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I I I I

Tran.Icltion 'No. T-701-1

Author: U.F. Gruber, Basel, Switzerland

Tit1: Intestinal factors in shock: enterotoxin (Intestinale Faktoren im

Schock: Dar.tcoxine).

Jour.-ml: Lanyenbeck's Archives for Clinical Surgery (Langenbecks Archiv fur

Klinische Chirugie). 319: 909-925 (1967).

March 1969

Briefly and in sum nary, th course of the hemodynanic changes in the

splanchnic region during severe shock can be represented as follows:

As a renilt of the decrease in tho cardizc minute-volune (in suriory limited

mostly to cardiogenic- or hypo-volemia), there is a relatively markeJ decrease

in the timic-flo volume with a significant increase in resistnce (1, 56, 123).

This is the rsult of the particularly strong adrenergic intervention and consi-

tivity of catecholamine in the splanchnic region in comparison with the other

vascular flow regions (9, 60, 70, 90, 101, 107).

Hypoxic chnnges (6L4, 113), therefore, appear relatively early in a region

* lo; in 02 but with a high 02 consunption (13, 137). As a result, the 02 absorption

can re;main decreased in soite of restored flow even after transfusion (33, 125).

Other regions, such as the liver, are able to convert Lmmediately to aerobic nieta-

boliem.

As a consequence of these changes, large amomnts of plasma are lost (87, 91,

93, 131) as a result of the increased permeability of the capillaries (97, 106).

Under certain conditirns, a temporary poolirg can be observed in the upper intes-

tinal regions (78, 80). In this regards, the erythrocytes become sequestered (55,

133) since the pro-capillary sphinctors lose their tonus earlier than do the post-

capillary ores (88). In this manner, the loss of volume, especially plasma volume,

intenrifies the hypovolemia in the sense of a postive feed-back mechanism (scheme).

Not all of these findings have been confirmed in humans. The partially

contradictory results can be explained on the anatomical differences in the species

tested, various means of narcosis, nature, severity, and duration of the chock

model employed as well as by factors involving methodology (1, 16, 37, L4, 56, 108,

122, 128, l12). However, basically these n:'hanisms should follow the same course

in laboratory animals and in humans.

0 -2 --

;s a result, it is understandable why several authors deuling with various

fonin of shock involving intestinal and liver bleeding and also chances of

sur-ival ach- cved favorable results after the administration of the following

vaco-=tivc zu:bztances:

ibensnyia. (15, 5L, 67, 80, 10h, 131)

Chlorproaszine (72, 80, 121)

iscproterenol (11, 79)

Fhe nylalnine-lysine-vasopressin (6, 7, 69, 68, 66, 95) not, however, in

the case of the employment of cltecholanines (11, 70, 75, 88, 98).

In this connection, good results have also been obtained by the use of low

molecular wiziht dextrans (10, 38, 42, 3, 84, 129, 130, 133), celior block or

denervrtion (17a, 10h, 105, 110) and hypothermy (87) for amelioration of the

intestinal perfusion and elimination of the state of shock.

The splonchnic region has a special significance in the event of shock when

viewed from a hcmodynamic view point. Tn this case, it is a caestion os to Whether

these circulatory factors are implicated in the secondary changes in the tissues

which affect the entire organism and could be responsible for the more rapid

onset of irreversibility before overall 02 deficit makes survival impossible.

in this regard, the following observations are presented:

1. In the upper intestine, there are significant pathological-anatomical

alteraticns.

IT. Resection of the intestines in rats and dogs during hemorrhagic (80, 975

112) znd cndotoxic ohock (48, 133) leads to a significant prolongation of the

survival time. The only investigation (lO) that led to a contrary conclusion had

so many methodological errors that it does not have to be taken into consideration

during this discussion.

-3-.

111. An, increase in the intestinal blood flow as a result of isolated

perfusion of the arteria mosenterica suporior (AMS) improves survval chances

of animal,- undcrgoin,, ehock (18, 86, 87, 93, 135),

Blattberr (29), however, made thc assu~rption that the protective effect is

not the result of perfusion as such since the animal's own blood is not effective.

