Advanced Therapy in Gastroenterology and Liver Disease - part 6 pdf

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
n
utrient 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 chloride, 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.
INTRAVENOUS REPLACEMENT
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-
me
nt o
f 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 ␣
2
-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 contact

t
ime between intestinal luminal contents and the mucosa,
increasing absorption. Experimentally, opiates have proab-
sorptive and antisecretory effects, but it is unclear if these
mechanisms are operative in humans. Synthetic opioids such
as Lomotil (2.5 mg diphenoxylate plus 25 µg atropine per
tablet) and loperamide (Imodium) (2 mg/tablet) have fewer
central 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 times
daily
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 substances
because of their potential for misuse or addiction. At high
doses, Lomotil can also cause CNS side effects, whereas lop-
eramide, because it does not cross the blood-brain barrier as
efficiently, has fewer side effects at higher doses.
The main side effects from the use of opiates are abdom-
inal discomfort, constipation, nausea, vomiting, and CNS
symptoms (drowsiness, respiratory depression, and altered
mental status). Lomotil, because of the presence of
atropine, can cause anticholinergic side effects. Physical
dependence can occur with prolonged use, although it is

reduced with Lomotil by combining the diphenoxylate
with atropine.
Long-Acting Somatostatin Analogues
Octreotide and lanreotide are synthetic analogues of somato-
statin that, because they are much more resistant to degra-
dation than native somatostatin, have a much longer
duration 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
cause
d by
car
cinoid syndrome
.
These somatostatin analogues
inhibit both the ectopic release of hormones and neuro-
transmitters by these tumors and secretion from the large
and smal
l intestine stimulated by a number of agents
(prostaglandin E
1
, serotonin, VIP); they also stimulate
sodium chloride absorption in animal studies. Because of
these a

ctions, somatostatin analogues have been used to treat
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-
c
iated with acquired
i
mmune deficiency syndrome
(A
IDS
)
,
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”).
O
CTREOTIDE
Treatment 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 w
hic
h 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 o

ctreotide-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 somato-
statin analogues include cramping or nausea, which usu-
ally resolve with continued treatment, and pain at the
subcutaneous injection site, which may be reduced by slow
i
njection and warming the vial. Worsening of glucose tol-
erance develops in some patients, and it is advisable to
obtain a serum glucose determination when beginning the
medication. A small percentage of patients may develop fat
malabsorption. Long term, the principal side effect is the
development of
biliary sludge or gallstones, thought to be
due to the ability of somatostatin to inhibit gallbladder
emptying. In various studies with long-term treatment, 10
to 50% of patients have developed biliary sludge or gall-
stones, but in only 1 to 10% is it symptomatic. With long-
term treatment, an ultrasound examination of the
gallbladder before the treatment and every 6 to 12 months
should be considered (Redfern and Fortuner, 1995).
␣
2
-Adrenergic Agents
CLONIDINE

These 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 treat
diarrhea associated with short bowel syndrome, usually in
combination with opiates. Clonidine is usually started at
0.1 mg/d and increased slowly to 0.1 to 0.3 mg 3 times a
day. A major limitation to the use of clonidine is its anti-
hypertensive effect mediated centrally, resulting in postural
hypotension. Clonidine should be reserved for patients
with SDs that are refractory to opiates. When clonidine is
discontinued, the dose should be tapered slowly over 3 to
5 da
y
s to avoid rebound symptoms (hypertension, nausea,
vomiting, headache). This agent is discussed in the chap-
ter on diabetic diarrhea (Chapter 71, “Management of
Diabetic Diarrhea”).
Glucocorticoids
Glucocorticoids stimulate absorption of water and elec-
trolytes and have been used in refractory patients with
VIPomas. The recommended dose is 60 mg of prednisone
per day. If it is effective, the dosage can be decreased to
the lowest level controlling the diarrhea. Glucocorticoids
are now rarely needed with the availability of the somato-
statin analogues, which are effective acutely and long term
in most patients with VIPomas.
Prost
aglandin Synthetase Inhibitors
T

