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1986

The mortality of sepsis in a portal hypertensive ratmodelMargaret N. AlexanderYale University

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Recommended CitationAlexander, Margaret N., "The mortality of sepsis in a portal hypertensive rat model" (1986). Yale Medicine Thesis Digital Library. 2331.http://elischolar.library.yale.edu/ymtdl/2331

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The Mortality of Sepsis in a Portal

Hypertensive Rat Model

Margaret N. Alexander, B.A. I i >

A Thesis

Submitted to the Yale University School of Medicine In Partial Fulfillment of the Requirement for

the Degree of Doctor in Medicine April 1986

Department of General Surgery

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ACKNOWLEDGEMENTS

I would like to take this opportunity to thank these

people who were intimately involved with the completion of

this project. Without their help and guidance, this work may

never have realized its fruition. I would like to thank Dr.

Collin Smikle for his suport and diligence in motivating me,

Dr. Richard Gusberg, for his help, resourcefulness, patience,

and meticulousness in overseeing and correcting the final

work. Dr. V.T. Marches! for his time, effort, and advice in

helping me to organize the project, the staff in clinical

chemistry, hematology, and special thanks to Mrs. Ruth Adams

in animal microbiology for her diligence and meticulous work.

With the help of these people my thesis is finally complete.

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ABSTRACT

Portal hypertension has been recognized as a clinical

entity since the early decades of the twentieth century.

Attempts to classify it based upon the location of the

disease processes within the portal venous system resulted in

prehepatic, intrahepatic, and posthepatic lesions being

described.

The "forward" and the "backward" flow theories were

proposed to explain chronic portal hypertension. The forward

flow theory is based upon the development of a hyperdynamic

splanchnic circulation while the backward flow theory is

based upon the development of collaterals from portal

systemic shunting, attempting to lower the portal pressure.

Based on the work done by previous authors, a pre¬

hepatic lesion was experimentally created by patrially

ligating the portal vein of 44 Sprague-Dawley rats. 49 rats

were used as controls. Portal hypertension was induced and

then sepsis was induced by ligating and puncturing the cecum

of 24 of the portal hypertensive and 24 of the control rats.

Leucocytosis, percentage of immature bands, blood chemist¬

ries, blood and peritoneal cultures were derived from all the

study groups at 12 and 24 hours.

Results demonstrated that there was a statistically

significant difference in the-degree of leucocytosis and the

percentage of immature band forms between the control group

and all the other study groups (p < 0.05) at 12 hours

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as well as between the portal vein stenosed group of rats and

the two septic groups. No difference was noted when the

information from the blood chemistries were analyzed.

Similar organisms were isolated from the blood and the

peritoneal fluids from both groups with cecal ligation and

puncture.

At 48 hours, only 1 rat from the cecal ligation and

puncture group survived. There was no statistical signi¬

ficance between the control and the other remaining study

groups.

Results from this study demonstrated that a prehepatic

lesion resulting in portal hypertension did not significantly

alter the immunodynamics of the host. Further studies are

needed to explain the improved outcome in the portal vein

stenosed group with cecal ligat ion and puncture over the

other septic group.

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Introduction

Portal hypertension has been recognized as a clinical

entity since the early decades of the twentieth century.(1)

In 1928 and 1932, Mclndoe and McMichael respectively, used

the term portal hypertension in their studies on the portal

circulation.(2,3) The first manometric measurements in the

portal circulation were reported in 1937 by Thompson et.

al.(4) In 1944, the method of hepatic vein catherization to

obtain blood samples directly from the hepatic vein in man

was developed by Warren and Brannon.(5) Subsequently, Brad¬

ley reported on an indirect method of measuring hepatic blood

flow.(6) By 1945, Blakemore and Whipple performed the first

shunt surgery in a patient with portal hypertension.(7)

Later that year, Whipple divided portal hypertension into

two groups - intrahepatic and extrahepatic.(8) In the early

1950’s many investigators utilized hepatic vein wedge pres¬

sures as a reflection of portal pressure in post - sinusoi¬

dal portal hypertension.(9,10,11,12) Since then, though

much has been learned about the pathogenesis of portal

hypertension, much is still unknown about portal hyptension

in man, its complications and treatment.

Cirrhosis of the liver is the most common cause of

portal hypertension in the United States and Western

Europe.(13,14) Sixty to ninety five percent of the patients

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with cirrhosis have a history of alcohol abuse.(13) The

second most common cause of portal hypertension is mechani¬

cal obstruction of the extrahepatic portal vein. This obstru¬

ction may be a direct result of tumor invasion or thrombosis

of the portal vein.(14) However, only five percent of the

patients with cirrhosis and portal hypertension have portal

vein thrombosis. The major causes of portal hypertension

outside of the western hemisphere are schistosomiasis and

Hepatitis B associated chronic active hepatitis.(13) To

understand the pathogenesis of portal hypertension and cir¬

rhosis, one must first be familiar with the vascular anatomy

of the liver.

The portal vein is formed by the union of the superior

mesenteric vein, which drains the intestinal tributaries, and

the splenic vein. As the portal vein enters the liver it

divides into many small branches which deliver blood into the

hepatic sinusoidal system.( 15) The hepatic artery, which

has its origin from the celiac axis, enters the liver adja¬

cent to the portal vein. The hepatic artery is also responsi¬

ble for perfusing the hepatic sinusoids. After the blood has

flowed through the hepatic sinusoids, the blood recollects by

way of the hepatic venules, then through the hepatic veins

and finally to the inferior vena cava en route to the heart.

The liver receives about 1500 ml of blood each minute,

of which 2/3 is supplied by the portal vein. The hepatic

artery supplies 40 - 60% of the oxygen supply to the

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liver.(16) The portal vein differs from a systemic vein in

three ways. First, the pressure in the portal vein is usually

higher than systemic veins. Second, the oxygen content in the

portal vein is normally higher than systemic veins. Finally,

the portal veins are valveless. Due to the absence of valves

in the portal system, an increased resistance to flow at any

point between the splanchnic venules and the heart will

increase the pressure in all vessels on the intestinal side

of the obstruction.(16)

Portal hypertension represents a sustained increase in

the hydrostatic pressure within the portal vein and/or its

tributaries.(16) The increase in hydrostatic pressure is

usually the result of an anatomic or functional obstruction

to blood flow in the portal system at any point from its

origin in the splanchnic bed to its exit into the systemic

circulation.(15) Quantitatively, in humans, portal hyperte¬

nsion is considered present when the portal pressure is 5mm

Hg greater than the pressure in the inferior vena cava. One

can now localize the site of abnormal resistance to blood

flow; and the portal hypertension can be classified according

to the site of obstruetion.(17,18 ) Prehepatic portal hyperte¬

nsion occurs when there is a functional or anatomic obstruc¬

tion in the portal flow before it enters the liver e.g

( thrombosis of the splenic or portal vein secondary to ompha¬

litis, pyelophebitis, pancreatitis, trauma, tumor or hyper-

coagulopathic states ).(19) These examples may result in

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total or regional portal hypertension with clinical signs of

portal systemic collaterals, splenomegaly, and

hypersplenism,(19) The development of ascites is rare. The

patient’s first symptom may be an esophagogastric variceal

hemorrhage. From a quantitative viewpoint, the pressure pro¬

ximal to the obstruction is increased; however, the hepatic

venous pressure gradient is normal.

Based on the anatomy of the liver, intrahepatic portal

hypertension can be subdivided into three groups; presinusoi-

dal, sinusoidal, and postsinusoidal. Presinusoidal intrahepa¬

tic portal hypertension occurs when there is a major resista¬

nce to flow in the portal venules. Schistosomiasis is consi¬

dered to be the prototypical example. The degree of portal

hypertension is proportional to the severity of schistosomal

infestation and the load of ova deposited in the portal ve¬

nules.(19) However the resulting PHT is due to the peripor¬

tal granulomatous reaction against these foreign bodies and

not due to mechanical obstruction. Other examples include

congenital hepatic fibrosis, myeloproliferative disorders and

metastatic liver disease. As in prehepatic PHT, the initial

signs include the development of portal systemic collaterals,

amd splenomegaly, with the formation of ascites being rare.

Quantitatively, the hepatic veous pressure gradient is nor¬

mal .

Sinusoidal intrahepatic, portal hypertension occurs when

the major resistance to blood flow is in the sinusoids.