The don~or blo,- J must ccrc frar. a healthy rabbit.

Tho resul.ts msentioned in 1, 11, and 111, however, car. o~nly be explained on a

hecdynzr.ic bz-sis and do not prvide definite Proof for the presence of spccific

intestL:.r~nl factcors.

Additionol aspectz. are provided by the follo-oing facts:

IV. Since the entire intestinal tract repres.ents a large reservoir of bacteria,

rcrocr,.n sm -ere considered veryj early as an asserntial element in shock patho-

genesic. As oar'li -- : 19UT, J.C. Aub (Ib) in an extrenely clear work explainecd that,

in aJ.dt-i;n To los-s of vulumie anid bacterial factcrs, no other toxic eonponents of

rny oth.;r kic ould Ix f to explain the -shock probLsr1.

in the invustigatic'ns ;:! Firw (50,51) and his c-ULIrkers (5il, 7L1 , 10h, 110,

ll5, ,131) ~.~~zdin '3 114), art attempt WC;E mado t,: OIttritlutu (10finite

&.ignifczc t.o endotoxin in the pathogenesis of ircesbcshock. Although

the comprehensive in1testigAtIons stirvi]'ted thorough rczcarc,-. 1nto the 51iock

prbeit has been assmned that very Li1ttle significance can be attributed to

endctcxin as being an important factor fcr th-e following rcasons (67, 81, 103,

1316):

(1) In germi-free animals, the s3bock- proceedr- in exactly the same manner as in

ordinary animals (J.47).

Fine had argued thc-t erndotoxins were prcent in the food. H{owever, the same

reactiona were obverved in germ-free vniro.le which had Ition fed a sai-ynthetic

fcod sterilized in a dry oven

(2) The cxpcritcnts of Fine have not been reproducible in other laboratories

and pre-treatment with antibiotics has turned out to be unsuccessful even in his

ow. hn63 (7, 2h, 65, 76, 86, 96).

(3) Fine himnelf has shown that incubated aurecmycin, which is practically

without effect on microorganisns, VIl neverthelesz protect against shock (7W).

Lin and Zwcifach (89) assumed that antibiotics have a protective effect on the

mucous memlranes of the intestines and that this effect is unrelated to their

bacteriortatic effect.

(L) Chlocr.phenicol, which is an effective antibiotic for gram-negative

microorganis s, has no protective effect (74, 89).

(5) Mice, that have been made 10 times more sensitive to endotoxin, cannot

be killed by the injection of blood of dogs irreversibly shocked with endotoxin

(132).

(6) A hypotensive peptide has been detected in the cecum of germ-free rats

(59). The amount of this substance decreases.markedly upon the introdction of

microorganisms (13). Certain bacteria, therefore, could exert a protective

function (12, hl).

V. in the case of mechanical ileus, in addition to the loss of volume,

bacteria or their products have also been implicated as responsible for the toxic

propcrties of the peritoneal exudates and the intestinal contents (9, 7, 30).

kc.nundsen (8) also observed in germ-free rats a protein originating from the

intestinal wall which increased toxicity. It was not hemoglobin or one of its

derivatives. The results allow a comparison with the conditions during irreversi-

ble shock and indicate a possible participation of the intestinal wall.

Because the intestines and liver are dependent on each other anatomically and

functionally, it seemed advisable to consider the latter also in our observations

VT. Blockage of the reticulo-endothelial system (RES) increases the sensi-

tivity to shock (145). Durirg shock, the ability of the RES to eliminate endo-

toxin from the blood is dccreased (115, lh). Also, its ability to eliminnte

bacteria (50) and colloid particles (23, IL 6 ) is diminished. This tmpairu:nt

of the, so-called granulopectic activity is considcred by mary authors to be a

Cignificant factor in shock ptthogencsis (3, 27, 53, l10). In that regards,

one must also consider substances which block the RES to be hepato-toxic.

Administration of citrated blood increasos the limited dotoxifying function

of the RES (109) and it was shown earlier thrat citratu in vito iinfluences the

activity of leucocytes (2).

