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GASTROENTEMROLOGY 1988;95:500-7

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SCIENTIFIC REPORT

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Prospects for Management ofGastrointestinal Injury Associated Withthe Acute Radiation Syndrome

ANDRE DUBOIS and RICHARD I. WALKERD~igestive Diseases Division, D~epartmnent of Meidicine, Uniformed Services University of theHealth Sciences and Armed Forces Radiobiology Research istitiute. Bethesda, Maryland

The effect of total-body ionizing radiation on the heightened the general awareness to nuclear haz-digestive tract is dose-dependent and time-depe- ards. The medical experience in Russia should alertndent. At low doses (1.5 Gy), one observes only a physicians that high-dose total-body radiation injuryshort prodromal syndrome consisting of nausea, can occur and we must be prepared to treat suchvomiting, and gastric suppression. At doses >6 Gy, injuries,the prodromal syndrome is more marked, and it is The first comprehensive description of the acutefollowed after a 2-5-day remission period by a radiation syndrome in humans was provided bysubacute syndrome, characterized by diarrhea and Hempelmann and colleagues (1] based on the expe-hematochezia. This gastrointestinal syndrome is rience they acquired while treating 10 patients in-superimposed onto a radiation-induced bone mar- volved in two radiation accidenta. at Los Alamosrow suppression. The combination of intestinal and National Laboratory on August 21, 1945, and onl Mayhemopoictic syndromes results in dehydration, ane- 21, 1946. These cases pointed ouit the Complexity 3fmia, and infection, leading eventually to irrevers- the pathophysiology of radiation injury.ible shock and death. The treatmnent of prodromal Il i lsi 96ppr uslr()hptosymptoms is based on the administration of anti- . hcasize 1956 toa-oyiratr. uarrstse2 bpote-emnetics; and gastrokinetics, although an effective sioneo that totld riatio ael rrest te crpsoduftreatment devoid of side effects is not yet available tinone ptlalclsfo tecrtsffor human therapy. The treatment of the gastroin- Lieborkuhi. The diminished replacement of opithe-testinal subacute syndrome remains difficult andi hal cells combined with normal sloughing of differ-untsuccessful after exposure to total body dose~s enitiated cells lead., to the depletion of mature intes->8a-10 Gy. Supportive therapy to prevent infection tial surface epitholial cells. This loss of opithelialand dehydration may he effective if restoration or (-.(tlt, causes a breakdown of the barrier betweenl therepopulation of the intestinal and bone marrow ittstitiial Itlutial contents and pt inits entry ofstein cells does occur. In addition, bone marrow toxic substances into the systemic circulation, whichtransplantation imay impirove the prospect of treat. can he lethal. In addition. as discussed by Moore (3).ing lit, hernopoietic synudronme, although the experi- changes of thet iettibolic batlance, cbsirved after

*elicit gained in Chernobyl sugges(s that this troat- total-body irradiation mnay bear similarities withmnl~t is; difficult to apply in the caset of nuclear those seen after surgicail injury. In both situatiotns,accidents. Admninistrattion of radioprotectanlts he. Ibu(ro! is aln incrp'lsel in tho pxtra(:Llliubtrl conlipoltit atfore irradiatiotn decreases uiatage to healthy cells, tlt, toxpoet of intracollular itetabohisin, incroasedwhile not protecting cancerous tisues. Ill thet fit- urinary nitrogen excretion, loss of nlitroglin and pa-ture, stimulation of gastrointestinal and hientopoiet- tassium, and at tundentcy to rotain sodiuim.ic progenitor cells may bet possible using cell growth Ill l965, Biond lld his colleagues (4) revioweid tileregulators, lilt( much remains to bie done to imnprove OCCutnu1 llatod hiu ad alnial expurience; theyIthe treatment of radiation damage to the galitroin. pt)tlillo at disturhmnce! of celultar kinetics il nIul-testinal tract. tiple-organ11 sy'steis thi Iittiiiustod itself i di: tillct

t irIing, t~li~ ,tst m1 yr. mnutch bus1 beenl [Iltuned tcatnpotteitts: tilt houmopoict it' synldrotntt, the galstrte-houtI tho pdiysiologh: imeo;hanistnls (;itttsltg tad i-

at iIol injury. 11tho r ectet oelets ill ( :ltobvl have nt5rnt$~0~ -

Augusl 1988 RADIATION INJURY 501

intestinal syndrome, and the cardiovascular or ceii- as rats and mice (7). The median effective dose fortral nervous system syndrome. They also recognized vomiting is -2 Gy for total body exposure to -rays;that the acute radiation syndrome is characterized by it is believed to be -2 Gy for neutron irradiationan acute phase, also called prodromal syndrome, also, although some differences may exist in animalsand a subacute phase. also called bone marrow and (8). In humans, radiation-induced vomiting is pre-gastrointestinal syndromes. These two phases of ceded and accompanied by nausea and anorexiaradiation sickness are separated by an apparent (1,4); in animals, hypersalivation, chewing, andremission during which the patient may be com- yawning are observed, and these symptoms may bepletely symptom-free. considered to be the physiologic equivalents of nau-

