Argon Plasma Coagulation Plus Injection Sclerotherapy Versus Injection Sclerotherapy Alone for the...

8/7/2019 Argon Plasma Coagulation Plus Injection Sclerotherapy Versus Injection Sclerotherapy Alone for the Prevention of Va

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Argon Plasma CoagulationPlus Injection Sclerotherapy Versus

Injection Sclerotherapy Alone For ThePrevention Of Variceal Recurrence And

RebleedingBY

Tarek Fouad El Sayed MohamedM.B.B.Ch.

Resident of internal medicineFaculty of medicine, Mansoura university

ThesisSubmitted for Partial Fulfillment of the Master DegreeIn Internal Medicine

Supervisors

Prof. Dr.

Magdy Hamed Abdel Fattah

Professor of internal medicineFaculty of medicine, Mansoura

university

Prof. Dr.

Ayman Nassem MohamedMenessy

Professor of internal medicineFaculty of medicine, Mansoura

university

Dr. Mohamed Mahmoud Fahmy El-SaadanyLecturer of internal medicine

Faculty of medicine, Mansoura university

2006

Mansoura University

Faculty of Medicine

Internal Medicine Department

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CONTENTS

SUBJECT PAGE

INTRODUCTION AND AIM OF THE

WORK

REVIEW OF LITERATURE:

The Portal Venous System

Portal Hypertension

Management of esophageal varices

Argon Plasma CoagulationPATIENTS AND METHODS

RESULTS

DISCUSSION

SUMMARY AND CONCLUSION

REFERENCES

ARABIC SUMMARY

1

3

3

8

16

27

55

65

97

104

108


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LIST OF TABLES

PageSubjectTable

30Setting of argon plasma coagulation (APC)

parameters.Table (1)

33Conventional methods of haemostasis

compared with APC in different types ofhaemorrhage.

Table (2)

45Scoring system for pathologic analysis of

argon plasma coagulation tissue effects onesophageal and gastric tissue.

Table (3)

46Gastric tissue damage score for different

combinations of pulse duration and power.Table (4)

47Esophageal tissue damage score for 1- and 3-

second pulse durations.Table (5)

60Pugh's modification of Child's classification.Table (6)

80Baseline demographic and clinical data of both

groups.Table (7)

81Laboratory data and Child-Pugh score in bothgroups at randomization and at the end oftreatment.

Table (8)

82Virological markers of the studied groups.Table (9)

82Aetiology of liver cirrhosis in the studied

groups.Table (10)

82Child-Pugh classification in the studied groups

at randomization.Table (11)

83Initial Endoscopic Results .Table (12)

84Data of variceal obliteration in both groups.Table (13)85Complications of sclerotherapy in both groups.Table (14)

86Complications of argon plasma coagulation in

group I.Table (15)

87Complications of APC in group I versus

complications of EST in group II.Table (16)

88Data of variceal recurrence in both groups of

patients.Table (17)

88Data of rebleeding in both groups of patients.Table (18)


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LIST OF FIGURES

PageSubjectFigure

3Schematic representation of the portal and

hepatic venous system.Figure (1)

4Variation in origin of portal vein.Figure (2)

14Regulation of vascular tone by endothelins and

nitric oxide.Figure (3)

15Schematic representation of portosystemtic

collaterals.Figure (4)

49The tissue effect of argon plasma coagulationon esophageal mucosa.

Figure (5)

89Child-Pugh classification in the studied groups

at randomization.Figure (6)

90Virological markers of the studied groups at

randomization.Figure (7)

91Aetiology of liver cirrhosis in the studied

groups at randomization.Figure (8)

92Initial Endoscopic Results (according to grade

of varices).

Figure (9)

93Kaplan-Meier analysis of the cumulative

recurrence-free curves.Figure (10)

94Kaplan-Meier analysis of the cumulative

rebleeding-free curves.Figure (11)

95Endoscopic application of argon plasma

coagulation.Figure (12)

95Endoscopic appearance of the loweresophageal mucosa at the end of an APC

session .

Figure (13)

96Endoscopic appearance of the lower

esophageal mucosa in the same patient one

month after the APC session.

Figure (14)

96Endoscopic appearance of the lower

esophageal mucosa in the same patient 6

months after the APC session.

Figure (15)


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List of Abbreviations and Acronyms

ACE

ALT

APC

AVM

c-GMP

DM

ELISA

EMR

ESTET-1

EVL

GAVE

GIT

H.&E.

HBsAg

HCVHF

HVPG

INR

ISMN

IVC

Nd/Yag

NO

NOS

NSAIDs

NSBBs

PHG

PT

TNF-

TIPS

W

Angiotensin converting enzyme

Alanine aminotransferase

Argon plasma coagulation

Arteriovenous malformations

Cyclic guanosine monophosphate

Diabetes mellitus

Enzymes linked immunosorbent assay

Endoscopic mucosal resection

Endoscopic sclerotherapyEndothelin-1

Endoscopic variceal band ligation

Gastric antral vascular ectasia

Gastrointestinal tract

Hematoxylin and Eosin

Hepatitis B surface antigen

Hepatitis C virusHigh frequency

Hepatic venous pressure gradient

International normalizing ratio

Isosorbide mononitrate

Inferior vena cava

Neodymium yttrium aluminum garnet

Nitric oxide

Nitric oxide synthase

Non steroidal anti inflammatory drugs

Nonselective beta-blockers

Portal hypertensive gastropathy

Prothrombin time

Tumor necrosis factor alpha

Transjugular intrahepatic portosystemic shunt

Watt


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INTRODUCTION AND

AIM OF THE WORK


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Introduction & Aim of the Work

1

INTRODUCTION

AND AIM OF THE WORK

Gastrointestinal bleeding is the most severe complication of portal

hypertension, and esophageal and gastric varices are by far the most

common sources of bleeding in these patients (DAmico and Luca,

1999). After an initial variceal hemorrhage, the frequency of recurrent

bleeding ranges from 30% to 40% within the subsequent 6 weeks

(D'Amico et al., 1997).

Endoscopic injection sclerotherapy (EST) has long been the most

widely used technique to achieve variceal fibrosis (Kitano et al., 1990

and Narayanan and Patrick, 2006). Endoscopic injection sclerotherapy

involves injecting a sclerosant that subsequently results in variceal

thrombosis and fibrosis. It is usually performed every 10-14 days until the

varices are eradicated, which usually takes 5 or 6 sessions. After

obliteration, varices tend to recur over time in 50% to 70% of individuals

(Waked et al., 1997).

Argon plasma coagulation (APC) is a non-contact thermal coagulation

method in which high frequency current is applied to the target tissue

through an argon plasma jet (Consensus statement on therapeutic

endoscopy and bleeding ulcers, 1990). A distinctive feature characteristic

of argon plasma coagulation is safe, uniform and effective shallow

coagulation over extensive areas (Johanns et al., 1997).

In this study, argon plasma coagulation will be used to induce fibrosis

of the esophageal mucosa after eradication of esophageal varices with

injection sclerotherapy.


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Introduction & Aim of the Work

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Aim of the work:

The aim of the present clinical trial is to assess safety and efficacy of

endoscopic sclerotherapy (EST) plus Argon plasma coagulation (APC)

versus endoscopic sclerotherapy alone for the prevention of variceal

recurrence and rebleeding.


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REVIEW OF

LITERATURE


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Review of Literature

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The Portal Venous System

The term portal venous system is applied to a system that begins and

terminates in capillaries. In the abdomen, this system springs up as the

capillaries of the intestine, and ends in the hepatic sinusoids (Kapoor and

Sarin, 2002). A schematic representation of the main splanchnic venous

channels is shown in Fig (1).

Fig (1): Schematic representation of the portal and hepatic venoussystem, SMV: superior mesenteric vein; IMV: inferior mesenteric vein;SV: splenic vein; MPV, RPV, LPV: main, right and left portal vein;LGV: left gastric vein, IVC: inferior vena cava; RHV, MHV, LHC,right, middle and left hepatic vein (Kapoor and Sarin, 2002).

Anatomy of the portal venous system

The portal vein is formed behind the neck of the pancreas as the

superior mesenteric joins the splenic vein.

The portal trunk divides into 2 lobar veins. The right branch drains the

cystic vein, and the left branch receives the umbilical and paraumbilical


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veins.

The portal vein is rarely variable. It often receives the left gastric vein,

and may also receive an accessory splenic, inferior phrenic branch, pancreaticoduodenal, a pulmonary vein or right gastroepiploic vein

(Bergman et al., 1988) .Variation in origin of portal vein are shown in

figure (2).