In addition, vasoactive substances such as histamines, scrotonin, and

bradykinin, depending on dosage, restrict the function of the RES (27).

Furthermore, there is the Questicn whether the large quantity of denatured

proteins and cell aggregates in transfused blcod can restrict the blood supply

of the liver by increasing viscosity and in this manner restrict its function

(TLl).

Blattberg and Levy have assumed that in the course of severe shock, a RES

depressor substance (RES-DS) is produced in the gastrointestinal tract and enters

the system via the portal vein (22, 25). This material is formed during AMS

shock (arteria mesentericurn superior occlusion) in the rat and in the dog (2b,

25) as well as during hemorrhagic shock in the dog (21-23). The RES-DS can be

trans.mitted via various carriers (blood, plasma, plasma-dialysate) frcn rat to

rat and from rat to dog. On the basis of chromatographic separations and puri-

fications, it appears to a small molecule. Its mechanism of action does not

involve blockage of the RES (26).

Levy and Blattberg and co-workers (9, 28, 18, 20, 85) have found that in

the post-transfusion phase after hemorrhagic shock in the dog, the irmune system

becoces involved. This appears to ultimately correlated with damage to the

RES function.

Various authors have asstied that during severe shock, there is no formation

of enterotoxins but that the liver loses its ability to inactivate metabolites

which are normally present (15, hi, 80, 113).

Battbeg (23) and Lillebei (196) have demonstrated that perfusion of the

liver does not have any effect. On the other hand, chIorprcmazirn and diberzylin

i-Prorv chances of survival only as long as the liver is present (15, 80, 86, 121).

IMI. Bounous and co-workers (33) (sjr.-arized in 62) after extensive examina-

tions believe that the metabolism of the mucous mebrarns of the intestires and

the production of protective macin are affected before pathological-anatmical

alterations can be observed and before other regions shcw similar changes (35,

3h, 31, 36). These investigators were able to demonstrate that purification of

isolated coils of the intestine or prophylactic administration of trasylol inhi-

bited the typical symptoms of hemorrhagic necrosis frCa appearing during irreversible

shock in the dog and the rat (3A, 32). They assumed that trypsin and chymotrypsin

have a special significance but pointed out there is much less trypsin present in

the human intestine. The prophylactic ligature of the pvncreatic ducts also has

a protective effect on the intestines and prolongs survival time. Therefore, it

is possible that toxic products of the intestinal constituents pass through the

previously dcmaged mucous membranes (see E.E. Smith, Surg. Gynec. Obstet. 125: 15

(1967)).

TIII. Barii and Allgower (39, 4o) found a toxic substance in the intestinal

walls of burned animals =f:in animals with hemorrhagic shock. This factor is

active zgainst mice which are refractive to endotoxin. They assumed that it was

forzed during the hypoxic phase in the intestinal wall.

The results mentioned in V - VIII do not present absolute evidence for the

formation of toxic substances in the intestinal tract or for a decreased function

of detoxiCication of the liver. There are many gaps - severe controls, too small

anoants of experimental material, missing statistical evaluations, confirmation

F4-7-

in other animals by other authors, and lack of data for humans. 'Tcverthlcss,

they certainly deserve our full attention.

For purposes of studying intestinnl factors during irro\,'rsible shock, many

investigators in recent years have emplcyed the so-called AMS shock model:

In rats (6,7, hl, 89, 121)

In dogs (76, 77, 96, 105, 131)

In rabbits (15, 24, 67, 81, 82, 91, 9h, 105, 116, 119, 127, 138)

TABLE I

Survival ttirs, RabbitsTotal Ligature of the

AT£T,

n a 10

9+ 3 hr

Several experiments on anaesthetized (pentobarbital) rabbits; dorsal, retro-peritoncal access, ligature with 000 sIlk.

TABT 2

Survival times, rabbitsL, standard AV.S occlusions

+ openring

n -10

11 hr (10 min to 3 hr)

see table 1. The survival time after ligature and reopening of the AMSclosure is shorter than in the case of total ligature.

