Advanced Therapy in Gastroenterology and Liver Disease - part 6 pdf

Some patients with severe diarrhea may have normal absorptive function retained, and oral rehy-dration or replacement can be effective in them.. Factors that Increase the Risk of Periope

426 / Advanced Therapy in Gastroenterology and Liver Disease

this can frequently be accomplished using oral rehydration

solutions (ORSs) Some patients with severe diarrhea may

have normal absorptive function retained, and oral

rehy-dration or replacement can be effective in them Because

nutrient absorption is coupled with sodium absorption,

glu-cose or amino acids in combination with sodium can

enhance the absorption of electrolytes and water It is

impor-tant to remember that standard ORSs are primarily designed

to increase electrolyte and fluid absorption and may not reduce

stool output, and, in fact, stool output may increase The World

Health Organization’s (WHO) ORS recommendation

con-tains sodium (90 mmol/L), potassium (20 mmol/L),

chlo-ride (80 mmol/L), citrate (30 mmol/L), and glucose (111

mmol/L) This is prepared by adding 3.5 g of sodium

chlo-ride, 1.5 g of potassium chlochlo-ride, 2.9 g of trisodium citrate

dihydrate, and 20 g of glucose per liter of water Rice-based

ORSs have been shown to not only increase absorption but

also to decrease stool volume Most sport drinks, such as

Gatorade, are designed to replenish electrolytes primarily

lost from sweat and do not have enough sodium to fully

replace diarrheal sodium loss Commercial solutions

avail-able that approximate the WHO’s ORS include Resol,

Ricalyte, Ceralyte, Pedialyte, and Rehydralyte

INTRAVENOUSREPLACEMENT

In patients with severe diarrhea, such as frequently occurs

with VIPomas, with the need to adequately correct the

dehy-dration, hypokalemia, and metabolic alkalosis, the fluid and

electrolyte replacement needs to be given intravenously This

can be accomplished by using parenteral hyperalimentation

or administration of saline solutions supplemented with

potassium and sodium bicarbonate Restoration of

hydra-tion and electrolytes can best be monitored by serial

assess-ment of serum electrolytes and urine output

Pharmacologic Control of SD

A number of different agents are used to control acute and

long-term chronic diarrhea As pointed out above,

defini-tive treatment requires a correct diagnosis In this section,

the general use of pharmacologic agents in SD is dealt with,

and in the following section, specific comments on some

of the specific diseases are made Opiates and synthetic

long-acting somatostatin analogues (octreotide, lanreotide)

are the most commonly used Other agents that may be

helpful are a2-adrenergic agonists, corticosteroids,

absorbent agents, prostaglandin synthetase inhibitors,

cal-cium channel blockers, and phenothiazines The use of

each is briefly discussed below

Opiates

Opiates are usually the first-line therapy for most mild to

moderate diarrheas Commonly used preparations include

paregoric, tincture of opium, codeine, Lomotil (diphenoxylate

with atropine), Imodium (loperamide), and difenoxin with

atropine These agents inhibit transit throughout the

gas-trointestinal (GI) tract; therefore, they increase the contacttime between intestinal luminal contents and the mucosa,increasing absorption Experimentally, opiates have proab-sorptive and antisecretory effects, but it is unclear if thesemechanisms are operative in humans Synthetic opioids such

as Lomotil (2.5 mg diphenoxylate plus 25 µg atropine pertablet) and loperamide (Imodium) (2 mg/tablet) have fewercentral nervous system (CNS) side effects than morphine.The recommended doses are as follows:

1 Loperamide, 2 to 4 mg 4 times daily

2 Diphenyloxylate plus atropine, 1 to 2 tablets 4 timesdaily

3 Codeine, 30 to 60 mg 4 times daily

4 Paregoric (0.4 mg morphine/mL), 5 to 10 mL 4 times

daily

5 Tincture of opium (10 mg morphine/mL), 5 to 20

drops 4 times daily All of these drugs except loperamide are controlled substancesbecause of their potential for misuse or addiction At highdoses, Lomotil can also cause CNS side effects, whereas lop-eramide, because it does not cross the blood-brain barrier asefficiently, has fewer side effects at higher doses

The main side effects from the use of opiates are inal discomfort, constipation, nausea, vomiting, and CNSsymptoms (drowsiness, respiratory depression, and alteredmental status) Lomotil, because of the presence ofatropine, can cause anticholinergic side effects Physicaldependence can occur with prolonged use, although it isreduced with Lomotil by combining the diphenoxylatewith atropine

abdom-Long-Acting Somatostatin Analogues

Octreotide and lanreotide are synthetic analogues of statin that, because they are much more resistant to degra-

somato-dation than native somatostatin, have a much longerduration of action than native somatostatin and therefore

can be used by intermittent subcutaneous injection Like native somatostatin, these synthetic analogues suppress most intesti-

nal secretions (gastric, pancreatic, biliary, intestinal), inhibit release of most GI hormones and neurotransmitters, and can inhibit GI motility At present, only octreotide is available in

the United States Octreotide is the drug of choice for most

large-volume, severe diarrheas Numerous studies have

demonstrated its effectiveness in VIPomas and diarrhea caused by carcinoid syndrome These somatostatin analogues

inhibit both the ectopic release of hormones and transmitters by these tumors and secretion from the largeand small intestine stimulated by a number of agents(prostaglandin E1, serotonin, VIP); they also stimulatesodium chloride absorption in animal studies Because ofthese actions, somatostatin analogues have been used to treat

neuro-Secretory Diarrhea / 427

a number of secretory and nonsecretory diarrheal

condi-tions, both hormonally and nonhormonally mediated These

include, in addition to VIPomas, carcinoid syndrome,

medullary thyroid carcinomas, glucagonomas, diarrhea

asso-ciated with acquired immune deficiency syndrome (AIDS),

diarrhea owing to short bowel syndrome, diarrhea owing to

dumping syndrome, and diarrhea owing to chemotherapy or

bone marrow transplantation treatments The specific use of

octreotide in the various secretory hormonal diarrheas is

discussed in the following section on these specific diseases

Octreotide use is also discussed in the chapters on AIDS (see

Chapter 46,“Gastrointestinal and Nutritional Complications

of HIV Infection”), short bowel syndrome (see Chapter 64,

“Short Bowel Syndrome”), and stem cell transplantation (see

Chapter 48,“Gastrointestinal and Hepatic Complications of

Stem Cell Transplantation”)

OCTREOTIDETreatment with somatostatin analogues is usually lim-

ited to severe diarrheas or those refractory to other

treat-ments because of its cost and because parenteral

administration is required (Farthing, 2002) The usual

starting dose of octreotide, which is the only synthetic

analogue available in the United States, is 50 to 100 µg

2 to 4 times a day administered subcutaneously The dose

and frequency can then be titrated to control the

symp-toms Doses as high as 750 µg 3 times daily have been

used The half-life of octreotide is 100 minutes compared

with 2 to 3 minutes for native somatostatin, and

octreotide has been shown to be 70-fold more potent

than native somatostatin at inhibiting growth hormone

release and 80-fold more potent at inhibiting acid

secre-tion There have been a small number of reports of cases

in which intermittent subcutaneous administration is

not effective and a continuous infusion of octreotide is

more effective With continued treatment, octreotide

may become less effective and increased dosage is

fre-quently required (Fried, 1999)

Recently, a long-acting formulation of octreotide

(octreotide-LAR [long-acting release]) has become

avail-able This formulation is administered once per month

intramuscularly Three dosage forms are available,

includ-ing 10, 20, and 30 mg formulations We usually begin with

the 20 mg formulation in a patient in whom extended

con-trol of the SD will be required and who responds to the

subcutaneous formulation It is important to continue the

subcutaneous formulation for at least 2 weeks after

start-ing the octreotide-LAR because it takes that long to reach

appropriate blood levels with the long-acting form In

patients with carcinoid syndrome or VIPomas, even after

octreotide-LAR has been given for a number of months, it

may have to be supplemented with subcutaneous

octreotide periodically for acceptable symptom control

(Szilagyi and Shrier, 2001)

The side effects of treatment with synthetic statin analogues include cramping or nausea, which usu-ally resolve with continued treatment, and pain at thesubcutaneous injection site, which may be reduced by slowinjection and warming the vial Worsening of glucose tol-erance develops in some patients, and it is advisable toobtain a serum glucose determination when beginning themedication A small percentage of patients may develop fatmalabsorption Long term, the principal side effect is the

somato-development of biliary sludge or gallstones, thought to be

due to the ability of somatostatin to inhibit gallbladderemptying In various studies with long-term treatment, 10

to 50% of patients have developed biliary sludge or stones, but in only 1 to 10% is it symptomatic With long-term treatment, an ultrasound examination of thegallbladder before the treatment and every 6 to 12 monthsshould be considered (Redfern and Fortuner, 1995)

gall-a2 -Adrenergic Agents

CLONIDINEThese agents slow GI transit as well as promote absorption

Clonidine is the frequently used drug in this class and has

been recommended particularly for diabetic diarrhea based

on a small number of reports It also has been used to treatdiarrhea associated with short bowel syndrome, usually incombination with opiates Clonidine is usually started at0.1 mg/d and increased slowly to 0.1 to 0.3 mg 3 times aday A major limitation to the use of clonidine is its anti-hypertensive effect mediated centrally, resulting in posturalhypotension Clonidine should be reserved for patientswith SDs that are refractory to opiates When clonidine isdiscontinued, the dose should be tapered slowly over 3 to

5 days to avoid rebound symptoms (hypertension, nausea,vomiting, headache) This agent is discussed in the chap-ter on diabetic diarrhea (Chapter 71, “Management ofDiabetic Diarrhea”)

Glucocorticoids

Glucocorticoids stimulate absorption of water and trolytes and have been used in refractory patients withVIPomas The recommended dose is 60 mg of prednisoneper day If it is effective, the dosage can be decreased tothe lowest level controlling the diarrhea Glucocorticoidsare now rarely needed with the availability of the somato-statin analogues, which are effective acutely and long term

elec-in most patients with VIPomas

Prostaglandin Synthetase Inhibitors

These agents have been used in a number of SDs becauseprostaglandins stimulate water and electrolyte secretion

Indomethacin has been reported to be effective in a small

number of patients with SDs

428 / Advanced Therapy in Gastroenterology and Liver Disease

Other Agents

Absorbent agents such as psyllium husk, kaolin,

methyl-cellulose, and cholestyramine are frequently used in mild

to moderate diarrheas Cholestyramine and other binding

resins are principally used in diarrheas for which binding

bile acids may be helpful, such as after cholecystectomy

or ileal resection Some series, but not others, report that

patients with chronic diarrhea have idiopathic bile acid

mal-absorption, and cholestyramine could reduce stool weight.

It is important to remember that these agents may

inter-fere with absorption of other drugs; therefore, the timing

of their use needs to be carefully considered

Bismuth-containing compounds such as Pepto-Bismol

are used primarily for the prophylaxis and treatment of

infectious diarrheas They may have effects on toxin

pro-duction or action as well as antibacterial effects

Calcium channel blockers (verapamil) can inhibit GI

motility and have an antidiarrheal effect Hypotension may

limit their usefulness

Trifluoroperazine and chlorpromazine act to decrease

intestinal secretion by inhibiting the calcium-calmodulin

complex They have been occasionally used in patients with

VIPomas or other SDs and have been largely replaced by

somatostatin analogues

Specific Conditions

VIPomas

Almost all patients with VIPomas have large-volume

diar-rhea frequently resulting in hypokalemia and

dehydra-tion—hence the acronym WDHA syndrome (watery

diarrhea, hypokalemia, achlorhydria), which is also used

to name this syndrome in addition to Verner-Morrison

syndrome Diarrhea occurs in 100% of these patients and

is due to the net secretion of fluid and electrolytes,

pri-marily in the jejunum, caused by ectopic release of VIP by

the tumor In adults, 90% of these patients have a

pancre-atic endocrine tumor, which is usually malignant, whereas

in children and a small percentage of adults, it is due to

neural (ganglioneuroma) or adrenal tumors These patients

can have very large daily losses exceeding 400 mmol of

potassium and 700 mmol of sodium and, therefore, require

vigorous rehydration Octreotide is the agent of choice to

control the diarrhea in these patients

In addition to controlling the diarrhea and rehydration,

tumor localization studies using computed tomography

(CT) and somatostatin receptor scintigraphy to define the

location and extent of the tumor are indicated In addition

to medical treatment of the diarrhea, treatment directed

against the tumor, including surgical debulking, and

chemoembolization or chemotherapy for metastatic tumors

are recommended

Carcinoid Syndrome

In the 32 to 84% of patients with carcinoid syndrome withdiarrhea, similar to patients with medullary thyroid can-cer or thyrotoxicosis, the diarrhea is primarily caused by

increased intestinal motility and increased fluid and trolyte secretion These actions are mediated in part by sero-

elec-tonin secretion and possibly ectopic release of tachykinins (substance P, substance K, neuropeptide K), motilin, and

prostaglandins Almost all patients with carcinoid syndrome

have metastatic disease in the liver, usually from a midgutcarcinoid (75 to 87%), foregut (2 to 9%), or hindgut (1 to8%) tumor or from a carcinoid tumor of unknown loca-tion (2 to 15%) The treatment for the diarrhea is similar

to that for VIPomas with somatostatin analogues Octreotide

controls the diarrhea in > 80% of patients by decreasingrelease of serotonin (5-hydroxytryptamine [HT]) andother mediators and is reported to decrease their synthe-sis by the tumors (O’Toole et al, 2000) Other agents that

are effective are 5-HT 1 and 5-HT 2 receptor antagonists, such

as methylsergide, cyproheptadine, and ketanserin 5-HT 3

receptor antagonists (ondansetron, tropisetron, alosetron) are

now increasingly being used to control the diarrhea andalso help control the nausea and occasionally the flushing

In carcinoid syndrome caused by a foregut carcinoid tumor

of the gastric mucosa, frequently a combination of H 1 and

H 2 receptor antagonists is effective The carcinoid tumors

causing carcinoid syndrome are usually unresectablebecause of diffuse hepatic metastases, and treatment needs

to be directed against the tumor itself The primary

anti-tumor treatments are chemoembolization, use of interferon alone or in combination with somatostatin analogues, or

somatostatin analogues alone (Jensen and Doherty, 2001)

Systemic Mastocytosis

In the 23 to 43% of patients with systemic mastocytosis, thediarrhea is mild to moderate in the majority, with > 90%having a stool volume < 1 L/d In systemic mastocytosis, the

primary cause of the most troubling diarrhea is gastric

hypersecretion owing to hyperhistaminemia; therefore, it has

a pathogenesis similar to that seen in patients with

Zollinger-Ellison syndrome However, villous atrophy and

a secretory component, perhaps owing to prostaglandins, may

be important diarrheal factors in some patients with temic mastocytosis The diarrhea in these patients is usu-

sys-ally controlled by a combination of H 1 and H 2 receptor antagonists The mast cell membrane-stabilizing drug cro- molyn sodium (disodium chromoglycate) has been reported

to be useful to treat diarrhea and other GI symptoms in asmall number of patients with systemic mastocytosis Inpatients with the malignant forms of mastocytosis, treat-

ment with interferon alpha-2b, as well as chemotherapy and

corticosteroids, has been used (Jensen, 2000).

Secretory Diarrhea / 429

Surreptitious Use of Laxatives or Diuretics

Patients with a factitious cause frequently have large-volume

diarrhea (> 1 L/d) It should be remembered that this

con-dition is not infrequent, occurring in 15 to 20% of patients

referred to a referral center with chronic diarrhea The

pri-mary treatment of these patients is having a high suspicion

for the diagnosis because no clinical feature except for a

his-tory of psychiatric illness or macroscopic melanosis coli on

sigmoidoscopy assists in the diagnosis Some patients have

a medical or veterinary background Some laxatives

increased the osmotic gap in the stool (magnesium), and

its detection will help lead to the diagnosis (Phillips et al,

1995) However, with others, the osmotic gap is not

increased, and only screening for laxatives in the stool or

urine will establish the diagnosis There is a chapter on

man-aging patients with factitious or exaggerated illnesses (see

Chapter 42, “Exaggerated and Factitious Disease”)

neu-Jensen RT, Doherty GM Carcinoid tumors and the carcinoid drome In: DeVita VT Jr, Hellman S, Rosenberg SA, editors Cancer: principles and practice of oncology Philadelphia: Lippincott Williams & Wilkins; 2001 p 1813–33.

syn-O’Toole D, Ducreux M, Bommelaer G, et al Treatment of noid syndrome: a prospective crossover evaluation of lan- reotide versus octreotide in terms of efficacy, patient acceptability, and tolerance Cancer 2000;88:770–6 Phillips S, Donaldson L, Geisler K, et al Stool composition in fac- titial diarrhea Ann Intern Med 1995;123:97–100.

carci-Redfern JS, Fortuner WJ II Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management Am J Gastroenterol 1995;90:1042–52 Szilagyi A, Shrier I Systematic review: the use of somatostatin or octreotide in refractory diarrhoea Aliment Pharmacol Ther 2001;15:1889–97.

CHAPTER 73

R EDUCING C ARDIOVASCULAR R ISK WITH

M AJOR S URGERY

Similarly, patients who are asymptomatic with one or morecoronary risk factors but who do not have established CADalso have been shown to be at very low risk The excep-tion is diabetic patients; those with long standing diabetesare at particularly higher risk (Eagle et al, 2002)

Clinical predictors can be classified as major, intermediate,

or minor High risk clinical predictors include the following:

1 Unstable coronary syndromes

2 Recent MI (> 7 days but < 1 month before surgery)

3 Severe angina

4 Decompensated congestive heart failure (CHF)

5 High grade atrioventricular block

6 Symptomatic ventricular arrhythmias in the ence of underlying heart disease

pres-7 Supraventricular arrhythmias with uncontrolledventricular rate

8 Severe valvular disease

If any of these major indicators are present, tion should be given to delaying or canceling nonemergentsurgery until medical stabilization can be achieved

considera-Background

Of the 27 million people undergoing surgery in the United

States each year, approximately one-third have coronary

artery disease (CAD) or significant risk factors for

cardio-vascular disease (Mangano and Goldman, 1995; Grayburn

and Hillis, 2003) Thus it is not surprising that myocardial

events are the most common serious complication of

surgery An estimated 50,000 patients per year will have

perioperative myocardial infarctions (MI) with a

periop-erative mortality rate of approximately 20% (Fleisher and

Eagle, 2001; Sprung et al, 2000; Badner et al, 1998)

Most cases occur within the first 3 days after surgery with

atypical symptoms being the norm Another 1 million

patients annually will have perioperative cardiac

complica-tions with a concomitant $20 billion per year in hospital

and long term care costs (Fleisher and Eagle, 2001)

The purpose of preoperative cardiovascular evaluation

is more than simply “giving clearance for surgery.” The

goals are (1) to assess clinically the patient’s current

med-ical status and estimate a cardiac risk profile, (2) to

iden-tify patients who would benefit from further noninvasive

or invasive testing, (3) to make recommendations for

peri-operative management that reduces risk for cardiac

com-plications, and (4) to identify those patients who would

benefit from postoperative risk stratification and

modifi-cation (Cohn and Goldman, 2003)

American College of Cardiology/

American Heart Association Guidelines

The American College of Cardiology (ACC)/American Heart

Association (AHA) guidelines for perioperative

cardiovas-cular evaluation for noncardiac surgery were initially

pub-lished in 1996 and subsequently revised in 2002 (Eagle et al,

2002) The strategy is based on the following five factors:

1 Clinical risk predictors

2 Functional capacity of the patient

3 History of previous cardiac evaluation or treatment

4 Urgency of the surgery

5 Surgery-specific risks

Patients with no cardiac risk factors are generally at very

low risk for perioperative cardiac complications and

require no further evaluation or therapy (Eagle et al, 2002)

TABLE 73-1 Factors that Increase the Risk of Perioperative Cardiac Complications in Patients Undergoing Noncardiac Surgery and Indications for Use

of Perioperativeββ-Blocker Therapy

(especially insulin-requiring)

renal insufficiency is due to diabetes or vascular disease

to be due to CAD or heart failure

From Fleisher and Eagle, 2001.