8

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8

Alcoholic cirrhosis is the prototypal example. The initial

signs include the development of portal systemic collateral

circulation, with, vascular and metabolic consequences super¬

imposed on the underlying cirrhosis.(19) Unlike the above

groups, ascites is common. Quantitatively, the hepatic venous

presure gradient and the portal venous pressure gradient are

elevated.(19)

Postsinusoidal, intrahepatic portal hypertension is the

result of the major resistance to blood flow in the hepatic

venules. A brief list of examples include thrombosis of the

hepatic venule within the liver, venoocclusive disease, ( e.g

following the ingestion of senechio alkaloids ), congen¬

ital hepatic venous webs, and metastatic tumor. This clinical

picture is indistinqiushable from Budd-Chiari syndrome.(19)

The first signs include the development of portal systemic

collateral vessels and ascites. Also, like sinusoidal intra¬

hepatic PHT this entity creates an elevation in both the

hepatic venous pressure and the hepatic venous pressure gra¬

dients.

The third type of PHT is post hepatic obstruction, caused

by the blockage of blood flow in the inferior vena cava,

above the site of entry of the hepatic veins.(19) Examples

Include constrictive pericarditis and severe congestive heart

failure. Intractable ascites is common. Quantitatively,

there is an increase in the absolute portal venous pressure

but the hepatic venous pressure and the portal pressure

9

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gradient are not elevated.

To understand the development and maintenance of portal

hypertension, the underlying pathophysiology must be clari¬

fied. As previously noted, many diverse conditions can result

in portal pressure elevation. Basic fluid mechanics used to

describe the principles of blood flow can be applied to

the pathophysiology of portal hypertension. The formulae,the

change in pressure is equal to flow multiplied by the resis-

tence. Thus, the effective pressure gradient between the two

ends of a vessel depends on the Interrelationship between the

flow within the vessel and the resistance that impedes that

flow. (20)

The pathogenesis of portal hypertension can be des¬

cribed on the basis of changes in vascular resistance. Vascu¬

lar resistance can be altered by both physiologic and patho¬

logic factors. The physiologic factors include the opening

of capillary beds related to changes in metabolism, passive

dilation or contraction of vessels in response to pressure

changes, and changes in the state of contraction of smooth

muscle in vascular walls mediated by vasomotor nerves and

humoral substances.(20) The factors involved in pathologic

changes are due to thrombosis of vessels, extravascular com¬

pression or intrinsic obstruction to flow secondary to colla¬

gen deposition.

When there is increased resistance to portal blood flow.

10

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(OS) .woXi

.'.nb ad neo colenadTiaq^rf Icdioq io aiaanegoridaq ariT

-uoeeV .sonsdEXEax laXua^av fii adgnario aXaad arid flo bsdiio

-oridcq bns axgcEoxa^rlq ddod '(d baiadifi ad oaa aonadaiaai "jaX

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9vx8EX>q .maxXodfcdficn ni aagnerlo od bsdaiai «bad xaaillqao lo

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.noldicoqab aag

.woXil booXd i^dioq od aonadeXMl baeaaiaal aX aiarid oedW

there is an increased portal venous pressure. As a result,

preexisting collaterals dilate forming portal systemic

shunts. These shunts, are attempting to decompress the portal

venous system. However, by so doing, they are carrying a

major portion of blood away from the portal into the systemic

veins. While these naturally - occuring shunts partially

counteract the increased resistance to portal blood flow, the

portal hypertension persists.(21,22) This persistence of

elevated portal pressures implies that there must be a

factor maintaining the portal hypertension, even in the pre¬

sence of portal systemic shunting.

Though the maintainance of portal hypertension has been

attributed to splanchnic hemodynamics, this subject re¬

mains controversial. Two theories have been proposed to ex¬

plain chronic portal hypertension: the " backward flow " and

the ” forward flow " theories. The ” backward flow ** theo¬

ry: The development of collaterals form portal systemic

shunts which lower portal pressure. As the portal pressure

is lowered, the hepatic resistance increases to maintain

portal hypertension. The end result yields congestion of the

portal venous system and a hypodynamic splanchnic and syste¬

mic circulation.(23,24) Works published by Bradley et al,

in 1952, and Moreno et al in 1967 support the" backward flow

" theory. The " forward flow " theory supports the develo¬

pment of a hyperdynamic splanchnic circulation. As in the

backward flow model, portal systemic shunting occurs to lower

the elevated portal pressure. However, there is an increase

11

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if

in total splanchnic blood flow, hepatic and collateral,

which maintains the portal hypertension. (25) There are

several pieces of information in support of the forward flow

theory. In 1958, Murray et al, working with chronic liver

disease, found a hyperdynamic systemic circulation in pa¬

tients with cirrhosis.(26) Gitlin et al in 1970, supported

the forward flow theory while observing splenic blood flow

and resistance in patients with cirrhosis before and after

portocaval anastomoses.(27) The forward flow theory was

further supported by Cohn et al in 1972 who reported in¬

creased splenic blood flow in patients with cirrhosis and

alcoholic hepatitis. (28) Also in 1972 Wotelanski et. al.

noted a shortening of the mean transit times of labeled

albumin in the splanchnic circulation in cirrhotic pa¬

tients.(29) The Vorobiof group, has recently reported a

hyperdynamic splanchnic circulation in a portal vein stenosis

rat model. They observed an increase in splanchnic blood

flow in the maintainence of chronic portal hypertension.(20)

The sequelae of chronic portal hypertension are often

times associated with portal systemic shunting and the main¬

tainence of elevated portal pressures. This is secondary to a

decrease in blood supply to the liver from the portal vein.

This decrease in hepatic blood flow may be associated with an

increased hepatic arterial component in order to maintain the

portal blood pressure at near normal levels.(15) As men¬

tioned earlier, the splanchnic circulation has been theorized

12

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to be a factor contributing to the maintanence of the

elevated portal pressures. Another important contributing

factor is portal shunting of by - products of intestinal

origin around the liver and into the systemic circulation.

The development of splenomegaly and ascites is not uncommon

in the face of portal-systemic shunting.

Clinically, an important consequence of portal systemic

shunting is the formation of collaterals at any site along

the gastrointestinal tract.(19) " The collateral blood

vessels usually develop between the coronary vein of the

portal system and the azygos veins of the caval system in the

submucosa of the lower esophagus and upper stomach." (15)

The thin walled vessels are better known as esophagogastric

varices. These varices are inadequately supported by connec¬

tive tissue and are a common site for a lethal hemorrhage in

portal hypertensive patients. Gastric and hemorrhoidal va¬

rices are also sites of hemorrhagic derangements. One third

of deaths in patients with portal hypertension secondary to

alcoholic cirrhosis are related to variceal hemorrhage.(14)

However, the most important consequences of these col¬

laterals may be functional derangements rather than hemor¬

rhagic. These derangements include portal systemic encepha¬

lopathy, the hepatorenal syndrome, ascites, spontaneous

bacterial peritonitis, and septicemia.(19,27)

Portal systemic encephalopathy is principally the result

of portal systemic shunting of blood around the liver cells

13

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into the systemic circulation, and the presence of hepatocel¬

lular dysfunction. (15) Hepatic coma is a common complica¬

tion of hepatic encephalopathy. The coma accounts for fifty

percent of the deaths in patients with cirrhosis.(14) The

associated neurologic syndrome is due to the presence of one

or more of the intestinal toxic products normally metabolized

in the liver. Ammonia has been incriminated frequently in the

pathogenesis of hepatic encephalopathy but is unlikely to be

the sole etiologic factor as neurologic dysfunction has been

noted with various levels of ammonia.(15) Attempts to iso¬

late other predisposing factors have been disapointing.

The hepatorenal syndrome, or progressive renal failure

with azotemia and oliguria, is often associated with

hypotension and hyponatremia.(15) This is a frequent ter¬

minal event in patients with end stage liver disease. The

overall prognosis during a hospitalization from liver failure

or from a portal hypertensive complication is greater than

ninety percent if the patient develops the hepatorenal syn¬

drome.(16) The pathogenesis of this syndrome is unclear. At

autopsy, the kidney has been found to be anatomically normal.

Clinical studies have shown the renal function to improve as

the hepatic function improves. There appears to be an intense

intrarenal vasoconstriction and a redistribution of blood

flow. Plasma levels of renin and aldosterone are elevated.