Although we recognize that bone marrow depres- sea (9). In addition, gastric emptying, gastric moti-sion with its hematologic and immunologic sequelae ity, and gastric secretion are temporarily suppressedis of extreme importance and represents a medical 110,11). For doses >9 Gy, diarrhea is often observed,problem frequently encountered in irradiated per- and the prognosis is particularly poor if diarrhea issons, we have elected to review specifically the less explosive and bloody. These symptoms may be ex-commonly considered gastrointestinal component of plained by the gross alterations of the myoelectricthe acute radiation syndrome. The large amount of activity of the small intestine that were observed ininformation on the pathophysiology of radiation- dogs exposed to 9.4-Gy abdominal y-radiation; aninduced gut dysfunction is summarized along with initial increase of intestinal motility immediatelyits implications for current and future therapeutic after exposure was followed by decreased motilityintervention. The long-term effects of radiation (such 1-4 days later (12).as enteropathy, fibrosis, and .:arcinogenesis) will not These symptoms are potentially important from abe considered here, and the reader is referred to the diagnostic standpoint because they can be usedreviews by Morgenstern et at. (5) and Fry (6). within 1 or 2 h of exposure to qualitatively estimate

It must be remembered that the degree of gastro- the dose of radiation received. Similar symptoms areintestinal injury following irradiation will depetl observed after local irradiation, although to a lesserupon a variety of conditions. For example, many of extent. In the case of local irradiation, the thresholdthe side effects described in this review are not for vomiting and diarrhea is lowest for the abdomen,observed after exposure to similar doses during local the irradiation of which causes nausea and vomitingirradiation or in preparation for bone marrow trans- after (loses greater than about 1.5 Cy (8).plantation. It is not known whether this is entirely The mediators involved in these early effects of(lu to the low close rate, it the fractionated irradia- radiation are unknown. Direct or indirect radiationtion, or to concurrent treatment with antibiotics or effects ott the central nervous system probably play abone marrow infusion. Furthermore, neutron radit- pivotal role, although areas of the brain that arelion is much more destructive to intestinal crypt involved remain ill defhned, its is the nature of thecells tlhan are similar quantities of y-photons. Once nou rot ransinitters mediating these effects (13). Theiniury to the gastrointestinal tract has reached suffi- vomiting center and the vagal nuclei are thought tocient levels to produce symptomls associated with he necessary, but the prec:ise role of the areathe acute radiation syndrome, mcdianisms of organ postrema is still controversial (14-16). The stimula-failure and int(erventions would be expected to be lion of the central nervous centors could result fromtht' same regardless of the circumstanc:es of their the radiation-induced release of free radicals, ororigin. 'I[herefore, this review reports primarily data frout other substances such as the elndotoxins pro-obtained front experiences wibth photons delivered duced by intesti nal microorganisms that have beenproiptly, as inay occur in all at.citlent. Ihtowever, shown to en ter the bloodstream of animals (17) andthose filldillgs should be pertinlet to ally situatit ill htunans (1m1) after irradiation, Alternatively, tit pil-which It' total tose received anli l dose rate are ripheral afforent nerves could he directly stinulatedthove a given threshold, by these elndogenllons substallces, Whatever initiates

the guttural respotse of tit body, a releaset of variousPathophysiology of Gastrointestiinal circtating chemicals (i.e., -ondorphin, histanine,

Injury prostglanditis, etdotoxins) hItas been obstrved afterototal-hotly irradiaion, but their role it producing the

Arctic lhcchotiht Sickitess orl" IProdrntl early effects of radiation rentains to )h deined.Sitcfrcnne pl-~tlidorpliin could play a role btcttis endogenous

h1lttediathly after totatl hody irradiat iot w lilt ail exogtnous opiates are ktown to cause vomitingcloses .1.5 Cv, votttit is frequently tl)servttl i alt (19). io slow gastrit: eniptying, aind to suppressthe ittattmal's that rtan vomlit, i.e., vat, clog';' ttno stri. ,cd output (20). The rth, of hi,:taclitnt il tiekeys, antid httios, bitt to! ill those Ilat t:iatot, stlch pathogenesis of the syniptons of the prodrotnul

502 DUBOIS AND WALKER GASTROENTEROLOGY Vol. 95. No, 2

'syndrome remains unclear and probably involves findings of Fine and coworkers (32-34), who de-

histamine H-receptors; histamine H2-receptor agon- tected bacterial endotoxin of intestinal origin in the

ists do not cause vomiting and they stimulate gastric plasma of animals after a variety of severe trauma

secretion and gastric emptying (21), whereas the episodes. Endotoxin-containing particles in the in-

opposite is observed after total-body irradiation (11). testine may penetrate the epithelial barrier via the

In contrast, prostaglandins could be candidates as intercellular route. The incidence of disrupted inter-

mediators of the observed symptoms because (a) cellular tight junctions followed a biphasic pattern

they are released after irradiation (22,23) and (b) similar to that seen for the detection of andotoxin in

their effects are similar to those occurring after mouse livers after irradiation (35). This increase in

total-body irradiation (24,25). Finally, the fact that intestinal permeability after irradiation could be due

combined vagotomy and high spinal cord section to the action of humoral mediators on this organ. A

prevents radiation-induced vomiting (16) suggests variety of vasoactive substances have been shown tothat an afferent or efferent nervous mechanism. or increase intestinal permeability to endotoxin (36).

both, is involved, although the neurotransmitter me- For example, severe disruption of the tight junction

diating this effect has not yet been defined (26). In complex was seen in rabbits infused with histaminegeneral, there are no morphologic changes of gastro- but not in those animals given saline (37).intestinal smooth muscles or intestinal mucosa dur- Although not always associated directly with mor-

ing the prodromal syndrome (12), although some talh y, endotoxin may have profound effects on radi-alterations of parietal cell ultrastructure have been ation victims. For example, endotoxins may contrib-

described (11). ute to immunosuppression in the host, but they canalso produce subsequent beneficial effects in com-