*Data from Lee et al, 1999 and Reilly et al, 1999.

CAD = coronary artery disease; CHF = congestive heart failure; CI = confidence interval.

† Ischemic heart disease includes angina and prior myocardial infarction.

‡ High risk surgery includes intraperitoneal, intrathoracic, and supra-inguinal vascular procedures.

§ Poor functional status is defined as the inability to walk four blocks or climb two flights of stairs.

Reducing Cardiovascular Risk with Major Surgery / 431

The patient’s functional status prior to surgery has been

shown to be a strong predictor of perioperative risk

Functional status can be expressed in metabolic equivalent

(MET) levels Both perioperative and long term risks are

significantly increased in those patients who are unable

to achieve a 4-MET demand during most normal daily

activities (Reilly et al, 1999; Older et al, 1999; Bartels et al,

1997) As a comparison, 4-METs is approximated by

climb-ing 1 flight of stairs carryclimb-ing a bag of groceries or walkclimb-ing

on level ground at 3 to 4 mph (Cohn and Goldman, 2003)

Surgery-specific risk, grouped into high, intermediate,

or minor risk procedures, is defined by the type of surgery

and the associated hemodynamic stress High risk

proce-dures, associated with a cardiac risk of > 5%, include

emer-gent major operations, particularly in the elderly, and

prolonged operations associated with large fluid shifts

and/or blood loss Intermediate risk procedures with a

car-diac complication rate of 1 to 5% include most routine

intraperitoneal and intrathoracic operations Low risk

surgeries include endoscopic procedures and superficial

procedures; these are associated with a cardiac risk < 1%

Step-Wise Approach to Risk Stratification

Step 1: How urgent is the surgery? If surgery is deemed

emergent, then the patient should proceed to the

oper-ating room without further assessment

Step 2: Has the patient undergone coronary

revasculariza-tion (coronary artery bypass grafting or percutaneous

coronary intervention) within the past 5 years? If so,

and the patient is without recurrent signs or symptoms,

the patient can also proceed to the operating room

directly without further cardiac testing

Step 3: Has the patient had a coronary evaluation (cardiac

stress test or coronary angiogram) in the past 2 years?

If a sufficient evaluation with favorable results was

per-formed within the past 2 years and the patient has not

experienced a change or new cardiac symptoms, then

no further testing is necessary

Step 4: Does the patient have an unstable coronary

syn-drome or high risk features? In the setting of

non-emergent surgery, any of the major clinical predictors

reviewed above usually leads to cancellation or delay

of surgery until correction and treatment of the

prob-lem

Step 5: Does the patient have intermediate predictors of

risk? Intermediate clinical predictors include mild

angina pectoris, history of remote MI (> 1 month

before surgery), compensated or prior CHF, renal

insufficiency (as defined by a serum creatinine

≥2.0 mg/dL), and diabetes mellitus The presence of

an intermediate clinical predictor, in addition to either

a high risk surgery or low patient functional capacity,

would warrant noninvasive testing for further risk

stratification prior to surgery

Step 6: Patients with intermediate predictors of risk andmoderate to excellent functional capacity can gener-ally undergo intermediate-risk surgery with low like-lihood of perioperative death or MI On the otherhand, further cardiac testing is often necessary inpatients with low functional capacity or those under-going high risk procedures

Step 7: Noncardiac surgery is generally safe for patientswith low risk predictors (ie, advanced age, abnormalelectrocardiogram [eg, left ventricular hypertrophy(LVH), left bundle branch block (LBBB), or ST-Tchanges], rhythm other than sinus [eg, atrial fibrilla-tion], history of stroke, or uncontrolled systemichypertension) with moderate to high functional capac-ity (≥4 METs)

Step 8: The results of noninvasive testing can be used todetermine the need for additional evaluation and treat-ment In some patients with documented CAD, the risk

of PCI or CABG may even exceed the risk of the posed noncardiac surgery This approach may beappropriate, however, if it increases the long term prog-nosis of the patient

pro-Noninvasive Testing

Although a careful history and physical examination arethe most crucial component of any preoperative evalua-tion, exercise or pharmacologic stress testing can con-tribute significantly to a patient’s risk stratification prior

to surgery

Exercise ECG Stress Testing

Exercise stress testing with or without imaging remains thetest of first choice in those patients who can exercise It pro-vides a functional estimate of the patient’s overall car-diopulmonary system and yields helpful prognosticinformation The main limitation of ECG exercise testing

is that only about half of the patients tested achieve peakexercise heart rates > 75% of the age-predicted maximum(Cohn and Goldman, 2003) Ischemia induced by low levelexercise identifies a subset of patients at particularly highrisk However, a negative test in a patient who achieves thetarget blood pressure–heart rate product ratio predicts alow risk for perioperative complications

Pharmacologic Stress Testing

Pharmacologic stress testing with imaging, primarily tamine stress echocardiography (DSE) and dipyridamole/exercise thallium, are excellent predictors of cardiac risk.Numerous studies have demonstrated a high negative pre-dictive value (93 to 100%) of both thallium and DSE Thepositive predictive value for thallium (4 to 67%) and DSE(7 to 23%) are much lower The choice of the optimal test

dobu-432 / Advanced Therapy in Gastroenterology and Liver Disease

in the patient who cannot exercise depends on institutional

expertise and physician comfort in interpreting results

Specific Preoperative Cardiovascular

Conditions

Hypertension

Despite earlier concerns, it is now abundantly clear that

stable and reasonably well-controlled hypertension, and

the drugs used to maintain this control, should not present

an important risk for patients undergoing surgery

Antihypertensive medications should not be discontinued,

tapered, or omitted prior to surgery because of concern

over interaction with anesthetic agents Stage 3

hyperten-sion (systolic blood pressure ≥ to 180 mm Hg and

dias-tolic blood pressure ≥100 mm Hg) should be controlled

before surgery (Eagle et al, 2002) Most patients can be

ade-quately controlled by titrating antihypertensives over days

to weeks in the outpatient setting.β-Blockers are a

par-ticularly attractive choice given their perioperative

protec-tive effects (as will be discussed later) We strongly

recommend preoperative antihypertensive medications be

continued throughout the perioperative period to prevent

a hypertensive crisis

Valvular Heart Disease

The major complication one faces in dealing with patients

with significant valvular heart disease is the potential for

CHF The indications for evaluation and treatment of

valvular heart disease are identical to those in the

nonpre-operative setting Symptomatic stenotic lesions are

associ-ated with substantial risk of perioperative heart failure or

shock and often require percutaneous valvulotomy or valve

replacement prior to surgery (Reyes et al, 1994; Raymer

and Yung, 1998; Torsher et al, 1998) In contrast,

sympto-matic regurgitant lesions are better tolerated

periopera-tively and may be stabilized with intensive medical therapy

and monitoring An exception occurs when severe

regur-gitation exists with reduced ventricular function in which

myocardial reserve is so limited that destabilization

dur-ing perioperative stresses is likely In such cases,

consider-ation should be given to valve repair prior to nonemergent

noncardiac surgery

Two other problems should be mentioned that are

nearly unique to the patient with valvular heart disease

First is the potential risk of endocarditis, which is

partic-ularly important in patients with prosthetic heart valves

Antibiotic prophylaxis should be given prior to any surgery

with even the slightest risk of bacteremia The second area

of specific concern is the management of anticoagulation

therapy This applies primarily to patients with

mechani-cal prosthetic valves Thomboembolic complications are

an inescapable hazard of artificial heart valves, even when

anticoagulation is rigorously monitored and controlled.The potential is substantially greater when normal clottingstatus is maintained for more than 5 to 7 days Fortunately,the risk is relatively low if this time range is respected.The simplest strategy for managing warfarin in the face

of upcoming surgery is to discontinue the drug 2 or 3 dayspreoperatively, then restart it the second or third postop-erative day, assuming the risk of surgical bleeding has sub-sided (Tinker and Tarhan, 1978) A more conservativeapproach from the standpoint of preventing prostheticvalve thromboembolic complications is to give heparin orlow molecular weight heparin up to 6 hours preoperatively,and then again beginning 18 to 24 hours postoperativelyuntil warfarin levels are therapeutic (Katholi et al, 1978).The latter approach may be preferable in patients withmechanical mitral valves, which are at higher risk for clot-ting than valves in the aortic position

Cardiac Arrhythmias

One of the most frequent reasons for preoperative ology consultation is the discovery of an arrhythmia onroutine ECG or the detection of some pulse irregularity onexamination This should prompt a careful search forunderlying cardiopulmonary disease, drug toxicity, ormetabolic abnormality (Eagle et al, 2002) In the majority

cardi-of patients, these abnormalities are either intrinsicallybenign or are a marker of a correctable problem such asdiuretic-induced hypokalemia or a relative excess of anantiarrhythmic agent (eg, digoxin) Therapy is indicatedfor symptomatic or hemodynamically significant arrhyth-mias (Eagle et al, 2002) Patients already on chronic oralantiarrhythmics should be maintained on their usualdosages that give standardized therapeutic blood levels up

to the time of surgery and then have them reinstituted aspromptly as possible postoperatively

Several studies have demonstrated that frequent mature ventricular contractions or nonsustained ventric-ular tachycardia do not increase the risk for nonfatal MI orcardiac death in the perioperative period; therefore, aggres-sive monitoring or treatment is not recommended (O’Kelly

pre-et al, 1992; Mahla pre-et al, 1998; Eagle pre-et al, 2002) In the spre-et-ting of a patient with an implantable cardiac defibrillator,the device should be programmed off immediately beforesurgery and reprogrammed on postoperatively (Eagle et

a randomized controlled trial of atenolol versus placebo in

Reducing Cardiovascular Risk with Major Surgery / 433

200 patients with or at risk for CAD undergoing

noncar-diac surgery and followed them for 2 years They found

that, although there was no difference in perioperative MI

or death during initial hospitalization, ischemic episodes

were significantly lower in the atenolol group (24% vs

39%) In addition, mortality at 2 years was 10% in the

atenolol group versus 21% in controls (p = 019) The

prin-cipal effect of atenolol was a decrease in mortality during

the first 6 to 8 months Of note, there was no difference in

β-blocker use between groups over the follow-up period

(approximately 15% in each treatment group)

Poldermans and colleagues (1999) randomized 173

patients undergoing major vascular surgery who had

pos-itive DSE on preoperative testing to bisoprolol versus

stan-dard care Patients were excluded if (1) they had extensive

wall motion abnormalities at rest or with dobutamine or

(2) they were already on β-blocker therapy Patients in the

treatment group received bisoprolol for at least 1 week

pre-operatively (mean 37 days) and were continued on

biso-prolol for 30 days The primary endpoints of cardiac death

and nonfatal MI occurred in only 3.4% of patients in the

bisoprolol group versus 34% in the standard care group

(p < 001) The majority of events occurred during the first

7 days after surgery The study was subsequently extended

to follow long term outcomes in 101 of 112 surviving

patients remaining on bisoprolol compared with those

receiving standard care (Poldermans et al, 2001) During a

median follow-up period of 22 months, the bisoprolol

group had a markedly decreased risk of MI and cardiac

death versus standard care group (12% vs 32%)

Current recommendations suggest starting oral

β-blocker therapy days to weeks before elective surgery and

continuing for a week to a month postoperatively (Eagle

et al, 2002) The dose should be titrated to achieve a

rest-ing heart rate of 50 to 60 bpm There may even be benefit

to starting therapy intraoperatively if it has not been

ini-tiated beforehand; evidence comes from a small study

showing a decreased incidence and duration of ischemic

events with intraoperative esmolol followed by

postoper-ative metoprolol in patients undergoing total knee

artho-plasty (Urban et al, 2000)

αα-2 Agonist

Several trials have evaluated the use of clonidine in

reduc-ing cardiac event rates in subsets of patients with known

CAD undergoing vascular surgery Clonidine has been

shown to decrease the incidence of ischemia in a study of

297 patients undergoing vascular surgery (24% vs 39%)

(Stuhmeier et al, 1996) In the European Mivazerol Trial

(EMIT), mivazerol, an α-2 agonist not currently available

in the United States, was studied perioperatively in 2,854

patients with known CAD or significant CAD risk factors

undergoing noncardiac surgery (Oliver et al, 1999) No

effect was found on the rate of perioperative MI; however,

a statistically significant reduced rate of cardiac death wasseen in patients undergoing both general and vascularsurgery

Overall, perioperative clonidine may have a similar effect

on myocardial ischemia, infarction, and cardiac death as operative β-blockers, but further research is needed beforeits role in perioperative management can be fully elucidated

peri-Summary

In summary, preoperative risk stratification should beundertaken with consideration of the patient’s clinicalmarkers, functional status, and surgery-specific risks.Cardiac stress tests are helpful in predicting risk but there

is no clear-cut evidence they improve perioperative care.Current guidelines suggest their use in patients undergoingnonemergent surgery with two of the following three fea-tures: (1) intermediate risk profile, (2) low functional capac-ity, or (3) high risk surgery The indications for coronaryrevascularization are the same as in the nonpreoperativesetting Lastly, perioperative β-blockers should be used inall patients with intermediate or high risk of cardiac com-plications in whom they are not absolutely contraindicated

Supplemental ReadingBadner NH, Knill RL, Brown JE, et al Myocardial infarction after noncardiac surgery Anesthesiology 1998; 88:572–8.

Bartels C, Bechtel JF, Hossmann V, Horsch S Cardiac risk stratification for high-risk vascular surgery Circulation 1997;95:2473–5 Cohn SL, Goldman L Preoperative risk evaluation and perioperative management of patients with coronary artery disease Med Clin North Am 2003;87:111–36.

Eagle KA, Berger PB, Calkins H, et al ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery—Executive Summary A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Circulation 2002;12;105:1257–67 Fleisher LA, Eagle KA Lowering cardiac risk in noncardiac surgery N Engl J Med 2001;345:1677–82.

Grayburn P, Hillis LD Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy.Ann Intern Med 2003 Mar 18;138:506–11 Katholi RE, Nolan SP, McGuire LB The management of anticoagulation during noncardiac operations in patients with prosthetic heart disease A prosthetic study Am Heart J 1978; 96:163–5.

Lee TH, Marcantonio ER, Mangione CM, et al Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery Circulation 1999 Sep 7;100:1043–9.

Mahla E, Rotman B, Rehak P, et al Perioperative ventricular dysrhythmias in patients with structural heart disease undergoing noncardiac surgery Anesth Analg 1998;86:16–21.

434 / Advanced Therapy in Gastroenterology and Liver Disease

Mangano DT, Goldman L Preoperative assessment of patients with

known or suspected coronary disease N Engl J Med 1995;

333:1750–6.

O’Kelly B, Browner WS, Massie B, et al Ventricular arrhythmias in

patients undergoing noncardiac surgery The Study of

Perioperative Ischemia Research Group JAMA 1992;268:217–21.

Older P, Hall A, Hader R Cardiopulmonary exercise testing as a

screening test for perioperative management of major surgery

in the elderly Chest 1999;116:355–62.

Oliver MF, Goldman L, Julian DG, Holme I Effect of mivazerol

on perioperative cardiac complications during non-cardiac

surgery in patients with coronary heart disease: the European

Mivazerol Trial (EMIT) Anesthesiology 1999;91:951–61.

Poldermans D, Boersma E, Bax JJ, et al The effect of bisoprolol on

perioperative mortality and myocardial infarction in high-risk

patients undergoing vascular surgery Dutch Echocardiographic

Cardiac Risk Evaluation Applying Stress Echocardiography

Study Group N Engl J Med 1999;34124:1789–94.

Poldermans D, Boersma E, Bax JJ, et al Dutch Echocardiographic

Cardiac Risk Evaluation Applying Stress Echocardiography

Study Group Bisoprolol reduces cardiac death and myocardial

infarction in high-risk patients as long as 2 years after successful

major vascular surgery Eur Heart J 2001;22:1353–8.

Raymer K,Yang H Patients with aortic stenosis: cardiac complications

in non-cardiac surgery Can J Anaesth 1998;45:855–9.

Reilly DF, McNeely MJ, Doerner D, et al Self-reported exercise tolerance and the risk of serious perioperative complications Arch Intern Med 1999;159:2185–92.

Reyes VP, Raju BS, Wynne J, et al Percutaneous balloon valvuloplasty compared with open surgical commissurotomy for mitral stenosis N Engl J Med 1994;331:961–7.

Sprung J, Abdelmalak B, Gottlieb A, et al Analysis of risk factors for myocardial infarction and cardiac mortality after major vascular surgery Anesthesiology 2000 Jul;93(1):129–40 Stuhmeier KD, Mainzer B, Cierpka J, et al Small, oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery Anesthesiology 1996;85:706–12.

Torsher LC, Shub C, Rettke SR, Brown DL Risk of patients with severe aortic stenosis undergoing noncardiac surgery Am J Cardiol 1998;81:448–52.

Tinker JH, Tarhan S Discontinuing anticoagulant therapy in surgical patients with cardiac valve prosthesis Observation in

180 operations JAMA 1978;239:738–9.

Urban MK, Markowitz SM, Gordon MA, et al Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia Anesth Analg 2000;90:1257–61.