Figure 2

Variation in origin of portal vein

(PV: portal vein, IM: inferior mesenteric, LG: left gastric, S: splenic, SM:superior mesenteric).

(Bergman et al, 1988)

The portal vein itself is approximately 6-8 cm long and 1-1.2 cm indiameter. It runs in the free edge of the lesser omentum from the pancreas


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to the right end of the porta hepatis. The superior mesenteric vein forms

from the draining jejunal and ileal veins, its major tributaries being the

ileocolic, right colic and middle colic veins. The left and right gastric

veins and the gastroepiploic veins drain into the main portal vein. Two

major tributaries of importance in portal hypertension are: -

Left gastric (coronary) vein. Inferior mesenteric vein. These enter the portal system close to the

splenic portal vein junction, the left gastric vein superiorly and the

inferior mesenteric vein inferiorly.

Portal vein flow in man is about 1000-1200 ml/ minute (Sherlock

and Dooley, 1997).

An important feature of this system is that a number of its tributaries

also communicate with the systemic circulation. These include the

intrinsic and extrinsic veins of the gastroesophageal junction;

hemorrhoidal veins of the anal canal; paraumbilical veins and the

recanalized falciform ligament; the splenic venous bed, the left renal vein;

and the retroperitoneum.

In portal hypertension, these venous collaterals dilate and allow portal

venous blood to return to the systemic circulation. Clinically, the most

significant collaterals are the intrinsic veins of the gastroesophageal

junction, which are located close to the mucosal surface. They are the

collaterals most likely to bleed when dilated because of increased blood

flow (Garcia-Tsao, 1999).

The other important surgical anatomy in portal hypertension is the

venous anatomy of the gastroesophageal junction, which has been

extensively studied by several investigators in the past two decades

(Vianna et al., 1987).


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Angioarchitecture of the gastroesophageal junction:

The lower part of human osophagus has a characteristic vascular

structure (Vianna et al., 1987, Arakawa et al., 2002 and Obara, 2006):-

1- Gastric zone: it lies 2-3cm below the gastroesophageal

junction (junctional zone). Veins run longitudinally towards

esophagus rather than via an irregular network as seen in the rest

of the stomach.

2- Palisade zone: it lies 2-3 cm above the gastric zone extending

into lower esophagus. Evenly distributed longitudinal veinscorrespond to major mucosal folds of the esophagus; there is no

perforating veins.

3- Perforating zone: it lies 2cm above the palisade zone. There

are large looping collaterals between internal and external

venous plexuses of the esophagus.

4- Truncal zone: it lies 8-10cm above the perforating zone.

There are 4-5 longitudinal veins in the lamina propria and

perforating veins from the submucosa to external venous plexus.

The veins of the gastroesophageal junction are classified as intrinsic,

extrinsic, and venae comitantes. The intrinsic veins form a subepithelial

and submucosal plexus starting at the gastric cardia (upper stomach) and

running the length of the esophagus. In healthy persons, these veins drain

into the extrinsic plexus through perforating veins 2 to 3 cm. above the

gastroesophageal junction. Flow through the perforating veins is

unidirectional toward the extrinsic plexus and systemic circulation. When

portal hypertension develops, however, the valves of the perforating veins

become incompetent and allow reversal of flow from the extrinsic to the

intrinsic system(Hegab et al., 2001).


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It has been reported that bleeding from esophageal varices mostly

occurred in the caudal portion of the esophagus, but the reason was

unclear(Arakawa et al., 2002).

Normal physiology of portal circulation

Portal pressure (P) - like pressure in any vascular bed - is determined

by the product of portal venous inflow (Q) and the vascular resistance (R)

to this flow, that is:

P = Q R

The normal hepatic blood flow is about 1.5 L/min of which

approximately four-fifths is contributed by the portal vein. The portal

vein pressure ranges from 5 to 8 mmHg and that of the hepatic veins as

well as the inferior vena cava is approximately 1-2 mmHg. The pressure

gradient between the portal venous and hepatic outflow venous system is

thus approximately 4 mmHg. The hepatic microcirculation is peculiar in

that the ratio of pre-to-post sinusoidal resistance is about 49: 1, in contrast

to that seen in skeletal muscle, where the pre- to post-capillary resistance

ratio is 4:1. The high ratio in hepatic bed which translates into a lack of

outflow resistance at the level of sinusoids, is in fact a protective

mechanism considering the fact that the hepatic endothelium is

discontinuous and the wide pores between endothelial cells would favour

the exudation of plasma proteins if the post-capillary sphincter pressure

were to be high(Laut and Greenway, 1987). Another peculiarity of the

hepatic macrocirculation is the interrelationship between hepatic artery

and portal vein blood flow. A decrease in portal venous blood flow or

sinusoidal pressure, reflexly increases the hepatic arterial flow, thus

maintaining adequate perfusion of the lobule. This response is possibly

mediated by adenosine, which has a vasodilatory action. Conversely, an


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increase in sinusoidal pressure decreases the hepatic arterial flow. The

hepatic arterial flow however, lacks the potential to cause changes in

portal venous flow in response to physiological or metabolic stimuli

(Arakawa et al., 2002).

Portal Hypertension

Definition

The normal portal venous pressure is 5-8 mmHg (or 7-14 cm water).

Portal hypertension is defined as a hepatic venous pressure gradient

(HVPG) of greater than 6 mmHg. Alternatively, a splenic pulp pressure

of more than 15 mmHg or a direct portal vein pressure of greater than 21

mmHg (or 30 cm water) at surgery also constitutes portal hypertension

(PHT) (Kapoor and Sarin, 2002) .

Classification

The classification of portal hypertension is based on the site of

increased resistance to portal flow.

The possible sites are:

Pre-sinusoidal - extrahepatic.- intrahepatic.

Sinusoidal. Post-sinusoidal - extrahepatic.

- intrahepatic

1)Presinusoidal

a) Extrahepatic

- Portal vein thrombosis


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b) Intrahepatic

- Schistosomiasis.

- Idiopathic portal hypertension.

- Congenital hepatic fibrosis.

- Granulomatous diseases (e.g. sarcoidosis).

- Feltys syndrome.

- Arsenic poisoning.

- Primary biliary cirrhosis.

2) Sinusoidal

- Alcoholic cirrhosis.- Non-alcoholic cirrhosis.- Vitamin A intoxication.- Nodular regenerative hyperplasia : pathogenesis probably is

obliterative venopathy. The presence of nodules that press on the

portal system also has been postulated to play a role, although

nodularity is present in most cases without clinical evidence ofportal hypertension.

3)Postsinusoidal

a) Extrahepatic

- Inferior vena cava (IVC) obstruction.- Right sided heart failure.-

Constrictive pericarditis .- Tricuspid regurgitation.- Budd Chiari syndrome.- Congenital web.

b) Intrahepatic

- Veno-occlusive disease.- Central hyaline sclerosis (alcoholic hepatitis).As can be seen, a particular condition can contribute to portal


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hypertension in more than one way and at more than one site. Apart from

the conditions enumerated, portal hypertension may rarely result from a

communication between a splanchnic artery to the portal venous system,

for example traumatic arterio venous fistula arising from splenic artery or

that between hepatic artery and portal vein (Kapoor and Sarin, 2002).

Pathophysiology and hemodynamics of portal

hypertension

From the equation P = Q R, it is evident that the pathophysiology of

portal hypertension is dependent on two important factors :- vascular

resistance to portal blood flow (R) and blood flow in this bed (Q).

Changes in either (R) or (Q) affect the portal pressure. In most types of

portal hypertension, both the resistance to blood flow and the blood flow

are altered (Garcia-Tsao, 1999).