This elevation may be secondary to a reduced effective plasma

volume in some patients.(16)

14

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A.{

In other patients, the effective plasma volume is normal

and the causes for the renal vasoconstriction is unclear.

(16) Ascites is decribed as an accumulation of serous fluid

within the peritoneal cavity.(30) The formation of ascitic

fluid is believed to be due to an increased hydrostatic

pressure and a decreased intravascular osmotic pressure.

Fluid retention occurs as a response to an unknown hepatic

sinusoidal baroreceptor; thus, as the plasma volume increases

the ascites overflows.(19) The consequences of ascites are

many. There is an increased risk of all types of abdominal

hernias, a rise in the absolute pressure, which may precipi¬

tate hemmorhage from varices, the hepatorenal syndrome, and

spontaneous bacterial peritonitis (SBP).(19) SBP is thought

to be present when there is bacterial contamination of the

ascitic fluid. The mortality of ascites with spontaneous

bacterial peritonitis is aproximately seventy five to ninety

five percent during a hospitalization.(13) This fatal com¬

plication of ascites involves microbes of enteric origin

primarily aerobes. The presence of portal-systemic shunting

bypasses the hepatic reticuloendothelial system (RES). The

absence of this RES filter is believed to predispose the

individual to infection and the development of septicemia in

patients with portal - systemic shunting.(15,19) Though

sepsis is a well recognized fatal complication of portal

hypertension in man. Little is known about the development of

sepsis in portal hypertensive patients.

15

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. e:^j;d i ii'q av j tns J^loJioq ox Eiaqaa

Sepsis is defined as the presence of various pus forming

and other pathogenic organisms, or their toxins, in the blood

or tissues.(30) Sepsis, like any other infectious process,

is the result of an interaction between microbial challenge

and host defense mechanisms.(15) However, septicemia re¬

fers to a systemic disease caused by the multiplication of

microbes within the circulating blood.(30) Intraabdominal

sepsis is an infection external to the lumen in the gastroin¬

testinal tract and within the abdominal cavity.(31) Most of

the abdominal infections are the result of normal colonizing

flora. The pathogenesis of intraabdominal sepsis involving

the serosal surfaces is based upon a breech in the normal

mucosal barrier secondary to an associated disease process.

The microbial innoculum, chemical irritants, lymphatic drain¬

age, and the inflammatory response are important pathogenetic

factors in the development of intraabdominal sepsis.(31) The

relative roles of hepatic dysfunction, portal -systemic shun¬

ting, and other splanchnic or systemic hemodynamic changes

which predispose to sepsis remains poorly defined

Animals models in scientific research:

The use of animals models in experimental research has

become an integral part of the study of disease processes in

humans. Animal experimentation, although limited in clinical

application by differences in species, has been responsible

for much of our present knowledge of pathologic deviation

from normal function.(32) Reproducible models for portal

hypertension and intraabdominal sepsis have been avidly

16

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sought. Several animals have been used to create a portal

hypertensive model. The methods utilized can be divided

into intrahepatic, extrahepatic and/or a combination of the

two types.(33) The models for an intrahepatic portal

hyper-tensive rat consists of injecting hepatotoxins or for¬

eign matter into the portal vein or liver, and the use of

deficiency diets.

In 1976, Koo and his group injected carbon tetrachloride

into the liver to induce cirrhosis.(34) Recently, Shibayama

has used deficiency diets in rats to localize increased

hepatic resistance in cirrhosis.(35) He created cirrhosis

by feeding the rats a choline deficient diet.

Extrahepatic models of portal hypertension usually invol¬

ve mechanical manipulation of the portal, hepatic or splenic

vein. These models are created by stenosis or ligation of a

vessel. Many groups have used extrahepatic manipulation of

the portal vessels. In 1976, Saku attempted to induce portal

hypertension and esophageal varices by using ameroid con¬

strictors around the portal trunk.(36) He reported com¬

plete constriction of the portal trunk with a twice normal

increase in portal pressure. Angiography revealed splenorenal

collaterals with collaterals overbridging the ameroid con¬

strictors in all rats with the constrictors.

Orda and Ellis induced portal hypertension by partial

constriction of the portal vein.(37) Angiographic studies

demonstrated the spontaneous development of portal systemic

and porto-pulmonary shunting. A coincident decompression of

17

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the portal system was associated with the shunting. However

release of the portal vein stricture led to the disappearance

of the collaterals in the majority of the animals.

Halvorsen and Myking, in a series of experiments, deve¬

loped a model of prehepatic portal hypertension by using a

calibrated stenosis of the portal vein. A stenosis to 1.2mm

lead to a sustained elevation in portal venous pressure two

times the control. This increase in portal venous pressure

lasted approximately eight weeks. Subsequent studies done by

this group compared a graded stenosis in tubes to vessels of

small calibres.(39) This was an in vitro vs. in vivo compar¬

ison of changes in flow variation. In vitro studies showed a

prestenotic pressure variation with a coefficient of varia¬

tion in repeated stenosis less than three percent. In ani¬

mals stenosis repeatedly produced the same high level of

portal pressure. As a result, Halvorsen and Myking concluded

their portal vein stenosis model to be satisfactory when

compared to the theoretical standard.(39)

A two stage portal vein ligation with subsequent total

occlusion in the rat was described by Kibria in 1980.(40)

This model of portal hypertension demonstrated a collateral

circulation of varicose, anastomotic vessels. Marked esopha¬

geal varices developed in six out of twenty three animals.

Uvelius et. al. ligated the hepatic branches of the portal

vein to create a portal hypertensive model.(41)

By 1981, Hamilton created a partial ligation of the

portal vein to induce portal hypertension.(42) He reported

increased prostacyclin levels one week after ligation of the

18

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portal vein. Hamilton postulated, if this process occured in

man, then this may be responsible for local wound vasodila¬

tion and inhibition of platelet aggregation. This may be an

important factor contributing to the severity of hemorrhage

from esophageal varices.

In 1983, Vorobioff et. al. created a portal hypertensive

model by stenosing the portal vein to the diameter of a

twenty gauge, blunted, hypodermic needle.(43) Radioactive

microspheres were used to determine splanchnic hemodynamics.

They found generalized splanchnic arteriolar vasodilation

occuring in the presence of high grade portal systemic shun¬

ting. Studies showed increases in portal venous inflow with

elevated portal venous pressures were not due to changes in

portal vascular resistance. These findings supported the

forward flow theory for maintenance of chronic portal hyper¬

tension.

Sikuler's group partially ligated the portal vein to

create a model of portal hypertension.(44) Radioactive

microspheres were utilized in order to study portal hemodyna¬

mics. They found increased portal venous inflow to be respon¬

sible for the maintenance of chronic portal hypertension.

These results support the forward flow theory for maintenance

of chronic portal hypertension and, are in agreement with

result reported by Vorobioff et. al.

Benoit studied forward and backward flow mechanisms of

portal hypertension and the relative contributions in a

portal vein stenosis model.(45) Portal venous inflow, portal

19

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Vi VM

91

systemic shunting and portal venous pressure were all ele¬

vated ten days post stenosis of the portal vein when compared

to controls. Portal venous resistance was forty percent high¬

er in portal vein stenosis animals. Increased portal vein

resistance was due to high resistance in the portal venous

collaterals. Model predictions indicated the forward flow to

account for forty percent of the increased portal pressure,

and the backward flow to account for sixty percent of the

increased portal pressure.

The selection of an animal for expeimental research is

important. The rat can be considered as one of the most

suitable animals for experimental research.(46) This is

primarily because this animal is strong, inexpensive, easy to

handle , breed requiring little room, and offers the possibi¬

lity of assembling large series of simiiar animals.(46) Male

rats are preferred because of their docility, stability of

endocrinologic state, and a more pronounced growth rate.(46)

Among the numerous strains of outbred rats, the Sprague

Dawley and Wistar strains are the most commonly used for

experimental liver investigations.(46)

Septic animal models:

Dogs, baboons, pigs, rabbits, guinea pigs, and mice have

been used to study sepsis. (47-60) However, we will limit

our discussion to rat models. There are three well recognized

and reproducible animal models for intraabdominal sepsis.