CHAPTER 74

A CUTE A PPENDICITIS

DORRYSEGEV, MD,ANDPAULCOLOMBANI, MD, FACS

On physical examination, there is usually focal ness and localized peritoneal irritation in the right lowerquadrant of the abdomen, over the appendix Although theappendix is classically located at McBurney’s point (two-thirds the distance from the umbilicus to the right anteriorsuperior iliac spine), anatomic variations are common andinclude retrocecal, intrapelvic, left lower quadrant, or rightupper quadrant positions

tender-A number of clinical signs can be used to discern ized peritonitis Tenderness to percussion over the appen-dix is more sensitive, more specific, and certainly more kind

local-to the patient being examined than rebound tenderness.The unsolicited complaint of pain in the right lower quad-rant with maneuvers such as palpation of the left lowerquadrant (Rovsing sign), cough (Dunphy sign), internalrotation of the flexed right thigh (obturator sign), or exten-sion of the right hip (iliopsoas sign) all indicate an inflam-matory process in the right lower quadrant

Laboratory values can be notoriously misleading, butthe classic patient has a mild leukocytosis with a left shift

of neutrophils to immature forms Urinalysis should benegative, although pyuria without bacteria can occur in thesetting of appendicitis from periureteral inflammation

Differential Diagnosis

The diagnosis can be even more difficult in a number of

clinical settings Patients who are immunocompromised,

through diseases or medications, and patients at both

extremes of age commonly have atypical histories and

phys-ical findings Radiographic studies can be helpful in these

patients Gynecological conditions can be distracting in

female patients A pelvic examination, if not a pelvic sound, is always warranted in this population Young

ultra-patients with conditions such as otitis media, streptococcal

pharyngitis, meningitis, and mesenteric lymphadenitis may

have abdominal complaints which can masquerade asappendicitis Inflammatory bowel disease should always beconsidered in a patient with right lower quadrant abdom-inal pain A final important consideration is the differen-

tial diagnosis of typhlitis, or neutropenic enterocolitis, in

neutropenic patients undergoing chemotherapy for logic conditions

onco-Acute appendicitis continues to be one of the most

com-mon causes of abdominal pain in both the adult and

pedi-atric populations, with a lifetime risk of about 6% It is

the most common surgical emergency in the child The

etiology of appendicitis varies from lymphoid

hyperpla-sia in children and teenagers to appendicolith or tumor

in adults, but the common pathophysiology is thought to

consist of appendiceal outlet obstruction leading to

inflammation, venous congestion followed by ischemia,

and necrosis The natural history includes either

local-ized perforation, in the form of phlegmon or abscess, or

free perforation with peritonitis Diagnosis remains a

clinical one and treatment remains surgical, but the roles

of computed tomography (CT), percutaneous drainage,

interval appendectomy, and minimally invasive surgery

are evolving

Diagnosis

Even in the era of inexpensive and easily accessible

radi-ography, acute appendicitis is a clinical diagnosis that can

often be difficult and is made with the goal of minimizing

negative appendectomies but avoiding perforation It is a rare

patient that embodies the textbook presentation of this

dis-ease, but a combination of historical features, physical

find-ings, laboratory values, and occasionally radiography,

should reliably lead to a diagnosis and appropriate

treat-ment

Classic Patient

The classic patient with appendicitis complains of

peri-umbilical pain 1 or 2 days prior to presentation that has

subsequently migrated to the right lower quadrant The

patient has a low grade fever The patient may have one

or two episodes of vomiting, which are self-limiting, and

is usually anorexic Diarrhea, persistent vomiting, or a

patient requesting food or drink would be unusual A

clin-ical course exceeding 2 or 3 days would also be unusual A

protracted course beyond 72 hours may indicate that the

appendix has perforated, with the patient initially feeling

better, and then worsening systemically as a phlegmon or

abscess was being formed

436 / Advanced Therapy in Gastroenterology and Liver Disease

Preoperative Management

Figure 74-1 outlines a management strategy for patients

suspected to have appendicitis Early fluid resuscitation is

essential, as patients with any intra-abdominal

inflamma-tory process will more than likely present in a dehydrated

state The mainstay of management planning is the level of

clinical suspicion for appendicits, which we have divided

into three categories requiring continued management

Any patient with a 1 or 2-day textbook presentation of

appendicitis as outlined above and no other distracting

conditions should have an appendectomy Perioperative

care should depend on the presence of peritonitis, with

broad spectrum antibiotics and bowel rest reserved for these

patients Acute appendicitis with peritonitis, even after

treatment, can lead to significant morbidity and possible

mortality in an elderly or debilitated patient

The most difficult decisions arise in the patient with

high suspicion for appendicitis but an atypical

presenta-tion, lack of classic physical findings, potential for

gyne-cological etiology, or confounding medical conditions

Common masqueraders to consider include perforated

cecal or appendiceal tumors in the elderly, typhlitis in

neu-tropenic patients, and pelvic inflammatory disease and

mit-telschmerz in females It is for these patients that CT scan

or ultrasonography should be considered, and transvaginal

pelvic ultrasound can also be helpful in ruling out

tubo-ovarian disease The combination of a worrisome CT scanand this level of clinical suspicion would support surgicalmanagement, with other patients followed carefully by ser-ial examinations as below

Patients with some evidence of a right lower quadrantintra-abdominal process but little to implicate the appendix

as a source should be admitted for serial observation andrehydration There is no role for antibiotics in this scenariounless another source of infection has been documented.Most of these patients will improve in 1 to 2 days and can

be discharged with precautions to return if symptoms shouldrecur Serious consideration should be given to operativeintervention in a patient who remains undiagnosed butworsens clinically with conservative management

Abdominal Pain Suspicious for Appendicitis Careful History and Physical Examination, Basic Laboratory Tests

Very high likelihood of

Suspicion increases

Suspicion decreases

Does not improve

Improves

Late presentation after 7 days Consider:

CT scan (elderly, atypical) Ultrasound (child, female) Laparoscopy (female)

Abcess:

Percutaneous drainage Interval appendectomy

or Antibiotics Interval appendectomy

or Appendectomy

Peritonitis:

Perioperative resuscitation

Full course of antibiotics

Postoperative bowel rest

No peritonitis:

Immediate surgery Perioperative antibiotics Early refeeding

No abcess: Appendectomy

CT scan Observation

Discharge Appendectomy

FIGURE 74-1 Management strategy for patients with suspected appendicitis CT = computed tomography.

Acute Appendicitis / 437

Special Considerations

During pregnancy, the gravid uterus displaces the

appen-dix superiorly and sometimes laterally as early as the

sec-ond trimester The diagnosis can be more difficult, and the

ensuing morbidity more serious if the diagnosis is missed

The fetal morbidity rate is as high as 10% for acute

appen-dicitis and 30% when perforated, whereas morbidity to

mother and fetus from negative appendectomy are

mini-mal As a result, there is little role for nonoperative

man-agement when the diagnosis of acute appendicits is

suspected during pregnancy

In the past, incidental appendectomy was a common

maneuver during other surgical procedures There is

increased morbidity with an incidental appendectomy and

currently indications for such are rare and occur mainly

when appendiceal pathology is incidentally discovered

When the 3-day window of the acute presentation of

appendicitis has passed before the patient seeks medical

attention, there should be a higher index of suspicion for

peri-appendiceal phlegmon or abscess Patients may present

with fevers and leukocytosis higher than the usual low

grade nature of acute appendicitis, or be afebrile with an

unimpressive examination despite a perforation and

col-lection walled off from the peritoneum CT scan plays an

important role in the workup of these patients and their

subsequent management Nonoperative management of

patients presenting after 7 days of symptoms may be safer

with less morbidity than appendectomy

A peri-appendiceal collection in a patient who is afebrile

and nonperitonitic can be initially treated with antibiotics

and observation A collection in a symptomatic patient with

an impressive examination warrants at least CT guided

per-cutaneous drainage Failure to resolve symptoms in a patient

in these more conservative manners or clinical

deteriora-tion with the development of high fevers and peritonitis

are indications for open drainage and appendectomy A

patient treated successfully with antibiotics or

percuta-neous drainage for ruptured appendicitis should undergo

an interval appendectomy 6 weeks later.

Operative Management

The definitive therapy for appendicitis is surgical

appendec-tomy This can be performed either in the classic open

man-ner using a right lower quadrant incision or laparoscopically

using typically three small port incisions The choice of

sur-gical approach depends on a number of factors, including

operator experience, need for abdominal exploration beyond

the right lower quadrant, likelihood of necrosis at the base of

the appendix, and size of patient and abdominal wall On

occasion a third option, exploration and appendectomy

through a midline incision, should be considered in elderly

patients where the diagnosis of an intra-abdominal process

may be certain but involvement of the appendix is unclear

Although the incisions for open appendectomy vary,the general principle is a small incision over McBurney’spoint or the area of maximal tenderness, in the direction

of Langer’s lines of skin tension The incision is carriedthrough the subcutaneous tissues and external obliqueaponeurosis sharply or using electrocautery, and sequen-tial layers of internal oblique and transverses abdominis

muscles are split in the direction of the fibers This is known

as a muscle splitting approach, and the length of the

inci-sion depends primarily on the size of the patient and theabdominal wall The laparoscopic approach consists of aninfraumbilical camera port and at least two additionaloperative ports The use of laparoscopy varies according tosurgeon preferences but relative indications include obesepatients who would otherwise require a large incision andfemale patients where exploration of the pelvis is necessarybased on typical clinical presentation

Once the abdominal cavity is entered, the appendix isidentified, mobilized, and freed from the adhesions likelyformed by the inflammatory process The mesoappendix

is ligated and the appendix is excised at its base Purse stringinversion of the appendiceal stump is unnecessary unlessthe base of the appendix is necrotic Abdominal drains ingeneral are not indicated

When appendectomy is attempted and a normal ing appendix is encountered, the abdomen is explored forthe following pathologic processes, depending on patienttype and presentation, including the following:

appear-1 Terminal ileum to evaluate for inflammatory bowel

disease

2 Distal 2 feet (60 cm) of small bowel in search of a

Meckel’s diverticulum

3 Sigmoid colon to exclude diverticulitis

4 Right upper quadrant to evaluate for cholecystitis or

duodenal perforation

5 Female adnexa to evaluate for tubo-ovarian pathology

One of the advantages of laparoscopic appendectomy isthe relative ease with which the remainder of the abdomencan be explored If no clear cause for the patient’s symptomscan be identified, an appendectomy is performed because anormal appearing appendix can later demonstrate histologicevidence of acute or chronic inflammation

Postoperative Care

Patients with simple acute appendicitis can be treated with

one to two doses of perioperative antibiotics and oral intake

can begin on the first or second postoperative day In the

setting of peritonitis or perforation, a 5-day course of broad

spectrum antibiotics should be used, and initiation of oralintake should wait until bowel function begins to return.Ileus is not uncommon after perforated appendicitis anddiet should be advanced slowly

Complications following appendectomy include wound

infection, appendiceal stump leak, and peri-appendiceal

abscess or fluid collection, with a much higher incidence of

these in the setting of perforation and peritonitis Because

these problems usually occur once the patient has left the

hos-pital, it is critical to educate patients and families regarding

the signs and symptoms of these complications and to return

for follow up after discharge In patients having

appendec-tomy for perforated appendicitis and abscess, follow-up

should include rectal exam to rule out recurrent abscess

Patients managed nonoperatively by antibiotics and

percu-taneous drainage of peri-appendiceal abscess should undergo

interval appendectomy 6 weeks from the drainage procedure

because of the high incidence of recurrent appendicitis

Supplemental ReadingEmil S, Laberge JM, Mikhail P, et al Appendicitis in children: a ten-year update of therapeutic recommendations J Pediatr Surg 2003;38:236–42.

Jones PF Suspected acute appendicitis: trends in management over 30 years Br J Surg 2001;88:1570–7.

Paulson EK, Kalady MF, Pappas TN Suspected appendicitis.

N Engl J Med 2003;348:236–42.

Stephen AE, Segev DL, Ryan DP, et al The diagnosis of acute appendicits in a pediatric population J Pediatr Surg 2003;38:367–71.

438 / Advanced Therapy in Gastroenterology and Liver Disease

CHAPTER 75

C ONSTIPATION

initiating evacuation, or a feeling of incomplete tion Physicians should therefore not rely only on the cri-teria of defecation frequency when examining patients andmanaging constipation

evacua-It is important to identify treatable causes of tion, which include many diseases and the side effects ofmany drugs If these are absent, functional constipationshould be considered

constipa-The initial management of chronic constipationincludes educating the patient and correcting any mis-conceptions as to the wide range of normal bowel habits.Broad treatment principles include increasing fluid andfiber intake, and reducing excessive or incorrect use of lax-atives and cathartics Taking advantage of normal post-prandial increases in colonic motility, patients shouldattempt to defecate after meals, particularly in the morn-ing when colonic motor activity is highest Most patientswill respond to these measures together with the judicioususe of laxatives A summary of available laxatives is shown

in Table 75-1 followed by the approximate costs of thecommon laxatives summarized in Table 75-2

Constipation is one of the most common digestive

com-plaints in the general population Over 2.5 million people

consult a physician and hundreds of millions of dollars are

spent on laxatives each year Although constipation is often

defined as a frequency of defecation twice weekly or less,

constipated patients may complain of excessive straining

with defecation, passage of hard or small stools, difficulty

TABLE 75-1 Laxatives Used in the Treatment of

Enemas

bid = twice daily; qd = every day; tid = 3 times daily; tbsp = tablespoon.

*In each category, laxatives are listed with the most preferred at the top and least preferred at

Stimulant laxatives

Prokinetic agents

bid = twice daily; tid = 3 times daily; qd = every day.

440 / Advanced Therapy in Gastroenterology and Liver Disease

Agents Used in the

Management of Constipation

Bulk-Forming Laxatives

Dietary fiber and bulk laxatives with adequate fluid intake

are the most physiologic and safest of medical therapies

However, they may be counterproductive in patients with

idiopathic slow transit constipation or with constipation

associated with irritable bowel syndrome (IBS) because

they often worsen bloating and abdominal distension in

these populations

DIETARYFIBERDietary fiber in cereals contain cell walls that resist diges-

tion and retain water within their cellular structures,

whereas those found in citrus fruits and legumes stimulate

the growth of colonic flora and increase fecal mass Wheat

bran is the most effective fiber laxative with a clear dose

response on fecal output Patients with poor dietary habits

may add 2 to 4 tablespoons of bran to each meal, followed

by a glass of water or another beverage A laxative effect

may not be observed for 3 to 5 days Patients should be

cautioned that large amounts of bran can cause

abdomi-nal bloating or flatulence; therefore, they should start with

small amounts and titrate slowly to the desired effect

Psyllium (Metamucil), calcium polycarbophil (Fiber-Con),

and methylcellulose (Citrucel) are natural or synthetic

poly-saccharides or cellulose derivatives, which primarily exert

their effects by water retention and increasing fecal mass,

thus decreasing colonic transit time They should be well

diluted to ensure adequate mixing with food and may be

consumed before meals or at bedtime They are more refined

and concentrated than bran but are more expensive

Osmotic Laxatives

These agents include magnesium salts, sorbitol, lactulose,

and polyethylene glycol (PEG) solutions They may be used

in patients who do not tolerate or respond poorly to fiber

The decision to use a particular laxative is often determined

by individual preference, costs, and underlying medical

conditions

Sorbitol and lactulose are poorly absorbed sugars that

are hydrolyzed to acidic metabolites by coliform bacteria,

which stimulate fluid accumulation in the colon and

usu-ally produce soft, well-formed stools As sorbitol is less

expensive and as effective as lactulose, we prefer sorbitol as

the low cost choice Major side effects of these agents are

abdominal bloating and flatulence.

Magnesium salts, such as magnesium sulfate or citrate, are

an alternative to poorly absorbed sugars However, they should

be used with caution in patients with renal insufficiency

PEG solutions, with or without electrolytes, have been

used to treat chronic constipation A powdered form that

does not contain electrolytes (MiraLax) is more palatable

and may be mixed with any fluid The amount taken daily

is adjusted based on clinical response As colonic bacteria

do not hydrolyze PEG, abdominal bloating or flatulenceare not as problematic as with fiber or poorly absorbed sug-ars This agent is costly and, as with lactulose and sorbitol,available by prescription only

Stool Softeners

Docusates (Colace, Surfak) work by lowering the surface

tension of stool and allowing water to move easily into the

fecal mass These agents have marginal value in treating

chronic constipation

Mineral oil also softens stool as a result of its emollient

effect It is particularly effective in enemas to soften hardimpactions However, aspiration with lipoid pneumonia is

a major hazard associated with oral administration, especially

in patients with impaired swallowing or severe reflux disease

Therefore we limit its use to rectal instillation in our practice.

Stimulant Laxatives

Stimulant laxatives, such as anthraquinone compounds,diphenylmethane derivatives and may be considered inpatients who fail to respond to or are intolerant of bulk

or osmotic agents These agents alter intestinal electrolytetransport and increase intestinal motor activity They may

be used intermittently or chronically when patients fail torespond adequately to bulk or osmotic laxatives Somephysicians recommend that they be taken for no longerthan several weeks However, there is no convincing evi-dence that chronic use of stimulant laxatives causes dam-age to enteric nerves or intestinal smooth muscles nor arethey associated with colorectal or other cancers Stimulantlaxatives often cause superficial damage to surface epithe-lial cells, but this is of no functional significance and isreversible when laxatives are discontinued A reasonableregimen is to use stimulant laxatives when no spontaneousbowel movement occurs after 48 or 72 hours They may beused alone or combined with bulk or osmotic laxatives.Major side effects occur only with excessive and prolongedabuse, usually by emotionally disturbed or misguided indi-viduals

The anthraquinone-containing laxatives (ie, senna,

cas-cara sagrada) are widely used Senna is best administered

at bedtime with fluids 2 to 3 times weekly if no defecation occurs spontaneously Cascara also produces a soft or

formed stool with little or no colic Most

anthraquinone-containing laxatives discolor the colonic mucosa (melanosis

coli) if used chronically The pale-brown to jet-black

dis-coloration of melanosis coli occurs throughout the colonand is more prominent in the proximal colon Withdrawal

of laxatives is normally accompanied by resolution of mentation after many months

pig-Constipation / 441

Bisacodyl is the only diphenylmethane laxative available

since the removal of phenolphthalein from the market

because of a possible relationship to cancer in animal

stud-ies The onset of action is between 6 to 12 hours and the

duration of action may be occasionally prolonged (3 to 4

days) It is absorbed in the upper gastrointestinal tract,

undergoes an enterohepatic circulation, and is excreted

largely in the stool Bisacodyl suppositories may be useful in

patients who prefer a rapid onset and shorter duration of

bowel activity

Prokinetic Agents

Drugs that act via serotonin receptors (5-HT 4 ) to stimulate

acetylcholine release in the myenteric plexus and produce

coordinated contraction have been studied in constipation

Cisapride was the best studied of these drugs, but the

asso-ciation with potential lethal cardiac dysrhythmias led to its

withdrawal in the United States Tegaserod (Zelnorm) is a

partial 5-HT4agonist that was recently approved for

treat-ment of constipation predominant IBS in women In four

prospective randomized placebo controlled trials, women

with constipation predominant IBS reported response rates

ranging from 5 to 19% in excess of placebo Recent

stud-ies indicate that some women with functional constipation

may respond as well, and is a new indication for the drug

Another agent that is advocated for patients with

chronic refractory constipation is the prostaglandin

ana-logue misoprostol Several studies have shown an

accelera-tion of intestinal transit in healthy individuals and in those

with chronic constipation We usually start with 200 µg

daily together with PEG (Miralax) and increase the dose

progressively, based on efficacy and side effects This drug

should not be used in young women who wish to become

pregnant as stimulation of uterine contractions may result

in abortion of the fetus

Colchicine was reported to be effective in refractory

chronic constipation in one small randomized double blind

study in a dose of 0.6 mg by mouth 3 times daily We have

been disappointed by the failure of any of our patients to

respond

Examination and Treatment of Patients

with Intractable Constipation

Testing

Patients with functional constipation who fail to respond

to diet, fluids and standard laxatives should undergo

test-ing, including colonic transit using radio-opaque markers

and anorectal manometry with balloon expulsion, as

out-lined in the algorithm Both tests must be obtained, as

symptoms do not predict the underlying pathophysiology

These studies allow us to categorize such patients in what

appears to us to be biologically plausible subgroups

Slow Transit Constipation

In slow transit constipation (STC), there is a failure to move

luminal contents through the proximal colon This may be

associated with dietary factors, such as severe caloric ciency, with medications that alter motility or with certain

defi-neurologic, metabolic, and endocrine disorders Attention to

such factors may lead to improvement in colonic transit

Patients with idiopathic STC who fail to respond to

con-ventional laxatives may have abnormalities of the entericnerves, such as decreased volume of interstitial cells of Cajaland reduction of myenteric neural elements We usuallystart with colon cleansing using enemas with or withoutmineral oil If these are unsuccessful, a water-soluble con-trast enema (Gastrografin or Hypaque) administered underfluoroscopy may be very effective After this, the colon may

be further evacuated with twice daily high volume enemas

or by drinking PEG solution until cleansing is complete.The patient should then be maintained on a daily osmoticagent with stimulant laxatives every 2 to 3 days if there are

no spontaneous bowel movements Other agents such asmisoprostol or tegaserod may be tried if the patientresponds suboptimally to osmotic and stimulant laxatives