Hemodynamic factors in portal hypertension

1- Increased resistance to portal blood flow (initiator)

a) Fixed component:

- Extrahepatic venous obstruction- Intrahepatic fibrosis and capillarization of sinusoids- Vascular distortion by cirrhotic nodules, granulomas, etc.

b) Variable component:

- Hepatocyte swelling- Stellate cell response (to endothelins, nitric oxide, endotoxins, etc)- Stellate cell activation (alpha-actin levels and contractile state)

2 Increased portal blood flow (sustainer)

- Nitric oxide synthase system- Glucagon


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- Prostaglandins- Tumor necrosis factor-alpha- Carbon monoxide

3 Collateral circulation.

1-Increased vascular resistance

As already mentioned, the major site of resistance within the portal

circulation is at the level of sinusoids. Increased resistance to portal

venous blood flow constitutes, the backward component of portal

hypertension. This may result from a fixed component that is, distortionof vascular anatomy by fibrotic septae separating cirrhotic nodules

(Popper et al., 1952) or by pericellular, perivenular fibrosis(Miyakawa et

al., 1985). Architectural derangements like capillarization of sinusoids

(i.e. loss of fenestrae) and appearance of collagen in the Space of Disse

contribute to increased sinusoidal resistance(Orrego et al., 1981). More

significant however, are the variable factors which modulate the

intrahepatic vascular resistance. Portal flow may be obstructed by

compression of simusoids by swollen hepatocytes in alcoholics, even

before frank cirrhosis appears(Vidins et al., 1985). One of the important

reversible factors mediating vascular resistance may be endothelin-1 (ET-

1) (Stanley and Hayes, 1997). Two types of endothelin receptors have

been identified, ETA and ETB. The primary response mediated by ETA

is vasoconstriction (Rockey, 1997). Binding of endothelins to ETB

receptors on endothelial cells results in nitric oxide (NO) release and

smooth muscle relaxation, while action on ETB receptors on vascular

smooth muscle cells causes vasoconstriction. The production and actions

of endothelins in liver are diagrammatically represented in Fig (3). The

livers response to chronic injury of any kind is one of scarring and

fibrosis and the principal cell type responsible for fibrogenesis is the


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stellate cell (Friedman, 1993). The stellate cells, when activated show

high expression of alfa actin and assume the shape of myofibroblasts. In

response to endothelins, these cells can contract and thus mediate

increased resistance to blood flow(Ballardini et al., 1988).

2-Increased portal blood flow and the hyperdynamic systemic

circulation:

Almost a decade ago, it was proposed that peripheral arterial

vasodilation was an important event contributing to the maintenance of

portal hypertension. The increased splanchnic flow resulting from thisperipheral vasodilatation constitutes the forward component of portal

hypertension. One of the first vasodilatory mediators studied in portal

hypertension was glucagon. It - however - became clear that it accounts

for only about 30% of the splanchnic vasodilation(Pak and Lee, 1994).

The production of prostacyclin is increased in experimental PHT and in

patients with chronic liver disease (Sitzmann et al., 1991).

Administration of the cyclo-oxygenase inhibitor indomethacin improves

the hyperdynamic circulation of cirrhosis, as well as improving the

vascular hyporesponsiveness of these subjects to vasoconstrictors like

nonrepinephrine. Treatment with indomethacin leads to a significant

decrease in superior mesenteric artery blood flow in cirrhotics(Roberts

and Kamath, 1999).

Recently, nitric oxide (NO) has received great attention as a peripheral

vasodilator agent in cirrhosis. The main factors favoring the role of NO

are:

i. Reduced vasopressor response to vasoconstrictors in cirrhotics isreversed by inhibition of nitric oxide synthase (NOS) or endothelial

denudation(Claria et al., 1994).


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ii. High concentration of cyclic guanosine monophosphate (c-GMP),an intracellular mesenger of NO in aortic tissue from cirrhotic rats,

which is reduced by NOS inhibitors(Neiderberger et al., 1995).

iii. Normalization of arterial pressure, cardiac index and total systemicvascular resistance that is, the hyperdynamicity of portal

hypertension on administration of NOS inhibitors.

Two types of NOS exist, the eNOS (endothelial or constitutive) and

the iNOS (inducible). The former is calcium dependent and membrane

associated and is rapidly activated by changes in local blood flow andcirculating hormones. Histochemical staining of liver shows increased

eNOS levels in portal hypertension, but it is not known with certainity

whether the increase is actually the result of increased splanchnic blood

flow and shear stress seen in portal hypertension (Shah et al., 1998). The

levels of eNOS are decreased by sepsis, while those of iNOS are

increased by lipopolysaccharide (LPS), interleukin-1 and tumor necrosis

factor alpha (TNF-). Indeed, the iNOS levels are high even at the stage

of pre-ascitic cirrhosis and probably these cytokines are responsible for

this(Pierre-Yves et al., 1998). Increased NO levels in portal hypertension

are in part responsible for the hyporesponsiveness of mesenteric

vasculature to vasoconstrictive stimuli like alpha adrenergic agonists as

methoxamine. This is partly mediated by c-GMP as administration of

NOS inhibitors only partially restores this responsiveness. However, if

potassium channel blockers like tetraethylammonium are co-administered

with NOS inhibitors, this vasoconstrictor responsiveness is completely

restored(Atucha et al., 1998). It has also been recently shown that agents

which increase the entry of extracellular calcium into arterial smooth

muscle cells may decrease cirrhosis induced vasodilation and also reduce

the hyperdynamicity of portal hypertension (Moreau et al., 1998).


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Studies have recently focused on carbon monoxide (CO) as a regulator of

stellate cell contractility and simusoidal blood flow. Carbon monoxide,

which is derived from degradation of heme by heme oxygenase, is not as

potent as NO in stimulating c-GMP synthesis and causing smooth muscle

relaxation. Also, CO may inhibit NO mediated c-GMP production, thus

countering the relaxing effect of NO.

Fig (3): Regulation of vascular tone by endothelins and nitric oxide.Endothelin (ET) acts on vascular smooth muscle (VSM) ETA receptors to

induce smooth muscle contraction (left) and on endothelial cells (ETB) tostimulate endothelial nitric oxide synthase (eNOS) which in turn leads to VSMrelaxation (right) through its second-messenger cGMP. Inducible NOS isstimulated by interferon gamma, lipopolysaccharide and TNF alpha- the stimuliwhich inhibit eNOS (Kapoor and Sarin, 2002).

3- Collateral circulation:

Beyond a critical value of portal pressure, an attempt is made by the

body to dissipate further increase in the portal pressure, by formation of

portosystemic collaterals. In alcoholic cirrhosis, and HVPG of 12

mmHg appears to be necessary for the development of esophagogastric

varices (Garcia-Tsao et al., 1985).


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Fig (4): Schematic representation of portosystemtic collaterals. Arrows reflectthe direction of blood flow which is reversed in the coronary vein (CV) and theinferior mesenteric vein (IMV) leading to esophagogastric and anorectalvarices. There is resumption of flow in the obliterated paraumbilical vein(PUV) which forms the abdominal caput. SMV, superior mesenteric vein,

SG, short gastric collaterals; LRA, leino-renal adrenal collaterals (Kapoor andSarin, 2002).

These collaterals (Fig 4) are, in fact, a system of resistance channels in

parallel with the portal venous system. The collaterals however, are not

passive conduits and respond reflexively and independently to various

hemodynamic and pharmacologic stimuli. The resistance to flow of blood

in these channels is governed by the Poiseuille Law:

R = 8l/r4

Where R = resistance, = viscosity of fluid, l = length of the vessel

and r = radius of the vessel. As is evident, slight changes in the diameter

of the collateral can exquisitely alter the resistance to flow in the

collateral and this fundamental is made use of in managing portal

hypertension pharmacologically.


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MANAGEMENT OF ESOPHAGEAL VARICES

Gastro-esophageal varices develop in 50% to 60% of cirrhotic patients

and approximately 30% of them will experience an episode of variceal

haemorrhage within 2 years of the diagnosis of the varices (Navarro et

al., 1969 and De Paulo et al., 2006).

Up to third to half of the patients with advanced liver disease and large

varices die after the first attack of variceal bleeding (Silverstein et al.,

1981).

Many factors contribute to the high mortality: torrential bleeding from

the varices causing blood loss and added hepatic ischaemia, compromised

hepatic functions, coagulopathy, infection and the time taken to control

the bleeding. Pharmacological therapy, endoscopic intervention, balloon

tamponade, surgical shunting and more recently, radiological treatment

have been part of the therapeutic protocol used to stop variceal bleeding

and to prevent recurrence and subsequent complications.

A multidisciplinary approach often depending on the patient's clinical

presentation and the optimal availability of the expertise and the

resources available decides the choice of treatment modalities.

Endoscopic management of variceal bleeding has unquestionably become

the main stay since its rapid evolution in the last two decades (De Paulo

et al., 2006).

Diagnosis of Varices

Endoscopy is the gold standard for the diagnosis of varices (LaBerge

et al., 1993).

Adequate air insufflations to the distal oesophagus are a must for

correct estimation of the variceal size.


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Although esophageal varices are easy to detect, gastric varices may

some time pose difficulty in identification.