Simple ligature leads to death with all of the species within a few hours

(table 1). Vhy? If the AT- in closed off for a few hours and afterwards the

closure is released, death occurs earlier than .ithout this procedure (Table 2).

This situation corresponds closely to the hod'om~ ic conditions during severe

shock. The significance of the loss of volume in this case can be..seen in

Table 3.

-8-

TABLE 3

H.matocrit, Rabbitsh standard A?.LS occlusions

+ opening

initVial: 39°0 (n = 18)h hr: 07.5 (n 18) opening

L5 min: 55.0 (n = 7)90 min: 56.5 (n - 5)

There were great losces of plasma during the occlusion phase. This bcame evenvorse after the reopening. The animals lost abat 50 % of their plasma volumewith 1 - 2 hours afier reopening.

?lasma volume loss in percent a 1 - Hct I x Pct2Hct2 x Fcta

Pct - plasmacrit

Several, investigators have made a great effort to explain the reasons for

this phencmenon. The various substances listed in Table 4 have a possible

ctiual significance in the rapid deAruction of circulation during hemorrhagic

and AS shock.

It is quite likely that the interstitial fluids are likewise reduced. This

explains the significance of the loss of volume.

In order to prove the some or several of the substances mentioned in Table

play an important role in eliciting irreversible changes during shock, the

follring criteria were necessary in my opinion.

(1) isolaticn and identification of the toxic substance in the portal

vein and in the peripheral blood. If the latter is not possible, one should

at least be able to show the destructive effect of the toxic substance in the

liver or in the RES.

(2) Determination of the area of formation of the toxin and explanation of

its mechanism of action.

(3) Proof that the toxic substance is effective and attributes significantly

to death in the case of proven normovolemia.

-9-

T;-LF, IL

Pcszj' ble Enterotoxins

Substa nce Reftrcncr Y mib shehd

Forrirr -P 3e -V .;sodcresrsor sub:;tarnce FcQrzc (6k) 1Vascieprcior b eeSl:<-Urt(16NO'r-idrenalin inhihitor (~71yPoten,-.",r n-ptide CGorjOn (19) 16v~OczciCtvc polypeotide Kobold (82) I P,")3Vsctjesubzt;nue Peters (111) I(.1Vis.'Otoxic -,A zt once Sc' kurt (127) lr;9fliLntor + Constrictors Rothie (ipo) 1461Ca' c cholimire Kobold kiF) ) 19635-hydr-' xytryptami ne B-acz (15) 1961Scrotonin Jnnofi' (976)

ScZrotonin Kobold(2)13Histc-nine Yobold(2)96

T:-znBouncus (33) 9( 'Chyrmotrypsin Bounous (3) 196hKalligrein Yobold (81) 1962Cothepsin Jinoff (77) 1 (2Czithersin-likc acid proteinase Reich (1!6) 16Acid phosphatase Janoff (7)1965Lcta-glucuronidase janoof (77) 196?D'Nia Jancff (77) 196?~ZNasJanoff (7)1902Eenclobin degradation product-o Inir (107) 1959Potassium Vavor (90 ~ 1961,E-idotoxin Fire 5~0) 1955Exotoxjn Ab(14) 191.?Intestinal Wall factor Burni (39) 1965

-13-

T () r:ansfcraci'-ity of the toxic principle to another an-.al, for example,

by inj..-ction, tranz:.usion, c;.- y crossed (syste...ic) circulation.

In these ca::es, the shocked aninal does not have to die since a healthy

o.'nI can :etuslv combat the toxin succezsfully. It app-ars, therefore,

poazihie that the subst.ances in question have been exanined several times in

arinl,; ;-roinrc.-,versible shock. They can also be tested after liver

d:-> nrodu by 13 blockage for exanple. In this regards, one must consider

at cq i,. likely the vasonotor control has to be also influenced if a vasonctive

scbsta.: should lad to the collapse of the circulatory system.