If a patient with disabling symptoms from STC is sponsive to medical therapy, surgery may be considered.The most common operation recommended is subtotalcolectomy with ileorectal anastomosis for which overallsuccess rates of approximately 90% have been reported.Although our experience approximates that of the litera-ture, we have also observed complications such as abdom-inal pain or bloating, adhesive obstruction and debilitatingdiarrhea after surgery, as have others Because of this expe-rience, we emphasize the importance of careful patientselection The following four criteria should be met beforesurgery is undertaken: (1) chronic, severe, and disablingsymptoms from constipation that are unresponsive tomedical therapy, (2) slow colonic transit of the inertia pat-tern, (3) no evidence of intestinal pseudo-obstruction byradiologic and manometric studies, and (4) normalanorectal function Diagnostic studies to rule out pelvicfloor dysfunction are critically important, as subtotal colec-tomy with ileorectal anastomosis is unlikely to help if thelatter is not corrected Another reported surgical approach

unre-is antegrade colonic enema, although we use it very quently For patients who have impaired continence mech-anisms, an ileostomy is a viable option We are reluctant torecommend subtotal colectomy in patients when pain is asignificant component of their complaint, because it can-not be assumed that it will relieve pain

infre-Outlet Dysfunction Constipation

In outlet dysfunction constipation, the primary failure is

an inability to adequately evacuate contents from the tum This may be due to failure of coordinated relaxation

rec-442 / Advanced Therapy in Gastroenterology and Liver Disease

of the striated muscles during attempted defecation (pelvic

floor dyssynergia), weak expulsion forces due to pain or

neuromuscular disorders, or misdirection of expulsion

forces secondary to a large rectocele We recommend

biofeedback in conjunction with conservative therapy if

pelvic floor dyssynergia is demonstrated with

appropri-ate testing (Figure 75-1) The purpose is to train patients

to relax their pelvic floor muscles during straining to

achieve defecation Biofeedback sessions are held weekly

or more often until abnormal defecation efforts are

achieved (approximately three to eight sessions) The rate

of success for biofeedback has been reported to be 60 to

90% by some, but not all, investigators, but there have been

no randomized controlled studies in adults and the

expe-rience in children has been disappointing in large

con-trolled studies In our experience, less than 50% of patients

with constipation associated with pelvic floor dyssynergia

respond to biofeedback The cost of each session is about

$60 to $100 We normally refer those who are motivated

and have failed conservative treatment to biofeedback

Botulinum toxin injections into the anal sphincters for

the treatment of dyssynergic defecation has been reported

in small uncontrolled studies We are not convinced that

there is sufficient evidence to use botulinum toxin for this

disorder nor do we recommend myotomy for the

pub-orectalis muscle because of a high risk of incontinence

Surgical repair of a rectocele is considered only if we can

demonstrate improved rectal evacuation when pressure is

placed on the posterior wall of the vagina during defecation

and there is no evidence of pelvic floor dyssynergia Mostpatients with megarectum can be treated conservatively withenemas or suppositories We rarely consider proctocolec-tomy with an ileoanal pouch and only if anorectal conti-nence mechanisms are intact and symptoms are intractable

Combined Slow Colonic Transit and Outlet Dysfunction

Constipation

If both outlet obstruction and slow colonic transit coexist,combined treatment with laxatives, prokinetics (see Figure75-1), and biofeedback therapy should be offered Failure

of conservative therapy may lead to proctocolectomy withileal pouch anal anastomosis or end ileostomy for thosewith untreatable anorectal dysfunction

Normal Transit Constipation

Constipated patients with normal colon transit and mal anorectal function often misperceive bowel frequencyand exhibit increased psychological distress It is impor-tant to reassure these patients that there is no evidence ofabnormal function of the colon or rectum Patients should

nor-be educated to increase fluid and finor-ber intake, take tage of gastrocolonic responses, and avoid excessive use

advan-of laxatives We advan-often screen these patients for underlyinganxiety, depression or other psychological distress using apreviously validated psychological symptom form, theSCL-90R Pharmacotherapy to reduce underlying anxiety

or depression may be helpful in some individuals

Colonic transit (CTS), Anorectal manometry with balloon expulsion (ARM)

Normal CTS Normal ARM Normal CTSAbnormal ARM Slow CTSAbnormal ARM Slow CTSNormal ARM

Absence of rectoanal inhibitory reflex

Full thickness rectal biopsy to rule out Hirschsprung disease

Pelvic floor dyssynergia

Bisacodyl or glycerine suppositories or enemas Biofeedback

Consider diverting colostomy

Osmotic agents + stimulant laxatives every 2–3 days

Misoprostol, tegaserod or colchicine

Consider surgery

Reassurance Education

Constipation / 443

Constipation with IBS

In a patient with constipation-predominant IBS, we will

attempt a high fiber diet, starting with small amounts and

increasing gradually Wheat bran, at doses of 10 to 30 g, is the

best known and perhaps the most effective fiber supplement

but commercial products may be more acceptable to some

patients Abdominal pain and bloating occur with fiber

sup-plements in many IBS patients PEG may be substituted in

patients who do not tolerate fiber supplements, but we

min-imize the use of stimulant laxatives Tegaserod may be useful

in women with constipation-predominant IBS, although the

cost of the drug far exceeds other available agents

Constipation in Pregnancy

Dietary modifications, such as increased fluid and fiber intake,

are the most physiologic and safest approachs to constipation

during pregnancy As with all patients, pregnant women

should be warned that fiber can cause abdominal bloating

or flatulence and that sufficient amounts of fluid should be

consumed daily Fiber supplements should be started with

small amounts and gradually increased as tolerated

In our experience, PEG is not as problematic in terms of

abdominal bloating and flatulence as is sorbitol and

lactu-lose Although safety during pregnancy has not been

estab-lished (Federal Drug Administration pregnancy Category C),

PEG is inert, absorption is minuscule, and toxicity is unlikely

Of the stimulant laxatives, senna is both safe and

effec-tive when combined with bulk-forming agents in

preg-nancy Cascara is also mild and produces little or no colic

Although bisacodyl is safe for use in pregnancy, it tends

to produce more colic than the anthraquinone laxatives,

especially when administered orally

Agents to be avoided during pregnancy include castor

oil, which can cause premature uterine contractions, and

osmotic agents such as magnesium laxatives and

phos-phosoda, which may produce sodium and water retention

Chronic Megacolon

Chronic idiopathic megacolon in the adult should be

viewed as chronic colon failure, which is managed by

min-imizing colon contents with periodic evacuations Initialdisimpaction with colon cleansing is necessary for success-ful long term management We prefer to institute a low fiberdiet together with daily PEG solution to minimize stool andgas buildup and to keep stools soft Twice weekly, a glycer-ine suppository or a tap water enema should be adminis-tered to prompt defecation As a rule, these patients respondpoorly to stimulant laxatives and prokinetic agents.Occasionally, surgery may be indicated for chronic mega-colon when bowel distension becomes too uncomfortable

In patients with megacolon and megarectum, a divertingileostomy or ileoanal anastomosis may be considered Formegacolon with normal anorectal function, an ileorectalanastomosis may be appropriate whereas in megarectumwith normal colon, a coloanal anastomosis, divertingcolostomy, or Duhamel procedure may be effective

Supplemental ReadingLocke GR III, Pemberton JH, Phillips SF AGA technical review

on constipation American Gastroenterological Association [review] Gastroenterology 2000;119:1766–78.

Wald A Slow transit constipation Curr Treat Options Gastroenterol 2002;5:279–83.

Wald A Constipation, diarrhea and symptomatic hemorrhoids during pregnancy Gastroenterol Clin North Am 2003;32:301–22 Wald A Anorectal manometry In: Schuster M, Crowell M, Koch K, editors Schuster atlas of gastrointestinal motility, 2nd

ed Hamilton (ON): BC Decker Inc; 2002 p 289–303 Wald A, Hinds JP, Caruana BJ Psychological and physiological characteristics of patients with severe idiopathic constipation Gastroenterology 1989;97:932–7.

Wald A Is chronic use of stimulant laxatives harmful to the colon.

J Clin Gastroenterol 2003;36:386–9.

Wald A Approach to the patient with constipation In: Yamada

T, editor Textbook of gastroenterology, 4th ed Philadephia: Lippincott, Williams and Wilkins; 2003 p 894–910 Wald A Outlet dysfunction constipation Curr Treat Options Gastroenterol 2001;4:293–7.

CHAPTER 76

M ANAGEMENT OF A BDOMINAL W ALL

D EFECTS

Complex abdominal wall defects can occur both acutelyand as a delayed consequence of surgery or injury Acutedefects may be the result of trauma, tumor excision, wounddehiscence and evisceration, necrotizing fasciitis, or someother intra-abdominal catastrophe The acute complex defectmay be divided into two types: (1) unstable and (2) stable.Those with unstable abdominal contents are those whereurgent surgical intervention is typically required for intra-abdominal injury or the acute deterioration of intra-abdominal disease (eg, diverticular abscess) An example of

an acute complex defect with stable intra-abdominal contents

is necrotizing fasciitis A detailed discussion of the ment of these acute defects is more esoteric to the nonsurgeonand will not be discussed further in this chapter

manage-Patient Examination

A number of factors become important in the examination

of the patient with a chronic abdominal wall defect The

loca-tion of the defect and, in particular, its relaloca-tion to previouschest and abdominal scars is very important whether laparo-scopic or open repair is being considered The latter espe-cially can involve substantial areas of tissue rearrangementand advancement The presence of previous incisions canhave a substantial impact on the blood supply to both theskin and soft tissue and the myofascial components of theabdominal wall The extent of the fascial defect is also vitallyimportant and is likely best determined by a combination

of physical examination and radiographic imaging, ularly computed tomography or magnetic resonance imag-ing In the setting of an open wound, cultures of the woundcan guide antibiotic use both in the preoperative period andafter surgery In patients who have undergone previoustumor excision within the abdomen or abdominal wall, tis-sue biopsy within the confines of a complex wound would

partic-be important to rule out tumor recurrence

The overall stability of the skin and soft tissue in the ting of a complex abdominal wall defect can also be clas-sified as stable (type I) or type II, indicating absence orinstability of the skin and soft tissue coverage overlying themyofascial defect (Mathes et al, 2000) As previously dis-cussed, the perfusion of both the soft tissue and the myofas-cia can have a significant impact on reconstruction, and,

set-The management of the complicated abdominal wall defect

can be quite complex As more and more patients with an

increasing number of co-morbidities undergo

sophisti-cated abdominal operations, an increasing number of

physicians will have the opportunity to participate in the

management of these patients Moreover, it is clear that a

multidisciplinary approach affords the best possible

out-come, particularly in those patients whose defect includes

gastrointestinal (GI) complications such as

enterocuta-neous fistulas The purpose of this chapter is to provide a

broad discussion of the management of these problems

Incidence

The incidence of incisional hernia after abdominal wall

surgery is at least 10% (Mudge and Hughes, 1985) In some

studies of high risk patients, the occurrence rate is as high

as 20% Repair is commonly unsuccessful, with recurrence

rates ranging from 20% to greater than 50% (Flum et al,

2003; Van’T Riet et al, 2004) This obviously represents a

sub-stantial management problem for the gastroenterologist and

surgeon and their associated patients Regrettably, a large

retrospective population cohort study examining over 10,000

patients demonstrated that there had been no improvement

in important measures of adverse outcome in the last

sev-eral decades in these patients (Flum et al, 2003)

Nomenclature

The typical definition of the complex abdominal wall

defect would include one or more of the following:

1 Large sized defect (>40 cm)

2 Absence of stable skin coverage

3 Recurrence

4 Infected or exposed prosthetic material

5 Compromised abdominal wall soft tissue secondary

to co-morbidities, such as irradiation or

cortico-steroid dependence

6 Simultaneous visceral complication (eg,

enterocuta-neous fistula)

7 A systemically compromised patient (eg,

posttrans-plant, concurrent malignancy, immunodeficiency

disease) (Steinwald and Mathes, 2001)

Management of Abdominal Wall Defects / 445

therefore, angiography can be helpful in those patients who

have undergone multiple previous procedures or in whom

regional or distant tissue flaps are being considered to aid

in reconstruction Finally, an evaluation for the presence

of GI pathology, including enterocutaneous fistula,

inflam-matory bowel disease, other inflaminflam-matory processes

including diverticular disease, or recurrent tumor is vitally

important before allowing the patient to enter the

oper-ating room Optimization of these problems and their

asso-ciated comorbidities, including malnutrition, abscess

drainage, and assessment and control of the extent of any

underlying GI pathology are of the utmost importance

both in the short term postoperative outcome and in long

term results of abdominal wall reconstruction

Surgical Techniques

The appropriate technique for abdominal wall

reconstruc-tion has been, and continues to be, a major topic of

dis-cussion in the surgical literature Selection for a particular

patient will depend on a number of factors, including size

of the fascial defect, stability or lack thereof of the skin and

soft tissue, the presence or absence of complicating GI

pathology, the extent of previous abdominal surgery, and

surgeon experience and preference The two most widely

discussed issues are the use of laparoscopic techniques or

open surgery and the performance of a primary repair

ver-sus the use of prosthetic material.

Laparoscopic Techniques

Laparoscopic repair of ventral and incisional hernias

con-tinues to be studied and has been demonstrated to be a safe

and effective alternative to open surgical techniques

(Franklin et al, 2004) There is, however, no consensus in

the surgical literature regarding the minimum or

maxi-mum size of the fascial defect for which laparoscopic

tech-niques should be used Certainly this methodology would

be contraindicated in those with unstable soft tissue

cov-erage or complicating GI pathology such as

enterocuta-neous fistulas Essentially all laparoscopic techniques employ

the use of prosthetic material to achieve repair of the

abdominal wall defect

Prosthetic Material

The use of prosthetic material in open ventral and incisional

hernia repair continues to be studied as well (Luijendijk et

al, 2000) The initial report of the use of mesh in the

recon-struction of large abdominal wall defects appeared in the

surgical literature in 1903 and described the use of silver

wire mesh (Bartlett, 1903) Use of this material was

aban-doned because of a significant degree of erosion into other

structures The use of modern material began in 1959 with

the introduction of polypropylene (Marlex) mesh (Usher,

1959) This material along with polytetrafluoroethylene

(Goretex or Teflon) or a composite material of the two

rep-resents the majority of prosthetic materials used today Theclassic use of these materials is either as an inset patch or

as reinforcement of a primary tissue repair of myofascia.Placement of these materials can be done extrafascial orabove the fascia, extraperitoneal and subfascial, orintraperitoneal This too continues to be a much-debatedtopic Complications of the use of mesh include separation

of the mesh from the fascia, contact injury (eg, adherence

to other structures, erosion, and fistula formation), and

infection Autogenous tissue is considered by some to be the

ideal material to close complex myofascial defects Thesource of the tissue can be regional musculofascial flapsmost commonly represented by rectus abdominis advance-ment, which can be achieved using one of several plasticsurgery tissue advancement techniques, or the use of dis-tant flaps, including the tensor fascia lata or rectus femoris

of the thigh or latissimus dorsi

Inguinal Hernia

Inguinal hernia, a subset or particular variety of

abdomi-nal wall defect, although usually less complicated, is a ject in the ongoing debates of prosthetic material versusprimary tissue repair and laparoscopic versus open tech-niques In these defects the laparoscopic repair can occur

sub-by using a transabdominal preperitoneal approach or atotally extraperitoneal technique, both of which use pros-thetic mesh The most widely accepted current open

inguinal hernia technique, the Lichtenstein repair, as

described by Amid, also uses prosthetic mesh The priate methodology continues to be debated but likelyinvolves the following two important concepts: (1) surgeonexperience and (2) whether the planned procedure repre-sents repair of a recurrence (Neumayer et al, 2004)

appro-Summary

In conclusion durable reconstruction of a complex inal wall defect requires a complete evaluation of the defectand optimal preparation of the patient along with thought-ful surgical planning Certainly a multidisciplinaryapproach is ideal and more times than not should likelyinclude gastroenterology involvement, particularly in thosepatients who present with GI co-morbidities complicatingtheir abdominal wall defect and its reconstruction

abdom-Supplemental ReadingAmid PK, Shulman AG, Lichtenstein IL Open “tension-free” repair of inguinal hernias: the Lichtenstein technique Eur J Surg 1996;162:447–53.

Bartlett W An improved filigree for the repair of large defects in the abdominal wall Ann Surg 1903;38:47.

446 / Advanced Therapy in Gastroenterology and Liver Disease

Flum DR, Horvath K, Koespell T Have outcomes of incisional

hernia repair improved with time?: a population-based

analysis Ann Surg 2003;237:129–35.

Fr anklin ME Jr, Gonzalez JJ Jr, Glass JL, Manjar rez A.

Laparoscopic ventral and incisional hernia repair: an 11-year

experience Hernia 2004;8:23–7.

Luijendijk RW, Hop WCJ, Petrousjka van den Tol M, et al A

comparsion of suture repair with mesh repair for incisional

hernia New Engl J Med 2000;343:392–8.

Mathes SJ, Steinwald PM, Foster RD, et al Complex abdominal

wall reconstruction: a comparison of flap and mesh closure.

Ann Surg 2000;232:586–96.

Mudge M, Hughes LE Incisional hernia: a 10 year prospective

study of incidence and attititudes Br J Surg 1985;72:70-1.

Neumayer L, Giobbie-Hurder A, Jonasson O, et al Open mesh versus laparoscopic mesh repair of inguinal hernia New Engl

J Med 2004;350:1819–27.