Linear array endoscopic ultrasound, contrast-enhanced computed

tomography scan, magnetic resonance angiography, transabdominal

ultrasound and examination have recently been added to the list of

investigation that has been used to locate the varices. Angiography can

also be used to identify varices. Angiography is usually performed when

severe upper gastrointestinal bleeding precludes adequate diagnostic

endoscopy (Woon Chang,2006).

Treatment of esophageal varices

The treatment of esophageal varices includes the prevention of

variceal hemorrhage in patients who have never bled the treatment of the

acute bleeding episode and the prevention of rebleeding in patients who

had survived a bleeding episode from esophageal varices. An additional

scenario may come into practice: the pre-primary prophylaxis or

treatment of compensated patients without varices in order to prevent the

development of varices (Woon Chang,2006).

1. Pre-primery prophylaxis:

Studies to explore whether long-term therapy with nonselective beta-

blockers may prevent or delay the development of varices and othercomplications of portal hypertension, such as ascites, in patients with

compensated cirrhosis have been prompted by the results of studies

showing that:

i. Development of portal systemic collaterals is significantlylower in animals with experimental portal hypertension

treated chronically with beta-blockers than in controls (Sarin

et al., 1991).


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ii. In patients with cirrhosis, varices decreased in size and mayeventually disappear when hepatic venous pressure gradient

(HVPG) is reduced below 12mmHg (Casado et al., 1998).

iii.The hepatic venous pressure gradient (HVPG) reductionachieved by non-selective beta-blockers is significantly

greater in patients without varices than in those who already

have developed esophageal varices, and most achieve or

maintain a HVPG below 12mmHg (Abraldes and Bosch,

2002b).

2. Primary prevention

Continued propranolol or nadolol therapy markedly reduces the

bleeding risk, from 25% with non-active treatment to 15% with beta-

adrenergic blockers (DAmico and Luca, 1997). Therapy with beta-

adrenergic blockers should be maintained indefinitely, because when

these are withdrawn the risk of variceal hemorrhage returns to whatwould be expected in an untreated population. Moreover, it seems that

patients who discontinue beta-adrenergic blockers experience increased

mortality compared with an untreated population (Abraczinskas et al.,

2001). Variceal banding ligation is the only effective alternative for

primary prophylaxis, but its use should be restricted to patients with large

varices and intolerance or contraindications to beta-adrenergic blockers(Garcia-Pagan, 2002).

Soliman (2003) concluded that endoscopic ligation of the varices is

safe and more effective than propranolol for the primary prophylaxis of

variceal bleeding in patients with cirrhosis complicated by esophageal

varices at high risk for bleeding.

Sarin S.K. et al., (1999) randomly assigned the two treatments to 89

patients with varices of more than 5 mm in diameter that were at high risk


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for bleeding. 44 patients received propranolol at a dose sufficient to

reduce baseline heart rate by 25%; 45 patients had varices ligated until

they were either obliterated or too small to ligate. After 18 months, the

cumulative probability of variceal bleeding was 43% in the propranolol

group and 15% in the ligation group.

Endoscopic sclerotherapy is not indicated for the prevention of first

variceal haemorrhage in cirrhotic patients. More than 20 trials have

studied this issue enrolling in excess of 1000 patients. The trial protocols

were extremely heterogeneous, variceal size varied considerably, and

only one required a HVPG of greater than 12 mm Hg (Woon Chang,

2006).

Sclerotherapy technique also varied, with a variety of sclerosants in

different doses injected intravariceally or perivariceally or both. Although

some early trials showed a reduction in bleeding in the sclerotherapy

group, more recent and larger trials have shown either no value or a

deleterious effect of sclerotherapy (McCormick and Burroughs, 1992).

3.Treatment of acute variceal bleeding:GENERAL MANAGEMENT

Large bore intravenous access is necessary to allow rapid transfusion

if required. Initial fluid resuscitation should be titrated to restore thesystolic blood pressure to 80 or 90 mm Hg, further fluid requirements

should aim to maintain haemoglobin at 100 g/I and urine output above 30

ml/hour. Overly aggressive fluid replacement should be avoided as

overfilling may increase portal pressure leading to rebleeding (Woon

Chan,2006).


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Drug therapy still improves the results of endoscopic treatment even if

started just after sclerotherapy or band ligation (Corley et al., 2001).Terlipressin, somatostatin, octreotide or vapreotide are the drugs of

choice (Abraldes and Bosch, 2002a). If these drugs are not available,

vasopressin plus transdermal nitroglycerin is an acceptable option.

Pulmonary aspiration of blood or gastic secretions is common due to

the combination of encephalopathy and impaired consciousness due to

shock. In patients with significantly reduced conscious state early

endotracheal intubation is mandatory.

Bacterial infection complicates variceal haemorrhage in cirrhosis in up

to 66% of patients. A recent meta-analysis has demonstrated that short

term prophylactic antibiotics significantly reduces the incidence of

infection and increases short term survival (Bernard et al., 1999).Prophylactic antibiotics therefore, should be routinely used in all patients

for seven days after admission for variceal haemorrhage.

ENDOSCOPIC MANAGEMENTIn the acute bleeding episode, either sclerotherapy or band ligation

may be used(De Franchis and Primignani, 1999).

Failures of medical therapy (drugs plus endoscopic therapy) should

undergo a second course of endoscopic therapy before proceeding to

transjugular intrahepatic portosystemic shunt (TIPS) or, in rare occasions,

to portosystemic shunt surgery. Administration of recombinant activated

factor VII may decrease the number of treatment failures among patients

with advanced liver failure (Child-Pugh class B and C) (Abraldes et al.,

2004).


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4.Prevention of recurrent bleeding from esophageal varices

First-line treatments

Both pharmacological treatment and endoscopic therapy are

accepted first-line treatments to prevent rebleeding(Bosch et al., 2003).

a) Pharmacologic Therapy

1- Nonselective beta-blockers (NSBBs):

NSBBs (e.g. propranolol and nadolol) have been extensively

evaluated for the prevention of variceal bleeding in randomized

controlled trials. These agents decrease the splanchnic blood flow

by means of reduction of cardiac output and unopposed splanchnic

arterial vasoconstriction by blocking beta 2-receptors. They also

have a direct effect on portocollateral resistance, decreasing azygos

and gastroesophageal collateral blood flow. The effect of

propranolol on hepatic venous pressure gradient HVPG is moderate

(mean reduction, 12% to 16%), and is achieved in about one third

to one half of treated patients (El-Sayed et al., 1996 and Garcia-

Pagan et al., 1999).

2- NitratesIsosorbide dinitrate and, most commonly, isosorbide

mononitrate [ISMN] have been shown to reduce portal pressure by

selective venodilation in the splanchnic circulation, via promoting

reflex splanchnic vasoconstriction as a response to reduced mean

arterial and cardiac filling pressures, and also by reducing

intrahepatic resistance (Navasa et al., 1989, Hamed et al., 1998

and Abraldes et al., 2004). The latter effect may be mediated by

relaxation of myofibroblasts and activated stellate cells. However,


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22

it is well known that patients with advanced cirrhosis have marked

vasodilatation and that the fall in arterial pressure and hepatic

blood flow, together with the reduction of preload and cardiac

output caused by nitrates, may have deleterious effects, including

the deterioration of renal function (Moreau and Lebrec, 1990).

Thus, nitrates should not be used on their own as therapy for portal

hypertension(Mela et al., 2003).

b) Endoscopic Therapy:

This treatment does not decrease portal pressure and therefore has noeffect on other complications of portal hypertension (Bosch et al., 2003).

1. Endoscopic sclerotherapy (EST):

EST was established during the past decade as a cornerstone treatment

for the prevention of recurrent esophageal variceal hemorrhage. EST

involves injecting a sclerosant material that subsequently results in

variceal thrombosis and scarring. It is performed every 10-14 days until

the varices are eradicated,which usually takes 5 or 6 sessions (El-

Ghawalby & Yassin, 1986; El-Zayadi et al., 1988 and El-Sayed et al.,

1996). After obliteration, varices tend to recur over time in 50% to 70%

of individuals. Such varices are at risk of rebleeding, and surveillance

endoscopy must be performed, initially at 6-month and later at 1-year

intervals (Waked and Korula, 1997).

Complications:

Each EST session can cause local or systemic complications. These

complications are greater with paravariceal than intravariceal injection.

Almost every patient will experience fever, dysphagia and chest pain.This is usually transient. Bleeding is not usually from the puncture site


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23

but from remaining varices or deep ulcers that have opened in

submucosal channels. Rebleeding takes place in about 30% of patients

before the varices have been obliterated (El-Sayed et al., 1996). Further

sclerotherapy is indicated if the haemorrhage comes from varices. If from

an ulcer, omeproazole is the drug of choice (Gimson et al., 1990).

