Early hepatic dysfunction in a large animal model of ... · Des cristallo"ides one cce adrni...

EXPERIMENT AL GASTROENTEROLOGY

Early hepatic dysfunction in a large animal model of nonhypotensive sepsis

S rI· l'l lEN Slll l lVAN, MD, FRCPC, FRCP(LOND), M lt'llAEL TROSTER, MD, FRCPC, AnMt LINTON, MB, FRCP(EDIN), FRCPC

S SULLIVAN, M TROSTER, A LINTON. Early hepatic dysfunction in a large animal model of nonhypotensive sepsis. Can J Gastrocnterol 1991 ;5(6):219-223 . epsis was induced in 12 sheep by cecal deva~cularization and perforation . lmravenous crystallo id was administe red to maintain th e pulmonary capillary wedge pressure a t preseptic levels. By 24 h t he re was ,1 significant drop in albumin and a lka line phosphatase with inc reases in aspartatc aminotransferase (AST), laccate dehydrogenase and bilirubin. By 48 h the alkaline phosphatase had returned to presepsis levels, the bili rubin continued co rise, t he AST and lacrn te deh•1drogenasc had plmeaued while the a lhumin remained low. T hese biochemi­cal alterations were confirmed by exam ining da ta from 25 sheer used in simi lar epsis experiments. These data revealed that marked elevations in AST were

as~ociared with a high er cen tral venous pressure an d worse ren a l impa irment, but there was no relationshi p with any other hemodynamic parameter, P02, pl-! or ~erum lactare. l listologically these biochemical alterat ions were associaLed with extensive m icrovesicular fan y change a l 24 h and centrilohula r necros is at 48 h. Electron. microscopy revea led mi tochondrial degeneration , hyperplas ia of th e smooch endoplasmic reticulum :rnd intrace llular ch o lestasis.

Key Words: Cholestasis, l lepatic dysfunction, Liver, Multiorganfailure, Sej)sis

Debut de dysfonctionnement hepatique clans un grand modele animal de septicemie non hypotensive

RESUME: On a provoquc une septicemic chez 12 moutons en cffectuant une dcvascularismion et perforation J u caecum. Des cr istallo"ides one cce adrni nistres par voie intraveineuse afin de maintenir la pression capilla ire pulmo na ire au nivcau a nterieur a la sept icemie. En 24 he ures, on a note unc dimin ut ion significat ive des concentratio ns d'a lbumine et de phospharases alcalines ai nsi qu'u ne e lcva Lion de l'asparrate aminotransferase (AST ), de la lacticodes­hydrogenasc (LOH) et de la bilirubine. A u bout de 48 heures, les valeurs des phosphmases alcalines ctaienr remurnecs a lcur n iveau initial, la bilirubinc continuait a augmenter et les AST et LOH eraienr station naires randis que l'a lbumine restait fa ible. Les resultats portan t sur 25 moutons ayan t serv i a des experiences du meme type on t confi rmc ces modifications biochimiques. Ces

Det,m-m1<mL, ofM~Jici11e and Paclwlo,{f.)', V1cwru1 I lmJ,iwl, London, ( )111mw

Cmws/>onJ.!11c.!: /)1 Steplie11 S111/im11, De/ummenr of Medic me. 1'i11~ Flllwd r los/ntal, I'() Box 22490, R1:,otUlh I /.f26, Smuli Ara/)f(r. Fm 966 I 49/ /876

