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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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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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