These models were developed by Bartlett et. al.(61) Wichte-

rman,s group (62) and Short et,.al (63)

20

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Bartlett's group standardized int rabdoininal abscess

formation with generalized sepsis. Gelatine capsules contai¬

ning B. fragilis and E. coli in a standard mixture with rat

colonic content and barium sulfate, a known irritant added to

increase the toxicity of the implant, were implanted intra-ab

dominally.(61) There is an initial acute peritonitis, E,co¬

li bacteremia, and a high mortality. This model would enable

one to study the roles of various microbes in terras of

septic complications after colonic perforation.

Wichterman et al, reviewed the literature for repro¬

ducible and clinically relevant septic models. His group

approved only the aforementioned model. However, the model

proposed by Bartlett et al although satisfactory , was not a

simple model.(62) Wichterman's group developed an animal

septic model by using cecal ligation with subsequent pun¬

cture. The bacterial challenge following cecal ligation and

puncture is continuous, and of such tremendous magnitude that

this initiating trauma is almost always lethal.(62) This

model is simple, inexpensive and reproducible. This is a good

model if one wanted to study alterations in tissue metabo¬

lism, energy production, and hormonal responses during

sepsis.(62) These studies are possible because this model

enables one to study sepsis in an initial hyperdyanmic circu¬

lation and a later hypodynamic circulation. Work done by

Wichterman was reproduced by Martinell’s group in 1985.(64)

In 1983, Short et. al. standardized an intraperitoneal

E.Coli injection model of septic shock.(63) This model is

21

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I

suitable to study pharmacological treatment of septic

shock.(63) Martinell's group also found this work to be

reproducible,(64) Both models were found to closely mimic the

clinical situation as found in posttrauraa and postoperative

periods.(64) The two attributes of both models include the

gradual development of shock and the time allowed for the

aminal to use natural defense mechanisms inorder to overcome

the disease.(64) These models are thought to be useful in

studying pathophysiologic mechanisms and in evaluating

treatment regimens in posttraumatic and postoperative septic

shock.(64)

The sepsis models mentioned above were all induced in

healthy animals. In human conditions, sepsis usually develops

in the face of an already present disease process. As men¬

tioned earlier, little is known about intraabdominal sepsis

in portal hypertension. This study will address the impact of

sepsis on portal hypertensive rats as compared to controls.

As stated previously, portal vein stenosis has proved

to be a reliable method of inducing portal hypertension. (38,

39, 42-45) Given the relative ease in creating this model as

well as the reproducibility of the technique, it was decided

to create a model for portal hypertension utilizing the

technique described by Halvorsen et.al. (38) Benoit

described an increase in the portal venous pressure and

portacaval shunting after 10 days.(45) In accord with his

observations, and to allow adaptation to the new hemodynamic

state, sepsis was induced in the portal hypertensive models

in 15 - 18 days.

22

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aiaqo?. Ianifflobd88iini luoda owon.;^ si aXllM baaoil

ioeqmi odi Hesibb£ TXXw Bid? , fiotananBqvfl ladioq ni

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novoiq v.Bii eiKOnajs nisv lojjoq ,^XauoXv»iq zk

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slaboos 9vxan&ilaq^ii iBdioq 8d3 ni bBiwbnl esw alaqaa ,sia3a

The technique for ligating and puncturing the cecum, as

described by Wichterman et.al., will be utilized to study the

differences between the portal hypertensive and the control

groups given the lethality, reproducibility, ease, and cost

of this procedure. Given the relative short time course

between the time that the cecum was punctured and the death

of the animal, it was decided to study the animals at 12 and

48 hours as this would demonstrate the animals’ initial

response to the bacterial load and their subsequent response.

It was postulated that, within 12 hours, the animal would

react to the bacterial challenge by recruiting the

circulating leukocytes to fight the foreign substance. After

48 hours, maximum recruitment from the initial circulating

leukocytes should have occurred and the body would respond by

generating new cells, increasing the percentage of immature

bands seen in the peripheral smear.

23

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' - * 4^ * 1^# f 4^1

MAATERIALS AND METHODS

Male albino Sprague-Dawley rats ( Charles River Labora¬

tories, Cambridge, MA ) were housed in screened top cages and

allowed free access to food ( Purina Rat Chow, St.Louis, MO )

and water throughout the of experiment. The surgical

techniques described below were performed on rats weighing

between 300 and 350 grams. After each portion of the ex¬

periment requiring manipulation of the rats, the animals were

placed in clean cages. The animal facility was temperature

and humidity controlled. The animals were divided into the

following groups.

Group A: Portal vein stenosis

Group B: Cecal ligation and puncture

Group C: Portal vein stenosis and cecal ligation and puncture

Group D: Sham control

Anesthesia :

An airtight plastic container with a hinged lid, mea¬

suring 10 cm X 15 cm X 25 cm, was used as the ether chamber

to initially anesthetized the rats prior to manipulation.

Cotton padding, measuring approximately 1 cm in depth, was

placed at the bottom of the container. Prior to mani¬

pulation, approximately 2 cc of ether was placed into the

container. The rat was remved from the cage and placed into

the ether filled chamber for 30 seconds. After this time,

the animal was removed from the chamber and injected with

O.lcc/O.lkg body weight of ketamine hydrochloride ( Ketaset )

24

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.eq.vC'is SJilufOflol

ai^'K9:r^ *»'€*v IwJ'ii-i jA quoid

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:aifidddUdflA

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f - ' • ' I . :l j • ■'•.: A® r> <-, , ; q ,i :;.-i i4i4fr‘>4 t i bbaq no? ?oO

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rj ■bnt 'rsdRSfi.'i sd* aoT^ bavoms j Lmmiat, ftiiJ

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At

fjjga

intramuscularly. An additional 0.15 cc of Ketaset was given

if additional anesthesia was required during surgical mani¬

pulation of the animal.

Production of portal hypertension:

Group A: 19 rats underwent partial portal vein ligation to

induce portal hypertension and portal systemic shunting. This

method of inducing portal hypertension has been described in

detail by previous work done by Chojkier and Groszmann.(65)

Each animal was anesthetized as described above. The ab¬

dominal cavity was opened through a two centimeter midline

incision under sterile conditions. The omentum and part of

the intestine were gently lifted out of the abdomen and kept

moist with warm normal saline gauze pads. After separating

the hepatic artery and the bile duct, the portal vein was

exposed. A twenty gauge blunt tip hypodermic needle was

placed alongside the length of the portal vein and one liga¬

ture of 3-0 silk was placed proximal to the bifurcation of

the vein and secured around the needle and the portal vein.

The needle was removed, and the portal vein was allowed to

reexpand. The abdominal viscera were placed back into the

abdomen. The abdomen was then closed in two layers with 3-0

silk. Once hemostasis was acheived, the animals were given

cc/cc normal saline volume replacement for blood loss.

Cecal ligation and puncture:

Group B: In accord with the technique described by Wichter-

man et. al.(62), the cecum of 24 were isolated, ligated and

25

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BHW sibseji Dxiuiaboqx*^ ^^ inuid agut.g ^Xnswj A .bsaoqxs

-H,qj.r sno bitfe nidv lej-joq adJ Yo riJgndX adx abXagnoIfi beoeXq

iv BOXJBOJoiid add od it«ixoiq b-i3»Iq aaw >}XXe U-€ 5o aiuJ

.niov Xad^oq odd bne eXb.ian siij bnums bojvosB bae nXav arid

oj bawoile bbw tixav ledioq add bna /bavotnsi e«w sXbaao »dT

arid odni jir*Bd baoulq ©law Ri&aeiv Xealaobda ariT .bnaqxaai

0-X ridiv aisyBl ovd ni baaolo aatij »ew uaaobda »dT .naaobda

ovvig B19V aXsoXcB arid ,baYl9d38 eew eXeadeoaad fioaC ,MXJte

• KEoX booid Toi JnamsDsXqa'j aaixloY aaXXoa Xaaion oa\oa

:airud3nixq bna nolditgll isdsD

-TaddoXW yd badiioasb Baplnda®:} arid d.iXv bioDoa «I ifl quoiO

bnfi badsgll ,b9deXoei sisw AS io ffluoao add ,(Sd).la .da nsM

punctured. At operation, the rats were anesthetized and a

two centimenter midline incision was made under sterile tech¬

nique, and the cecum was divided carefully avoiding all blood

vessels. The cecum was filled with feces by gently milking

stool back from the ascending colon. The cecum was then

ligated just below the ileocecal valve with a 3-0 silk liga¬

ture. Ligation at this point permitted bowel continuity to

be maintained. The antimesenteric cecal surface was punctured

once with a 25 gauge hypodermic needle. A small amount of

fecal content was expressed from the cecum and the bowel was

replaced into the peritoneal cavity. The abdomen was closed

in two layers with 3-0 silk. All operated rats received 5cc

of normal saline/ 100 gram body weight subcutaneously plus an

additional cc/cc normal saline replacement for blood loss.