Steinwald PM, Mathes SJ Management of the complex abdominal wall wound In: Cameron JL, Evers BM, Fong Y, et al, editors Advances in surgery.Vol 35 St Louis: Mosby, Inc; 2001 p 77–108 Usher FC A new plastic prosthesis for repairing tissue defects

of the chest and abdominal wall Am J Surg 1959;97:629–33 Van’T Riet M, De Vos Steenwijk PJ, Bonjer HJ, et al Incisional hernia after repair of wound dehiscence: incidence and risk factors Am Surg 2004;70:281–6.

of inflammatory cells in the right and left colon, which mayprovide insight into the abrupt cessation of inflammation

at the line of disease demarcation We histologically uated the “line of demarcation” in an attempt to under-stand the aggressive and protective balance occurring atthe inflammatory interface Much to our surprise, there

eval-were numerous mast cells on the normal side of the line

of demarcation and in the terminal ileum of patients withwell-defined left-sided UC Evolving understanding of therole of the mast cells in UC suggests that the mast cells may

be providing a degree of protection rather than active

inflammation Until recently, the homeostatic role of mastcells has been ignored because they have always been given

a pathobiologic role in human physiology The interactionbetween the mast cell and the eosinophil has importantimplications for IBD The inflammatory response is depen-dent on eosinophilic chemoattractant factor released bythe mast cell The mast cell also modulates the effect ofeosinophil function and engulfs major basic protein, whichlimits tissue injury

From a practical perspective, the advent of doscopy permits frequent assessment of the degree ofmucosal inflammation and response to therapy as well asproviding an opportunity to histologically evaluate a biopsy

videoen-of the mucosa Endoscopic examination is essential to themanagement of UC because it permits the assessment ofthe severity and extent of mucosal inflammation Biopsiesare easily obtainable and play an important role in distin-guishing the severity and nature of the inflammation Inleft-sided UC, the laboratory evaluation is often normaland the only method to assess disease severity is history,physical examination, and videoendoscopy with biopsy.During the initial evaluation, laboratory assessment isessential in order to exclude a treatable infectious cause

of colitis and to assess the immunologic pressure on thepatient in terms of inflammation and metabolic home-ostasis Stool studies for enteric pathogens, parasites,

Clostridium difficile, leukocytes, eosinophils, and

Charcot-Dramatic changes have occurred in the understanding and

management of inflammatory bowel disease (IBD) over

the past decade The interaction of luminal contents with

the gastrointestinal (GI) immune system has enhanced our

understanding of mucosal inflammation and has improved

the focus of general management Biologic therapy is

com-ing of age and dozens of new “silver bullet” compounds are

being developed to treat both Crohn’s disease (CD) and

ulcerative colitis (UC) In the midst of the excitement about

what the future holds, it is important to focus on

maxi-mizing the treatment options that are currently available

I will review the current understanding of left-sided UC

and issues regarding management of mucosal

inflamma-tion and symptoms of this disease

Pathophysiology and Diagnosis

Inflammation and Extent of Disease

Left-sided UC describes colonic inflammation that begins

dis-tal to the splenic flexure and extends in a generally uniform

pattern to the anal canal margin Ulcerative proctitis involves

the last 15 to 20 cm of colon and always involves the junction

of the anal canal and the rectum It is often taught that

left-sided UC is an extension of ulcerative proctitis This is

prob-ably not true The area of most severe inflammation in

left-sided UC is the sigmoid colon The rectum often is less

inflamed, and may appear nearly normal Prior to the advent

of flexible endoscopy, the explanation for less active

inflam-mation in the rectum was that the “rectal sparing” was due

to topical rectal therapy As new drugs have become available,

it is clear that the rectum has less inflammation than the

sig-moid colon The other interesting observation that arose

dur-ing the numerous drug studies evaluatdur-ing the response to

therapy in left-sided UC was that there is often a cecal patch

of inflammation in an otherwise normal right colon The skip

lesions of left-sided UC support a unique pathophysiology

that we do not fully understand Ulcerative proctitis differs

from left-sided UC because the intense inflammation does

begin at the anal margin and extend for a short distance

prox-imally The distinction between these two disorders helps

explain the different clinical courses of these two entities

Inflammation involving only part of the colon is a

curi-ous phenomenon The mystericuri-ous line of demarcation of

448 / Advanced Therapy in Gastroenterology and Liver Disease

Layden crystals, provide support for idiopathic colonic

inflammation as well as directing management

IMPORTANCEOFHISTOLOGY

During the initial stage of evaluation, mucosal biopsies

should be obtained to determine the chronicity of disease

and to exclude other causes of colitis The principle

alter-native diagnosis that needs to be considered in the first

attack of UC is acute self-limiting colitis (ASLC) The

endo-scopic appearance is indistinguishable from idiopathic UC,

but the microscopic changes are more acute and the

mucosal atrophy and the crypt changes of chronic colitis

(crypt branching) are absent ASLC may last for several

months, but the long term prognosis is excellent with no

chronic disease issues that need to be considered For the

consultant, it is often impossible to reconstruct the initial

illness Long term remission following an acute attack raises

the possibility of ASLC and supports a trial period of

man-agement without maintenance therapy C difficile may

masquerade as chronic colitis or may cause relapse of

symptomatic disease The characteristic “explosive volcano”

seen microscopically is a useful histologic marker of this

infectious colitis All patients with distinct ulceration of the

rectum require biopsies to exclude solitary rectal ulcer

syn-drome (SRUS), which has a pathognomonic histologic

pic-ture of disrupted submucosal muscle fibers SRUS is an

ischemic lesion that does not respond to the

immunosup-pressive treatment offered for IBD and requires special

attention to the physiology of defecation to prevent the

internal prolapse of rectal mucosal into the anal canal

There is a separate chapter on this topic (Chapter 89,

“Rectal Prolapse, Rectal Intussusception and Solitary Rectal

Ulcer Syndrome”)

EOSINOPHILS

A second issue regarding the histopathology of IBD has

emerged over the past few years In the 1950s, the eosinophil

was recognized as a dominant cell in the microscopic

pic-ture of IBD Because it was believed the function of the

eosinophil was limited to parasitic infections and allergy,

considerable research focused on identifying either of these

problems as the etiology of IBD Parasitic infections were

easily dismissed, but it took over a decade to eliminate

defin-itively the allergic etiology of IBD The eosinophil, which

had captured the interest of pathologists studying IBD,

sub-sequently was declared to be a surrogate marker for

inflam-mation In the 1990s, the homeostatic role of eosinophils

began to be understood An extended pathobiologic role of

eosinophil function emerged during the national epidemic

of the “tryptophan-eosinophilic-myalgia syndrome” in

which eosinophils caused extensive tissue injury unrelated

to parasites or allergies Tissue resident mast cells release

eosinophilic chemoattractant factor to recruit eosinophils

to the tissue from the circulation Once recruited, a variety

of events need to occur to activate the eosinophils, one ofwhich is the presence of Intracellular Adhesion Molecule(ICAM-1), which not only traffics the eosinophils to theinflammatory site, but also is required for eosinophils acti-vation The importance of eosinophils in the activation ofdisease may be determined by examination of the biopsy or

by stool studies In the biopsy, the number of eosinophilsgives an estimation of the intensity of the inflammatoryresponse, but the presence of eosinophils in crypt abscesses

or mucosal migration of eosinophils indicates sufficientimmunologic pressure to force the eosinophils into theintestinal lumen These histologic findings identify activatedeosinophils Eosinophils in the stool indicate migration ofeosinophils Charcot-Layden crystals, which are related tothe intracellular products of the eosinophil, reflect proba-ble eosinophil-induced tissue injury and suggest the needfor aggressive treatment of the increased number ofeosinophils

Anorectal Physiology in Health and with

Inflammation

The complex physiology of the anorectum is adverselyinfluenced by inflammation with increased sensitivity tosensation and an amplification of muscular responses stim-ulated by stool in the rectum Tenesmus is the sensation ofincomplete evacuation of the rectum or nonproductivestraining to defecate It occurs when rectal contraction isaccompanied by internal anal sphincter relaxation In thepresence of inflammation, there is sensitivity to lower thannormal volumes of balloon distention and exaggeratedrelaxation of the internal anal sphincter (IAS) The sensa-tions accompanying this response are perceived rectal full-ness, urgency to defecate and a sense of incompleteevacuation Occasionally, tenesmus continues when visi-ble inflammation is no longer present When this occurs,treatment for microscopic inflammation or pharmacologicmanipulation of rectal contractility and IAS relaxationimproves these symptoms In addition to the influence ofrectal inflammation on anorectal physiology, left-sided col-itis changes the physiology of the normal appearing prox-imal colon This was recognized as early as 1964 whenLennard-Jones described proximal constipation in patientswith left-sided UC Recent studies demonstrate inhibition

of stool movement proximal to the line of demarcation ofdisease The changes in motility have important implica-tions for topical rectal therapy

Why Patients Relapse

IBD is characterized by periods of relapse and remission

These are not random events although the reason an

indi-vidual relapses may not be identifiable The four most mon reasons patients relapse are the following:

com-Left-Sided Ulcerative Colitis and Ulcerative Proctitis / 449

1 A change in medication

2 Seasonal variation

3 Infection

4 Nonsteroidal anti-inflammatory drugs (NSAIDs)

Changes in medications needs little explanation,

although I emphasize to my patients that this is the only

reason for a relapse in disease for which I hold

responsi-bility because all medication changes should occur under

my guidance Seasonal variation is well recognized,

how-ever the reason this occurs remains a mystery Seasonal

variation is influenced by geographic latitude with a

blunt-ing of the seasonal variation at higher latitudes

Environmental allergens are assumed to be responsible for

these relapses with nonspecific activation of the immune

system through mast cells and eosinophils When this

occurs, there is an increase in intestinal permeability, which

changes the relationship between the luminal contents and

the mucosal immune system The reason infection

acti-vates IBD is unclear Enteric infections obviously activate

the GI immune system with deleterious consequences for

mucosal integrity Systemic infections probably activate the

immune system nonspecifically with activation of IBD

related to increased immune activity NSAIDs have

numer-ous effects that may alter the mucosal integrity or immune

activation Of the plausible mechanisms, I favor the change

in intestinal permeability because this is a common theme

in activating the GI immune system with exposure to

potential antigens increased in proportion to the increase

in mucosal permeability In the management of IBD

patients, seeking a cause of disease relapse may guide

ther-apy and should permit the anticipation of relapse with the

potential for prophylactic intervention

Specific Treatment of Inflammation

Aminosalicylates

The aminosalicylates are the backbone to the treatment of

left-sided colitis (see Table 77-1) The special

characteris-tics of each of the compounds, as described in the

follow-ing chapter, may be used to advantage in the management

of IBD, however, it is particularly important to emphasize

the benefit of topical rectal therapy in proctitis and

left-sided UC The impaired motility of the colon proximal to

the line of demarcation of active disease decreases the

amount of medication in contact with the inflamed mucosa

During an acute relapse, rectal suppositories (500 mg) or

enemas (2 to 4 g) have excellent contact with the inflamed

mucosa Oral mesalamine compounds are effective in

man-agement, but further enhances the response rate Once in

the colon, there are no differences in the medications The

therapeutic recommendation focuses on the delivery of 4 g

of 5-ASA to the colon for at least 8 weeks before labeling

the patient as having disease resistant to 5-ASA 5-ASA

drugs are considered very safe, although there are patients

who are sensitive to the 5-ASA and develop a chemical itis manifest by edematous and often ulcerated mucosalwhich appears similar to Crohn’s colitis In a careful exam-ination of patients with indisputable mesalamine sensitiv-ity, we were unable to identify a serologic marker orhistologic findings unique to mesalamine toxicity Ifmesalamine sensitivity is suspected, discontinue themesalamine drug for 72 hours If symptomatic improve-ment occurs, this withdrawal trial supports mesalamine sen-sitivity The different efficacies of the various 5-ASAproducts are discussed in the chapter on UC (see Chapter

col-78, “Ulcerative Colitis)

For patients with left-sided UC, maintaining remissionwith mesalamine follows the guidelines that have beenestablished for UC Mesalamine should be continued with

at least one-half of the dose required to establish a sion, or more if the initial attacks were prolonged or severe

remis-We have successfully used 1 g mesalamine enemas andevery other day 4 g enemas to maintain remission inpatients with left-sided UC The data is more ambiguous

in patients with ulcerative proctitis Primary therapy withmesalamine suppositories is favored The direct rectalapplication of a 500 mg mesalamine suppository provides

a concentrated dose to the distal 15 to 20 cm of the colon,which is superior to rectal mesalamine concentrations withoral medications Because the rectum effectively moves aliquid enema out of the rectum and into the proximal sig-moid and descending colon, the concentration ofmesalamine delivered to the rectum with a suppositorymay be higher than the dose provided by a 4 g mesalamineenema In these patients, I treat to obtain remission andthen taper the mesalamine and wait for a symptomaticrelapse Each relapse should be treated and if the intervalbetween relapses is short, then continuous maintenance isrecommended.*

TABLE 77-1 Mechanisms of Action of Aminosalicylates

Inhibition of mucosal prostaglandin production Inhibition of leukotriene B 4 production Decrease interleukin-1 production Reduce the production of reactive oxygen radicals Scavenge free oxygen radicals

Correct impaired butyrate metabolism Modify monocyte and lymphocyte function directly as well as secondary to cytokine changes

Reduce expression of interleukin-2 receptors Inhibit tumor necrosis factor upregulation

*Editor’s Note: This is a realistic approach since proctitis is so able in course and many patients do not take preventative medica- tion until they have had several recurrences However, occasionally that first episode proceeds into severe left-sided UC, especially in teenagers or young adults.

vari-450 / Advanced Therapy in Gastroenterology and Liver Disease

Glucocorticoids

The general immunosuppression caused by glucocorticoids

often induces symptomatic remission in patients with

left-sided UC However, avoiding glucocorticoid therapy has

become the mantra of the gastroenterologist caring for IBD

patients Many questions focus on the cost of the short term

benefit of steroids in terms of changing the character of

dis-ease and the iatrogenic medical complications that arise

from steroid use Glucocorticoids follow mesalamine in the

“induction of remission” treatment algorithm Their use

should be accompanied by a strategy to minimize the

cumu-lative systemic exposure to steroids Topical rectal therapy

applies the steroid dose to the area of the inflammation with

the same distribution characteristics demonstrated for

mesalamine enemas The inflamed mucosa poorly absorbs

steroids and systemic glucocorticoid effects are least likely

with topical rectal therapy As the mucosa heals,

glucocor-ticoid absorption improves and systemic effects of steroids

may occur

ROLE OFEOSINOPHILS INRELAPSES

Seasonal or infectious relapses can be linked to high

num-bers of eosinophils by identifying increased numnum-bers of

fecal eosinophils, Charcot-Layden crystals in the stool, or

with biopsy evidence of eosinophilic mucosal migration

When eosinophils are implicated in the symptomatic

relapse of disease, high dose, short-term steroids are often

effective The diurnal variation of eosinophil function often

provides a useful clinical clue that eosinophil activation is

related to the current flare of colitis Eosinophils are most

active between 11 pm and 2 am, thus a patient with

domi-nant colitis symptoms during this time likely has active

eosinophils that should be modulated Eosinophils are

usu-ally sensitive to high plasma levels of steroids, thus an

intra-venous (IV) dose of steroids (eg, solumedrol 60 mg IV)

or a rapidly tapering daily dose of oral steroids (eg, 60, 50,

40, 30, 20 and 10 mg of prednisone) may induce a durable

remission lasting weeks, months, or until a new stimulus

activates the colitis Even without documented eosinophilic

activation of a colitis flare, an excellent clinical response to

the first 48 hours of steroids suggests eosinophils are

piv-otal in the current flare of the disease and a short course of

steroid may be all that is required for inducing remission

Lessons from the tryptophan-eosinophil-myalgia

syn-drome include the recognition that approximately 15%

of eosinophils are resistant to steroids making this

sub-group of patients difficult to manage

When chronic glucocorticoids appear necessary, I favor

moving as quickly as possible to every other day dosing as

this often controls the colonic inflammation with less acute

prednisone toxicity If continuous steroids are required to

control a relapse, immunomodulation therapy should be

considered because there is no place in the treatment of IBD

for maintenance steroids.

BUDENOSIDE/BECLOMETHASONEEarly in the development of budesonide, an enema for-mulation (2 mg) was determined to be beneficial, however,budesonide is only commercially available in an ileal releaseform for CD (Entocort EC, AstraZeneca LP, Wilmington,DE) The theoretical advantage of budesonide revolvesaround the efficient first pass hepatic clearance of thissteroid from the portal blood This should decrease the sys-temic availability of the steroid and permit local steroidsuppression of the disease without systemic toxicity It isunfortunate that further studies were not conducted withtopical rectal budesonide, however, approximately 15%

of the blood flow from the distal colon escapes the portalsystem increasing the amount of drug that may be avail-

able in the systemic circulation Oral beclometasone in a

delayed release formulation was successful in treating sided UC The same principle of high first pass clearanceresulted in few systemic side effects (Campieri et al, 2003)

left-Immunomodulation

Immunomodulation with 6-mercaptopurine (6-MP) or

aza-thioprine (AZA) has become the standard of practice in the

management of patients with difficult CD Initial concernsabout the toxicity of these drugs has become less of an issuethan the toxicity of chronic steroid use The experience inpatients with CD led to the management of pancolitis with6-MP/AZA Success with UC management has permittedthe expansion of the patients suitable for treatment to thosewith relatively refractory left-sided UC I begin with 50 mg6-MP and increase the dose to as high as 2 mg/kg in 25 mgincrements until there is control of the disease or emergingtoxicity Most of the toxicity occurs in the first few months

of treatment and blood tests are followed carefully forleukopenia, hepatitis, and pancreatitis

Methotrexate (MTX) (25 mg intramuscularly [IM] once

a week) may also be used to induce remission, but manyresponsive patients have only a short period before a MTX-resistant relapse occurs Once symptomatic control isachieved, the dose may be lowered to 15 mg IM a week Areturn to 25 mg for a symptomatic recurrence can be help-ful The cautions advocated by the American RheumatologicAssociation regarding the emergence of liver disease after alifetime cumulative dose of 1500 mg should be applied topatients receiving MTX, although this seems to be less of anissue with once weekly IM MTX Studies are in progress todetermine if inflixamab may play a role in inducing remis-sion in UC The published anecdotal use of inflixamab and

my experience with inflixamab in UC do not support its usefor this indication at this time

Left-Sided Ulcerative Colitis and Ulcerative Proctitis / 451

Other Treatment

Numerous new drugs are being evaluated for use in UC

Heparin was briefly advocated for management of

refrac-tory UC, but a recent properly conducted trial with low

molecular weight heparin failed to demonstrate

therapeu-tic benefit Short chain fatty acid (SCFA) enemas are not

commercially available, but have been reported to improve

left-sided colitis ICAM-1 antisense enemas were reported

to induce remission as often as mesalamine enemas with

the benefit of prolonged remission Epidermal growth

fac-tor enemas have also been shown to be effective in

treat-ing left-sided UC in a small double-blind study (Sinha et

al, 2003).†

Surgical Intervention

Occasionally, the symptoms of left-sided UC or steroid

tox-icity may be so severe that colectomy may be considered

The proper intervention is a total colectomy Recently, the

success of total colectomy and ileoanal pouch construction

has been reported for patients with refractory left-sided

UC (Hassan et al, 2003)

Modifying Symptoms

Controlling mucosal inflammation is the cornerstone of

management of left-sided UC Proper management also

includes attention to the symptoms of the disease In

gen-eral, the diarrhea of left-sided UC has little to do with the

accelerated passage of digested material, as the diarrhea

occurs due to mucosal inflammation with blood, fluid and

colonic spasm contributing to the symptoms For this

rea-son and the inhibition of proximal colonic motility

described earlier, antidiarrheal agents are not only

inef-fective, but they may increase the symptoms Metamucil

has been used effectively in UC, although the mechanism

of action is not well understood Improved symptoms may

be related to the ability of Metamucil to modulate colonic

fluid, which will increase the fluid in desiccated stool

prox-imal to the line of demarcation of disease and also absorb

any excessive fluid in the lumen Recent attention to the

effect of the luminal environment offers another possible

mechanism of action as Metamucil may dilute luminal

contents and reduce the concentration of any proteins,

chemicals or toxins that might play a role in activating the

mucosal immune system Studies in the 1960s and 1970s

found disaccharidase deficiency occurred with a higher

incidence in patients with IBD than in the normal

popu-lation Most believe this is a linked genetic factor, but a

mucosal abnormality of the small intestine may be

associ-ated with UC I decrease the simple sugars in the diet of

patients with left-sided UC to try to reduce the symptoms

of intestinal gas and some of the diarrhea.‡

Perineal dermatitis presents with perineal itching, pain,

and occasionally bleeding The attempt to maintain ineal hygiene in the presence of diarrhea often leads tophysical trauma of the perineal cleansing Patients should

per-be instructed in proper perineal hygiene including gentlecleansing following a stool and with bathing The perineumshould not be scrubbed, but gently flooded with water, pat-ted dry (not rubbed) with the use of a hair dryer to evap-orate the residual moisture Care should be taken not toburn the skin A barrier can be gently applied to protectthe skin from the acidic stool contents that remove the pro-

tective oils and injure the skin I recommend Balneol

(Solvay Pharmaceuticals), although recently I have been

using a 3.3% concentration of cholestyramine in white

petroleum, which is formulated locally and provides

con-siderable symptomatic relief In addition to the diarrhealstools, spontaneous relaxation of the IAS occurs commonlywith rectal inflammation The IAS relaxation is associatedwith small amounts of rectal mucus leakage, which dam-ages the skin through the same mechanism Because hist-

amine is related to normal IAS relaxation, antihistamines

are useful in decreasing the perineal soiling and injury.§Tenesmus occurs with rectal contraction and IAS relax-ation In IBD patients, tenesmus is related to rectal inflam-mation and often improves with control of rectal

inflammation Antihistamines decrease rectal spasm and

restore the physiologic integrity of the anal sphincter plex Topical rectal therapy including mesalamine and/orcorti-foam can be initiated to control the tenesmus or anti-histamines can be used to change the anorectal dynamicsand improve this troublesome symptom

com-Maintaining Remission

Maintenance therapy with mesalamine prolongs the

dura-tion of remission and should be continued The role ofmaintenance therapy in ulcerative proctitis is less clear.Many patients will have attacks of ulcerative proctitis thatlast for weeks or months, but they can be managed with-out maintenance therapy, although each episode should beaggressively treated I recommend continued treatmentwith mesalamine if relapses occur within 8 weeks of dis-continuing topical or oral treatment, but the data is insuf-ficient to support this suggestion and many of my patientsprefer intermittent treatment of symptomatic diseaseThe reasons patients relapse have been discussed Animportant aspect of patient education revolves around help-

con-trol trials of active UC and in preventative relapses of pouchitis in

patients who were staying in remission on antibiotics.

sugars are converted to SCFA, which may aid left colon cellular metabolism.

salt-induced diarrhea.