hese agents have been used in a number of SDs because
prostaglandins stimulate water and electrolyte secretion.
Indomethacin has been reported to be effective in a small
n
umber of patients with SDs.
428 / Advanced Therapy in Gastroenterology and Liver Disease
Other Agents
A
bsorbent 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
I
n the 32 to 84% of patients with carcinoid syndrome with
diarrhea, similar to patients with medullary thyroid can-
cer or thyrotoxicosis, the diarrhea is primarily caused by
increased intestinal motility and increased fluid and elec-
trolyte secretion. These actions are mediated in part by sero-
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 midgut
carcinoid (75 to 87%), foregut (2 to 9%), or hindgut (1 to
8%) 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 decreasing
release of serotonin (5-hydroxytryptamine [HT]) and
other 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 and
also 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 unresectable
because 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 Mastocy
tosis
In the 23 to 43% of patients with systemic mastocytosis, the
diarrhea 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 sys-
temic mastocytosis. The diarrhea in these patients is usu-
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 a
smal
l number of patients with systemic mastocytosis. In
patients with the malignant forms of mastocytosis, treat-
ment with interferon alpha-2b, as well as chemotherapy and
c
orticosteroids
,
has been used (Jensen, 2000).
Secretory Diarrhea / 429
Surreptitious Use of Laxatives or Diuretics
P
atients with a
f
actitious cause
f
requently 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”).
Supplemental Reading
Farthing MJ. Novel targets for the control of secretory diarrhea.
Gut 2002;50:III15–8.
F
ried M. Octreotide in the treatment of refractory diarrhea.
Digestion 1999;60:42–6.
Jensen RT. Overview of chronic diarrhea caused by functional neu-
roendocrine neoplasms. Semin Gastrointest Dis 1999;10:156–72.
J
ensen RT. Gastrointestinal abnormalities and involvement in sys-
t
emic mastocytosis. Oncol Hematol Clin North Am
2000;14:579–623.
Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syn-
drome. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors.
C
ancer: principles and practice of oncology. Philadelphia:
Lippincott Williams & Wilkins; 2001. p. 1813–33.
O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of carci-
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.
Redfern JS, Fortuner WJ II. Octreotide-associated biliary tract
dysfunction and gallstone formation: pathophysiology and
manag
ement. 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.
430
CHAPTER 73
REDUCING CARDIOVASCULAR RISK WITH
MAJOR SURGERY
MICHAEL Y. CHAN,MD,AND STEPHEN C. ACHUFF,MD
Similarly, patients who are asymptomatic with one or more
coronary risk factors but who do not have established CAD
also have been shown to be at very low risk. The excep-
tion is diabetic patients; those with long standing diabetes
are 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 pres-
ence of underlying heart disease
7. Supraventricular arrhythmias with uncontrolled
ventricular rate

8. Severe valvular disease
If any of these major indicators are present, considera-
tion should be given to delaying or canceling nonemergent
surgery until medical stabilization can be achieved.
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-
o
p
erative 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
Underg
oing Noncardiac Surgery and Indications for Use
of P
erioperative
β
β
-Blocker
Therapy
Odds Ratio Perioperative
Risk Factor
(95% CI)*

β-Blocker Indicated
Ischemic heart disease
†
2.4 (1.3 to 4.2) Yes
CHF 1.9 (1.1 to 3.5) Yes
High risk sur
ger
y
‡
2.8 (1.6 to 4.9)
Uncer
tain, but pr
obably
Diabetes mellitus
3.0 (1.3 to 7.1) Yes
(especially insulin-requiring)
Renal insufficiency 3.0 (1.4 to 6.8) Uncertain, but probably if
renal insufficiency is due to
diabetes or vascular
disease
Poor function status
§
1.8 (0.9 to 3.5) Yes, if poor status is thought
to be due to CAD or heart
failur
e
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 hear
t disease includes angina and prior myocar
dial infar
ction.
‡
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
s
ignificantly 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 carrying a bag of groceries or walking
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
st
r
ess 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
b
efore 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 and
m
oderate to excellent functional capacity can gener-
ally undergo intermediate-risk surgery with low like-
lihood of perioperative death or MI. On the other
hand, further cardiac testing is often necessary in
patients with low functional capacity or those under-
going high risk procedures.
Step 7: Noncardiac surgery is generally safe for patients
with low risk predictors (ie, advanced age, abnormal
electrocardiogram [eg, left ventricular hypertrophy
(LVH), left bundle branch block (LBBB), or ST-T
changes], rhythm other than sinus [eg, atrial fibrilla-
tion], history of stroke, or uncontrolled systemic
hypertension) with moderate to high functional capac-
ity (
≥ 4 METs).
Step 8: The results of noninvasive testing can be used to
determine 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 pro-
posed noncardiac surgery. This approach may be
appropriate, however, if it increases the long term prog-
nosis of the patient.