Subacute Gostrointeslinal Syndrome promised subjects (38). such as stimulation of bonemarrow repair after irradiation (39). Sublethal ei~do-

Radiation-induced vomiting usually ceases toxemia may be beneficial in other types of trauma aswithin 24 h of total-body irradiation, and gastric well. For example, Spiller! et al. (40) reported thatfunction is normal 2 days after 8-Gy v-exposure (11). endoloxin decreased burn severity when given toPatients and animals then experience a relatively mice immediately after thermal injury. On the othersymptom-free period that may last 2-7 days, de- hand, endotoxins released shortly after irradiation ofpending on the dose received. If this dose is >5 Gy. animals (17) or humans (18) may also contribute toa second phase of radiation sickness appears within early performance decrements associated with radi-1 wk of irradiation. One observes stomatitis. abdom- ation.inal bloating, gastrointestinal ileus, diarrhea, and Endogenous enteric bacteria appear not to play aguaiac-positive or bloody stools (4) as well as sepsis, major role in pure intestinal radiation death de-dehydration, and shock. This syndrome is character- scribed after doses >12 Gy as there was no sepsis orized by electrolyte imbalance (27,28) and, as shown endotoxemia at the time of death in rats with acuteby metabolic balance studies (3). bears similarities intestinal injury (41). Furthermore, preirradiationwith the situation observed during the postoperative contamination of the gastrointestinal tract withperiod and after surgical injury. ________ Pseudomonas aeruginoso did not modify survival

The cause of these symptoms is complex, and their time of animals dying from pure intestinal syndromepathogenesis is still not completely understood. Af- within 3-4 days of irradiation (42). In contrast,ter doses of radiation >2 Gy, the turnover of intesti- postirradiation infection from endogenous entericnal cells is decreased, leading to atrophy of the villi bacteria was an important factor after exposure to the

(4). In addition, radiation produces alterations of lower doses of radiation that cause later death by atransport in the rabbit ileum as evaluated in vitro combination of intestinal and hemopoictic injurieswith Ussing chambers. Short circuit current, trans- (42).epithelial potential. and resistance were all in- Intestinal microorganisms are a major source ofcreased dose-dependently 1-4 days after total-body infection in irradiated individuals. Changes in theexposure to 7.5-12-Gy y-radiation (29). These numbers of facultatively anaerobic bacteria, whichchanges are similar to those observed after adminis- could become opportunistic pathogens after irradia-tration of bacterial toxins or secretagogues, and they tion. have been monitored in experimental animalsmay be responsible for decreased intestinal absorp- (35]. lIlea were removed from rats at intervals afterlion of electrolytes, fluids, and nutrients in vivo sublethal (5 Gy) or lethal (10 Gy) cobalt 60 irradia-(30,31). lion and cultured quantitatively for microorganisms.

An intestinal injury with immunologic and phys- The facultative flora were significantly reduced iniologi: consequences is increased permeability of numbers 24 h after sublethal irradiation but reachedthe epithelial barrier. This concept is consistent with preirradiation levels 7-11 days later. Lethal (10 Gy)

August 1988 RADIATION INJURY 503

radiation also caused a reduction in numbers of alteration of normal intestinal barrier function couldfacultative flora at 24 h after irradiation but, in enhance the likelihood of systemic infection as wellcontrast to sublethally irradiated rats, facultative as permit intestinal contents to damage the epithelialpopulations began to increase by 7 days postirradi- lining. Irradiation may cause a reduction of mucusation and were increased several times above normal secretion either through a decrease in the number oflevels by day 11. This period of excessive coloniza- goblet cells in the mucosa or through lymphocyte (Ttion of the ileum by facultatively anaerobic flora cell) loss from radiation exposure (49). Bile secretioncoincided with the beginning of the time that deaths could also affect mucus integrity (50). Although theoccurred in rats. Disturbed intestinal microecology mechanism is unknown, it was recently shown thathas also been seen in other animal models of irradi- the continuity of the mucous blanket can be de-ation injury and has been associated with sepsis and graded after irradiation (51). Although other physi-death (35). Changes in the intestinal flora, coupled ologic and immunologic changes are prol ably alsowith impairment of the normal barrier function of involved in influencing postirradiation ,aicrobio-the gastrointestinal tract, allow the bowel to serve as logic events in the intestine, destruction of thea reservoir for pathogens that can enter the portal mucous barrier could alter colonization resistanceand systemic circulations and fuel the ongoing sep- and permit pathogen access to the epithelium.tic process. This process may become rapidly over-whelming in a subject further compromised by mar- AUCi-o1s of Intestinal Blood Flow androw failure and profound immunosppression. Microcirculation