Superficial ulcers resulting from tissue necrosis is the most common

complication (70% at 1 week), with stricture formation representing the

most significant long-term complication (Kahn et al., 1989). Esophageal

stricture may be related to chemical esophagitis, ulceration and acid

reflux. Esophageal dilatations are usually successful, but occasionally

surgery becomes necessary (Taibibian and Graham, 1987).

Perforation occurs in about 0-5% of cases and is usually delayed 5-7

days. It may be an extension of the ulcerative process (Pasricha et al.,

1994).

Pulmonary complications include chest pain, aspiration pneumonia

and mediastinitis (Badra, 1990 and Baydur and Korula, 1990).

Pleural effusions are found in 50% of cases (Azzam et al., 1990).

Sclerotherapy is followed, one day later, by a restrictive defect in

respiratory function possibly due to sclerosant embolization in the lungs

(Samules et al., 1994).

Pyrexia is frequent and significant bacteremia may occur. Bacterial

peritonitis may follow injection sclerotherapy (Hamed et al., 1999 and

Sherlock & Dooley, 2002).

Portal vein thrombosis complicates 36% of the patients treated with

sclerotherapy. This may be important if subsequent shunt or liver

transplantation is required. Varices at other sites including the stomach,

ano-rectal area increase in size. Other recorded complications are cardiac


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24

tamponade, pericarditis and brain abscess (Sherlock and Dolley, 2002).

2. Endoscopic variceal band ligation (EVL):

EVL is highly effective in obliterating varices. An elastic band is used

to strangulate the superficial varix, resulting in thrombosis,

inflammation, necrosis, and sloughing of the mucosa and mural scar

formation up to, but not including, the muscularis propria.Similarly to

sclerotherapy, ligation is performed every 10-14 days until the varices

are eradicated, which typically requires 3 or 4 sessions, i.e. fewer than

with sclerotherapy (Farag et al., 1998).

Complications

Endoscopic variceal band ligation is generally associated with fewer

complications than sclerotherapy. Minor complications such as transient

dysphagia and chest discomfort are not uncommon. Shallow ulcers at the

site of each ligation are the rule and rarely bleed (Stiegmann and

Yamamoto, 1992).

The most worrisome complication is bleeding due to untimely

sloughing of bands caused by inadvertent contact with the endosocpe

during follow-up endoscopy (Battaglia et al., 1996).

Second line treatments

Patients experiencing a significant episode of rebleeding while treated

with beta-adrenergic blockers isosorbide mononitrate (ISMN) or

endoscopic therapy should be considered for rescue' derivative therapies.

Both TIPS and surgical shunts are very effective in preventing rebleeding

(Burroughs and Patch, 1999),but surgical shunts, preferably an H-graft


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25

or a distal splenorenal shunt, should only be offered to patients with good

liver function (Child A class) in centers with qualified surgeons.

Liver transplantation is a definitive treatment for patients withadvanced liver disease who have bled and should be considered in all

such patients (Russel et al., 2003).

TIPS, unlike surgical shunts, does not seem to compromise

subsequent transplant surgery and has been used as bridging therapy to

liver transplantation in patients who have bled (Woon Chang,2006).

Prevention consolidation therapy (mucosal-fibrosistherapy) of esophageal varices using argon plasma

coagulation (APC)

Endoscopic injection sclerotherapy (EST) has been established as the

cornerstone for the prevention of recurrence of esophageal variceal and

rebleeding. It should be performed at 10-14 days intervals until the

varices are eradicated,which usually takes 5 or 6 sessions (El-Ghawalby

& Yassin, 1986; El-Zayadi et al., 1988 and El-Sayed et al., 1996).

However, recurrence of varices occurs in 41.7% of patients within one

year of obliteration, whereas rebleeding occurs in 15.6% of patients

within one year of obliteration (Krige, 2000 and Madonia et al., 2000).

In view of this unacceptably high rate of recurrence, the availability of

other supplemental prevention consolidation therapies has been earnestly

desired (Furukawa et al., 2002). Mucosal-fibrosis therapy has been

reported as being ideally suited for this purpose. There are several

different techniques for achieving mucosal fibrosis therapy, but the most

common are perivariceal injection of 1% polidocanol (Matsui et al.,

2004) and thermal coagulation of the esophageal mucosa using Nd/Yag


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26

laser, high frequency coagulation, microwave coagulation (Obara et al.,

1994) or - recently- argon plasma coagulation.

Since argon plasma coagulation is theoretically well suited formucosal fibrosis therapy, it can be used for the complete elimination of

esophageal varices and for fibrosis of the distal esophageal mucosa

(Nakamura et al., 2001).

Watanabe et al. (2001)and Furukawa et al. (2002) demonstrated that

argon plasma coagulation is an effective prevention consolidation therapy

after endoscopic variceal band ligation (EVL) or sclerotherapy without

serious complications.

Matsui et al. (2004) compared argon plasma coagulation and

paravariceal injection sclerotherapy with 1% polidocanol as a mucosa-

fibrosing therapy for esophageal varices. They concluded that the one and

three-year cumulative recurrence-free rate in the APC group is higher

than those in the 1% polidocanol group.


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Argon plasma coagulation (APC)

Introduction

The argon plasma coagulation (APC) is a non-contact method of

delivering high-frequency monopolar current through ionized and

electrically conductive argon gas, which is called argon plasma (Frank et

al., 2006). It was originally developed for use in open surgery(Brand et

al., 1990). It has also been used at laparoscopy (Daniell et al., 1993) and

thoracoscopy (Lewis et al., 1993).

APC was adapted for use in flexible endoscopy in 1991 and has many

potential applications in therapeutic endoscopy (Farin et al., 1994)

including ablative and palliative treatment of esophageal, gastric, and

colonic tumors, hemostatic electrocoagulation of angiodysplastic lesions

and peptic ulcers, and the mucosal ablation of Barrett's esophagus(Sumiyama et al., 2006).

Argon gas is passed through a coagulation probe with an electrode at

its tip. The electrode is activated by means of a foot switch and

electrosurgery frequency current passes through the argon cloud, ionizing

it, enabling it to conduct a spark to the nearest point of contact with

tissue. The circuit is completed by means of a return electrode plate on

the patient.

Physical principle

APC is a noncontact electrocoagulation device that uses high-

frequency (HF) monopolar current conducted to target tissues through

ionized argon gas (argon plasma). Electrons flow through a channel of

electrically activated, ionized argon gas from the probe electrode to the


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28

targeted tissue. Current density on arrival at the tissue surface causes

coagulation.

Coagulation depth is dependent on the generator power setting, flow

rate of the argon gas, duration of application, and distance of the probe tip

to the target tissue(Watson et al., 2000).

In contrast to other high frequency (HF) techniques, the HF current is

not conducted to the target tissue via monopolar, bipolar or multipolar

active electrodes in direct contact, but via ionized and thus electrically

conductive argon (which is called "argon plasma").

The argon arc contacts tissue closest to the electrode allowing for

en-face or tangential coagulation. With thermal coagulation of tissue, a

thin, superficial, electrically insulating zone of desiccation and a steam

layer (from the boiling of tissue) result, both contributing to limit

carbonization and depth of coagulation (Farin et al., 1994). The

insulating zone of desiccation produces increased electrical resistance in

the treated area. This prompts the current to move to another point on thetissue surface where resistance is lower(Grund et al., 1998).

In addition, APC does not cause carbonization or vaporization and

therefore does not generate smoke, so it is well suited for endoscopic

application.

Equipment

Components of the APC equipment for endoscopy include a high-

frequency monopolar electrosurgical generator, argon gas source, gas

flow meter, flexible delivery catheters, foot activation switch, and

grounding pads.

The disposable probes consist of a Teflon tube coupled to a ceramic

nozzle housing a tungsten monopolar electrode. The probes are available

in two diameters (2.3 or 3.2 mm) and lengths (220 or 440 cm for the 2.3


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29

mm probe, and 220 cm for the 3.2 mm probe). Nozzle orientation

includes a location at the tip of the catheter as well on the side of the

catheter tip, 90 degrees from the longitudinal axis of the probe.

The current generators can deliver between 5000 and 6500 V. Gas

flow settings can be adjusted between 0.5 L/min to 7 L/min. Power

adjustments can be made between 0 and 155 W.

Upon activation of the APC system via a foot switch that synchronizes

the delivery of the electrical current and argon gas, the argon becomes

ionized, thus allowing for current application to the target tissue. The

ionized argon gas contacts the tissue closest to the probe, which allows

for either en-face or tangential application.