Thus far, no investigator has been able to fulfill all of these criteria.13 I. Of the substances mentioned in Table h, it is most likely that the

vazoactivu ones are the one Vhich are the toxins. The effect is probably due

to a rIxturc of vasoconntrictive as well as vasodilatative substances. At present,

there is not evidence available (for serotonin, ace (118)).

ad 2. The fact that such substances are prsent in the blood of the portal

vein is uncontestable. On the other hand, there is still the question as to

v:hether they are derived from the intestinal wall or intestinal contents. Also

thero ir still the question as to which of kinds of cells they originate from

(-ec tables 5 and 6).

ad 3. An extremely small n=.ber of irnestigators have considered the sig-

nificance of the voltme factor. From the plasma volume and hematocrit determina-

tions-carried out by various authors (41, 44, 93, 121, 131), it is assumed that

in the intestiral tract, the whole plasma volume can disappear into the wall or

into the lumen. Only strict volumetric controls can be used as proof for m.echan-

isms other than the loss of plasma. It is possible to conceive that ultimately

toxins that happen to be present intensify the loss of plasma.

-11-

ad L. The transportation of a toxic principle du-ing hemorrhagic shock

has been demonstrated in rabbits (103, 124,) and in dogs (115, 124).

Janoff (76) vas able to detect a toxin in the blood of the portil vAin

of rabbit undergoing AYS shock but not in tha plasma.

Portal vein blood, rabbit4 hours of A:.S occlusion + opening

n - 7 controls -2

nortolity/ n r.ccOccl. controls

14/61 2/18

The blood of the portal vein was removed with a sterile syringed imdcdiatelyafter opening the A.S occlusion and injected into mice intrncritoneally incuantities of 10 Z of the KG weight. Vu were not able to demonstrate moretoxicity in the blood of the portal vein of the experimental animals as com-parud to the control animals.

TABLE 6

Carotis blood, rabbitshours AMS occlusion + opeaning

n -1 controla n - h

Nortality/ n mice

occlusion control

yornal mice 1/1? 2/25RES mice 0/25 1/36

For procedure, see table 5. Toxicity of the peripheral blood could not bedetected after injection into RES blocked mice. It is possible that thetoxins are so unstable that they lose their activity very ouickly. Technicsand the tire when the blood was taken could explain the differences betweenthese and the results published in the literature.

Tice (138) after AMS shock found a toxic factor in the ductus thoracicus lymph

of tho dog. The injection of such lymph into rabbits whose RES had boon blocked

by means of thorotrast, led to death of the animals. The circulation of the

lymph has certainly not been given sufficient consideration in the study of

shock.

L

-12-

,O.,cLusiO:,S

The con n:-unc-2 of te he. n-.ic d-str -b'.ncez in each ..a.Sive decrease in

the clrdiac t%--vol1L-c arc eczpcialYy covere in the -planchpic r-egion oa co-

pnod to t othr vascular flow rei,-onr ovn after trznsfusion. Alco, they

PPOae oz-lier. "he loss of vol,-,e in the intestinal tract is espcially large

due to anoxic dann~. es. Fow:vr, these circilatory alterations alonn cannot be

usecd to cc.-pietcly explain t:ho appcaarmc of irreversilelity; suitablo validations

ar not available at this tirr.e.

Scecniltic s,-.rnry of the hcm.dynanic charnzcs in the splanch:ic changesin shock. The importarce of the loss of vol=,o beccmas evident.

cardiocn hypovolerda centralK 1/cardiac mintte vol, " a

resistance +++ adrenergic innervation ..+

intestinal vascularity

02 requirement t i t I disturbed 02 absorption

hypoxemia +++

pooling I

capillary p-rneability

plasna outlet .

Scheme: Positive feed-back mechanism.

It is very likely that basoactive substances fran the intestinal tract

travc to the liver via the blood of the portal vein whereby the liver and

the RES particularly are injured by the vasotoxin or other noxious substances

-13-

during detoxification and phagocytosis. This would explain the offect on the

whole organism that is observed.k

The bacterial factor, cspecially endotoxin, if at all.will play a si ni-

cantly smaller role in hyoovalemic shock than has been azsu-iod in the past.