Recerwd /or Jnihlinwon Ma'/ 31, / 991. AcceJnd Nm•emher 8, / 9',) I

CAN J G1\STROl·NTFRUI VL11 5 Nl 1 6 NlWE~lllER/l)WEMnl,R 1991

HEP/\ TIC IWSl·UNC TION ( 1C< 'UR­

ring during the course of systemic sepsis b well recognized ( 1-6). If hypo­rensinn docs not occur the major ah­norma I iue, me increase~ in alkaline phosphatase and bil iruh in with the oc­Gb11mal development of dinical jaun ­dice. Pcrs1,1 ing hyperhil irubinemra 1, a,sociat ed wirh poor prognosi:, (2). The pathogenc,i, uf Lhcse abnormalit ies rc1m1 ins an cn1gm,1, bur may be due to an endmoxin inducL·d reduction in bile flow (5). li\'er histul1>gy b 11,ually mild­ly abn1mn,1l ,md ,hnw, n1mspecific ch,mges ( l .Z). In wntra,t tn the chole­sLauc changes uf nurm,11cn,ive sepsis, hypotensron and hypoxia can produce mmked elevauuns 111 ,L·nrm I rans­am rna,es , a:,:,ociated wr rh cemri lnhu lar hepmic nccrn:,is (8).

ln the present sr udy the auth1ws clocumenL the early biochem ical and histo logical changes associated with nunhyp111 ens1vc sepsis mduccd by ex­pen mem,11 peritnniris in ,heep.

MATERIALS AND METHODS The exper imental protocol has been

described previously (7-10). Twdve sheep aged between nine and 18 mnmhs, weighing hetween 10 and 50 kg were used. Twenty-four hums prior to initial surgery solid luod wa, wllh­held, hut rhe sheep were allowed free ,1Ccess to water. Under halothane anes­thes ia and af ter end,1trache,il intuh:1-

219

SUI.IIV,\N ~L Lii

donnees ont de p lus revele quc les hausscs marquees d'AST crnient assoc,ees l1 unc prcssion veincuse centrale plus c levee et a une insuffisance hcpntique plus grave, mais qu'il n'cxisrnit aucun lie n avec d'aurres para metres hemn<lynamiqucs, P02, pH ou lactates seriq ucs. Sur le plan histologiquc, ccs modifications hiochi miques s'accompngnaient d'unc dcgcncrescencc gra isseusc micro­vesicu laire etenduc a 24 heures et d'unc nccrnsc centro-lobulaire a 48 heurcs. Un examen au m icroscope c lcctronique a revelc une dcgcnere~cence mito­chondrialc, une hypcrplasie du reticulum endoplasmmique agranulaire ct une cho le.stase intracellula ire.

Linn rhe .1orta was cmhcteri:ed with a

si last ic GHhe1er, the pulmonary artery

with c1 tnplc lumen fl nw directed right heart catheter, and the urinnry hladder with a self rewin1ng Foley c.nheter. The~hcep wcre allmvcd l\l recover 111 a

metahnlic cage with free :1CCL'ss 10 food and water fnr m least 24 h hcfc1rc induc­

tion ot scpsis. J 111 raven nus Ringers' lac­rate wns adm1n istercd HI a rnte of 8 L/24 h to volume In.id rhc animab.

Control measun.?menrs n( hemndy­namic, ren,1 I and hepatic (unction were

obrnined 4 h hcfme induct ion o( sepsis. Under general ant::sthesi:i a mid-linc laparotomy was perfimrn:d. The cccum and ilencecal junction were 1dcnttficLI and al l of the cecum to with in 5 cm nf the ileoceca, valvc was dt::\'ascu lari:ed. A quanmy llf fecal material wa, al­

lowed to remain in the cccum and the distal cecum wa, lig,iu.:d w1Ch ~ 2 silk . A

local omcntcctomy was rerformed tn

prevent locali:arion of° int'ect ion . A 2 cm perforatilln was 1nc1de 1n the cecal lip and fec.11 material wa;, a llowed ro spill into the pern111,1l C.l\'i ty. T he ahdomcn

was ckised with a running sutu rc. Animals were ,1lluwed to recover in a mt::tnbol,c cage. Over 1hc ensuing 12 h all animals hcg;1n ro , how cli nic.1 1

TABLE 1

evidence of ~Yl:>temic infection as evi­dcnccd by increasing re:.piratory ratc

and devclopmem of fever, lethargy and ,morexia.

PoMoperatively, fluid admin1Mra­t inn was guided by the pulmonary

capillary wedge pressure. Sufficient 1ntravenou:. cry:.talloid was infused to

111ainta111 the balloon occluded wedge pressure at presepsis levels.