Coagulation depth is a function of the power generator setting, the

distance from the target tissue, and the duration of the application

(Watson et al., 2000).

Generally, the zone of coagulation is 1 to 3 mm. The physical

properties of the incident tissue also may play a role in determining thedepth of tissue injury. By using fresh surgical specimens, Watson et al.,

(2000) found the depth of tissue injury in gastric tissue to be a function of

the power setting and pulse duration. In esophageal specimens, there was

only a marginal relationship between the depth of tissue injury with pulse

duration and no relationship to the power setting. Three zones of tissue

effect are encountered. The desiccation zone is located at the point ofcurrent contact with the incident tissue; deeper layers of tissue effect

include a coagulation zone and devitalization zone.

Technique

The device settings used have varied by manufacturer, indications, and

study protocols. In vitro APC experiments demonstrated that depth and

diameter of the coagulation zone increased with duration of application


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30

and increase in power settings. In general, low power and low argon flow

rates are used for hemostasis of superficial vascular lesions whereas

higher output settings are used for the tissue ablation.

Recommended dosages of APC energy in practice are shown in table

(1).The recommended values in the table refer to the standard equipment:

ICC 200 or ICC 350, APC 300 and flexible APC probes, all

manufactured by ERBE Electromedizin, Tuebingen, Germany (Grund et

al., 1999).

Table (1) Setting of argon plasma coagulation (APC) parameters(Grund et al, 1999)

Activation time

(seconds)

Power

limitation(setting)

(W)

Target tissue

1-360 - 80Normal settings of oesophagus,

duodenum, small bowel and rectum

1-360 - 80Stomach

3-560Stent in / Overgrowth

3-1099Large tumour (diameter > 15 mm)

3-580Medium sized tumour (diameter = 5-15

mm.)

1-560Small tumours

0.1-0.540Right colon

1-340-50Remaining colon

Very high flow rates may result in prompt gaseous distention and

patient discomfort.

The operative distance between probe and tissue ranges from 2 to 8

mm. At low power settings, the probe tip must be close to - but not

touching - the tissue to allow the argon plasma to contact the targeted

tissue. The surface of the targeted tissue should be free of liquid

(including blood). If the surface is not clear, a coagulated film develops

leaving the tissue surface beneath inadequately treated. This limits use inactive hemorrhage. Surface fluids should be cleared by washing and


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31

suctioning as necessary.

APC is performed with applications of 0.5 to 3 second duration

(Grund et al., 1994). A series of brief activations is superior to few

prolonged activations (Grund et al., 1999).

The probe tip can be directed to paint confluent or near-confluent

surface areas. A double channel endoscope allows concomitant aspiration

of the argon gas.

Precautions during endoscopic application of APC

- HF output power should be strictly limited according to the valuesgiven in table (1)

- The ignition and electric arc must be properly tested outside the

endoscope before advancing the probe into the working channel.

- Tissue contact with the probe tip should be avoided during activation.

When the tip makes tissue contact, it functions as a contact monopolar

probe. Deep thermal injury will allow argon gas to flow into thesubmucosa producing pneumatosis and even extraintestinal gas. The

dissected gas usually resorbes rapidly. However, this complication may

produce symptoms and may compromise the completeness of the

treatment session(Waye, 1999).

- When treating tissues in contact with metal implants such as stents,

current and/or power settings should be decreased accordingly.

- During application of APC to the target tissue, care should be taken to

avoid misdirection the plasma jet to the endoscope tip that could result

in damage to the video chip (Johanns et al., 1997).

- Aspiration should be done frequently during the procedure to avoid

overdistention with argon gas. In certain cases, such as treatment of

extensive GAVE, use of a double channel endoscope is helpful for

removal of the insufflated argon gas.


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32

- Furthermore, care should be taken during application of APC in

patients with cardiac pacemakers since malfunction of those can occur,

as reported previously with conventional monopolar electrocoagulation

methods (Canard and Vdrenne, 2001).

Clinical applications of argon plasma coagulation (APC)

The uses of the APC can be broadly categorized as hemostatic or ablative.

A. Hemostasis

Hemostasis represents one of the most important problems in

gastrointestinal endoscopy. Many different endoscopic methods have

been developed during the last 20 years (Soehandra et al., 1997),

resulting in revolution in treatment of different types of bleeding ( Table

2 ) (Grund et al., 1999) .No single method, however, covers all kinds and

sources of haemorrhage. All the currently used methods are insufficient

in the treatment of some difficult types of bleeding: diffuse bleeding

arising from large areas, bleeding as a result of coagulation disorders or

haemorrhage from a tumour which is diffuse and difficult to control (Lee

and Leiubermann, 1996).

To achieve hemostasis in these problematic lesions, argon plasma

coagulation (APC) was taken into consideration.

According to previous experience in open surgery, where APC has

proved to be an efficient method in the management of haemorrhage from

the liver, spleen or kidney, (Farin and Grund, 1994), the method was

modified to be applied in flexible endoscopy by developing flexible

probes and optimizing generators and gas sources (Grund et al., 1999).


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Table (2)Conventional methods of haemostasis compared with argon

plasma coagulation (APC) in different types of haemorrhage

(Grund et al, 1999).

APCNd:YAGlaser

HeaterprobeSclerosants

Injectiontechniques

Rubberband

ligation

ClipType ofbleeding

-

+

?

?

?

+

-

-

+

+

-

-

+

?

Peptic ulcer

(visible vessel)

Spurting

Oozing

?--+++-Varices

++?-+--Tumour+??-+??Post-

intervention

+?-----Inflammation

++-----Post-

irradiation

+??++-?Angiodysplasia

+?-----Coagulation

disorders

1.Vascular ectasiaThe APC has been used successfully to treat vascular ectasia of the

upper and lower digestive tract including gastric antral vascular ectasia

syndrome (GAVE) (Nakamura et al., 2006) , sporadic angiodysplasia,

hemorrhagic telangiectasia, and radiation-induced enteropathy and

proctopathy (Johanns et al., 1997 Wahab et al., 1997, Casey, 2006 andKwan et al., 2006) .

Watermelon stomach or gastric antral vascular ectasia (GAVE) is an

uncommon source of G.I. blood loss, which typically presents with an

iron deficiency anemia. In one study, 17 patients with GAVE were treated

successfully with APC, achieving eradication in 1 to 4 treatment sessions

(Probst et al., 2003). Over a mean follow-up of 30.4 months, recurrent

GAVE occurred in 5 patients requiring further treatment.


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34

Five retrospective studies evaluated 78 patients with radiation

proctopathy treated with APC (Silva et al., 1999 and Tam et al., 2000).

Using various definitions of success, all but 5 patients (94%) improved

after treatment with 8 to 28 months' follow-up. Recurrence of significant

bleeding was reported in 3 patients. Three patients experienced self-

limited anorectal pain after treatment, 2 developed chronic rectal ulcers,

and 2 developed strictures requiring rectal dilatation.

Successful APC therapy leads to the disappearance of these vascular

structures(Shudo et al., 2001). Typically, two to 3 sessions are requiredto achieve ablation, with an improvement in haemoglobin level and

obviation of transfusion requirements that is seen in up to 85.7% of

patients. Seventeen patients, 65% of whom exhibited iron deficiency

anemia, were treated with the APC for up to 4 sessions (Probst et al.,

2003).

Resolution of GAVE was seen in all patients, which was associated

with an improvement in the Hb from 7.8 to 11.5 gm/dL. Over a mean

follow-up of 30.4 months, GAVE recurred in 29.4% of patients, requiring

further therapy. In a retrospective case series, a mean of 2.6 treatment

sessions were used to treat GAVE, resulting in a loss of transfusion

dependency(Yussoff et al., 2002). Over a mean follow-up period of 20months, a 40% recurrence rate was noted, which responded to further

APC therapy.

Arteriovenous malformations (AVM) of the stomach, the small bowel,

and the colon have been successfully treated .In a case series of 25

patients, the APC was successfully used to treat AVMs, with a significant

improvement in hemoglobin values and cessation of overt bleeding

(Rochalon et al., 2000).An eight percent recurrence rate of anemia wasnoted over a 6-month follow-up period.


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The combination of 1% polidocanol and the APC has been used to

successfully ablate gastric AVMs in a patient with Osler-Weber-Rendu

disease(Kitamura et al., 2001).

Asymptomatic accumulation of submucosal argon gas at the treatment

site also has been noted (Johanns et al., 1997).