In addition, loss of colonization resistance is asso-ciated with shifts in microbial populations in com- The role of alterations of intestinal blood flowpromised individuals. Van der Waaij (43) has shown in the pathophysiology of the acute, subacute, andthat opportunistic pathogens in the digestive tract chronic radiation syndromes remains unclear. Mea-are the major source of infection in animals with surements of total small intestinal blood flow in ratsdecreased defensive capacity. Colonization-resistant exposed to 5-Gy total-body y-radiation failed toanaerobic flora contribute to the control of these demonstrate consistent changes. In contrast, intesti-facultatively anaerobic pathogens, but when coloni- cal blood flow decreased during the first 2 h afterzation resistance is lost, the opportunistic flora are exposure to 10 Gy but increased significantly by 4-6able to multiply excessively on niucosal surfaces. h postirradiation (52-54). In rats exposed to whole-This event is associated with invasion of normally body y-radiation of either 9 or 10 Gy. Suskevic andsterile tissues by endogenous flora. Selective decon- Uklonskaya (55) observed marked fluctuations intanination of the digestive tract with antibiotics that blood flow in the first hours after irradiation. Aneliminate pathogens but (1o not disturb anaerobic initial decrease was followed by a pronounced in-flora (which maintain colonization resistance) has crease at 6 h postirradiation and then by a sharpsuccessfully been used to provent infection in pa- decrease from the second to the tLird day.tents with burns (44) or granulocytopenia (45). Extended observations of postirradiation blood

There is a relationship between numbers of |ites- flow to the small intestine showed it continuedtinal microorganisms and their translocation to mies- decrease at 6 and 12 in after abdominal x-irradia-enteric lymph nodes (46). Increased numbers of tion. with a fractionated (1.91 Gy/day) exposure ofbacteria in the lunmen of irradiated subjects could 28.71 Gy. h owever, both the ejutuum and iloumcause o)portunistic infections through Itis process. showed a blood flow at control level when exposedRecent data may help identify the route by which to only a single dose of 5.74 Gy x-radiation (56). Intraslocation octurs, suggesting that M cells overly- contrast, 1lod flow to the hge intestine was ti-ing lymniphoid follicles of the gastrointestinal tract are creased through the 6 mn of postirradiation observa-part of a major antigen-sampling system 147). Some tion. buit begau a declitn to below control levels bybacteria can attbch to and be transported through 12 nii) postirradiatin.thest cells, where tht should he processt d by Thus, variations exist according to the species,macrophaiges and lymnphocytes as alt initial step in oro.ns, source of radiation, metthod of exposurethe iuUcosal imnune response. If the Iormal fuic- (fractiotted or sinilh), technique of blood flowtioi of this systent is iipairod by radiation or other measurentent. and timt of tueasuremont after irradi-traum, an easy route of ingress to the bodv would be utian. rht: r ;pmtion, ppuirN to be tiiphasic afterprovided. exposure to doses -ti Gy: an initial decrease in blood

Many organisms cohoiziug the intestineo, includ- flow is followed in a few hours by an increise thating those conferring colonization resistance, are lo- lasts a few days and. in turn. gives way to a long-calized in the mucous barrier, a major structure hlsting decrease in total blood flew.

450 tm thick overlying the opithelinui (48). Any '(he microcirculatuon of the intostine also appears

504 DUBOIS AND WALKER GASTROENTEROLOGY Vol. 95, No. 2

to be altered after irradiation. Seventy-two hours However, therapeutic doses of metoclopramide doafter exposure to 15-Gy mixed ncutron-y-radiation, not seen) to be effective in humans if given afterthe villous capillary network of the dog small intes- vomiting has started (64). In addition, this medica-tine appeared histologically intact and continuous, tion may cause extrapyramidal side effects, becausedespite mucosal cell destruction, but the intestinal it crosses the blood-brain barrier and inhibits striatalcapillary blood flow per gram of mucosa was in- dopamine receptors (65). In contrast, the peripheralcreased at that time (57). Occlusive endothelial dopamine antagonist domperidone does not causechanges were found in the submucosal arterioles central side effects because it inhibits only theof rats 4 days after exposure to 14.6-Gy x-radiation dopamine receptors located outside the blood-brain(58). Similarly, clinical evidence of microvascular barrier (66) and it prevents radiation-induced vom-changes in humans with radiation bowel disease has iting in the dog (10), However, domperidone doesbeen furnished by Carr et al. (59). These studies also not appear to be effective against either radiation-indicated that alterations were observed in the mu- induced gastroplegia or radiation-induced vomitingcosal vasculature in patients 1-28 mo after radio- in the monkey (10,11). In contrast, clinical trialstherapy. In addition. Suskevic and Uklonskaya (55) seem to indicate that domperidonc may be effectiveobserved that permeability increased fourfold in rats in humans (67), although double-blind placebo-3 days after exposure to whole-body --radiation of controlled studies will be necessary to confirm this9-10 Gy. finding.

In cats exposed to doses of up to 15 Gy, the A number of newer antiemetic and gastrokineticmicrovasculature of the intestine was found to be agents are currently being tested in both animals andnormal 4 days to 4 me postirradiation (60). However, patients. Recently, one of these medications (Zaco-after exposure to 15-30 Gy, decreased vascularity pride, A. H. Robins Co., Richmond, Va.) was foundwas observed in all layers ol the bowel, including to be effective in the prevention and treatment of thevariations in luminal width and obstruction of yes- prodromal syndrome (vomiting, retching, and gastricsels, which occurred more frequently at the higher emptying suppression) in monkeys while not caus-doses (60). These vascular changes may be respon- ing undesirable side effects (68).sible for a deciased capillary filtration coefficient,which has been observed after irradiation. In addi- Subacute Radiation Syndrometion, later experiments providfed evidence of ultra-structural changes that correlated with these changes The treatment of the subacute gastrointestinalin capillary filtration coefficient, suggesting that the syndrome is based on supportive therapy to preventearly decrease in this coefficient seen in the groups infection and dehydration, although ultimate sur-exposed to 20 and 25 Gy may result from paricapil- vival depends on bone marrow and intestinal stemlary fibrosis. cell restoration or repopulation. This therapy in-

cludes plasma volume exlansion, platelols, and an-

Prospects for Management tibiolics, which enhance survival after intestinalinjury caused by radiation. With these therapeutic