Cohen RD, Woseth DM, Thisted RA, Hanauer SB A meta-analysis and overview of the literature on treatment options for left- sided ulcerative colitis and ulcerative proctitis Am J Gastroenterol 2000;95:1263–76.

Frieri G, Pimpo MT, Palumbo GC, et al Rectal and colonic mesalzaine concentration in ulcerative colits oral vs oral plus topical treatment Aliment Pharmcol Ther 1999;13:1413–7 Gisbert JP, Gomollon F, Mate J, Pajares JM Role of 5-aminosali- cylic acid (5-ASA) in treatment of inflammatory bowel dis- ease: a systematic review Dig Dis Sci 2002;47:471–88 Hassan I, Horgan AF, Nivatvongs S Outcome of patients under- going ileal pouch-anal anastamosis for left-sided chronic ulcerative colitis J Gastrointest Surg 2003;7:567–71 Hebden JM, Blackshaw PE, Perkins AC, et al Limited exposure

of the healthy distal colon to orally-dosed formulation is ther exaggerated in active left-sided ulcerative colitis Aliment Pharmcol Ther 2000;14:155–61.

fur-Sandborn WJ, Hanauer SB, Katz S, et al Efficacy and safety of ASACOL 4.8 g/day (800 mg tablet) compared to 24 g/day (400 mg tablet) in treating moderately active ulcerative coli- tis Amer J gastro 2004;99:1–251.

Sinha A, Nightingale J, West KP, et al Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis N Engl J Med 2003;349:395–7 Sturgeon JB, Bhatia P, Hermans D, Miner PB Jr Exacerbation of chronic ulcerative colitis with mesalamine Gastroenterology 1995;108:1889–93.

Vecchi M, Saibeni S, Devani M, et al Review article: diagnosis, monitoring and treatment of distal colitis Aliment Pharmacol Ther 2003;17(Suppl 2):2–6.

ing each patient identify the pattern of his disease and the

fac-tors that precipitate a relapse An example would be a patient

with recurrent springtime flares In this patient, I would

rec-ommend increasing the mesalamine dose in the weeks prior

to the anticipated disease recurrence or intervene with

sepa-rate therapy as close to the onset of the flare as possible

Refractory Disease

Patients who fail to respond to treatment should be

re-evaluated in order to determine whether the initial

diagno-sis is correct or whether there has been extension of the

disease to include a larger proportion of the colon

Unrecognized problems may include infection, SRUS (see

separate chapter), ischemic colitis, Crohn’s colitis,

concur-rent irritable bowel syndrome, drug-induced colitis, or

mesalamine sensitivity Mesalamine sensitivity may occur at

any time in the course of treatment Our published cases

were documented to be sensitive to mesalamine by

with-drawing the drug and observing symptomatic improvement

This was followed by a mesalamine enema challenge and

repeat assessment of symptoms and endoscopic appearance

The response to withdrawal is dramatic and usually occurs

within 72 hours Reassessment should include physical

examination, laboratory tests including stool cultures with

an assessment for C difficile, visualizing the mucosa by

flex-ible sigmoidoscopy, or colonoscopy with biopsy evaluation

Supplemental Reading

Campieri M, Adamo S, Valpiani D, et al Oral beclometasone

dipropionate in the treatment of extensive and left-sided active

ulcerative colitis: a multi-center randomized study Aliment

Pharmcol Ther 2003;17:1471–80.

452 / Advanced Therapy in Gastroenterology and Liver Disease

Therapy of Distal Disease

For mildly active distal disease, 5-ASA preparations are our

first choice If the disease is limited to the distal 15 cm, a

suppository preparation of 500 mg each, given 1 to 2 times

daily for 2 to 4 weeks, may control the symptoms If the

ease is more extensive but limited to the colon that is

dis-tal to the splenic flexure, an enema containing 4 g of 5-ASA,

given at bedtime for 3 or 4 weeks, will be effective in 80%

of patients The patient who responds with symptomatic

improvement can then be switched to oral 5-ASA at a dose

of 2.4 to 2.5 g/d for long-term maintenance Flares

occur-ring infrequently, such as once or twice yearly, can be treated

with repeat suppository or enema preparations of 5-ASA

for 3- to 4-week intervals when needed If the flares recur

more frequently, a higher dose of oral 5-ASA (eg, 4.8 g/d)

may be necessary for maintenance treatment This may be

reduced slowly once the patient has been in remission for

several months to a lower dose (2.4 to 4.8g/d) by tapering

the daily dose by 1 tablet every 2 to 4 weeks Suppositories

or enemas of 5-ASA given once or twice weekly are another

option for maintenance therapy of distal disease if oral

5-ASA preparations are ineffective

When mild distal disease is not controlled with this

approach, or the disease is more severe, combined rectal

5-ASA (4 g/d enema) and oral 5-5-ASA (2.4 to 4.8 g/d) may

prove effective Alternatively, the addition of a

hydrocorti-sone enema or hydrocortihydrocorti-sone foam may be given once daily

in addition to the oral 5-ASA therapy for a period of 3 to 4

weeks If remission is not accomplished with this regimen,

then prednisone 40 mg/d for 2 to 4 weeks, in addition to oral

5-ASA, may be used Once symptoms are controlled,

pred-nisone may be reduced by decreasing the daily dose by 10

mg each week down to 20 mg/d, then reducing the daily dose

by 5 mg per day each week or 2 weeks until the prednisone

is stopped Oral 5-ASA therapy (2.4 to 4.8 g/d) may be

con-tinued for long term maintenance therapy For the patient

who responds to oral prednisone but promptly worsens as

the dose is reduced despite maintenance therapy with 5-ASA,

then azathioprine (AZA) or 6-mercaptopurine (6-MP) can

be added We check the thiopurine methyltransferase

(TPMT) red cell enzyme before starting AZA/6-MP, and if

the TPMT is normal, we start with a dose of AZA 2 to 2.5

mg/kg daily or 6-MP at a dose of 1 to 1.5 mg/kg daily A

lower dose should be used in patients with a low TPMT level

There is a separate chapter on AZA use in inflammatory

bowel disease (IBD) (Chapter 69, “Monitoring of

Azathioprine Metabolite Levels in Inflammatory Bowel

Disease”) We continue prednisone for about 2 months after

starting AZA/6-MP to allow time for the drug to become

effective Occasionally, we use nicotine patches for UC, in

patients who have not responded to steroids, particularly in

former smokers We start nicotine patches at an initial dose

of a 7 mg/d for a week, then 14 mg/d for a week, then a 21

mg/d patch for 4 weeks as described by Sandborn and

col-leagues (1997) With clinical improvement, the nicotinepatch dose can be reduced to the next lower dose every 2weeks until the patches are discontinued Once remissionhas been attained, prednisone can be tapered by 10 mg incre-ments until reaching 20 mg/d and then by 5 mg/d every 1 to

2 weeks until stopped

UNRESPONSIVEPATIENTSFor patients who have not responded adequately to any of

these measures, we recommend proctocolectomy with ileal

J pouch to anal anastomosis (IAP) if the patient is under age

65 years and is in good health, or end ileostomy if the patient

is obese or older Although cyclosporine is an option, we

con-sider the risks to outweigh the benefits compared withsurgery and we share this opinion with the patient We use

infliximab for UC only within the context of an

experi-mental trial, as it has unproved benefit for this indication

Therapy of Extensive Disease

Mildly active extensive (extending proximal to splenic ure) colitis is usually best treated first with oral 5-ASA.Sulfasalazine, the original 5-ASA preparation, is a prodrugthat releases 5-ASA after cleavage by bacterial action on thediazo bond with sulfapyridine However, the sulfapyridinemoiety has little anti-inflammatory activity, and it causesadverse effects in up to 40% of patients Most patients whoexperience adverse effects from sulfasalazine will tolerateoral 5-ASA preparations The adverse effects from sulfa-pyridine can be dose related, and this prevents use of highdoses of sulfasalazine, usually to a maximum of 4 g daily.Therefore, it is not possible to deliver as high a dose of 5-ASA with sulfasalazine as with other oral 5-ASA prepara-tions Other available oral preparations of 5-ASA includethe prodrugs, olsalazine (Dipentum) and balsalazide(Colazal), as well as the targeted delivery preparation of 5-ASA (Asacol), and the continuous delivery preparation of5-ASA (Pentasa)

flex-One of the oral 5-ASA preparations should be used as

ini-tial therapy for mildly active UC We usually start one of the

newer oral 5-ASA medications such as Asacol at a dose of 2.4g/d, balsalazide (Colazal) at 6.75 g/d (contains 2.4 g of5-ASA), or Pentasa at a dose of 2.5 g/d If there is no symp-tomatic response in 10 to 14 days, the dose may be increased

to 4.8 g/d of Asacol or 4.0 g/d of Pentasa (Sutherland et al,2000; Eaden et al, 2000) Some patients may respond well,except for persistent urgency or occasional blood streaks withmucous on stools This usually reflects persistent distal coloninflammation, and the addition of 5-ASA suppositories(Canasa) or enemas (Rowasa) at bedtime may control theselingering symptoms

The newer oral 5-ASA medications are several timesmore expensive than sulfasalazine, and when cost of themedication is a limiting factor for a patient, sulfasalazine

Ulcerative Colitis / 455

is a reasonable choice Sulfasalazine may be started at 1 g

daily with an increase in the dose by 1 g each day up to

the target dose of 3 to 4 g/d, if tolerated The complete

blood count should be checked after a week to look for

tox-icity, especially leukopenia However, there are several

drawbacks to using sulfasalazine instead of one of the

newer 5-ASA preparations Sulfasalazine should not be

used in patients with a history of sulfa allergy Besides

aller-gic reactions, some patients develop headaches, nausea,

anorexia, and other dose-related adverse effects

Sulfasalazine may cause reversible male infertility, which

does not occur with the other oral 5-ASA medications

For moderate symptoms, we start high dose oral 5-ASA

with Asacol at 4.8 g/d (may be available as 800 mg tablets)

or Pentasa at 4.0 g/d (available as 500 mg capsules); if the

symptoms do not improve in a week, prednisone should be

started at 40 mg/d as a single morning dose Once

symp-toms come under control, the prednisone can be tapered,

with reductions by 10 mg/d each week down to a dose of

20 mg/d, and with reductions of 5 mg/d each 1 to 2 weeks

thereafter until prednisone is discontinued If there is

ini-tial improvement but then symptomatic worsening while

tapering prednisone or within a few weeks of stopping, the

dose of prednisone can be increased again until symptoms

improve and then tapered more slowly For the patient who

again flares with the second prednisone taper, the

pred-nisone may be increased to the dose that controlled the

symptoms, with AZA 2 to 2.5 mg/kg/d or 6-MP 1 to 1.5

mg/kg/d added The prednisone may again be tapered after

another 2 months For those not responding to prednisone,

nicotine patches are a consideration, gradually increased to

a dose of 21 mg/d If major symptoms persist despite these

measures, consideration should be given to surgery with

proctocolectomy and IAP for the patient who is less than

65 years of age, or end-ileostomy for the obese or older

patient and for those with anal sphincter incompetence.*

Severe colitis symptoms can be very disabling and life

threatening with risks including toxic megacolon, sepsis, and

perforation Such flares may be induced by medications,

such as antibiotics and nonsteroidal anti-inflammatory

drugs, or by development of an idiosyncratic reaction to

sul-fasalazine or 5-ASA, even in the patient who has previously

tolerated these drugs for months or years Patients with

severe flares usually require hospitalization and intravenous

(IV) corticosteroids Bowel rest may be used but there is no

data to support that this hastens induction of remission and

patients will usually tolerate a liquid or low residue diet With

the possibility of an idiosyncratic reaction to sulfasalazine

or 5-ASA, it is usually worthwhile to stop this drug for a

while to make sure this is not the provoking agent Stool

cul-tures and assessment for Clostridium difficile toxin and ova

and parasites should be undertaken simultaneously with

ini-tiation of the corticosteroids Daily monitoring of the patientshould include examination of the abdomen and plain films

of the abdomen daily or on alternate days If symptoms donot improve with 5 days of IV steroids, such as Solu-Medrol

at doses of 60 mg over 24 hours up to 40 to 60 mg each

8 hours, then proctocolectomy or IV cyclosporine should beconsidered Although surgery may be the best alternative,some patients are unwilling to proceed with surgery, and IVcyclosporine (2 to 4 mg/d) is a reasonable alternative for 7

to 10 days Initial combined therapy with steroid andcyclosporine does not appear to be more advantageous thanstarting with steroids and later adding the cyclosporine, ifneeded After the patient improves from the severe flare, AZA(2 to 2.5 mg/kg) or 6-MP (1 to 1.5 mg/kg)†should be over-lapped with oral cyclosporine (5 mg/kg/d) with intendedblood levels of cyclosporine of 150 to 300 ng/mL for 3 to

6 months While the patient is on cyclosporine, antibiotic

prophylaxis for Pneumocystis carinii with trimethoprim

160 mg/sulfamethoxazole 800 mg (one double strengthtablet) once daily should be given For the patient whoresponds to this program, AZA or 6-MP should be contin-ued for years For some patients intolerant of AZA, 6-MPmay be better tolerated (Boulton-Jones et al, 2000).Concomitant 5-ASA seemingly adds little to the

immunomodulatory drug regimen Initial use of IV

cyclosporine without corticosteroids may be reasonable apy for severe UC in the patient with a history of steroid-induced psychosis, avascular necrosis, or other severe sideeffects from corticosteroids

ther-Medical Therapy during Pregnancy and Nursing

5-ASA and corticosteroids are safe to use during pregnancyand during nursing There is reassuring retrospective datathat AZA/6-MP and cyclosporine are safe and do not need

to be stopped if pregnancy occurs while on such therapy.Nicotine should not be used during pregnancy and nurs-ing There is a separate chapter (Chapter 84, “Pregnancyand Inflammatory Bowel Disease”) on pregnancy and IBD

Long-Term Maintenance Therapy

Inducing a remission can be a challenge and long-termremission is an important goal for all patients Both sul-fasalazine and the newer generation of 5-ASA preparationsare comparably effective for maintenance of remission.Effective 5-ASA maintenance doses are usually in the range

of 2 to 4 g/d of sulfasalazine (Azulfidine), 2 to 4 g/d ofPentasa (available as 500 mg capsules), 2.4 to 4.8 g/d of

*Editor’s Note: I am also concerned about IAP anastomosis in

patients with severe co-existent irritable bowel syndrome.

later 6-TG/6-MMP levels can also be used There is a separate chapter on this approach.

456 / Advanced Therapy in Gastroenterology and Liver Disease

Asacol (available as 800 mg tablets), 1 g/d of olsalazine

(Dipentum), or 6.75 g/d of balsalazide (Colazal) Another

benefit is that recent studies have demonstrated an

associa-tion between maintenance treatment with an oral 5-ASA

drug (over 1.2 g) and a reduction in the risk of colorectal

cancer in patients with UC (Eaden et al, 2000) For patients

who eventually require immunomodulatory therapy with

AZA/6-MP, these drugs should be continued indefinitely

It is usually unnecessary to continue 5-ASA along with AZA

or 6-MP For most patients, a lifelong maintenance

treat-ment program will prove beneficial and should reduce the

frequency of flares considerably (Kamm, 2002) Frequent

flares despite adequate doses of maintenance medications

are an indication for colectomy

Supplemental Reading

Boulton-Jones JR, Pritchard K, Mahmoud AA The use of

6-mercaptopurine in patients with inflammatory bowel disease

after failure of azathioprine therapy Aliment Pharmacol Ther

2000;14:1561–5.

Campbell S, Ghosh S Effective maintenance of inflammatory

bowel disease remission by azathioprine does not require

concurrent 5-aminosalicyate therapy Eur J Gastroenterol

Hepatol 2001;13:1297–301.

Cohen RD, Stein R, Hanauer S Intravenous cyclosporine in ulcerative colitis: a five-year experience Am J Gastroenterol 1999;94:1587–92.

Cohen RD, Woseth DM, Thisted RA, Hanauer SB A meta-analysis and overview of the literature on treatment options for left- sided ulcerative colitis and ulcerative proctitis Am J Gastroenterol 2000;95:1263–76.

Connell WR Safety of drug therapy for inflammatory bowel disease in pregnant and nursing women Inflamm Bowel Dis 1996;2:33–47.

Eaden J, Abrams K, Ekbom A, et al Colorectal cancer prevention

in ulcerative colitis: a case-control study Aliment Pharmacol Ther 2000;14:145–53.

Kamm MA Review article: maintenance of remission in ulcerative colitis Aliment Pharmacol Ther 2002:16 Suppl 4:21–4 Sandborn WJ, Hanauer SB, Katz S, et al Efficacy and safety of ASACOL 4.8 g/day (800 mg tablet) compared to 24 g/day (400 mg tablet) in treating moderately active ulcerative coli- tis Amer J gastro 2004;99:1–251.

Sandborn WJ, Tremaine WJ, Offord KP, et al Transdermal nicotine for mildly to moderately active ulcerative colitis (UC):

a randomized, double-blind, placebo-controlled trial Ann Intern Med 1997;126:364–71.

Sutherland L, Roth D, Beck P, et al Oral 5-aminosalicylic acid for inducing remission in ulcerative colitis (Cochran Review) The Cochrane Library Issue 4 Oxford: Update Software; 2000 Vecchi M, Meucci G, Gionchetti P, et al Oral versus combination mesalazine therapy in active ulcerative colitis: a double-blind, double-dummy, randomized multicentre study Aliment Pharmacol Ther 2001;15:251–6.