Portal Vein Stenosis plus Cecal Ligation and Puncture:

Group C: The above portal vein stenosis technique was per¬

formed on 24 rats. 15 - 18 days after the portal vein was

stenosed, cecum was ligated and punctured using the tech¬

nique described above. These rats received 5ccNS/lOOgrams

body weight subcutaneously plus cc/cc normal saline volume

replacement for blood loss.

Sham control rats:

Group D: The protocol for isolating the portal vein was

performed on 25 rats. However, the portal vein was isolated

but not stenosed. The abdomen was closed in two layers with

3-0 silk. These rats were given cc/cc NS volume replacement

26

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>;•.. . . ‘ ; 'mIj e-{Ab 1 - Cl .tJAT no bA**J05

.1 ^ortAt' M'^iu:)onuq b<iB IxtHs.Qj! RBv »uos3 «bo8on9J«

.t"4< Ill'll • h'JVfosoi ftjj&T oaadT nadj;‘3:)t9b supin

.‘ji’xffci? Ix.(Dioi» v?uXq yiftucs(»t>JfJgtaw

.seol boold lo'l 3a9ja#a6lq«7

:aJai loidJio) mBdZ

?iiv niov fn.JToq 9(1 J icniS&joftx 7ol XDDo:fo*q »dT :G quoiO

b33aIo£-i cow nisjv i£i3ioq sriJ , 7s»V9WoH .e:tSx ao baatolisq

(13 i v atdvsX ovj nx btaoCo uav r:«aobdfi ariT *i)9eotJ9Je Ao» Jwd

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di» '*■- M.<. h

subcutaneously for blood loss. At 15 -18 days, these rats

were reoperated with the CLP technique. The cecum was iso¬

lated, milked full on stool in the usual fashion, and divided

carefully avoiding all blood vessels. According to the pro¬

tocol described by Wicterman et. al., the cecum was replaced

into the abdominal cavity.(63) The abdomen was closed in

two layers with 3-0 silk. All rats were given 5ccNS/lOOgrams

body weight subcutaneously plus cc/cc NS volume replacement

for blood loss.

Study protocol:

93 rats were included in the study. These rats were

distributed into the various groups as noted in Table 1. In

accord with the divisions described in Table 1, 30 rats were

sacrificed at 12 hours. The surviving rats from the 24 hour

group were sacrificed at 24 hours.

The 29 rats remaining in the mortality study were

followed for 1 week. These rats were observed daily and the

number alive at the end of each day was recorded. After 1

week, the mortality rate was calculated by dividing the

number of rats remaining in each group by the number of rat

within the groups in the beginning of the 1 week period.

Blood Samples:

At the schedued time for sacrificing, each rat was

lightly anesthetized in the ether chamber. Cardiac puncture

was then performed and the blood withdrawn was divided into

smaller aliquots aseptically and sent to the various

27

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.: *-'i*| -J5»«.v,’ f '!*Mi lr> gn J n n X gitid rti' wquoig »f<l olftt3iw

bobifi

-aw MCI M:.":: . 1 Oi’.& lo'i e«r.i:i botibanlaa 31

i?y?ctni»rj -jurbi'aD . lacfoijsb.y J-»di9 b»»l 3«.*i3a»Q«

rii*)' ^f’ibivt’ h 'R«w rrve7ti,rt3'x;v b.coXd b/t J bn,# baatTiJinso noH3 aoV

aiioi7#T 9x13 OJ Jj&sii ba# #30fupJl:i« 3#II#itn8

laboratories for analysis.

Hematology:

Aliquots of blood were sent to the Hematology Lab for

analysis. The number of leukocytes was determined spectro-

photometrically. However, the differential for the types of

white blood cells were counted manually and recorded as the

percentage of the total number of leukocytes.

Chemistry:

Samples of blood were also sent to the Chemistry Lab

where sodium (Na), potassium (K), chloride (Cl), bicarbonate

(HCO ), lactic dehydrogenase (LDH), alkaline phosphatase (Aik

Phos), blood urea nitrogen (BUN), creatinine (Cr), serum

glutamic oxaloacetic transaminase (SCOT), and serum glutamic

pyruvic transaminase (SGPT) were determined using an

autoanalyzer.

Blood cultures:

Aliquots of blood from each study animal were sent to

the Animal Microbiology Lab for anaerobic and aerobic cultur¬

ing. Anaerobic cultures were placed into the Columbia single

vacutainer unit ( American Scientific Products) with cysteine

added. Blood samples for aerobic culturing were collected in

the Bac-tek blood culture system ( Whevetron Co,). The

cultures were examined daily and subcultures were done 2 days

and 7 days after culturing. In addition, subcultures were

done whenever there was evidence of growth in the culture

bottles ( turbidity or gas production ). Samples were placed

on McConkey's, blood agar, colimycin-naladixic acid (CNA)

28

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s^r.TJ odJ 3o: Ifci Jfi3i95)i b ^rdJ ,t!?v©wnH i©3j-i;#»«o30fiq

sflJ as nsbioosT bns ^XCisynsm bs^dnooa ei®w uIXa;> booXd adidw

. ees <( )u iftdotrtjn isJod »d3 5o ttjisjaaoisq

: X'l^ttXasafiO

riiJ ^’iJeicsriO ^#jI:> v3 Jpbh o&Ie eiiBw boold )o asIqxnaS

:?JarjodatiDid ,(iD) ©biTotrtD t(^) muisrssjoq .(«M) nuXboB sisriw

:{A) aaederiqe.oriq ,(HQJ) »«6n9fiOib^t1#b 3ld3«X ,{ ODH)

auzifc- ,(iD> siix/’i ji ij Bftin boold ,(eort^

aiaeJuIg naiac brie ,(TOJ)?-) ©qenXjbbrnsT3 dbdft.^aolsxo oifflflJuIg

na gniau b9nia”i93ab oiaw (T’IDS) db6iiX«i#*8nfti3 aivoixq

. 'TBXf XansoduB

: $fOiuiluD booXfi

g3 raiBw [oKtio^‘ i(bUJB rfD*(9 moTi boold )o KsoupXXA

oJdt>a&B bdb Didoieeoo to) deJ x8<^*^^XdOT oiM XaaXaA ariJ

sfianie eldoyloO 9d3 odnf hsoeXq sisw aBio.i Jf u:- DtdoTBBnA .gnX

9tii9Jer3 dilv (eJDuboT'J ijDidiidio? omdIt^kA ) iinu la.iiBduoav

ui bsdDalloa ©lav naifufiuo jhioi&b lol daXqflkBfi boolfl .b«bbs

•»riT .(.oO aoT39v©ffW ) oTo.iItio booid >l«3-3Btl ©rid

bftb £ Bnob 9T9v asloJIusduv* bnfi fltAb banlutAxu BTav aaiudluo

aT«w adTiiJii/odjj& .ooidibba iil .gnXisdXyo i©3)« ^

aiudl©:* bdJ nl dtwoig )o bbw BtadJ levaaodw «aoi>

b^oaXq 9i(iw >sBXqi>tA^ .( noXdouboTq asg lo -i^dXbXd'iud ) ssXddod

(AHO) bXoo olxAbBiao-Blot^cXXod «iBgb booid ,»’ ao

agar plates. All cultures were incubated at 37 degrees

centigrade. Microbial identification was done using standard

diagnostic methods.

Peritoneal Cultures:

Peritoneal specimen were obtained on Culturette swabs

( American Scientific Products ) and innoculated unto blood

agar, McConkey agar, CNA, and Kanaraycin agar plates for

recovery of aerobes. For culturing anaerobes, a Kanamycin

plate was inoculated and the swab placed in thioglycol broth.

The plates for anaerobic growth were placed in Gas-Pack jars

( BBL Laboratories, Cockeysville, Md. ). All cultures were

incubated at 37 degrees. Bacterial identification was done

using standard diagnostic techniques.