Noninvasive Testing
Although a careful history and physical examination are
the 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 the
test 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 prognostic
information. The main limitation of ECG exercise testing
is that only about half of the patients tested achieve peak
exercise heart rates > 75% of the age-predicted maximum
(Cohn and Goldman, 2003). Ischemia induced by low level
exercise identifies a subset of patients at particularly high
r
isk. H
o
w
ever, a negative test in a patient who achieves the
target blood pressure–heart rate product ratio predicts a
low risk for perioperative complications.
Pharm
acologic Stress
T
esting
Pharmacologic stress testing with imaging, primarily dobu-
tamine st
r

ess 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. The
p
osit
i
v
e predictive value for thallium (4 to 67%) and DSE
(7 t
o 23%) are much lower. The choice of the optimal test
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
sho
c
k 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-
ular
ly 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 clotting
status is maintained for more than 5 to 7 days. Fortunately,
the risk is relatively low if this time range is respected.
T
he simplest strategy for managing warfarin in the face
of upcoming surgery is to discontinue the drug 2 or 3 days
preoperatively, 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 conservative
approach from the standpoint of preventing prosthetic
valve thromboembolic complications is to give heparin or
low molecular weight heparin up to 6 hours preoperatively,
and then again beginning 18 to 24 hours postoperatively
until warfarin levels are therapeutic (Katholi et al, 1978).
The latter approach may be preferable in patients with
mechanical 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 cardi-
ology consultation is the discovery of an arrhythmia on
routine ECG or the detection of some pulse irregularity on
examination. This should prompt a careful search for
underlying cardiopulmonary disease, drug toxicity, or

metabolic abnormality (Eagle et al, 2002). In the majority
of patients, these abnormalities are either intrinsically
benign or are a marker of a correctable problem such as
diuretic-induced hypokalemia or a relative excess of an
antiarrhythmic agent (eg, digoxin). Therapy is indicated
for symptomatic or hemodynamically significant arrhyth-
mias (Eagle et al, 2002). Patients already on chronic oral
antiarrhythmics should be maintained on their usual
dosages that give standardized therapeutic blood levels up
t
o the t
ime of surgery and then have them reinstituted as
promptly as possible postoperatively.
Several studies have demonstrated that frequent pre-
mature ventricular contractions or nonsustained ventric-
ular tachycardia do not increase the risk for nonfatal MI or
cardiac death in the perioperative period; therefore, aggres-
sive monitoring or treatment is not recommended (O’Kelly
et al, 1992; Mahla et al, 1998; Eagle et al, 2002). In the set-
ting of a patient with an implantable cardiac defibrillator,
the device should be programmed off immediately before
surgery and reprogrammed on postoperatively (Eagle et
al, 2002).
Perioperative Management
β
β
-Blockers
S
everal recent trials have evaluated the benefit of medical
therapy initiated in the preoperative setting in reducing

cardiac events. Mangano and colleagues (1995) conducted
a r
andomized 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
w
ere 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).
α
α
-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 pat
ients 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 was
seen in patients undergoing both general and vascular
surgery.
Overall, perioperative clonidine may have a similar effect
o
n myocardial ischemia, infarction, and cardiac death as peri-
operative β-blockers, but further research is needed before
its role in perioperative management can be fully elucidated.
Summary
In summary, preoperative risk stratification should be
undertaken with consideration of the patient’s clinical
markers, 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 undergoing
nonemergent 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 coronary
revascularization are the same as in the nonpreoperative
setting. Lastly, perioperative
β-blockers should be used in
all patients with intermediate or high risk of cardiac com-
plications in whom they are not absolutely contraindicated.
Supplemental Reading
Badner 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
f
o
r Perioperative Cardiovascular Evaluation for Noncardiac
S
urg
e
ry—Executive Summary. A report of the American
C
ol
lege of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee to Update the 1996
Guidelines on Perioperative Cardiovascular Evaluation for
N
o
ncardiac Surgery). Circulation 2002;12;105:1257–67.
Fleisher LA, Eagle KA. Lowering cardiac risk in noncardiac
s
urge
ry. 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.
K
atholi RE,
N