Prodrmul Syndomo mneasures, survival may be possible up to 15 Gy, but

The prevention and troatment of radiation- total-body irradiation above 20 {y is not manage-induced voimiting can he achieved with neurolhptics able. Finally, tihe prognosis becomes much more(clhlorpromazine, Iprointhazinel or oven general an- serious if irradiatiou injury is combined with thor-esthetsia (611. However, this typ)e of approach is not inal or mechanical injury, as may occur in an acci.desirable because of the sidh effects of these medi- dlent such as the Chernohyl disaster.cations, which further depress gastric emptying and Current research is attlmpting to prevent tlir dame-appetitt, and may increase the risk of pulmonary ago it) the intestine by using a variely of radioprotect.infection. ants. h'lise coipounds appear to reduce Initial

A mor promising approach has been tIhe Use of daumimgo to steln colls in the crypts and therebyantidopaiinergic agents, 'Tihe olst dopanIie an- dcrease the ilffet of i givein dose of radiation.tgoliist is ietoclpramide Which, inl addition to its Ihidr experimental condlitions a dose reductionantihlinetic prolrties, has a potent gastrokinetic nf- factor cnil then be calculaied to quantitatively oval-fact and prevents radiation-hiduced vonilling and inte th eflicimcy of radieproecthnts. For oximlhi.giistroplegih in mionkeys (62). ''his gastrokinotic ac- the liil derivative group (ethiofos or WR-27211lion appears to ho hndlpdent of its ailidoplnlin- imi)proves sirvivl of the sltiil cells of the intslililorgic propertihs and iiay b related ito intoclopra- crypts ini addition to those of the hone marrow and

mid-induoedl release of acetylholine and ether has i dose reduction factor of 1.25 1.( 131,69).leuropeliiles within the liyonteric plxils (63). Furthermoreti, thiof'ons nmnis in rtils demionstratlid a

August 1988 RADIATION INJURY 505

dose reduction factor of 1.8 compared with controls ants, possibly in combination with growth factors(70). As the compound was not absorbed into the that enhance stem cell recovery, may soon be avail-circulation, it appears that ethiofos can exert its able to prevent or to rapidly repair gastrointestinalradioprotective action by a direct, nonsystemic effect damage. Selective decontamination with poorly ab-on gastrointestinal mucosa. Recent evidence has also sorbed antibiotics can now offset some consequencesbeen presented suggesting that the use of prostaglan- of immune suppression in the intestine and futuredins alone and especially in combination with WR- studies may reveal means to nonspecifically enhance2721 could prevent damage to the epithelial cells of mucosal immunity as systemic immunity can nowintestinal villi, being therefore truly radioprotective be stimulated.and cytoprotective (69).

Stem cell survival in the intestine is a probable Referencesevent, even if radioprotectants are not used. For this e en c~reason, the induction or administration of cell 1. Henwelmann LH, Lisco H. Hoffmlan IC. The acute radiation

syndrome: a study of nine cases and a review of the problem.growth regulators after radiation offers future possi- Ann Intern Med 1952.36:279-510.bilities for enhancement of intestinal recovery. This 2. Quastler H. The nature of intestinal radiation death. Radial

approach is already being applied to the stem cell Res 19564:303-20.

compartment of tho bone marrow of irradiated sub- 3. Moore FD. Metabolic care of the surgical patient. Philadel-

jects (71). phia: WB Saunders, 1959:921-4.Ohert m s t4. Bond VP, Fliudner TM, Archambeau 10. Mammalian radia-Other methods to promote intestinal recovery may tion lelhrlity: a disturbance in cellular kinetics. New York:

be closer at hand. Postirradiation enteropathy is ALademic, 1965.

exacerbated by bile and pancreatic proteases (72,73). 5. Morgenstern I, Thompson R. Friedman NB. The modern

Effects of these substances may be enhanced when enigna of radiation enteropathy: sequelae and solutions. Am

the mucous barrier is lost after injury (51,74). These I Surg 1977,1:14166-72.and c recovery 6. Fry RIM. Experimental radiation carcinogenesis: What have

roblems can be alleviated cellar learned? Radial Res 1981:87:224-39.enhanced in experimental animals fed elemental 7. Conard RA. Effet of x-irradiation onil intestinal motility in the

diets containing amino acids before irradiation rat. Am I Physiol 1951:165:375-85.

(74-76). Finally, therapeutic effectiveness of elemen- 8. Young RW. Mechanisms and treatmnt of radiation-induced

tal diets has also been shown ill patients undergoing nausea and vomiting. In: Davis Cl, laike-ilakaar CV. G rahame-Smith DC, ods. Nausea and vomiting: mechanisms and treat-radiation therapy (77) .and nm emrous other co n- n o Ll ol n p i g rV r 1 8 : 4 1 9men!. tiorlin: Sprinlger-Velrlag. 1986:94-|19.

pounds such as micronutrients (e.g., selenium, vita- 9. l)obois A. Mntoler G, O'Connell l, Durakovic A. Abnormalmins A and E) are also curretly under study as gastric omptying and prevention of radiation-inducd vomit-potential radioprotectants. ineg in primatus (abstr. Gastroentenlogy 1985:88:1371.

to, )ubois A. Jacobus 1I Grissom MP, Eng RR, Conklin II.Allerd gastric vmptying and provontion of radiation-induced

Summary retiaiting in clogs, Gastroenterology 1984:116:444-8.it. Iorval El), Muollor GP, iEng RR, Derakovic A, Conklin II.