Statisical analysis

All the results are expressed as mean and standard devia¬

tion. A two-tailed Student T test was used to analyze differ¬

ences between each group. Statisical significance is des¬

cribed as a P = 0.05 corresponding to a 95% confidence level.

29

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reaizijXuD lrt»no:J

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j.. I niavrpn'uf^Ji fcrtiiv , AKO ,T«gn taiaoDaM .ifigf

..I K ^ c . d V ''•--ens gnritf.'tiifn toH .aadoi’aa Ho

( it. fl f<' dffve Oif}3 bcB baiR/i;aonX taw 9JaX(^

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M‘'*w .*■'-I (< j r u j I/A .{ . liM , t) J A Xvai(5jji'DoD , «o,l 1 oJaiodaJ Jfl0 )

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. e»>t> 1 I fiiJ > ?3 aiXBongetb boifibnaia gnXeu

kX9xlt*n» taaiaXaai?

xiJvft') b I ob J t.' l.'i.'H i*e*-'*Mi ?•'fi -iH a aaiuaao &ti:3 IXA

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.'svv^; »’tnsbniio> X/.f*. & oJ gn;bnoqafiT303 cO.O • H z to b«dli:

««i >

»

RESULTS

Leukocytosis at 12 and 48 hrs:

Tables 2 and 5 report the leukocyte counts of each

experimental group at 12 and 48 hours respectively. As noted

in Table 1, the mean leukocyte count in Group D was 15.16

+ 2.75 wbc/mm . This was significantly different from the

mean leukocyte counts in Groups A - C which were 10.67 + 2.57

wbc/mm, 2.8 + 1.67 wbc/mm, and 5.83 + 3.2 wbc/mm respect¬

ively. There was also a difference noted between Group A

and both Groups B and C ( p < 0.05 ) at 12 hours.

Table 3 illustrates the disparity in the number of

immature bands in the peripheral smear of the various groups

at 12 hours. As shown, greater than 15% of the total

number of circulating leukocytes were immature bands in 80 %

of the rats in both Groups B and C while the number of

immature forms was less than 5% in Groups A and D. As a

result, there was a statistically significant difference in

the amount of bands between the combined groups [Groups A &

D vs Groups B & C] (p < 0.05).

Only 1 rat from Group B was alive at the end of 48

hours. As a result, no comparison could be made between this

group in the other groups. In comparing the leukocyte counts

between the 3 other groups at 48 hours, no statistically

significant difference was noted.

30

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j ' ' 'V , r Vw. ! 4 li.i’ ,«ioi\3dv

• I I'tj*? i-.gw'sd nftlC'nt a ) f ■ ’ i o "t I > k 3.W . i(i©vj

u ^1 , rUr'.y r, ) -i /.ifift H. hut

? f ''I'T. ,1 , , -*('.1 'aa T K'J 1®)> f L J K

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'' ■ *>•'•'. j ■' • I ‘Tc:' ' aA £I dj

•• ■ - %■ --;'v j y-aojluai pn E:tBiuo*3i.D Ic ladijur

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■' •/' 'I I*--5 * '.quo^O oc -■'c uad7 easl «ow ’r ia* onpdasBiJ

ni 5nfi:;ri2,'!T; i-? ^ 1.1 t j fj hiacjx « saw itno43 (jXttaai i,

4- * .•.rf.'/viO] Eq[{i<.-is is-cEdiu-u^ =-d7 ngewaad abfltfd J ©sNWR* dftJ

.(20.0 '■ q) ^3 If a aq&oid av C

:*■*' io biio unj an avilo bsv 3 t}i‘oiD moil rj.i&a ' tXoC^

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» ♦da BitiiSL^aoD nJ .aquoig tanac nria /»i: quoi^

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0£

Electrolytes and Liver Function Tests:

The electrolytes and liver enzymes were measured from

blood samples drawn at the time of sacrificing. As illust¬

rated in Table 9, no statistical significant difference was

noted between the groups.

Bacteremia at 12 and 48 hours:

Tables 4 and 6 illustrate the incidence of bacteremia

in each group at 12 and 48 hours. As noted. Groups A, B, and

C had a higher incidence of bacteremia than did Group D. The

most frequently cultured organism at 12 hours was Escherichia

Coli , with Bacteriodes species and Streptococci species

being the other common organisms cultured. Proteus mirabilis

and Clostridia were also demonstrated. No organisms were

cultured from the blood of the control organisms. As reported

in Table 4, 50% of the rats in Group A were bacteremic com¬

pared to 100% of Groups B and C. Only 1 out of 8 rats from

Group D had evidence of bacteremia. Staph. aureus was cul¬

tured from that rat.

At 48 hours, blood cultures were available from only 3

rats from both Groups B and C. No growth was noted from the

only surviving rat in Group B. No growth was noted in the

blood cultures from Group D and a single organism was

isolated from the blood of each of the 3 bacteremic rats in

Group A.

Peritoneal Cultures:

Tables 10 and 11 illustrate the results of the

31

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-j‘«iJlLl sA . gn iaJ-^iiase lo sffili srij nvetsi^ a^iqnae booX

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.equoif arii na®w3a<f b»3o

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niil ,3 quo^D bib /je/fj 6itejSTeJa»d Ic aonabianl 79118111 a bcri 1

ririi’i73fiori3 e*w aiaod SI 3« isftmJXna d»oi

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bsJioqai kA ^amelflegio loiJnoo ed7 lo booXcf «dJ aoii baiaditi;

-mo 3 a ta»793ofid saovf A qooTx^ fii 8Jfc7 srfJ 3© 50? ,A aldaT n,

mo7i aJuT 8 lo 3ao i ijXnO .D baft ff dqaoiiJ 3o XOOl o3 baisi

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,3«7 3iMt3 «07l bd7U;

£ aXdelievfi ©isw seiadlor* bdac.Xd «07aod 8A ?3A

arid moil b®4on aAw rljwoifi oYi .0 bjrc H aqyotO ddod HOil ala-

ado nt fasoofl saw rilwois oH .H quoiO ai lao galviviae

sow maxnsgTo olgnle « hae Q quo^O wool cBiulii/o bboXc

oi elai 3xfl:®i»loBd £ oriJ lo riaaa lo boold «iM aoil balaloaJ

.A quooc

laaoulIuO Xsanollie^i x

sdj lo eJiuBs-! aril a.IsoleKXXl XI bna 01' aaXdaT

peritoneal cultures at 12 and 48 hours. As noted in Table

10, 100 % of the rats from Groups B and C had positive

peritoneal cultures at 12 hours. Enteric organism and bowel

flora were the most commonly isolated organisms. Only 14.3

% of the rats in Group D and 33.3 % of the rats from Group A

had positive peritoneal cultures and Staphylococcus aureus

grew from one of the two positive cultures in each group.

Table 11 illustrates the results of the peritoneal

cultures from the study groups at 48 hours. Only 1 rat from

Group B was alive at the end of 48 hours and Enteric

organisms were isolated from its peritoneum. All 3 rats from

Group C had positive cultures. Growth was noted in the

cultures of 2/5 rats from Group D and 1/4 rats from Group A.

Mortality Study

The mortality rate of each of the four groups were

studied over a one week period. Each group was prepared as

described in the Materials and Methods. The rats were placed

in clean cages and the mortality rate was recorded. The

results found are illustrated in Figure 2. This demonstrates

that all the rats from Group B were dead after 3 days, with

an overall mortality rate of 100% over the one week period.

The rate of death in Group C was less with only 35% dying

during a similar period. None of the rats from either the

PVS or the sham groups died during this time course.