The pulmonary capi llary wedge pressure, mean arterial pressure, cemrnl venous pressure, h eart rnte, respiratory

rate, thermudilution cardiac output and systemic vascular resistance index wt::re measured prior to surgery and re­pcated daily for the duration of the ex­periment. Blood was obtained fro m the artt::rial line for daily measuremems of hlood gases and from the venous line

for hemoglobin, whire blood cell count, albumin, creatinine, urea, total bili ru­

bi n , asrartate aminotransferase (AST),

and lactate dehydmgenase. Blood was abn drawn for aerobic and anaerobic culture in broth and subculture on hlond and chocolate ag,1r. U rine was collected for measurement of creatin­ine ,md calcubtion nf creatinine clear-ancc.

ln six sheep I ivcr biopsies were per-

Hemodynomic parameters at baseline, and 24 and 48 h ofter induction of sepsis

Parameter

Number

Mean arterial pressure (mmHg)

Heart rate (beats/min)

Cardiac Index CL/min/m2)

Systemic vascular resistance index Cd·s·cm-5/m2)

Pulmonary capillary wedge p ressure (mmHg)

Central venous pressure (cm H20)

·change from baseline significant P<005

220

Baseline

12 108±13 87±24 5.0±1. l

1727±356

12+4

3±3

24 h

12 104±12 149±31 ' 5.3±1.8

1636±441

13:!.7

5.t6

48 h

10 115±8 152±21' 6.7±3.3'

1452±413'

13±4

3+3

formed at the rnne of induction uf scp·

sb. ln three Trucut li ver hll1ps1es were performed at 24 hand in nnocher three at 48 h . The t ts.sue for light micm,nipy wa~ immed iately fi xcd in IO'rc, tonnalm

and subsequently pruccs~ed hy the

usua l paraffin emhcdd111g techntques. All ~ect ions were sta111ed with hcma­toxylin and t'Osin, Chrnmotrupe­Aniline blue (for collagen) an,I

colloidal iron (for ulhum in). Thc speci­mens for e lectron 111 icmsc,1py were

fixed in 3% cold glurnraldchydl' anJ post fixed in I l}(, osmium lei rox1de. The

tissues were dehydrmcd in ;1 grndeJ series of a lcohols nnd cmheddcd 111

Epon-Aralvite. Sect ions nf 80 nm wen' cu t on the Reichcn Om-2 ulirn­microtome and , tamed wi t h akllhl1l1t

uranyl acetate and Rcynnld\ 11:aJ acetate. The section, Wl'rc examined

on a Ph ilips 410 clccrrnn microscope. This model of scpsts prnved uni­

formly fatal. no ani1m1l surviv 111g hc­

yllnd 72 h. S heep that appeared agnnal were immediately kill ed hy intr;11•enou, injection nf penroharhiwl. During rh~ studies sheep were cared for hy qualified

tcchniciam. Postnpcrmivc ancsthl!sta consisted of meperidine given tnlrn·

venously at 6 t() 8 h inrcrvab. Sheep showing a ny signs of distrcss were 1111-medimely killed as previliusly described. The study prntllCol wa, ap­

p roved by the local ethics com,nittce governing med ical research and 1he care of experimental animals.

T he data are cxprcsscd as t he mean ± standard deviat ion. Analysis of \';Jrt ·

ance was used to exam inc rhc effect of

time o n each o( the dcpendent vmi­ablcs. Data from the presenr group of sht::ep wcrc compared hy two ,ample Student '.s r test with darn from sheep used in similar ,cpsis expcriments (9, 13, 14 ).