Three types of injury o:cur in the gastrointes- iDubols A. Effct of ionizing nadilhtion on gastric: secretion andtinal tract after radiation. niesis and gastric sup- gastric motility in mnnktiys. Gastroenterology 1985:89:374-

_ rssion are caused by mechanisms still unknown, 1.anld have effects that complicate radiotherapy and 12. Summers RW, Flatl Al, Prihohla M. Mitros VA. Small illhe.ii-

teral e enal motility in (logs aftor irradiation Injury. )ig Dis SOho treatm~ent of teoplo receiving inxposures i acci- 19187:32:1402-10.

dent or weapon deonliation sclnarios. Sufficient 13. Ilorison Ill,. Borison R. Mcarthy I.E. Roln of thi area

daiage It) the epithelial barrier atnd the intestinal plstroiai in vomiting an rlated functions. Foil Pint: 1984:

tiicrocircuttion impairs gastrointestinal futnction, 43:21)55-it

which call have lethal coltsoqttetcs. ''lmo mticosal 14. chil It. Witg sc. I.ocus of mentic actiion following irracli-ation. Pr: Sot: lNp flint Mut 154:a5:4172-4.

immune; system and the ecology of tilt) cohoization 15, Ilrizzo KR, Noah I.M, Williams PM. Tiu cluhmorstxptor

resistant flora are also disrupted after radiation ox trigger zcam for oulmsls in the monkey. Am I Physlol 11155:psur Thas, tuorhality and morbidity are increased 1(10:659-62,

by itifectious complications. is well as physiologic 16, lirison Ill.. Site of eltic acticn of x-radiation In the caL. IComp Ni-orol 1957; 11t7:.439- 51s

faihlrte. 17. Walker RIt l hbedy GID. Callby :I. Asopti: ndtloxtmia inProgress is heing madeo h conttrol the p)hysiologic racdialo injury ant graft-vs-lhst diseats. Riallt Ris 1975:

and inmmtnologic conseteltnces of radiation injury 12:2.12 -it.

to Ite g. rointestinal tract. New-gotiertlion anti- 18. Maxwll A, Caflin 81.. Wells MT. Radiotheraly, ondolioxmia

ilntics alliy soon control sotne debilitating offects of antI oIiiiSain lancolo 1111:11411-11.rad~iationt, Frt~lhe~rmoresuptOivo therapy with i1. L.efehvr RA. Willms iL. Iligaert M. Gastrc relaxation mldrtt . u ro, poi ttp ivomIling liv alillirlI tiil, mortihiolit ad flltaniyl in tile

-luidus and ilittelets, as well its controlled tliets, ll cn cosc:ious dolt. Iunr I Pharmacul 19811ilil:i'3i 45.

tiow intltilniznie 53ne radiatioi iniry. Ridioprttect- 2e. Shita-ltniohil Vt'. Adlans N, Arnold I. linhois A. Effects of

506 DUBOIS AND WALKER GASTROENTEROL.OGY Vol. 95. No. 2

Met-enkephalin and naloxone on gastric emptying and secre- tract in experimental animals and its consequences for infec-tion in rhesus monkeys. Am I Phvsiol 1983;245:G196-20&. tion prevention, acquisition of new bacteria and the preven-

21. Dubois A, Nompleggi D, Myers L. Castell DO. Histamine H;2 lion and spread of bacteria b'etween cage miates. In: van derreceptor stimulation increases gastric emptying (abstr). Gas- Waaij D, Verhoef 1. eds. New criteria for antimicrobial thera-troenterology 1978,74:1028, py: maintenance of digestive tract colonization resistance.

22. Steel LK, Raffertyt MA. Wolfe WW. et al. Urinary excretion of Amsterdam: Excerpta Medica 1979:43-53.* cyclic nucleotides, creatinine prostaglandin K, and throm- 44, Van Saene HKF, Klasen Ji. Saner EWV. Selective decontami-

boxane B2 from mice exposed to whole-body irradiation from nation in burn patients: effects onl wound healing. Prelimi-an enhanced neutron field. lit I Radiat Biol 19116,50:695-715. nary results. In: van der Waaij D. Verhoef J. eds. New criteria

23. Dubois A, Dorval ED, Steel L. Fiala N. Conklin Ji. Effect of for antimicrobial therapy: maintenance of digestive tractionizing radiation on prostaglandins and gastric secretion in colonization resistance. Amsterdam: Excerpta Medica 1979:rhesus monkeys, Radiat Res 1987,110:289-93. 216-22.

24, Nomplegpi D. Myers L. Castell DO, D~ubois A. Effect of a 45. Mulder NH, Nieweg HO. Sleijfer DT, at al, Infection prevenl-proslaglandin E, analog onl gastric emptying and secretion in lion in granulocytopenic patients by selective decontamina-rhosus monkeys. J Pharmacol Exp Ther 1980;212:491-5. lion of the digestive tract. Ini: van der Waaij D. Verhoef 1. eds.