CHAPTER 79

I LEOANAL P OUCH A NASTOMOSIS

FEZAH REMZI, MD,ANDVICTORW FAZIO, MB, MS

In a few cases (up to 10% of RP cases) the procedure isdone in one stage, TPC and IPAA without loop ileostomy(Fazio et al, 1995) This is an alternative we will use in well-motivated and informed patients who are:

1 Aware of the 5 to 10% leak rate from the pouch analanastomosis and the possibility that an urgentileostomy may be required in the early postoperativeperiod (Tjandra et al, 1993; Remzi et al, in press)

2 Aware that recovery—both hospital stay and recoverytime (return of stamina) to return to work and socialactivities—may be double that of the usual 6 to 7 day

Restorative proctocolectomy (RP) with ileal pouch anal

anas-tomosis (IPAA) has become the gold standard of surgical

treatment for ulcerative colitis (UC) (Parks and Nicholls,

1978) In many series,>90% of procedures for UC involve

RP/IPAA This may be performed as (1) a primary

proce-dure, of total proctocolectomy (TPC) and IPAA, with

tem-porary loop ileostomy or (2) a multistaged with subtotal

colectomy oversew of rectal stump and end ileostomy,

fol-lowed by completion proctectomy IPAA and loop

ileostomy, with final (third) procedure being closure of

loop ileostomy Figure 79-1 outlines indications for surgery

Indications for Surgery

Diagnosis of ulcerative colitis Yes

Indeterminate Yes

Toxic

± megacolon

Indeterminate favor ulcerative colitis

Elective, nontoxic

No Crohn's disease

Rectal sparing diseaseRectal

Consider colectomy and ileoproctostomy

Colectomy or proctocolectomy and ileostomy

Favor Crohnʼs

Subtotal colectomy

and ileostomy Anal sphinctersadequate Poor sphincterfunction

TPC and ileostomy

Proctocolectomy and ileopouch anal anastomosis and loop ileostomy

*

**

FIGURE 79-1 Legend: Indications for surgery IPAA= ileal pouch-anal anastomosis; TPC= total proctocolectomy.

*Absence of perianal or small bowel disease

**Presence of adverse/clinical/radiologic indicators.

458 / Advanced Therapy in Gastroenterology and Liver Disease

hospital stay and the 2-month normal recovery time

This is due to the combination of recovery from a major

abdominal procedure as well as from the obligatory

early excessive stool frequency accompanying a

one-stage operation due to undesirable consequences of

early postoperative sphincter function

Thus, we will consider the one-staged operation

3 Where there is no toxicity or features adverse to

tis-sue healing (prednisone dose <20 mg/d, diabetes,

immunosuppressive therapy)

4 Where the operation has proceeded effortlessly with

minimal blood loss (no transfusion requirement) and

hemostasis is considered excellent

5 Where there has been no difficulty in getting the pouch

to reach the anus without excessive tension

6 Where intact tissue rings (doughnuts) have been

obtained using the double stapled technique

7 Where on table pouch/anastomotic testing with air has

shown no anastomotic or pouch leak

Paradoxically, this may be the procedure of choice in

obese patients who cannot lose weight preoperatively In

those individuals, addition of a temporary ileostomy may

produce such tension on the superior mesenteric artery

(the determining factor for the ease of reach of the pouch

to the anus) that we believe the completed IPAA may be

excessively vulnerable to leak or disruption

In our recent review, patients who had one-stage pouch

procedure were younger, more often female, smaller in

body surface area, on lesser doses of steroids, and required

less blood transfusions at the time of their surgery than

those who had required ileostomy at the time of the IPAA

(Remzi et al, in press) We believe avoidance of diverting

ileostomy with these stringent criteria is pivotal to prevent

postoperative septic complications and potentially pouch

loss in the long term.*

OTHERPROCEDURES FORUC PATIENTS

1 Subtotal or total colectomy and ileostomy This is

pre-ferred in patients:

• Where there is a diagnostic dilemma (features that

are ambiguous for Crohn’s disease [CD] versus UC,

eg, patchy colonic disease, backwash ileitis)

• Patients on very large doses (eg, 50 to 60 mg/d) of

prednisone

• Patients with toxic colitis or megacolon

• Gross obesity, where ability to lose weight is

pre-cluded by high dose steroid

• Malnutrition, especially hypoalbuminemia

We prefer suturing the stapled-across rectosigmoid

stump to the distal aspect of the incision This places

the suture line extraperitoneally, and if breakdown atthe staple line occurs, drainage from the rectal stumpcan be controlled via a lower incisional fistula withoutthe patient becoming septic Following subtotal colec-tomy (STC) and ileostomy, and favorable histologyreview, patients may undergo completion proctectomyand IPAA some 5 to 6 months later

2 Total colectomy and ileorectal anastomosis: This may bethe procedure of choice in two situations, both requir-ing absence of florid or significant rectal disease

• Patients with distant metastases (liver, lung) wherecolon cancer complicates UC

• The young(er) woman who is anxious to maximizeher chances of child bearing

There is evidence that RP/IPAA with its necessary pelvic sions postoperatively will diminish fertility due to peritubal andperi-ovarian adhesions (Ording et al, 2002) Additionally, weusually do oophoropexy and apply hyaluronidase/methyl cel-lulose film (Seprafilm, Genzyme, Cambridge, MA) to thegonadal structures to limit such adhesions Patients mayundergo rectal resection and conversion to a pelvic pouch in 30

adhe-to 50% of cases—should disabling proctitis occur or rectal cer risk become significant with future pregnancies Following

can-RP and IPAA, we recommend cesarean section due to the risk

of sphincter injury with episiotomy or prolonged or difficultlabor.Although data from several sources attest to the early goodpouch function with vaginal delivery, the studies are flawed bythe lack of adequate follow up of pouch function in the middle-aged woman, many years“out”from IPAA (Juhasz et al, 1995)

3 TPC and ileostomy: This has been the standard gical treatment of UC and is appropriate when:

sur-• The patient is not unduly concerned about ing a permanent ileostomy

hav-• Anal sphincter function is poor We note however,that preoperative anal incontinence may be due tovery active rectal disease reflecting urgency, ratherthan true sphincter deficiency Such patients meritanal physiology testing, with particular emphasis

on resting pressure Values above 35 to 40 mm ofmercury do not contraindicate RP when the con-cern is preoperative sphincter function (Halverson

et al, 2002)

• Cancer of the lower third of the rectum is present

• There is a history of radiation to the abdomen andconcern for radiation enteritis at the time of thelaparotomy

• The patient is elderly Our studies show that whenpatients over the age of 70 years undergo RP/IPAA,although they perceive quality of life to be good/sat-isfactory, pad usage and continence is considerablygreater than in their younger counterparts Carefuldiscussion must be had with these older patientsbefore offering them RP (Delaney et al, 2002)

*Editor’s Note: Patients and referring doctors should, as stated,

realize that the period of adjustment postoperatively can last 4

months However, they have avoided an ileostomy.

Ileoanal Pouch Anastomosis / 459

The Current Operation of RP and IPAA

Indications

It follows that RP/IPAA is a suitable and preferred

opera-tion for patients where subtotal colectomy or TPC and

Brooke ileostomy are not indicated In general, these are

patients who:

• are in good condition mentally and physically

• have had no previous small bowel (SB) resections

• have good anal sphincter function

• are without evidence of CD, such as perianal fistula

(past or present)

• may be diagnosed of indeterminate colitis

• have no history of radiation to the abdomen

• may undergo RP with curative intent if colorectal

cancer is present

• are particularly eligible if portal hypertension is

pre-sent in association with UC (Kartheuser et al, 1996)

Issues and Controversies

POUCHCONSTRUCTION

A variety of pouch techniques and configurations have

been described including the J, S, W, and lateral

isoperi-staltic (H) types The functional results of these various

pouch designs appear to be comparable, where the J pouch

is easiest to construct and has functional outcomes

iden-tical to those of more complex designs (Johnston et al,

1996) We prefer the J pouch, as it is simple to make using

a linear stapler cutting technique, can be done rapidly in

≤5 minutes, and has no obstructive defecation sequelae

The S pouch is occasionally used when excessive

anasto-motic tension is predictable in a given patient It usually

reaches 2 to 4 cm farther than does the J pouch and is

use-ful in patients with a short fat mesentery, and long, narrow

pelvis when the reach of the ileal pouch to the anal canal

can be a problem In our practice, this is especially true in

patients who are obese or where mucosectomy and

hand-sewn anastomosis is indicated due to neoplasia Care is

exercised to limit the exit conduit to ≤2 cm as obstructive

defecation—necessitating pouch emptying by periodic

catheter intubation—may ensue

ANASTOMOTICISSUESThe two main ways in which the pouch can be joined to the

anal canal are by stapling and by hand sutured techniques

For a stapled anastomosis, it is necessary to leave a 1 to 2 cm

strip of anal transitional mucosa to allow transanal

inser-tion of the staple head This zone is usually referred to as

the anal transitional zone (ATZ) This creates a controversy,

which centers on the potential advantages and

disadvan-tages of leaving a mucosal cuff of rectal mucosa The

poten-tial advantages include better functional results, lower rate

of septic complications, and ease of construction, whereas

disadvantages include possible malignant or premalignanttransformation of the columnar epithelial cells in theretained mucosal cuff, cuffitis, and a longer, more difficultsurgery The prospective randomized trials have not shown

a difference in functional outcome and septic complicationsbetween the two methods (Sonoda and Fazio, 2000).However these studies warrant careful analysis, because ofrelatively short term follow up and because the small num-ber of cases studied make them vulnerable to type II error.Our initial studies comparing the two types of techniquesshowed less septic complications and better functional out-come favoring stapled anastomosis (Ziv et al, 1996) Themost recent study of over 2,000 patients from our institu-tion continued to show superior functional results inpatients with stapled anastomosis, where the septic com-plications showed some increased trend in mucosectomygroup but did not reach the statistical difference of the priorstudy from our institution (Remzi et al, 2002)

We believe that the major complication of pouchsurgery is sepsis secondary to anastomotic dehiscence andthis, in turn, is due to excessive anastomotic tension Webelieve, the least septic complication rates occur when theileal pouch is stapled to the top of the anal columns 1 to

2 cm above the dentate line

This ATZ is vulnerable to neoplastic and/or acute tomatic inflammatory change Our studies show that in theabsence of synchronous colonic carcinoma at the time ofindex TPC and IPAA for UC, the risk of dysplasia is negli-gible and cancer in the ATZ has yet to be reported From anoncogenic standpoint, stapled IPAA is therefore safe (Remzi

symp-et al, 2003) We do, however, recommend ATZ surveillanceand biopsy Our current recommendation for the manage-ment of risk of ATZ dysplasia and selection of type of anas-tomosis to be used in creation of IPAA is summarized inFigure 79-2 Further data is needed before this examinationfrequency can be relaxed, in our view For patients with syn-chronous colorectal cancer, dysplasia in lower two-thirds ofrectum or primary sclerosing cholangitis, postoperative ATZdysplasia is a substantial risk and complete anal mucosec-tomy is recommended at time of RP (Kartheuser et al, 1996;Remzi et al, 2003; Marchesa et al, 1997)

If a patient has undergone stapled IPAA for cancer plicating UC (usually first diagnosed in the colectomy spec-imen), then close follow up (eg, annual or 6-month biopsies)

com-is recommended We were successful in preserving the pelvicpouch in two patients who underwent late transanal muco-sectomy and pouch advancement for late development ofATZ dysplasia (Fazio and Tjandra, 1994) So, why not domucosectomy in every case? We believe that anal sphincterstretch is considerable and protracted when hand-sewn tech-niques with mucosectomy are used.This produces signifi-cant and prolonged reduction in resting sphincter tone and

is associated with higher rates (compared to stapled IPAA)

of nocturnal incontinence, seepage, and pad usage, by

Ileoanal Pouch Anastomosis / 461

IPAA, are often indicative of CD, although not always (Shah

et al, 2003) The management ranges from intermittent

antibiotic therapy (ciprofloxacin and metronidazole with

or without local seton drainage) pouch advancement

flap-through to repeat IPAA with fistula exclusion The latter is

used if the former is unsuccessful

Bowel Obstruction

Patients undergoing RP are at particularly high risk for SB

obstruction because of the combined abdominal and pelvic

dissection, the need for multiple operations, and the

pos-sibility of septic complications SB obstruction is the

com-monest reason for unplanned major re-operation on RP

patients, occurring in 10 to 20% of cases, half of which

require surgery to release the adhesion(s) causing the

obstruction (Fazio et al, 1995) So far, the only factor

asso-ciated with lessening this risk is ileostomy avoidance at the

time of pouch construction, but at the price of possible

sepsis, symptomatic anastomotic leak, and prolonged

patient adjustment with ileostomy avoidance

Evacuation Disorders

Strictures are usually secondary to fibrosis followed by partial

dehiscence of the IPAA or ischemia If severe, the stricture may

obstruct the outlet of the pouch and result in evacuation

prob-lems, pouch dilatation, and bacterial overgrowth The anal

canal typically narrows by some degree after IPAA Short

stric-tures at the anastomosis generally respond to careful

dilata-tion Many strictures are webs and can be either dilated by

fingers or dilators For this reason, either at the initial 6-week

postoperative visit or at the time of the ileostomy closure, it

has been our practice to perform a routine digital and

proc-toscopic assessment and dilatation We believe that this

prac-tice prevents fibrous webs from progressing to subsequent

stricture development Transanal stricture lysis is occasionally

necessary for recurrent short strictures Long strictures (>1

to 2 cm) require stricture excision and neopouch anal

anas-tomosis either transanally or by abdomino anal approach

Ischemia and sepsis are the two commonest causes.*

Long exit conduit of S or H pouches These

obstruc-tions are managed by intermittent catheter intubation

about 4 times a day If this is deemed disabling by the

patient or perforative complication occurs, repeat IPAA or

ileostomy is usually needed (Baixauli et al, 2004)

PARADOXICALPUBORECTALISCONTRACTION

This is an infrequent cause of evacuation disorder, often

associated with pouchitis Diagnosis is readily made with

electromyelogram or pouchography Biofeedback is

usu-ally successful but requires 4 to 6 sessions (Hull et al, 1995)

“Cuffitis” or Inflammation of ATZ

The preservation of ATZ after stapled anastomosis is meant

to optimize anal canal sensation, to minimize sphincter injuryand septic complications, and to maximize the preservation

of normal postoperative resting and squeeze pressures Thiszone is susceptible to inflammation (cuffitis) This rarelyreaches significant proportions, and can be managed by top-ical agents such as corticosteroids or 5-aminosalicyclic acid(5-ASA) preparations Patients with symptomatic cuffitishave similar symptoms to those with pouchitis However,bloody bowel movements are more commonly seen inpatients with cuffitis This problem rarely required the needfor further mucosectomy in our experience Also, in ourrecent experience with usage of topical mesalamine suppos-itories (500 mg twice daily) in 14 consecutive patients withsymptomatic cuffitis was safe and effective (Shen et al, 2003)

Pouchitis

This term covers a spectrum of symptomatic tory conditions of the ileal pouch mucosa We understandthis to be a syndrome combining histopathologic evidence

inflamma-of ileal pouch mucosal inflammation with clinical featurescharacterized by one or more of the following:

1 Significant increase in stool frequency above thepatient’s usual base level

2 Low grade fever and malaise

3 Bleeding

4 Dull pelvic pressure/painMost cases respond to metronidazole with or withoutciprofloxacin given over a 5 to 10 day period A chronic vari-ety of pouchitis is much less common We usually will treatsuch patients with initial long term (6 months plus) antibi-otic therapy Probiotics have been used to replace long termantibiotics in some patients If there is little or no response,

we will use, 5-ASA orally and/or by enema The next ter (Chapter 80,“Crohn’s Colitis”) details treatment of pou-chitis, including a discussion of CD in IPAA Occasionallyileostomy with pouch excision is necessary

chap-IRRITABLEPOUCHSYNDROMEDiarrhea, abdominal pain, urgency, and pelvic discomfortare common after surgery Pouchitis with those symptoms

is the most common long term complication However,these most frequently reported symptoms in patients withIPAA are not specific for pouchitis Shen and colleagues(2001) showed that symptom assessment alone is not suf-ficient for the diagnosis of pouchitis, and that pouchendoscopy and biopsy may be required for diagnosis Based

on symptom, endoscopy and histology assessment usingthe Pouchitis Disease Activity Index criteria (the most com-monly used and validated diagnostic instrument for pou-chitis), we examined 61 consecutive symptomatic patientswith UC and IPAA, and found that 43% of patients with

*Editor’s Note: Regular anal examinations and dilatation, if

needed, has been used by some surgeons after mucosal stripping to

lessen stricture occurrence (Sitzmann et al, 1999).

462 / Advanced Therapy in Gastroenterology and Liver Disease

symptoms suggestive of pouchitis had no endoscopic or

his-tologic evidence of pouchitis or cuffitis These patients have

a condition resembling irritable bowel syndrome (IBS),

which we termed it irritable pouch syndrome (IPS) (Shen

et al, 2002)

IPS is common in patients with IPAA, and this new

dis-ease category has become increasingly recognized Patients

with IPS comprise a substantial portion of outpatient clinic

visits in tertiary care centers Clinical features of

pouchi-tis, cuffipouchi-tis, and IPS overlap, with the most common

symp-toms being increased stool frequency, abdominal cramps,

and pelvic discomfort The only way to differentiate the

three disease entities is by pouch endoscopy Patients with

IPS also share clinical features of IBS, such as abdominal

pain, bloating, urgency, and pelvic discomfort, which are

largely relived with defecation Similar to IBS, weight loss,

bloody bowel movement, and fever are not features of IPS

In a recent study, we found patients with IPS, similar to

those with pouchitis or cuffitis, had significantly poorer

quality of life scores than patients with normal pouches

Appropriate diagnosis and treatment are important for

improving a patient’s quality of life Currently, the

diag-nosis of IPS is based on the exclusion of structural and

inflammatory conditions (such as pouchitis, cuffitis,

anas-tomotic stricture or CD) using pouch endoscopy We

pre-fer the test-first strategy with diagnostic pouchoscopy

rather than the treat first strategy (empiric antibiotics for

5 to 7 days) in the management of patients who present

pouchitis-like symptoms We have recently shown that

test-first strategy with pouch endoscopy without biopsy is cost

effective and it avoids both diagnostic delay and adverse

effects associated with unnecessary antibiotics (Shen et al,

2003) If a patient has symptoms of abdominal or perianal

pain, diarrhea, or pelvic discomfort while having a normal

pouch endoscopy, he or she is diagnosed as having IPS

There are no published controlled drug trials for the

treatment of patients with IPS In our institution, we have

adopted some safe and effective drug regimens in patients

with IBS to treat patients with IPS The first line therapy

includes low dose antidepressants and antispasmodic

agents We believe that safer and more effective agents will

become available once we learn more about the cause and

mechanism of this new disease.*

Postoperative Management

After RP and IPAA with loop ileostomy, patients invariablyhave high ileostomy outputs of from 1,000 to ≥2,000 ccper 24 hours Effectively the “high” ileostomy bypasses

≥20% or more of the distal SB and this sets the stage fordehydration The following advice is given our patients:

• Be aware of added risk factors for dehydration (hotweather, exercise, air conditioning)

• Be aware of symptoms of dehydration (ie, lassitude,fatigue, headache, nausea)

• Maintain intake of adequate oral liquids, especiallysalty soups, electrolytes supplements Minimize caf-feine intake

• Avoid high solid fiber/indigestible foods for 6 weeks(as with all new ileostomates)

• Use bulking agents (eg, Konsyl, Citrucel, Metamucil)

• Use liquid loperamide or atropine diphenoxylatedosed on a weight basis to thicken enteric output

• Be aware of the fact that external ileostomy pouchesmay stay on for only 2 days or so (compared with 5

to 7 days for end ileostomies) Loop ileostomies tend

to be flush with the skin

• Follow the steroid-tapering schedule prescribed ondischarge

• Recognize symptoms of post discharge bowelobstruction

• After the ileostomy is closed, a similar program isinstituted

Long-Term Follow-Up

In patients with ATZ preservation, recommendations for low up surveillance are outlined in Figure 79-2 It should benoted that not all patients reported to have total mucosec-tomy in fact have had this done Theoretically, if the patienthas undergone mucosectomy as part of the RP and remainswell, no follow-up is necessary after bowel function has sta-bilized (usually within 6 to 12 months) Although stapledanastomosis with ATZ preservation has been the focus of risk

fol-of neoplasia, the majority fol-of the described cases fol-of carcinoma in UC patients arising at the pouch anal anasto-mosis have been in those who had undergone mucosectomy(Ooi et al, 2003) The answer may relate to the longevity ofthe follow-up and the number of patients in each group It islikely that diseased epithelium was left behind by incompletemucosectomy Thus mucosectomy with a hand-sewn anas-tomosis may give a false sense of security as compared to sta-pled anastomosis where good visualization and biopsy of theATZ can be performed Thus these patients may be vulner-able to ATZ neoplasia development as monitoring is rarelydone, least of all with biopsy surveillance As a separate issue,patients with a chronic type of pouch inflammation, char-acterized by severe villous atrophy and crypt hyperplasia, may

adeno-be vulnerable to the complications of pouch “colon-ization”,

*Editor’s Note: Sometimes a “predict-first” strategy is helpful

because some of the IBS patients give a very clear history of

irrita-ble bowel type symptoms for many years before they developed

recognized UC Because the small bowel is also “irritable”, an IPAA

may not be the best option for such patients (Bayless), one can

expect more than 10 evacuations per day in some because the

irri-table or “spastic” pouch can only hold 90 to 100 cc in contrast to

the “normal” pouch capacity of 300 to 400 cc In addition, the

patient with irritable pouch can only expel half of the diminished

pouch contents, thus this patient may have more than 10

move-ments per day (Schmidt et al, 1996) The next chapter (Chapter 80,

“Crohn’s Colitis”) has more details in high output IPAAs.