RESULTS ln all sheep 1he prcsence o( poll'­

microhial sepsis was cnnfirmed at 24 h by blond culture. The moM frequendy

grown organ isms inc luded Serrwia mar­cescens, En1ero/x1c1cr cloacae, Pseudo­m<mas spccics, /3acrernides speuc, and various strains ut £scheric/1ia coli Autopsy examination rcvealcd marked ahdrnninal distcnsi( ,n wi1 h di,tcmbl

loops o( howel and large quarn 111cs nf

free peritoneal iluid. An intlammatnry

ma~s was always present in the right

lower quaJrnnt. Hemodynamics: I lenwd yn amic, a t

ha~eline, 24 h .mJ 40 h a rc , hown in

Table I . The mt:,lll arte ria l pressure,

pulmnnar~ capillary ll"edge pre,surl' anJ

cen t ra l vcnnus pressu rl' 11 ere un­

changed whi le heart rate anJ cml1ac

index mcrcased and systemic vascuhr

re~iMance imkl, dl·creased sign ificantly

O\'Cf 48 h. Hematology: The henl(lglohm remain­

ed unchanged (lw,eline 98±1 10 g/L;

24 h I 05±122 g/L, 48 h 98±15 g/L). The

whne hlnod cell count dropped signi fi­

cantly (hasclm e 7.7±4.0 x109/L; 24 h

3.1±1.3; 4 8 h 2.HI.O). Renal parameters: Afte r the mducrilln

oi sepsis the hlood u rea n1tn1gen and

creaun1nc grndu,1 ll y rose while the crcarminc clc.1r:111el' fe ll (Tahk 2). These cl1,111ges were , ignific 1nt a t 48 h. Hepatic biocht:mi!>try: T he ch anges in

hepa tic hinchem is try ,ire shcl\\ n in

Table 2. Bv 24 h the albumin a nd .il kal i ne phc,,,,h.itn,c had d rnppt:d,

while rhc AST and !act ate dchyd ro­genas had nsen. Ar 48 h the a lkaline

pho~phatase had returned to prcseps1s

level~. the a lhumin n:mained lll,1' nnd

the AST and l.icrnte de hydrogen ,1se

had plateaued. Identical changes were

seen in 25 sheep fn,m nther sepsis ex­

periments (Ta hie 1 ). Four of the sheep in this expcn menr

had deq1t1om Ill AST greater than "300 IU/L at 24 h . Therefore, their he mo­

,lynamic and biochemical data wne comhi tll'd \.\ ith data from 25 .,cptic

sheep of orher l'Xperimcms. Fourteen

sheep with ASTs greater th:m 100 lU/L

(mean±Sl), 447±259) wt:re rnmpare,I with 2°3 sheep \\'Ith AST, le,s th,111 mo !U/L (menn±SD, 17 H I 50) . Thm· were no significan t dtffrrences in me,m

arteri a l pressurc, heart rate, card iac in ­

Jex, or ,yste111 1c va,cu lar rcs1stancc in ­

dex. The sheep with lw~h AST had

higher ccntrnl , ·cnous pressures

(6.5±15.8 mml lg \"Crsus 3.3±1.7

mmHg) P=0.02. There were nu di(­

ferences in />Oz, pl l m l.tetate. S imilar­ly, there wt:re no differences in albu­

min, hiliruhtn l,r alkal in e phosphatase.

The sheep with high AST h ;1d higher

Hepatic dysfunction in hypotensive sepsis

TABLE 2 Renal and hepatic parameters at baseline, and 24 and 48 h after induction of sepsis

Parameter Baseline 24 h 48 h Number 12 12 10 Blood urea nitrogen (mmol/L) 5.012 6.5.12.2 8.213.6" Creatinine (µmol/L) 73:t:11 130,78· 176172" Creotinine clearance (ml/min) 162.+47 1131.51 80130" Albumin (g/L) 30±3 22.13· 221_3· Bilirubin (µmol/L) 3tl 814 " 20± 10' Alkaline phosphatase (IU/L) 84t50 48125· 86±72 Lactate dehydrogenase (IU/L) 456±81 572:±.135" 685±208" Aspartate aminotransferase (IU/L) 153±52 241±97' 219± 101 "Change from baseline significant. P<0.05

TABLE 3 Hepatic parameters at baseline, and 24 and 48 h in 25 sheep from other sepsis experiments

Para meter Number Albumin (g/L) Bilirub1n (~1mol/L) Alkaline phosphatase (IU/L) Lactate dehydrogenase (IU/L) Aspartate aminotransferase (IU/L) "Change from baseline significant P<O 05

le,·eb n( urea (5. 3± 1.2 versus 4. 3±1.2 mmnl/L) ,md cre,lt inim· ( 126±73 ver­

sus 96±49 µm u l/L) bur these changes

were not significant.