Cecal perforation has been reported by Wahab et al., (1997). The

utility of obtaining a submucosal saline solution cushion before APC

therapy to prevent deep tissue injury has been demonstrated in a porcine

model(Norton et al., 2002a).

2. Treatment of bleeding peptic ulcers and the prevention of

recurrent esophageal varices :

In a small randomized controlled trial, the APC was compared with

the heat probe in 41 patients presenting with peptic ulcer disease with

major stigmata of recent hemorrhage, including active bleeding or a non-

bleeding visible vessel (Cipolletta et al., 1998).The groups were well-matched for clinical criteria such as active

bleeding and hypotension. Both APC and heat probe were similar in

clinical outcomes such as initial hemostasis, recurrent bleeding, 30-day

mortality, and the need for emergency surgery. It must be emphasized

that a treatment difference may have been present but could not be

detected because of the small sample size (i.e. type II error).

Cipolletta et al., (2003) explored the utility of APC in the prevention of

recurrent esophageal varices after ablation with endoscopic band ligation.

In this interim analysis of an ongoing randomized controlled trial, patients

receiving APC exhibited a lower recurrence rate (0/14 APC vs. 6/16

controls). Transient fever, retrosternal pain, and dysphagia were seen in

the APC group.


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Watanabe et al., (2001) and Furukawa et al., (2002) demonstrated

that argon plasma coagulation is an effective prevention consolidation

therapy after esophageal variceal ligation (EVL) or sclerotherapy with no

serious complications.

In a larger study,Nakamura et al., (2001) randomized 60 patients to

endoscopic variceal ligation (EVL) or EVL followed by APC (50-60 W,

1.5-2.0 L/min). Patients receiving argon plasma coagulation also were

treated with sodium alginate and thrombin granules. The cumulative

recurrence-free rate of variceal formation at 24 months was significantly

higher in the EVL/APC group than in patients receiving EVL

monotherapy (74.2% vs. 49.6%). The complication profiles were

equivalent except for significantly more episodes of post-treatment fever

in the group receiving combination therapy (63.3% vs. 33.3%).

3. Radiation proctopathy

Many case series have been published on the use of APC in the

treatment of radiation-induced proctopathy (Kaassis et al., 2000 andVenkatesh et al., 2002).Power settings vary from 40 to 60 W, with gasflows from 1 to 1.5 L/ min.

The majority of patients achieved symptomatic improvement after

approximately two treatment sessions. The number of treatment sessions

has been found to significantly correlate with the extent of the

proctopathy (Tjandra et al., 2001).

Relief from transfusion dependency was seen in 34 of 35 patients

(97.1%). No prospective comparative trials of the argon plasma

coagulation with other endoscopically directed treatment modalities exist,

nor is there any experience on the role of adjuvant medical therapy such

as the use of steroids, sucralfate or 5-aminosalicylic acid enemas betweenAPC sessions. Experience from the forementioned series indicates that


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APC is a good rescue therapy in patients who have failed Nd:YAG

laser, multipolar coagulation, heat probe therapy, and endoscopic

formalin therapy (Silva et al., 1999 and Venkatesh et al., 2002).APC should not be used in an inadequately evacuated colon for fear of

explosion (Soussan et al., 2003).

Villavincencio et al., (2002) compiled the most complete complication

profile of APC in treatment of radiation-induced proctopathy. Short-term

side effects occurred in 19% of patients and included tenesmus,

abdominal distention, and anisimus. A 19% long-term complication rate

included tenesmus, diarrhea, and rectal pain, which can persist for a

median of 2.5 months after argon plasma coagulation. Anismus may be

more common in patients who undergo treatment near the dentate line

(Silva et al., 1999). Transient urinary retention also has been reported

(Venkatesh et al., 2002). More serious reported complications include

rectovaginal fistula formation (Silva et al., 1999) and rectal stricturesrequiring dilation (Tam et al., 2000). Gram negative bacteremia has beenreported in two patients with a myelodysplastic syndrome who did not

receive preprocedure antibiotics(Tam et al., 2000). Kaassis et al., (2000) found that patients who were receiving

anticoagulation therapy may require more argon plasma coagulation

sessions but can achieve an equivalent clinical response as those who are

not on anticoagulation. Recurrent proctopathy has been reported andresponds to a second round of APC therapy.

4. Dieulafoy's lesions

Dieulafoys lesion is an uncommon cause of gastrointestinal bleeding

in which significant, and often recurrent, haemorrhage occurs from a

pinpoint non-ulcerated arterial lesion, usually high in the gastric fundus.Similar lesions have also been identified in the distal esophagus, small


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38

intestine, colon, and rectum. It has been identified more frequently in

recent years because of increased awareness of the condition (Al-Mishlab

et al., 1999).

Yoshino and his colleagues (2006) and Yarze (2006) successfully

used argon plasma coagulation in the management of gastrointestinal

bleeding originating from Dieulafoy lesions.

B. Ablation

1. Barrett's esophagusControversy surrounds endoscopic ablative therapy for Barrett's

epithelium. The possibility of residual nests of metaplastic cells

underneath the layer of neosquamous epithelium remains a concern.

As in other ablative modalities, variables to be considered in the

treatment of Barrett's esophagus include:

1. Length of the Barrett's segment.2. Acid suppressive regimendosage and documentation of

success.

3. APC settings.4. Treatment pattern.5. Post-treatment surveillance.

The argon plasma coagulation wattage settings varied from 30 to 90

W. All the studies used acid suppression during the ablation interval, but

only two of them used 24-hour pH probe monitoring to document

efficacy of the treatment (Van Laethem et al., 1998, Basu et al., 2002

and Kenneth and Richard, 2006).

In a subset of 20 patients undergoing pH monitoring, Van Laethem et

al, (1998) did not find a significant difference in the eradication rates


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39

between those with documented normalization of esophageal acid

exposure. When combining the case series, complete macroscopic

clearance of Barrett's epithelium was achieved in 82.6% of the patients.

However, microscopic foci of subepithelial Barrett's epithelium were

found in up to 50% of patients who achieved macroscopic clearance.

Transient complications included fever, odynophagia, and chest pain.

The data also suggests that it is more difficult to achieve complete

ablation in longer Barrett's (Mork et al., 1998 and Van Laethem et al.,

1998). Longer length Barrett's segments also were associated with asignificantly higher rate of complications (Pereira-Lima et al., 2000).

Four of the case series reported stricture formation that occurred in

4.3% to 10% of patients (Mork et al., 1998, Schulz et al., 2000 and

Tigges et al., 2001).

The development of intramucosal adenocarcinoma arising under

neosquamous epithelium has been documented despite achieving

macroscopic and apparent microscopic clearance (Van Laethem et al.,

2001).

Basu et al., (2002) treated 50 patients with a median Barrett's segment

length of 5.9 cm. In each case, a 24-hour pH probe was used to optimize

acid suppression. Thirty-four patients exhibited macroscopic clearance of

Barrett's epithelium. However 15 of these patients exhibited nests of

Barrett's epithelium underneath the neosquamous epithelial layer. Patients

with longer Barrett's segments were more likely to have residual

metaplastic epithelium after argon plasma coagulation therapy. Those

patients who reduced their dose of a proton pump inhibitor exhibited a

significantly greater rate of Barrett's recurrence. The post-treatment use of

acid suppression may be crucial in maintaining the histologic remission

of Barrett's epithelium (Mork et al., 1998).


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Control of symptomatic reflux also may aid in the decrease in the

Barrett's surface area during APC ablation (Byrne et al., 1998).

Morino et al., (2003)performed laparoscopic Nissen fundoplication

followed by argon plasma coagulation therapy in 23 patients. A 24-hour

pH probe study 3 months after surgical intervention was used to

document normalization of acid exposure before APC treatment.

Complete macroscopic clearance was achieved in 20 (87%) patients. An

additional two patients were found to have islands of Barrett's epithelium

underneath the neosquamous epithelium. In one patient with an abnormal

postoperative 24-hour pH probe study, acid suppressive therapy with

omeprazole was used with APC therapy, resulting in complete squamous

re-epithelialization.

In a different study, 30 patients with Barrett's esophagus underwent

either a Nissen or Toupet fundoplication after APC ablation (Tigges et

al., 2001). In this series, 22 of the 30 patients had been followed for at

least 1 year. Two of 22 patients at 1 year exhibited histologically proven

short-segment Barrett's epithelium. Both of these patients had abnormal

pH and manometric studies, which suggested a failure of the

fundoplication. No subepithelial nests of metaplastic cells were identified

in the surveillance biopsy specimens.