32

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.qiio'jji Cl r:o'iu:)Iuo avi:Ji&cq owl ad:> 5o ano moll wdig

•'nivq arf.i lo adloss*: '?dd aaifii^BuJlir II aldeT

i.f. i I y I uO , Kioutl’Sif- JB a.xtaoig xbt-'-Ja 9-{Ui moll etfiiiJlJLufi

i ii 11 bnB mood So lo bno an:? 3b aviie asv quoiO

V. i {A . atij an v'31 laq bjI aoil bo4cIoiii »iaw aaeinejiic

.j.i-' as boJoii ?ji>w ri^woiit) .eaiu^Iua avijlae<j,q bed D quoiO

tfL’Dio M<» I ^to" ‘^ \ I bne G qooiO moil t?3oi 3q eeiiidliia

>fbudSl tdtX«3io>^

'i-:avi aqiici-^ Tiioi add la daea io a.lei yJIXbJio® sdT

zt ^. ■ requiq 3mv qooig diti-H .boiisq )(»ay ano e imvo baXbole

^law »JUT "■n ! .cbtjH3a^^ hnn eipbisqaM arid ai bedlioaab

ort'^ . bs hi,/'.V. - aev ajri y^ilaJioa' s?riJ bne aagea neelo nX

i-.a "ailBoorn'^b axdT .i aius^l nr badmdeoXXx ate batiol ^Jloeei

ri.l±'* ,e^.Bb (' -radlic beab aiaw B qooii) moil adei sri3 lie 3exl3

• bobiaq -Jaow ono sri3 levo XOOi lo aiei yiiXelioffl Ileievo ne

gnl';[fa S’t!, yXrto rf3xw esal saw D quoiD ni rliaeb lo »3ei sriT

ott3 laridiw «oii edai arid lo anoH .fcoiia.l laXimie e gnXiub

.os'uo^ amid axrid gnxiob barb eqnoin ftsda arid lo 2V*l

DISCUSSION

The disparity in the leukocyte counts noted between

Groups B and C, compared to the control group, Group D, was

as expected. Similar results were reported by Hansson et.al.

and Martinell et.al. in their experimtents on abdominal sep¬

sis.(66, 64) Though both of these authors inoculated their

animals with pure cultures, they found that, after 12 hours,

the degree of leukocytosis was less in the septic model than

in the controls. The reduced number of circulating leuko¬

cytes is secondary to (a) margination into the areas of

infecton, and (b) phagocytosis of intravascular microorganism

by circulating polymorphonuclear cells. Work done by Postel

et.al supports this explanation for the reduction in white

cell count.

The increase in the number of immature cell forms are

expected in the two septic groups. Groups B and C, as the

body attempts to combat the infection by releasing immature

granulocytes ( > 15% bands). This difference was noted in

the above groups as compared to Groups A and D at the 12

hour interval ( < 5% bands). As the bacterial load in the

latter groups is much lower, the difference in the number of

immature white blood cells is as expected.

In their report on peritonitis using the CLP technique,

Wichterman, et.al. stated that the predominant organisms

cultured from the blood and peritonuem of the septic rats

were E, coli. Strep. bovis. P. mirabilis, and B. fragilis

33

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.J npo3 rI»3

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■ ‘t fj 1 £:’X'i i b Afti , d.'ixB «ji iq^oig Tgilal

-i'**j'>aqKb ea «i b<SMld ©ifdw

. oap ■-ir^'-nij » M jr» aril qri»j{j ell 1 noiltjsfq no Jioq^ i al

-uujf isipb® . q £,j!j bgjal* ^flauieiriolVl

tejat oni xo as-jy noj t leq baa Biii noiti baiuiXa:}

.a hftfi . BlXidtt-ilo. .<? .nlvod ..}#u2 ,lio3 .3 ®i»v

.(62) Tables 4, 6, 10, and 11 illustrates that similiar

findings were noted in this study group with E.coli and B.

fragilis being the predominant organisms isolated. Though

they inoculated pure cultures into the peritoneal cavity,

similiar hemodynamic results were described from their exper¬

iments, suggesting that a similiar pathophysiologic process

was taking place.

Though all the rats in the study groups were alive

after 12 hours, few rats survived from the septic group at 48

hours. Therefore it was difficult to evaluate leukocytosis,

the number of immature bands, or any other parameters in

Group B at this time period. No significant difference was

noted between Group C, the other septic group, and the other

groups. This was difficult to explain as both Group B and

Group C underwent similar techniques to induce sepsis. We had

sought to demonstrate differences between the portal hyper¬

tensive groups compared to the controls. The hypothesis

stated that portal hypertension would result in decreased

clearing of the organisms, resulting in an increased bac¬

terial load during the late phase of sepsis ( > 48 hours ).

As a consequence, the survival of this group would be less

than or equal to the control group (Group C < Group B). The

reverse was noted in most of the parameters evaluated.

Explantions fof this departure from the expected outcome

include (1) choice of techniques for inducing sepsis. Though

utilized by Wichterrman et.al. in their studies, repeated

puncturing of the cecum may have introduced an innoculum size

34

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that proved too overwhelming for the animal. However, this

doesn’t explain the disparity between Group B, rats that had

undergone cecal ligation and puncture, and Group C, rats that

had underwent stenosis of the portal vein prior to cecal

ligation and puncture.

The second explanation pertains to the choice of tech¬

niques for inducing portal hypertension. Prehepatic stenosis

of the portal vein reduces the flow of blood from the

intestines and the the attached mesentery. Therefore, the

amount of bacteria invading the systemic circulation may have

been less, or the rate of release into the circulation may

have been slower. This allowed these rats to mount an effect¬

ive response by the cellular immune system as well as the

reticuloendothelial system. Since similar organisms were cul¬

tured from the blood and the peritoneal fluid of both Groups

B and C compared to the control groups ( A and D ), one can

conclude that it was the size of the innoculum rather than

the type of organism that was the crucial factor in the

differences noted in survival [Tables 4,6,10 & 11]» Patho¬

logic examination of the liver, spleen and abdominal viscera,

as well as other organ systems would provide further insight

into the discreptancies from the expected versus the observed

outcome in between the two groups.

35

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.‘•API ,AA/;c£ .hcsN *ma3 .

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>1 r.^< I I. ,i !ib io 9i^ldoiL(i BiiJ .0»A *S .'. V ' ''.tAli . vi t r; . '’nA . ao.li:-1 ti.4'iO'»X»4eoJ »a!»rt cl fyoiSuL^i

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—'fpjioqvu l*i‘.i30*q 3fli99t3?.fia9*A ♦Xa .3a «*A ,fliO303 .Si ,3If*:X .ni97 5x3aq«*n I0 floi3«£jt’S9ilJBi* rd aolm

- I3i0u3 nsXli iKaaK . \gol^■i:?3rj-w JJeeO In-oiqt^XO .M.H ,03iq2 .CX imif ,.oU ftfllri

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-^a'»nl 5c »olqi3nX73 E'o^?E^t■^KH ,.3.S , iqobaiaJa^ .AI

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37

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27. Gitlin, N., Grahame, G.R., Kreel, L., Williams, H.S., Sherlock,S. Splenic blood flow and resistance in pa¬ tients with cirrhosis before and after portacaval anasto¬ moses. Gastroenterology 59:208-213, 1970.

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38

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38. Halvorsen, J.F., Myking, A.O. ; Prehepatic portal hypertension in the rat. Immediate and long term effects on portal vein and aortic pressure of a graded portal vein stenosis, followed by occlusion of the por-tal vein and spleno-renal collaterals. Eur. Surg. Res., 11(2): 89-98,1979.

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45. Benoit, J.N., Womack, W.A., Hernandez, al.. Granger, D. N. : " forward ” and " backward ” flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology, 89(5): 1092-6, 1985.

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49. Sharbaugh, R.J., Rambo, W.M.: A new model for producing

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experimental fecal peritonitis. Surg. Gynec. and Obstet., 133:843,1971.

50. Postal, J., Schloerb, P.R., Furtado, D.: Pathophysiologic alterations during bacterial infusions for the study of bacterial shock. Surgery. Gynec, and Obstet., 141(5):643- 692, 1975.

51. Swan, K.G., Reynolds, D.G.; Blood flow to the liver and spleen during endotoxin shock in the baboon. Surgery, 72(3):388-93, 1972.

52. Imamura, M., Clowes, H.A., Jr.: Hepatic blood flow and oxygen consumption in starvation, sepsis and septic shock. Surgery, Gynec. and Obstet 141:27-34, 1975.

53. Schilt,B.: Experimental peritonitis in irradiated ra¬ bbits. Acta. Chir. Scand., 135:61,1969.

54. Sisel, R.J., Donovan, A.J., Yellen, A.E.: Experimental faecal peritonitis. Arch. Surg., 104:765,1972.

55. King, D.W., Gurry, J.F., Ellis-Pegler, R.B., Brooke, B.N.: A rabbit model of perforated appendicitis with peritonitis. Br. J. Surg., 62:642,1975.