Ligh t m icroscopy: A lte r 24 h uf sepsb ,

the liver shl1wed quire extensive micro­

vesicular fa t ty c hm1gc and intraccll11lnr

t:dcma (Figure I ). There ,1·,1s Kupffcr

cel l h ypt:rplas1a a nd leukocytes in the

sinusoids. Isolat ed liver cell necmsis

was noted with formation of Counci l­

man hod ies. A ftt:r 48 h of sepsb, the

changes consisted o f cenrri lohular n ec­

rnsis of th e live r lnhulc and dcpos ib of alhumin in the smusl1ids.

Electron m icroscopy: Elccrmn micro­

scopy results uf liver hiups)' arc shuwn

1n Fi.i.:ure 2. A t 24 h the li ver Cl' ll,

shnwed l1p1d Llroplct s in the hcp. 11 0-cyres. The mi r, ichc llldri,1 were increased

tn size and numher with dcgener,ltlve

ch m1ges including luss llf crisrnc, 1ntn1-

mitL>chundrial c rystallrnds ,md mycl 1n

figure furmat ion. Ci.int mitlichnndri;i

were occastonall) seen. The smunth

e ndoplasmic rt:llcu lum was hyperplas­

t ic and in ,llrnc instances thc rough

cndnplasm1c reticulum abo slwwed in­

crc,1sed prnmmcncc with ddatiun ,rnd

Baseline 24 h 48 h

25 25 14 31±4 23±4" 25+4 ' 4±3 11±9" l7t9"

155155 86±33" 112178" 493±84 627±254' 6821311 · 132±48 291±244' 249198"

stacking. After 48 h of sepsts the mun­her of lipid droplets increased. Int racel-

1 u lar chnlc-,tasis was ~l'en with deposits

o(hile pigment and collagen deposition

in the space , if l'lissc. I ncrcascd numher,

ol lysnsome, and pcroxisomcs were al,n

noted.

D1SCUSS10N The c1usl' of the hepatic dysfunc­

L iLlll that uccurs in ~eptic sta tes is un­

clear. S tudies in humans are difficult

ht:c,1use n f the uimplexn ies of the c l in 1-

ca l ,it uat ion and the uncenaint y cau,ed hy the necessary concomit ant

use nf hlllml t ramf1l'tons and porenual heparot ox ms such as ant1h1mics ,md

parenteral nutrit ion.

In septic humans the mnjur hepalll hiochemic.11 ahnmm,1lity is cle,·,Hion

in rnnjugatt:d hilirubin with tnilJ lLl

mllderme increases in a lkalinc phn,­

phatasc and trnnsmnin,1st:s ( 1,2,6). Oc­casionally thl·rc may he marked clev;1 -

l11llls in alkaline phuspharasc ( 15). I(

h ypux ia llr se,crc h ypotenston dc­

vellips rhere may he marked e levation~

int ramnmina~c, (8).

In patients d),mg nf septic ~hPck,

CANJ (,A..;JR,11:N'JEKtlJ Vtll 5 No6 N,Wl:~IHl·R/l)l'( l~!l'IR ll/91 221

SULLIVAN er al

Figure I ) Light microsco/r; of liw r afL(.'1" 24 h of sepsis showing diffuse micrnvasicular fa uy change, degena aiin,g /11:/>awc'l!e.1 wiLh elll·ly formation of Councilman body (short arrow), and hy1>erplm 1ic K1 1/>ffer celL1 ( rnn•ecl amiw). l lemawxylm and eosin X 170

Figure 2 ) E/ectron microsco/>y of /iw r after 24 Ii of sepsis sliotl'ing li/Jid deposits ( L), /1)'/>ertro/>l1ied, smooth endopla,m11c recrcu/mn (SER) , m)'l.'lin fig11r~s ( long am,ws) and bile deposi1.1 ( short amJtvs). X 6700

post mo rtem li ve r histology sh ,1ws

changes ot venous congest inn , ische­m,c necni~is, fo rty ch ange, Kupffe r cel l hyperplasia and intrahepatic cho les­

tasi~. Occasio nally chnle~rasis may be evide nt m the c hola ngiolar level (2 ) .