This doas not mean, however, that b cterial factors are not cssontial in

soptic shockl It should also be mentioned that many authors have emplorcd

endotoxin in the laboratory to simulate shock. This shoiad not be interpreted

as meaning that endotoxin plays a major role in the initiation of irreversible

shock.

In our experiments, we could not demonstrabe a specific toxicity for

homogenates prepared fron the intestinal Walls of rabbits in Ak.5 shock.

The material was injected into both normal and RES-blocked mice (Tables 7-10).

TAB 1 7

Intestinal wall honogenate+ AB

6 hours - AvS ligaturerabbits n = 8injected into mice

mortality: 0 1 (n - 85)

mortality of mice after i.p injection of fresh smna] intestinal wallhoiogcnate with and without the addition of tetracycline (I mg/2rnl).Amount of homogenate injected was 10 O of the Kg weight.

TABLE 8

Intestinal wall hcnogenatc, sterile8 hcurs A.S ligature

rabbits: n = 8, ccntrols n - 9injected into mice

mortality: 26 1 (n - IC0)controls: 21 % (n - 130)

,ortality in r.ice after l.p. injection of a 10 % suspension of small andlarvae intestinal wall hcmogenate after lycphilization and sterilizationwith ethylene chloride. Technic in (39, LO).

Intcstinal -.all ha-~oge.-te,

L hoirs AS occlusion + o-r -rinrnbiitn r. - 6 con'ro!= n- 11

injected into nicz.not al4t): 74 (r. - 137)controls: .% (n - 300)

-or* .in-e a.*.e at,.r inJction r-,; a "0 1( =-=enion of the "all and lare'-n l (sterilized accord :- to tn~e prccedure dcscried in Table 8).

Tht incr:azc in mo-'ality is not =i.niflcant since thre L-.e larrc deviations inboth E.o,.ps (in so-r.z eries of exneari=tal znials thera vas no mortality -hilein sre of th control groups, there was a high -ortallty).

CCSTCJ'FN. -- T7-n RAC.TrE

Th results mentioned above also have zignificanco in practical surgery

(73, 83), that is, firstly, in the treatzr-e of acute (embolies) (58), thruobotie

(4) anI zrterimclerotic (20, 5, 6) (angina abdoinlis) Compressions of the

AI:S. In addition, there is no reason to doubt that intestinal necroses uithout

ctat.ue patholZicad-anatomical alterations of the vessels aloo occur in tumors

(37a, 99, 12) as =1ll as in shocx (71, 92, 93). On occasion in certain cases,

there is a connection "ith digitalis intoxication (fla). esonteric infractions

cccur in 2 % of all ileus cases (07) or in 0.2 % of all surgical cases (93).

Even todny, the mortality approaches 90 % (47, 93, 139). A procedure for treating

intestina1 ganlrcna with the most success has not yet been elucidated. Whether

an i-.-cdiae surgical restoration (61) of the circulation with actual closure of

th. ;.:.z rezprecents the best therapy in all cases is still much doubted (52)

:i*no., c.-ter opening an acute AM occlusion, a cf-ciiltion. collapse is practically

un:xvodzblc. Apparently, massive infusion 4herapy is effectiv only in a very

rcw ca ,. The extent of the dinnution of the blood fIo and the duation of

tie disturbanco appear to be mportant factors. These factort are very difficult

to evaluate. it is therefore necessary in case of meserveric infarctiors to

consiCier tx'oatm'cr~t ty iso1ntod rerifusion of the .. r:-,.-A'n (91t~), the pcrfoz-,imcc

of a splarmcnic blcckode (52, l10) ani~/or t-ne uz c of chiorpro:., sir, di1.onzylin,

and hypertonic solutions of lom:-mcocul32_-: , (c:ru,tce tnbln 1(t). Tt

in mre that in all cizes, !Lr,-c vi>r (2-3 U.,tc ;' Orn) of' t and

cdextranr s-hould I-- aonni.tcred. Az izir t'.c uoo cl' vniocitive subAt-irces are

concervcdp such zs octcpressir., xjith rQ.-rds to hurans, there is not erncuih

in~form-ation L.v.tilable (66). In a c.:ie of a sim'pe int-st rnol. necrosic, only a

surcical intervention (resection plus eventual vnscular operation) has any

chance ofl succeos.