Ileoanal Pouch Anastomosis / 463

including dysplasia This type C pouch inflammation has been

reported to develop such dysplasia (Gullberg et al, 1997) Also,

the recent reports of the malignant potential of the pouch

mucosa itself do not eliminate the necessity of pouch

sur-veillance (Ooi et al, 2003) Thus we recommend that all of our

patients have pouch surveillance and biopsy at regular

inter-vals There is no good data as to how frequently this should

be done, but every 2 to 3 years seems reasonable unless risk

factors for dysplasia in the preserved ATZ are significant, in

which case prudence dictates a closer surveillance schedule

Conclusion

Our long-term follow-up of pouch function and quality of

life indicates a very high degree of acceptance and

happi-ness level of the patients undergoing restorative

procto-colectomy This is on a par with age and sex matched US

citizens using SF36 assessment tool (Fazio et al, 1999) Bowel

movement frequency ranges from 3 to 9 per 24 hours,

aver-aging 6 times per day This however is not a good

indica-tion of success as many patients will evacuate their pouches

when it is convenient to do so, rather than defer defecation

Urgency, defined as inability to defer defecation for 15

min-utes, is a major concern for many patients preoperatively,

yet invariably this is negated by the pouch procedure (the

exception is when patients develop pouchitis)

Pad use, either due to need or for sense of security,

increases with age, episodes of pouchitis, and the

propor-tions of patients with mucosal stripping of the anal canal

as well as decreasing sphincter function Operative

mor-tality remains <0.5%, and we have reported impotence

rates of<1% (Fazio et al, 1995) Although dyspareunia may

occur post–pouch construction (Bambrick et al, 1996),

overall, there is an improvement in female sexual function

post-pouch compared to pre-pouch There are some

reports of infertility post-TPC

Perhaps the most singled out problem of the pelvic

pouch procedure is that of pouchitis; by eliminating one

disease, the patient is set up for another! Yet this has to be

viewed with the perspective that 90% of pouchitis cases are

transient and easily treated and that <10% of patients are

subject to repeated episodes Also, patients, in their quest

for preservation of their anal function, understand and

gen-erally believe they get a good deal with the trade off of RP

In conclusion, IPAA provides a very satisfactory

qual-ity of life and functional outcome in patients who require

proctocolectomy for their disease Patients <45 years of

age at the time of surgery experience the best functional

result Careful discussion of the procedure and outcome

with individual patients allows prudent case selection,

yielding a high percentage of patients of all ages who are

happy with their postoperative outcome and are happy to

recommend it to other patients with the same diagnosis

(Delaney et al, 2003)

Supplemental ReadingBaixauli J, Delaney CP, Wu JS, et al Functional outcome and quality of life after repeat ileal pouch-anal anastomosis for complications of ileoanal surgery Dis Colon Rectum 2004;47:2–11.

Bambrick M, Fazio VW, Hull TL, et al Sexual function following restorative proctocolectomy in women Dis Colon Rectum 1996;39:610–4.

Bayless TM Coexistant ir r itable bowel syndrome and inflammatory bowel disease In: Bayless TM, Hanauer SB, editors Advanced therapy of inflammatory bowel disease Hamilton (ON): BC Decker; 2001.

Delaney CP, Dadvand B, Remzi FH, et al Functional outcome, quality of life, and complications after ileal pouch-anal anastomosis in selected septuagenarians Dis Colon Rectum 2002;45:890–4.

Delaney CP, Fazio VW, Remzi FH, et al Prospective, age-related analysis of surgical results, functional outcome, and quality

of life after ileal pouch-anal anastomosis Ann Surg 2003;238:221–8.

Fazio VW, O’Riordain MG, Lavery IC, et al Long term functional outcome and quality of life after stapled restorative proctocolectomy Ann Surg 1999;230:578–86.

Fazio VW, Tjandra JJ Transanal mucosectomy; ileal pouch advancement for anorectal dysplasia or inflammation after restorative proctocolectomy Dis Colon Rectum 1994;37:1008–11 Fazio VW, Ziv Y, Church JM, et al Ileal pouch anal anastomosis: complications and function in 1005 patients Ann Surg 1995;222:120–7.

Gullberg K, Stahlberg D, Liljeqvist L, et al Neoplastic transformation

of the pelvic pouch mucosa in patients with ulcerative colitis Gastroenterology 1997;112:1487–92.

Halverson AH, Hull TL, Remzi FH, et al Perioperative resting pressure predicts long-term postoperative function after ileal pouch-anal anastomosis J Gastrointest Surg 2002;6:316–20 Hull TL, Fazio VW, Schroeder T Paradoxical puborectalis contraction in patients after pelvic pouch construction Dis Colon Rectum 1995;38:1144–6.

Johnston D, Williamson MER, Lewis WG, et al Prospective controlled trial of duplicated (j) versus quadruplicated (W) pelvic ileal reservoirs in restorative proctocolectomy for ulcerative colitis Gut 1996;39:242–7.

Juhasz ES, Fozard B, Dozois RR, et al Ileal pouch anal anastomosis function following childbirth: an extended evaluation Dis Colon Rectum 1995;38:159–65.

Kartheuser AH, Dozois RR, LaRusso NF, et al Comparison of surgical treatment of ulcerative colitis associated with primary sclerosing cholangitis: ileal pouch-anal anastomosis versus Brooke ileostomy Mayo Clin Proc 1996;71:748–56 Marchesa P, Lashner BA, Lavery IC, et al The risk of cancer and dysplasia among ulcerative colitis patients with primary sclerosing cholangitis Am J Gastroenterol 1997;92:1285–8 Ooi BS, Remzi FH, Gramlich T, et al Anal transitional zone cancer follow ing restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis Dis Colon Rectum 2003;46:1418–23.

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compared with a population sample Gastroenterology

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ulcerative colitis BMJ 1978;2:85–8.

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functional outcome and quality of life in patients undergoing

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anastomosis (IPAA) Presented at the Tripartite Colorectal

Meeting; 2002 Oct 27–30; Melbourne, Australia.

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treatment outcome of pouch-vaginal fistulas following

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Shen B, Achkar JP, Lashner, et al Irritable pouch syndrome: a new

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pouch-anal anastomosis Am J Gastroenterol 2002;97:972–7.

Shen B, Achkar JP, Ormsby AH, et al Endoscopic and histologic evaluation together with symptom assessment are required for diagnosis of pouchitis Gastroenterology 2001;121:261–7 Shen B, Lashner BA, Bennett A, et al Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following total proctocolectomy and ileal pouch-anal anastomosis Presented at the 67th Annual Meeting of American College of Gastroenterology; 2003 Oct 12; Baltimore (MD) Shen B, Shermock KM, Fazio VW et al A cost-effectiveness analysis

of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis Am J Gastroenterol 2003;98:2460–7 Sitzmann JV, Buano RC, Bayless TM Rectal squamous- mucosectomy and ilo-anal pull through procedures Single Surgeon Experience in 105 patients In: Becker J, editor Med problems in general surgery Philadelphia: Lippincott 1999:115–23.

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464 / Advanced Therapy in Gastroenterology and Liver Disease

including mucosal healing), to improve quality of life, and

to optimise timing of surgery if and when an operation

proves necessary to achieve the aforementioned General

treatment measures include correction of anemia and

nutritional deficiencies, antidiarrheal medications if

required, and cessation of smoking if at all possible

Infectious complications, in particular Clostridium

diffi-cile, should be excluded Specific medications used depend

on disease features such as site, extent, severity, presence of

extra-intestinal manifestations or complications, disease

behaviour (inflammatory, fibrostenosing or fistulizing),

and previous response to different classes of drugs The aim

is to deliver the maximum dose of the drug to the site of

maximal mucosal inflammation

Medical Management

Figure 80-1 shows a treatment algorithm for induction and

maintenance medical therapy for Crohn’s colitis, which for

simplicity and practicality divides severity into either

mild/moderate or severe disease

Mild/Moderate Acute Crohn’s Colitis

AMINOSALICYLATESAlthough debate continues regarding the role of aminosali-

cylates for the treatment of mild-moderate CD, there is good

evidence that sulfasalazine is efficacious for the treatment of

colonic CD There is less substantial evidence for alternative

mesalamine agents Nevertheless, the aminosalicylates are

advocated as a first line therapy for mild-moderately active

CD The use of sulfasalazine in divided doses of 3 to 6 g/d,

supported by the National Cooperative Crohn’s Disease Study

(NCCDS), is compromised, in up to 25% of patients, by side

effects attributable to the sulfapyridine carrier molecule, such

as headache, nausea, GI upset, and, in males, a transient

reduction in number and motility of sperm Rare but more

serious hypersensitivity reactions include hemolytic anemia,

neutropenia, rash, and hepatitis In contrast to UC, where

alternative azo bond delivery systems such as olsalazine and

balsalazide are effective alternatives, in Crohn’s colitis these

agents have not been shown to be effective There is more

evi-dence, however, that alternative mesalamine formulations are

comparable to sulfasalazine or antibiotics in Crohn’s colitis,

but less efficacious than corticosteroids Mesalamine in doses

up to 4.8 g/d has a similar side effect profile as placebo in

clin-ical trials Also, despite general use, there is scant available

data regarding the utility of rectal mesalamine suppositories

(1 to 1.5 g/d) for Crohn’s proctitis or mesalamine enemas (1

to 4 g/d) for left-sided colitis

ANTIBIOTICS

Metronidazole (0.75 to 2 g/d) and ciprofloxacin (1 g/d), alone

or in combination, are also commonly used as an alternative

or in addition to aminosalicylates for mild-moderate colonic

CD, particularly for patients with accompanying perianal ease or for individuals who have failed to respond to amino-salicylates and are not “sick enough” to warrant corticosteroidtherapy Colonic disease responds better to antibiotics than

dis-small bowel disease, and metronidazole is effective in treating

perianal CD The Cooperative Crohn’s Disease Study in

Sweden (CCDSS) showed 800 mg daily of metronidazole to

be successful in Crohn’s colitis that had failed to respond tosulfasalazine Approximately 55% or patients randomized to

ciprofloxacin, 1 g/d, or mesalamine, 4 g/d, will respond with

clinical remissions The combination of sulfasalazine and

cor-ticosteroids in the European Cooperative Crohn’s Disease

Study and a combination of antibiotics with budesonide are

more effective that either agents alone for patients with CD

of the colon

CORTICOSTEROIDS

Corticosteroids are effective inductive therapies for patients

with moderate-severe Crohn’s colitis or for patients withmild-moderate disease that has not responded to amino-

salicylates and/or antibiotics Controlled release budesonide

formulations are also efficacious for mild-moderate CDinvolving the right colon, but are not effective for more dis-

tal colonic disease Doses of 40 to 60 mg daily of prednisone

(or up to 1 mg/kg/d) are initiated until a clinical responsehas been established Subsequent tapering is “individual-ized” according to the rate of response Generally, thedosage is gradually reduced by 5 mg/week until the drugcan be ceased or symptoms flare In the NCCDS, 78% ofpatients responded to steroids given in this way Theresponse to budesonide is somewhat less and neither sys-temic nor nonsystemic steroids are efficacious at prevent-ing relapse Indeed, after a course of corticosteroids,approximately 75% of patients will either have a flare of

disease activity or become steroid-dependent within a year.

The use of corticosteroids is further limited by their nificant acute and chronic side effect profiles, includingshort term side effects of emotional lability, insomnia,hypertension, glucose intolerance, and acne; and long termcomplications that include cataracts, accelerated osteo-porosis, avascular necrosis, and growth impairment in chil-dren Glucocorticoid side effects are significantly reduced

sig-with budesonide formulations, but there is still a risk for

systemic side effects, particularly if the 9 mg dosage is used

as maintenance therapy There is substantial empiric use,

but no clinical trial data regarding the efficacy of topical

(rectal) steroid applications for Crohn’s colitis.

NUTRITIONALTHERAPIESNutritional therapy with elemental or polymeric oral orenteral feeding has been shown to be beneficial to smallbowel CD, but the benefits for Crohn’s colitis have yet to

468 / Advanced Therapy in Gastroenterology and Liver Disease

with an incomplete response to corticosteroids are

candi-dates for infliximab therapy, usually given as an

outpa-tient, whereas those presenting with severe-fulminant

symptoms or evidence of an abscess or peritioneal signs

require hospitalization

INFLIXIMABAnti-TNF therapy with the chimeric monoclonal antibody,

infliximab, has been embraced as an inductive and

main-tenance therapy for patients with active luminal CD not

responding to the above therapies (steroid-refractory or

dependent) or for patients with fistulizing disease

Enthusiasm for its’ efficacy must be tempered by knowledge

of the potentially serious side effects, limitations in

avail-ability due to its high cost, and need for long-term therapy

The clinical response is rapid and usually noted within the

first days or weeks after infusion Up to 80% of patients with

active CD will respond and over 50% of patients with

fis-tula have complete cessation of drainage after a series of

infusions at 0, 2, and 6 weeks with 5 mg/kg doses

Infliximab should be administered initially, at a dose of

5 mg/kg with the 3-dose induction regimen to reduce

immunogenicity, and the majority of patients who respond

will require continued maintenance therapy at an average

interval of every 8 weeks There is growing recognition and

acceptance that concurrent administration with an

immunomodulator and/or corticosteroids improves the long

term outcome of therapy by reducing

antibody-to-infliximab formation Potential side effects include

immunogenicity to infliximab, development of

autoanti-bodies, and the risk of opportunistic infections.*

Up to 3% of patients develop an acute, anaphylactoid,

infusion reaction that can usually be managed conservatively

by temporarily stopping the infusion, treatment with

diphen-hydramine, and restarting the infusion at a slower rate The

acute infusion reactions have been associated with

anti-infliximab antibodies and are also associated with decreased

duration of response to infliximab The acute infusion

reac-tions are in contrast to delayed hypersensitivity reacreac-tions that

occur in up to 19% of patients, many of whom who have

had a significant delay of many months to years between

infusions This serum sickness-like reaction is thought to be

due to the development of high-titer, infliximab

anti-bodies The incidence of antibodies to infliximab is reduced

by concomitant corticosteroids, azathioprine (AZA) or

6-mercaptopurine (6-MP) administration, and continuous

rather than episodic administration

Infliximab and other anti-TNF agents have also been

asso-ciated with increasing titers of antinuclear and anti-double

stranded DNA (dsDNA) antibodies that, rarely, can be

asso-ciated with a drug-induced lupus syndrome that resolves with

discontinuation of anti-TNF therapy Immunosuppression

and opportunistic infection can occur, particularly

intracel-lular infections such as Mycobacterium tuberculosis,

histo-plasmosis, cryptococcidiosis, and listeriosis, related toanti-TNF therapy such that skin testing and chest radiographsare recommended prior to initiating therapy with infliximab

or other anti-TNF agents

CYCLOSPORINE

Cyclosporine, used successfully in severe UC, can also be

used in colonic CD Continous intravenous infusion atdoses of 2 to 4 mg/kg/d may avoid colectomy, although oraldosing has not proved effective for either induction ormaintenance of remission Immunosuppression andnephrotoxicity are the primary side effects Renal functionand serum drug levels must be monitored regularly Othersignificant side effects are hypertension, seizures (especially

in hypocholesterolemic patients) (< 120 mg/dL), andopportunistic infection

Refractory Disease and Steroid-Dependent Disease

In patients whose disease becomes either steroid-resistant

or steroid-dependent, additional immunomodulatorydrugs have been shown to be effective in inducing remis-sion, reducing corticosteroid doses, or avoiding surgery.The purine antimetabolites AZA and 6-MP, are the firstline choices in this regard, but alternatives exist if patientsare unresponsive or intolerant to these drugs

The purine antagonists AZA (2.0 to 2.5 mg/kg daily) and

6-MP (1.0 to 1.5 mg/kg daily) have become accepted

ther-apies for steroid-dependent CD and to maintain remissionafter steroid-withdrawal Because of the high risk of relapse

or steroid-dependence they should be introduced with thefirst evidence of steroid-dependence (relapsing symptomsduring or shortly after steroid-tapering) Cochrane analy-ses have confirmed their utility for inductive therapy whencoadministered with steroids and for maintenance ofremission after steroid tapering Historical concerns regard-ing potential side effects have been abrogated by theexpanding experience with these agents over the pastdecade Still, debate continues regarding optimization ofdosing according to a mg/kg schedule, monitoring of thewhite blood cell count or measurement of the thioguaninemetabolites All methods have been successful and nonehas been evaluated prospectively, as yet, with pre-definedoutcomes These agents are generally well tolerated,although up to 20% of patients discontinue therapy due tosome form of intolerance, usually nausea or abdominalpain Pancreatitis occurs in 3 to 15% of patients after sev-eral weeks of therapy, resolves spontaneously on their ces-sation, but recurs again with reintroduction of either agent.Bone marrow suppression, particularly neutropenia, is dose

*Editors Note: Some physicians utilize azathioprine or

methotrex-ate therapy before starting infliximab.