In experimen tal enduw xic ~hock the early mo rpho logical changes in the

liver include inj ury to sinusoidal epi -

thelium , sinusoidal congest io n with J c­granulated leukocytes, fibrin and p latele t aggregates, focal mid zonal necrosis, Kupffcr disru ption , micro­vesicular fa t , swollen mitochondria and

pro life ration nf smooth enJopla~mic re ti culum ( 16-20).

In t he presen t st ud y the au thors used a large aninrnl mode l nf systemic sepsis

which m1m1cs the c hanges in ,ept ll:

humnns undergoing acti ve resuscna tio n (2 l ). [1 prnduces a normo tcmive ~tatc c ha racteri ::ed hy high card iac mn put, low peripheral res istance a nd the

gradua l developme nt of renal dysfunc­tion. The hepat ic biochemier1l change~

con~isted o f an early and plateauing 111·

c rease in A ST and lactate dchydrogl'· nase with progress ive inc reases in biliruhin. The emly d rop in albumin 1, no t due to impaired h epatic synthesi,. but rn ther w inc reased vasculc1r endo­thelial permeahil ity a nd lnss of alhumm fro m the vascular space ( l 0, l l).

While a portio n of the increase 111

biliruhin may represent inc reased bi! ,. rubin load from hemolys1s this is likely

a ~mall compone n t as rhere were 1111

significant changes 111 hemoglobin. It 1,

likely that the primary explanation for hype rbilirubincmia i~ decreased bile flow which ha:. heen sho wn in prev1ou., experiments to fo llow infusio n ot en­do toxin o r bacteria. A t whm level this

defect occurs is not c lc,ir, hut expl:n· mentally endom xin hns been shown t,i

decrease bile fl ow at the cana licular level poss ibly hy inhibitio n o f l l+K+.

A TPase (22). Elevated AST a nd lactate dchydro­

genasc arc b ioche mica l evidence of hepatoccllu[ar necrosis. I liswlogicallv

this was characterized at 24 h by focal hepatoccllular nccro~is with occasional

C ounc ilma n bodies while at 48 h there was ex te nsive centri!,)hular necrns1,.

As there was no h ypotensinn or hypox­emi a and no anc rial hcmodyna mic Jif­fercnccs between the sheep with or

wi thout high AST levels, it is like!} that this necrosis represents ischem1a

1>ccurring a~ a result of ~inusoidal events, perhaps from sinus,1ida l conges­

tion anJ collagen depositinn in the space o f Disse. It is possible rhm hepatocellular necrosis cnuld arise from cemrilo bular venous congestio n. The sheep wirh ve ry h igh AST s had higher central venous pressures tha n tho~e with normal AST s; however, the dif­

fe re nces were small and unlikely, by the mse lves, to he of c linical impm· tance. Fina lly, 'tox ic' even ts are a lso a possibility, particu larly in v iew of the marked microvc icular fatty changt and mitoc ho ndrial degenernrion .

222 CAN ] GASTROENTHl()l VOL 5 Nl) 6 NtWEMBER/DECEMRER 1991

Usually thl' h cr,nic dysfunction ,if the nnrmotl'nsi\'c ,cp~i~ syndrome in

hum.in~ b clurncu.:·ri:cd by cholesrn~is. Therefl>n', thl' early clrup in :dblinc phrn,phatasc wc1s unl'xp,:ctl'd a, it has

not been prl'viously dl',crihl'd in human ur animal ,tud ics. By 48 h alkaline pho,phat,1Sl' had returned t1i pre~epsis le\'els; hnwl'vcr, as a 11 an i 111,1b were lk:td hy 72 h it is unkn1>1vn whether thl' levels \\'1ltild hH ve cnn­tinued in rbe ii' the animab had sur­vived. The cau,e ,,r this ea rl y dmp and

~uhseq uent rise in ,ilb linc phn~ph:1tasc is unknown. A lkal11w phosph,1rn,e is

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7. Uu li R, Ahcrnaihy CU, Li mmerin:m HJ. Chol<.:,wt ic d"fen, nf Eschaid11a coli endllloxtn llll 1he is,1la1cd pcrfus<.:d rm liver. Ua, trn<.:ntcni log~ 1976;70:248-51.