25. Shea-Donohue PT, Myers L. Castell DO, Dubois A. Effect of New criteria for antimicrobial therapy: maintenance of diges-prostacyclin on~ gastric emptying and secretion in rhesus live tract coloni,.ation resistance. Amsterdam: Excerptamonkeys,. Gastroeterology~ 1980:78:1476-9. Modica 1979:113-6.

26. Carpenter DO, Blriggs DR. Knox AlP. Strominger Nb. Radia- 46. Steffen EK. Berg RD. Relationship between cecal populationtion-induced emesis Ii the dog: effects; of lesions and drugs. lovels of indigenous bacteria and translocation to the niesen-Radiat lRes 1986:108:307-16. teric lymph nodes. Infect Immiun 1983-.39:1252-9.

27. Caster WO. Armustrong WiD. Electrolyte metabolism after total 47. Sneller MC. Strober W. M cells and host defense. Iinfect Disbody x-irradiation. Radial R~es 1956;5:189-204, 1986;154:737-41.

28. Gits 1. Gerber Gli. Electrolyte loss. (t mnain cause of death 48. Roxee KR, Cooper 1). Lamn K, Coslerlon 5W. Microbial flora offromt the gastrointestinal syndrome? Radiat Res 1973:55:18- the miouse ileumn mucous layer and epithelial surface. AppI28, Einviron Microhiol 1982:43:1451-63.l

29. Gunter-Smith 11). Gamma radiation affects active electrolyte 4-1 Lake AM, Bloch KI. Neutra MR. Walker WA. Intestinal goblettransport by rabbit ileum: basal Nat and Cl transport. Am 3 cell mucus release, 1t. Ili vivo stimulation by antign In thePhlysiol Ioitti250:G540--5. immtunized rat, I himitinol 1979:122:834-7.

30. Lushbaugh (XC. Sullon j, Richmond C;R. 'he question of 50. Sullivan Ml1'. BoIse EV, Mole RH.'ll T uu-dhetnelectrolyte hiss; lin thet intestinal dfeath syndriome of radiation action of bile lin the small intestine of the irradiated rat. Brdamange. Radiat Hies 1960:13:814-24. Exp Patbol 19165:46:25-44.

31. H-errera I. Gage 't. Mohaupt '. Vigneul lo R, D~ubnis A. Eiffects 51, Walker RI. Brook 1, Costerton 1W, MacVittie ,~ Mvhal ML.of radiation oil intestinal absoarption Ii dogs: protection by Possile association of moucous blanket integrity with postir-WRt-2721 I abstri. Gastroenterology 19117:9'2:1414. radiation colonization resistance. Rdial Res 1985;104:346-

32. Ctiv'a P., lshivarra M, Koizui S. Woodruff P., Kaufman A. 57.Finle J. Role of endtotoxeila of intostinail origin it) early deoath 52. D~elgado G. Butterfield All, Dritschilo A. ait ait. Measure offromn large burns. Surg Gynicol Obstet 1974:138:725-31L blood flow by the mutltiple radioactive nitcrosphure technique

3.Ravin HA. Fine J. Biological implications of ites ti uno- inrdte atrltsiltss.AmIGn ncl18:toxins, Fed P~roc 19612:21%:5&\ 1:463-7.

34. Woodruff P'Wti, O'CArroll 11E, Koiy.unii S. Fine S. Role of the 5:3. lnossy (. Intestinal blond flow Ii gastrointestinal Irradiationintestinial flora Ii major trauma. I infect Dis 1973:1211:20-4, syndronIi int rat. Acda Medt Aced Sl flung 19119:216: 13 -2 1.

35. Waltker RI. Porvaznilk M. Association of bmaterin and nde- 54. janossy G. Cardiac output and its distribution Ii the terminalfoxin with post traum events. In: Ninnuan~ 1, tid. inunuino- stage of thei gastrointestinal Irradiation syndrome ("radiationlogic coulsequenaals of tthermial told traumnatic injury. Bailli- shuck"). Ada Mod Aced Sci fiung 19611:2t1:2:1.ALmuore: I 1nfivorslty Kirk Press, lilwlt' 15 55. Stiskovi. LN, Ilklonskayn 11 Changes tit certain functional

3t6. Cuelvas P1. Fineo 1. Production of fatal ontletosic shock by proptirfitis of the velsels of the intestines inl whole bodyvasuactive subsancuses. Gastrooentiology 1973;:64:2115-9t 1. ganunia irradiation at suporloihal doseys. Raditiblologlya 11175;

317, Potrvatzoik M, linker W. Welker 14I. Dlisrupt ion of the goblet 15:77 15.cell intercellular junction following histamtine infusion of the !)0. Volitme: K. Vudicka I. Clniir V. Brich 1P. Vavrova F.rabbit ihntun Esperientia 1913:ti1t4-I. Changes tit regional blond flow at late intervals after single

31L. %Valkt'r RI. Potential uses oif oudooxinl fit comnprniuilsml sub- and fractlonutod x-ray irradiation litnits. Sb) Vid Pr Lak Fakjects. lin: Nowotny A. ed.L llentili efaods of ondlotn.\in. New t iniv Karlovy 11179:22-4511-.titYork: Molenm 19113: 1117 -212. 57. Kabal 1 I.lla sI. wyanut IDE. Ca~lnn intestinal vas~oactivity

30. Mactlittle. TJ', Wealker Ri. Kuuoxnidue lterations inl th- ig till devellopmenut of the gaslnnintoestmal radttioa syn-tcanille granetlopuiesis: .:ulonvy-st i lt i ng factor, colony. dromet. Rail Res 1972:501:5211-:18,toriet:ll cells in culture, and growth of tcells lin dithlon 51it. Edy I 1A. ( asarvtt CW. IntilstInal vastaular changes In theuhtaulhnrs. Expi lloniatol 19711:10:1: 8. ~acili radialtion intestiteal syndrome. It.: Sullivan MF-% ad.

