exper. Med., 19, 79, Stotz, E., nd Bessey,. A., The blood lctte-pyruvte reltion nd its use in experimentl thimine deficiency in pigeons. J. Biol. Chem., 192, 13, Bueding, E., nd Wortis, H., The stbiliztion nd determintion of pyruvic cid in blood. J. Biol. Chem., 19, 133, Brker, S. B., nd Summerson, W. H., Colorimetric determintion of lctic cid in biologicl mteril. J. Biol. Chem., 191, 138, Frme, E. G., Russell, J. A., nd Wilhelmi, A. E., Colorimetric estimtion of mino nitrogen in blood. J. Biol. Chem., 193, 19, Folin, O., To revised copper methods for blood sugr determintions. J. Biol. Chem., 1929, 82, McShn, W. H., Potter, Vn R., Goldmn, A., Shipley, E. G., nd Meyer, R. K., Biologicl energy trnsformtions during shock s shon by blood chemistry. Am. J. Physiol., 195, 15, Le Pge, G. A., Biologicl energy trnsformtions during shock s shon by tissue nlyses. Am. 3. Physiol., 196, 16, Betty, C. H., The effect of hemorrhge on the lctte/pyruvte rtio nd rteril-venous differences in glucose nd lctte. Am. J. Physiol., 195, 13, Friedemnn, T. E., nd Brbork, C. J., The significnce of the rtio of lctic to pyruvic cid in the blood fter exercise. J. Biol. Chem., 191, 11, Lipmnn, F., A Symposium on Respirtory Enzymes. Univ. of Wisconsin Press, Mdison, 192.