8. Ldl11w1tch JI I. Men,k: L. Mnrphll­log1c features nf hepatic injury in cardiac d1se,lsl' and ,h,,ck. J I ll'pat<il 1986:2:"3 l 'l-27.

9. R,chmon,I JM, W,tlk<.:r JF, Avih1 A. cl al. R<.:n ,11,md c:ml1lw:1,c11 l:ir n:,pllnSl' lll nnnhypn1e1is1vl' ,q,-is 111 a large ,mimal m,ldcl wit h pc·ritonitis. Surgery I 985;97:2L15- I 'i.

111,mufacturcd hy the 11\'cr in resp,mse to ,1 variety of imults. The marked hy­pertrophy of rhc sm, lmh endopl.tsmic

reticulum may represent the lh-cr\ syn­thetic re,p11n,l' tu the sqisb. [ l,nvc\'er,

why the albline t'hosphmrn,e drnpped initi,11ly is unknown.

Cen l'ra ll y, physiciath arc more im­pressl·d hy increases in I iver en:ymcs than decreases. Ou:.as1,1rn1ll y, low levels ,,r li \'er cn:yme., m,1y .iid in diag-

11,1,i,. Perhaps an tmexpl:iinl'd d rop in

alkaline phosplwtase 111 a fehrilc, c riti ­rnlly ill patient might he ,tn cmly mantfcstal i\111 of l hl' scpsb syndrrnlll',

IL\ A"ila A, W:ir,h:11Vsk 1 r, S1hh.1kl W, c'I :ii. f\·npheral lymph fln,1 in ,hccp w11h hactl'l'l,tl pent,Hlllts: t\'tdcncc l<ir incr,a,ed p<.:riph<.:r.il microvascular permcahdtt y accllmpanymg sy,1em1c scp,i,. Surgery I 985;97:685-95.

11. Judges [). Sharkey I', Cheung 11, c1 .11. 1'11 l1mm.tr\' 111icnwasud,1r lluid nu ;.. Ill

:1 l:irgl' :1nimal nmdel ,if sep,": l:\'1dc•nce f,,r 111creas..:d ptdmnnary <.:ml,nh<.:l i,1! pcrmeahdny accompany­lllg ,urg1ctlly ,nduced pt·n1,,11111, 111 shc<.:p. Surgery I 986;99:222 14.

12. W:1 lker JF, C umnmg Al), L1nd,a1· RM, S,,le: K. Linwn AL. ·rhe renal r<.:,p1H1s.: pwdlll:cd hy nn11hypntl' t1'1vc ,cpsi., 111 a large ,tn 1m;tl lll<ltkl Am J J-:idncv Dis I 986;Vl ll :88-97.

I) . Cumming Al), Lind,a; RM, McDonald JWI), Lm1"n AL. Au11e dfrct nf a thn1111hn,i111e ,yn1 hetasc 1nhih11,>r ,m renal f11nc1 i,m in unanae,rhcu:cd slll'l'J', C lm Su 1987;73: 171 -6.

14. Cummmg Al), McDnnald JW I), Linds.ty RJ\1, S,,lc: K, Linton AL. The pnllecl i\'e effetl nf I hnimhnxane ,ynthcl:lst' inhih1t1,1n ,m ren,tl f11nll11>11 m ,ystemic sepsis. AmJ Kidney[),, I 989;X I II : 11 4-9.

15. Fang Ml I, G ,11,hcrg AL, l)nhhins WO. Marked clcv:1tinn m ,crum alka line pho,phat:1se ,icti v11y ,h :1m,mif,,1a110n nf ,ystemic mfcu inn.(. ;,1,rroenrcrnk,gy 1980; 78: 592-7.