Incc-:pp(hte series of test:; for detcrminin,- vhethcr various techn~iquies forrefinin- intestinal wall hcmiiogernnt.es exert zi in~fluen~ce on th(Ar toxicity 3,utor

injection into mice. Three rabbits wore ri-nrittcd to a L hour A"iS occlksion andtheir intestines were treated in vzarious Monys ai't~r the reopening of the occlu--ion. The intestines of tvo, healthy, oortrol animals vere trcated in the !;arlermarncr. From, these experinrents, no cconclusions car. be drziwn concernin~g theinfluence of time- and temperature.

Occluslon ControlTreat,'rnent Ru

mice % ice

Im-cdlhite in'Pctilon 30 0 30 0It "hours doer; frozen - 10 0hi hozur. -t L-03 10 0 --

1 hour ct 1800 20 502or A 37c,7- - 10 0Ithour-, ,t 37'C - 10 0Totajl intustino L hours,3700, 2yophilized atonce and sterilized 10 0 --

.After 30 ninr, lyophili-*edand sterililized 10 0 --

Af ter 60 min, lyophilizedan~d steriliznd 10 0 --

.:O C.lcnchriic rezicn has ani e:ze siz-aificance In c-evere shock as

tfc' C1ct 0±:n.z d*&z .-_o43-C?.cFF z'P':' carly Ard nro very pro-

acr.id ,z djr of i-.rcvcrs4i*1e d'i.z~z iz cspecially ;-reat (circ. rtois

~ :re cz-. b. decetcd in otzher vvtu~z retoz rLM leadz to l.-.rc losses

3:- _-z.. r c-n.1t of anoxic alerztioaz in t .tCzItr.:s tract.. Tt i ! v A; r

C~j ha~t va:ocwc-z arictve Zs -. Il zz vzzcd!il:-o-. rubztzr c',- travel fr= the

i~a~ cortont., or frcn thc ed wTl in'to t~c porta~l vef~n and dzr.oze

t'.x livc.r. 7rcy y b:e 1zo rcvporftle for the ir-ctof the furncticn of

L~ r:~ ~1 K.~Oh~l g yrter.. This &,=3 not apzczr 'Co cte recult of Ondo-

,:_a: the nunwrou su"C.tances hat have been~ considered o-- pocriblein?.e.4 ral t"-Pr, no Iv c- :lte r itified as a cauvativ ec.

Ce.r -!:,nifiecncc ir. hr-n ahock iz still not clear.

jco trxc~y~n'c alterations in the splancbr.±c region, as they teceir in

iri.wvv-ible chcckp zrr capable of Imir. reproduced in thc artecria rwentericz

curerior (A:-=) shock ne-5l. The inforztion obtvined from'. Vhis model haz

practical c1incai significance in the treatment of -wesenteric blcd flowa dis-

Qtr=incc., e:=ccially in accenteric irfzrctions, in which ca=e it is considered

a-~; t least to orteriez irst h.ve inferior blood flcw before

c1'.n-dcal .r. ',tc:-_ appear. These aspects ame probably more frequent than generally

:-i.nte'stinal gangrene without any detectable organic necroses in the A.S

reg;ion ca.n lso occur in hunrans. It is cuestionble wImhther an i-mediate vascular

r~r~ialrestoration of the intestinal blood flcj in cases of actual occl-usion is

tn best terapy except vhen there is a clear necrosiz. Isolated perfuzion of

the .03 rcgion, ad.inistration of chlorprca=sir., dibenzylin,, octopressin, and

lc--.ccur-%oight doxtrans, coliacal blockade, have to be considered, the

-17 -

most important treatment, hcver, is Luficic:;t rcplaceIcnt of pi. 3n • Several

liters of plasma may be necessary.

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