56. Browne, M.K.: Intraperitoneal noxythiolin in fecal peri¬ tonitis. Clin. Trials., 4:673,1967.

57. Browne, M.K., Stoller, J.: Intraperitoneal noxythiolin and faecal peritonitis. Br. J. Surg., 57:37, 1970.

58. Browne, M.K., Leslie, G.B.: Animal models of peritonitis. Surgery. Gynec. and Obstet., 143:738-40, 1976.

59. Haler, D.: The effect of noxyflex on the behaviour of animals which have been infected intraperitoneally with suspensions of faeces. Int. J. Clin Pharm. Ther. Tox., 9:160, 1974.

60. Smith, I.M., Hazard, E.C.: Anomalous results of high dose chemotherapy in experimental peritonitis. Surg.Gynec. and Obstet., 132:94, 1970.

61. Bartlett, J.G., Onderdonk, A.B., Louie, T., Kasper, D.L., Gorbach, S.L.: A review: lessons from an animal model of intraabdominal sepsis. Arch. Surg., 113:855, 1978.

40

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62, Wichterman, K.A., Baue, A.E., Chaudry, I.H.; Sepsis and septic shock - a review of laboratory models and a propo¬ sal. J, of Surg, Research 29:189-201, 1980,

63, Short, B.L,, Gardner, W,M., Walker, R.I., Fletcher, J.R., Rogers, J.E.; Rat intraperitoneal sepsis - a clinically relevant model. Circ, Shock 10; 351-359, 1983.

64, Martinell, S., Falk, A., Hagland, U., Myrvold, H.; Peri¬ tonitis and septic shock - an evaluation of two experi¬ mental models in the rat. Eur. surg. Res., 17:160-166, 1985.

65. Chojkier, M., Groszmann,R.J.; Measurement of portal - systemic shunting in the rat by using gamma labeled microspheres. Am. J. Physiol. 240: G371-375, 1981,

66. Hansson, L,, Alwmark,A., Christensen, P., Jeppsson, B., Holst, E., Bengmark, S.: Standardized intraabdominal ab¬ scess formation with generalized sepsis; pathophysiology in the rat. Eur. surg. Res., 17:155-159, 1985,

41

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Table 1. Number of rats in each study.group.

Group 12 hrs. 48 hrs. 1 wk. Total

Cnt r 1 7 12 6 25 PVS 7 6 7 20 CLP 8 8 8 24 PVS-CLP 8 8 8 24

Total 30 34 29 93

Table 2. Leukocytosis at 12 hrs.

Group # of rats

Mean Range S.D. p value vs. cntl

Cntl 7 15.16 7.6-18.9 2.75 PVS 7 10.67 7.9-17.1 2.57 0.05 CLP 8 2.8 0.8-4.4 1.67 0.001 PVS-CLP 8 5.83 2.1-8.9 3.2 0.001

Table 3. Presence of Bands at 12 hrs.

Groups Mean % Bands

Range Trend

Cntl 0.3 0-4 7/7 = < 5%

PVS 0.4 0-5 6/6 = < 5%

CLP 17.43 8-26 6/8 = > 15%

PVS-CLP 19.63 8-31 6/8 = > 15%

42

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Table 4. Blood cultures at 12 hrs

Organism Conti PVS CLP PVS-CLP

No growth 7 E.coli 0 Clostridia 0 B,fragilis 0 Strep, spp. 0 Proteus mir. 0 Lactobacillus 0 Staph, aureus 1

2 3 1 1 1 0 1 0

0 7 2 4 3 2 0 1

0 6 1 3 3 1 1 1

% of rats 12.5 50 100 100 bacteremia

Total # rats 8 4 6 8

Table 5. Leukocytosis at 48 hrs.

Group # of Mean Range SD P value rats vs . cnt 1

Cnt 1 12 11.63 5.4-15.3 3.53 PVS 6 10.68 6.5-15.6 3.66 < 0.05 CLP 1 2.4 - -

PVS-CLP 6 12.12 7.8-19.2 5.82 < 0.05

43

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Table 6. Blood cultures at 48 hrs

Organism Cntl PVS CLP PVS-CLP

No growth 6 E.coli 0 Strep.spp. 0 Staph.aureus 0 Pseudomonas 0 B.fragilis 0 Enterobacter 0

3 0 0 1 1 0 1

1 0 0 0 0 0 0

0 1 1 1 0 2 0

Total 6 6 1 2

Table 7. Comparison of leukocytosis in various

study groups at 12 hrs.

Investigator Mean leukocytosis p. value vs. control

Alexander control 15.16 (+ 2.75) PVS 10.67 (+ 2.57) CLP 2.8 (+ 1.67) CLP-PVS 5.83 (+ 3.20)

< 0.05 < 0.001 < 0.001

2.7 (±1.2) 7.9 (± 2.5)

Hansson et.al [66] Septic Control

< 0.001

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Table 8. Blood Chemistries at 12 hours.

Group A Group B Group C Group D

Sodium 139 (+ 3.5)

141

(t 3.0)

140 (+ 4.0)

140 (+ 3.0)

Potassium 4.2 (+ 0.3)

4.4

(to-^) 4.3 (+0.4)

4.5 (+ 0.5)

Chloride 108 (+10.5)

106 (+ 8.6)

115 (+11.2)

no (+5.8)

Bicarb¬ onate

24 (+2.8)

22 (+3.3)

21 (+2.6)

26 (+2.2)

SCOT 213 (tl8.5)

382 (+36.1)

353 (+24.7)

240 (+53.6)

Aik. Phos 68.5 (+7.9)

61.3 (+8.2)

69.8 (+11.3)

70.6 (+13.0)

BUN 15 (±2.5)

20.3 (+5.4)

14.4 (+3.4)

15.6 (+2.9)

Creat. 0.6 (+0.17)

0.6 (+0.20)

0.7 (+0.29)

0.7 (+0.12)

45

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Table 9. Blood Chemisrties at 48 hours.

Group A Group B Group C Group D

Sodium 137 (+4.5)

139 141 (+3.2)

138 (+4.0)

Potassium 4.0 (+2.1)

3.8 4.1 (+1.6)

4.0 (+2.3)

Chloride no (+6.0)

113 108 (+7.3)

111 (+4.1)

Bicar¬ bonate

20 (+3.7)

19 22 (+2.9)

23 (±5.1)

SCOT 234 (+34.5)

QNS 318 (+49.6)

256 (+27.6)

Aik. Phos 65 (+6.7)

QNS 64 (±8.1)

68 (+4.7)

BUN 17 (+2.1)

QNS 15 (+1.5)

14.1 (+0.9)

Great. 0.5 (+0.11)

QNS 0.7 (+_0.18)

0.6 (+0.14)

46

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Table 10. Peritoneal Fluid Cultures at 12 hours

Group A Group B Group C Group D

No Growth 4 0 0 6

Stap. aureus 1 4 6 1 Prot. mirabilis 0 4 3 0 Escherichia coli 1 8 5 1 Strep, faecalis 0 5 7 0 Clostridia spp. 0 1 0 0 Bact. fragilis 2 6 5 0

Total 6 8 8 7

Table 11. Peritoneal Fluid Cultures at 48 hours.

Group A Group B Group C Group D

No growth 4 0 0 3

Eschericia coli 0 1 2 0

Strep, faecalis 0 1 1 0

Bact. fragilis 0 1 2 1

Clostridia spp. 0 1 1 0

Enterobacter 1 0 1 0

Staph, aureus 1 1 0 2

Total 4 1 3 5

47

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Num

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of

Rats

Fig. 1 Cotparison of WBC at 12 and 48 hours.

1 2

Groups at 12 and 48 hours.

S PVS + CLP Q CLP

gi CNTL m PVS

Fig. 2 Mortality of Groups at 1 week.

12 3 4

Groups at 12 Hrs (1), 24 Hrs (2) , 48 Hrs (3) , and 1 week

S PVS + CLP

® CNIL

p CLP

® PVS

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YALE MEDICAL LIBRARY

Manuscript Theses

Unpuhlished theses suhinitted for the Master's and Doctor's degrees and deposited in the Yale Medical Library are to be used only vith due regard to the rights of the authors. Bibliographical references may be noted, but passages must not be copied without permission of the authors, and without proper credit being given in subsequent written or published work.

This thesis by has been used by the following persons, whose signatures attest their acceptance of the above restrictions.

mi iTAI-!E ABD ADDRESS

/Ira

DATE