16. f'x ,le r RI--:, l1ih1glrnus AJ. Ulira-,1 ruLI ur,1 I , dtlT,ll l<lllS nl dllg Ii \'ers during 1: mlntnxm ,l11Kk. Lah ln\'esl 1967;17:5>7-ol

17. Whitt· RR, Mela L. Fbc:11:o LV, Ulnfs,,,n K, Miller LI). I kp,11,l

Hepatic dysfunction in hypotensive sepsis

j11,1 HS 111cre,1si:s in G1rd1.i1. 011t pu1 and decreases in systemic vascular re,1s­ta11ce mdy hi: early hmhingns.

T he cl i111c,1I signific111cc nl t hi:,c ch :m ges is uncle.tr. (;cnn:illy, the poor progn,1s1s a,socimed wtth lin·rdy,func-

11,m m thc s1.·11 ingo( systemic infcct illll i:,, murc ,l reflection of the s1.·1·crity uf th<.: s<.:psis ,y11drn1111.• than uf a,,oci,11cd liver f: til11re. This is suppurt cd hy thl'

frequent ,1ccu1Tcnce of li ver dy,func­l inn in scptil patients whu :ibu ha,'l' renal failure, rcspirn tory di~Ml'" ,yn­

d rntnL', \11' cnccphalup,ll hy ilSS\lU,lll'd with scpsb (21-25).

ul 1 ra,t rue! urc In endnlllx<.:111 ia, ht·murrh.tg,, :ind hypwo:i: Empha,1, on miwch,mdnal changl''· Surt.!t'r\ 197>;7>:525-34.

18. l-\.1!1, JU, Rappapnn ES.(. ,nher L. cl ,11. A primate modl'I fnr pml,mgl'd endotnxin ,hock. L«h lnvl'st 1978;18:5 11 -2>.

19. Balis ,Ill, P;1t eN1n JF, Shdil'y SA. et a I. ( ,I ucn(ort icoid ,rnd ,111 ll hint ic cff<:us \lll hcpatK rnicnicirt ula11on and ass\ll 1;11 <.:d hl ist response~ 1 n let h:1 I C,ra111-nt•g;11 ivl' hactcre111ia. Lah ln vl'st 1979:4l\55-65.

20. Y, ,ung RSK, Wnn,I, C, To\\'figh i J. I lcpat 1c d:unage 111 neonatal rat d11t' In I:. co/1 cmlo1oxin. Dig Di, SLi 1986; l I :65 1 6.

21 S11ifrt·d1111 AI·. l·n1111m RE, Parker MM. ct al. The c1rd1tn·.1,ud.1r rl',ponse of normal humans to the ,1dmmi,trntinn nl <.:ndo1ox1n. N Engl J Med 1989; )2 1 :28(1.(1,

22. U1il1 R, Ahern,11h1 CO, /immcmrn11 I IJ . I nh1hn 1nn ,if Na ' ,K ' - adcnll,im· triph,,sph,Ha,c h; c11dotnx1n: A pos,ihle lll('lh:1111,m, fllrt•ndn1nx 1n­md11led chnlL"SL:t,is. J I nb:t Dis 1977; I )6:5/H 7.

2 \. W<.:rh R, L1n1on AL. Euol\lgy, d1agno,1,, 11,at 111cn1 and prognosis l ,f .1L11te renal f,1i lu re in an intcnsivl' care 11n11. l\<.:su,ci1,1tinn 1979;7:95- 100.

24. Slhwan: [) I\ Bone RC', Balk RA. S:idon J 11. I kp:11 ic dy,fun, 1 i, lll in I ht· ,1du lt rl',plr:tlllry di,trc~s syndrome. ( 'hc,1 1989;95:87l-'i.

25. Young(:n. l\1lton CF, Au, 1111 I"W, l' I ;11. The l'net·phalop.ithy ,hsi1t.1,11ed wi th 'l'Pl ll dln,ss. Clin ln v<·,1 l\,kd. (In press)

22)

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