The clinical outcomes of argon plasma coagulation in the treatment of

Barrett's esophagus with high-grade dysplasia or carcinoma in situ in

Barrett's esophagus are variable. Pereira-Lima et al., (2000) treated 14

patients with low-grade dysplasia and one with high-grade dysplasia by

using APC. After a mean follow-up of 10.6 months, there was no

microscopic recurrence of dysplastic lesions or progression to

malignancy. Another study evaluated APC treatment of high-grade

dysplasia or carcinoma in situ in 10 patients who were either not


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candidates for surgery or refused operative intervention (Van Laethem et

al., 2001).Even though there was visual evidence of complete re-

epithelialization, 50% of patients had subepithelial nests of metaplastic

tissue. One patient exhibited a persistent focus of high-grade dysplasia,

and another patient with high-grade dysplasia developed invasive

adenocarcinoma.

2. Polyps and remnant adenomatous tissue after polypectomy

Two case series describe the use of APC for ablation of intestinal

polyps as well as for ablation of residual adenomatous tissue after gastric

and colonic polypectomy (Farin et al., 1994 and Fukami et al., 2006).

The utility of APC for the eradication of postpolypectomy residual

adenomatous tissue was described in a series of 30 patients with residual

adenomatous tissue after endoscopic polypectomy, 15 had complete

eradication after one APC session and all had complete eradication after

two sessions (Zlatanic et al., 1999).

3. Management of gastrointestinal malignancies :

a. Treatment of early gastric cancer:

In recent years, there has been an increasing number of cases of early

gastric cancer (T1, NX) with intramucosal invasion, which are untreatable

by surgical or endoscopic mucosal resection (EMR) because of their high

risk.

Sagawa et al., (2003) proved that argon plasma coagulation (APC) is

an effective and safe modality for treatment of early gastric cancer with

intramucosal invasion untreatable by surgical resection or EMR. They

used an argon gas flow of 2 L. /min. at a power setting of 60 W. and a

maximum irradiation time of 15 s/ sq.cm.


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All lesions were irradiated easily, including difficult anatomical areas for

EMR such as the gastric cardia or the posterior wall of the upper gastric

body. In 26 of 27 patients (96%) there was no evidence of recurrence

during the follow up period (median 30 months).

b. Palliative debulking of obstructing G.I. malignancies

The APC has been used alone or in combination with other treatment

modalities in the palliation of esophageal, gastric, ampullary, and rectal

malignancies (Douglas and Todd, 2006).

Wahab et al., (1997) used the argon plasma coagulation in the

palliation of various obstructing G.I. malignancies. In 34 patients, APC

was used in concert with monopolar snare coagulation with or without

radiotherapy. The majority of the patients presented with malignancies of

the esophagus or gastric cardia. Savary dilation was used in some cases.

A mean of 3.5 sessions was used to achieve luminal patency of the

esophagus. The APC also was used successfully in one case of an

obstructing carcinoma of the ampulla of Vater and 7 patients with

obstructive and/or bleeding rectal carcinoma. There were no perforations

or uncontrollable hemorrhage. Repeat therapy was successfully used in

those with recurrent obstructive symptoms.

Akhtar et al., (2000) treated 18 patients with esophagogastric cancer

with obstructive symptoms or bleeding by using a 70 W. power setting

and 2 L. /min gas flow. Palliation was successful in 14 (78%) patients.

In the largest case series to date, 83 patients with malignant strictures

of the esophagus and gastric cardia were treated. In 53 patients, patency

was maintained until death, whereas 30 patients eventually required stent

placement. A perforation rate of 8% was noted (Heindorff et al., 1998).

In two case series of 20 patients with recurrent dysphagia caused by

tumor overgrowth of a previously placed endoprosthesis, the APC


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exhibited an 80% success rate in restoring luminal patency (Robertson et

al., 1996).

A transient accumulation of air in the mediastinum and/or peritoneal

cavity has been reported in the palliation of esophagogastric malignancies

(Johanns et al., 1997).

C. Miscellaneous

- Argon plasma coagulation has also been used to ablate dysplastic

heterotopic mucosa, to recanalize occluded or overgrown metal stents or

cut displaced metal stents.(Schulz et al., 2000, Demarquay et al., 2001and Sauve et al., 2001).

- Mulder et al., (1999) reported on extensive experience in treating

patients with Zenker's diverticulum endoscopically. In the hands of these

authors, the APC is a very useful effective tool for this indication (125

patients, mean number of sessions 1.8), although a number of patients

were also treated with additional endoscopic methods.- APC has also been used in skin surgery. In preliminary clinical tests,

48 patients with common warts, senile hemangiomas and actinic

keratoses were treated with APC. In all cases, APC was highly effective

and easy to perform. No severe problems or complications were

observed. The skin lesions were destroyed with minimal or no scarring

and without damaging the surrounding tissue (Brand et al., 1998).

-Tonsillectomy with the argon-plasma-coagulation-raspatorium leads

to an almost bloodfree woundground and to a reduction of operation-time.

The often associated extensive post operative pain and uncontrolled

tissue- damage, known from electrical and lasersurgical techniques, was

not found in APC-tonsillectomy patients-group (Bergler et al., 2000 and

Skinneret al., 2006).


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The tissue effect of argon plasma coagulation on

esophageal and gastric mucosa

The APC tissue effect was studied on the esophageal and gastric

samples at 40, 50, 60, 70, 80, 90, and 99 W at 90 degrees, 1 mm.

separation using pulse durations of 1 and 3 seconds. Each combination of

power and pulse duration was tested in triplicate for each type of tissue.

Each individual tissue sample was large enough for approximately 30

different pulses of argon plasma coagulation. Tissue samples were fixed

in formalin/saline, routinely embedded in paraffin sections, and stained

with H&E. Samples were coded and analyzed by the histopathologist

without knowledge of the coding. A scoring system for depth of tissue

destruction was created, with a high score indicating increased tissue

damage (gastric 0 to 5, esophageal 0 to 3, full scoring system in table 4

and table 5) (Watson et al., 2000).

Deep tissue damage that could lead to perforation was rare with argon

plasma coagulation. The depth of gastric mucosal damage increased with

increased pulse duration and increasing power settings, and although the

depth of esophageal mucosal damage was marginally related to pulse

duration, it was not related to the power setting.

Esophageal and gastric tissues were analyzed separately because a

different scoring system was used to assess tissue damage.


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Table (3) Scoring system for pathologic analysis of argon plasma

coagulation tissue effects on esophageal and gastric tissue

Esophageal tissue

0 None or minimal

1 Mucosa only

2 Damage extending to submucosa

3 Damage extending into muscularis

propria

Gastric tissue

0 None or minimal

1 Foveolar layer only

2 Damage extending to pit

3 Specialized glands affected

4 Lamina propria

5 Damage extending into muscularis

propria

The histologic effect consisted of coagulation necrosis that varied

from superficial cell damage to wedge-shaped defects. This was

associated with coagulation of the stroma in the mucosa and deeper

within the submucosa. Submucosal blood vessels did not appear to be

affected.

Effect of argon plasma coagulation on gastric tissue

Table (4) shows the probability of obtaining a particular gastric tissue

damage score for each combination of power and pulse duration.


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Table (4):Gastric tissue damage score for different combinations of

pulse duration and power (Watson et al, 2000)

Three-seconds pulseOne-second pulseTissue damage score

3/4/51/203/4/51/20

PowerSetting

(W)

0.240.490.270.670.270.0540

0.190.480.340.590.330.0850

0.140.440.410.510.390.1160

0.110.400.500.430.430.1370

0.080.340.580.350.470.1880

0.060.280.670.280.480.2490

0.040.230.720.220.480.2999

(For ease of interpretation, tissue damage scores 1 and 2 and damage

scores 3, 4, and 5 have been aggregated).

There was a significant increase in tissue damage with 3-second

compared with 1-second pulse durations (p = 0.003), and tissue damage

score also increased significantly with increases in the power setting (p =

0.031). However, only 2 of 42 gastric samples tested showed damage

extending into the muscularis propria (Watson et al., 2000).

Effect of argon plasma coagulation on esophageal tissue

The results suggested that the esophageal tissue damage score was

marginally related to pulse duration (p = 0.053) but not to the power

setting (p = 0.65). Table (5) shows the probability of obtaining a

particular esophageal damage score for 1- and 3-second pulses.

For esophageal tissue, using a 1-second pulse duration, the mean tissue

score was 0.72 (n = 21) and for 3 seconds it was 1.24 (n = 21). Only 1 of

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