411. 81pl1lert CR, Chuian S&, McGovern Ill Jr. lakazare HI, Effects uf Catonts~a radialtion injury. New York: Excurpta Mudticaete(lotoxin litnmarine burns, Adv' Shock lRes 11181:5: 163: -it. It611:3115-95.

41. Genaci 1IP. Jackson Kb., Marleno MAS. Thol intlestinal nadiation 5i. Carr ND. Pal len liR, Ifasleton PS. Stutiold F. Mlitrovascularsyndrome: sopils and onloloxie. Radial Res I110:III:44t2- studies lIn humaon radiation bowel disease, Got 1911l4:25:441--511. 54.

42. Ceneci Ill, Jackson KI,. Mariano MS. Eiffects of lioutlottonas 1111 Eirllkssoti It. Microtanglogriaphh.; patlris lin the sled ii Intestineconiataint on or antiblutit: Aecenl lltnt loll oft the intesinle of the cat aftatr Irradhatlon. Scand I Qastroeeterol 11182:17:on ilalto radiation lethality. Radial R~es t19t1114:3015 411(M 11117-01

41t Van der Wittlj 1), Tlhe colouizalbe: n'sistumne of thet digeosiv. ti 6. :erts RE. Anhmal-nmodeol shties tleit to.Inue

August 1988 RADIATION INJURY 507

emesis and its control. Technical Report SAM-TR-86-26. San 71. Monroy RL, Skelly RR, Davis TT, et aL. Enhanced hematopoi-Antonio, Tex.: U.S. Air Force School of Aerospace Medicine, etic recovery after bone marrow transplantation in a monkey1982. model using recombinant human granulocyte-macrophage

62, Dubois A, Danquechin Dorval E. O'Connell L, Durakovic A, colony stimulating factor (GM-CSF). Fed Proc 1987;46:1365.Conklin Ji. Treatment of vomiting and of gastric emptying 72. Geraci JP, Dunston SG, Jackson KL, Mariano MS, Holeski C,suppression in primates after gamma irradiation. J Nucl Mad Eaton DL. A reexamination of the role of -bile in radiation1984;25:96A. induced intestinal death in rats. Radiat Res 1987;109:47-57.

63. Crosswell AR, Buyniski JP. Metoclopramide mechanism of 73. Morgenstern L. Hiatt N. Injurious effect of pancreatic secre-action studies in the chemically or field stimulated guinea-pig tions on postradiation enteropathy. Gastroenterology 1967;ileum. Fed Proc 1984;43:3867A. 53:923-9.

64. Sokol GH, Greenberg HM, McCarthy S, Sledjeski L, Lyman G. 74. Langlois P, Williams HB, Gurd FN. Effect of an elemental dietRadiation induced nausea: the comparative efficacy of oral on mortality rates and gastrointestinal lesions in experimen-metoclopramide versus prochlorperazine and placebo. A tal burns. J Trauma 1972;12:771-6.double blind randomized study (abstr). Proc Am Soc Clin 75. Hugon JS, Bounous G. Elemental diet in the management ofOncol Annu Meet 1986;5:970. the intestinal lesions produced by radiation in the mouse.

65. Schulze-Delrieu K. Metoclopramide. Gastroenterology 1979; Can I Surg 1972;15:18-26.77:768-79. 76. Mohiuddin M, Kramer S. Therapeutic effect of an elemental

66. Laduron PM. Leysen JE. Domperidone, a specific in vitro diet on proline absorption across the irradiated rat smalldopamine antagonist, devoid of in vivo central dopaminergic intestine. Radiat Res 1978;75:660-3.activity. Biochem Pharmacol 1979;28:2161-5, 77. Bounous G. The use of elemental diets during cancer therapy.

67. Bernier J, Huys J. Domperidone in the symptomatic treaiment Anticancer Res 1983;3:299-304.of radiotherapy-induced nausea and vomiting. Postgrad Medj 1979;55(Suppl 11:50-4.

68. Dubois A, Fiala N, Bogo V. Prevention and treatment of thegastric symptoms of radiation sickness. Radiat Res (in press), Received November 12, 1987. Accepted March 7, 1988.

69. Hanson WR. Radiation protection of murine intestine by Address requests for reprints to: Andre Dubois, M.D., Ph.D.,WR-2721, 16-16 dimethyl prostaglandin E2 and the combina- Department of Medicine, Room A3075, Uniformed Services Uni-tion of both agents. Radiat Res 1987;111:361-73. versity of the Health Sciences, Bethesda, Maryland 20814.

70. France IIG Jr. lirtle RL, Mansbach CM II. tntracolonic WR The opinions and assertions contained herein are the private2721 protection of the rat colon from acute radiation injury, ones of the authors and are not to be construed as official policy orGastroenterology 1986;91:644-50. as reflecting the views of the Department of Defense.

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