olan 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
p
r
ospective 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
d
y
sr
h
ythmias in patients with structural heart disease undergoing
no
ncardiac surgery. Anesth Analg 1998;86:16–21.
434 / Advanced Therapy in Gastroenterology and Liver Disease
M
angano 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
p
atients undergoing noncardiac surgery. The Study of
P
erioperative 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.
O
liver 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
C
ardiac 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.
R
eilly 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
c
ompared with open surgical commissurotomy for mitral
s
tenosis. 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.
S
tuhmeier 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.
U
rban 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.
435
CHAPTER 74
ACUTE APPENDICITIS
DORRY SEGEV,MD,AND PAUL COLOMBANI,MD,FACS
On physical examination, there is usually focal tender-
ness and localized peritoneal irritation in the right lower
quadrant of the abdomen, over the appendix.Although the
appendix is classically located at McBurney’s point (two-
thirds the distance from the umbilicus to the right anterior
superior iliac spine), anatomic variations are common and
include retrocecal, intrapelvic, left lower quadrant, or right

upper quadrant positions.
A number of clinical signs can be used to discern local-
ized peritonitis. Tenderness to percussion over the appen-
dix is more sensitive, more specific, and certainly more kind
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 lower
quadrant (Rovsing sign), cough (Dunphy sign), internal
rotation 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, but
the classic patient has a mild leukocytosis with a left shift
of neutrophils to immature forms. Urinalysis should be
negative, although pyuria without bacteria can occur in the
setting 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 ultra-
sound, is always warranted in this population. Young
patients with conditions such as otitis media, streptococcal
pharyngitis, meningitis, and mesenteric lymphadenitis may
have abdominal complaints which can masquerade as
ap
pendicitis. Inflammatory bowel disease should always be

considered in a patient with right lower quadrant abdom-
inal pain. A final important consideration is the differen-
t
ial diagnosis of
t
yphlitis, or neutropenic enterocolitis,
in
neutropenic patients undergoing chemotherapy for onco-
logic conditions.
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
pat
ient 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
F
igure 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
o
r
u
ltrasonography
s
hould be considered, and
t
ransvaginal
pelvic ultrasound can also be helpful in ruling out tubo-
ovarian disease. The combination of a worrisome CT scan
and this level of clinical suspicion would support surgical
management, with other patients followed carefully by ser-

ial examinations as below.
Patients with some evidence of a right lower quadrant
intra-abdominal process but little to implicate the appendix
as a source should be admitted for serial observation and
rehydration. There is no role for antibiotics in this scenario
unless 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 should
recur. Serious consideration should be given to operative
intervention in a patient who remains undiagnosed but
worsens clinically with conservative management.
Abdominal Pain Suspicious for Appendicitis
Careful History and Physical Examination, Basic Laboratory Tests
Very high likelihood of
acute appendicitis
High likelihood Low to moderate
likelihood
Suspicion
increases
Suspicion
decreases
Does not
improve
Worsens
Serial examinations
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
D
uring
p

regnancy
,
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 mo
r
e 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
o
perator 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’s
point or the area of maximal tenderness, in the direction
of Langer’s lines of skin tension. The incision is carried
t
hrough the subcutaneous tissues and external oblique
aponeurosis 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 the
abdominal wall. The laparoscopic approach consists of an
infraumbilical camera port and at least two additional
operative ports. The use of laparoscopy varies according to
surgeon preferences but relative indications include obese
patients who would otherwise require a large incision and
female patients where exploration of the pelvis is necessary
based on typical clinical presentation.
Once the abdominal cavity is entered, the appendix is
identified, mobilized, and freed from the adhesions likely
formed by the inflammatory process. The mesoappendix
is ligated and the appendix is excised at its base. Purse string
inversion of the appendiceal stump is unnecessary unless
the base of the appendix is necrotic. Abdominal drains in
general are not indicated.
When appendectomy is attempted and a normal appear-
ing appendix is encountered, the abdomen is explored for

the following pathologic processes, depending on patient
type and presentation, including the following:
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 is
the relative ease with which the remainder of the abdomen
can be explored. If no clear cause for the patient’s symptoms
can be identified, an appendectomy is performed because a
normal appearing appendix can later demonstrate histologic
evidence 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
se
tting of peritonitis or perforation, a
5-da
y course
o
fbroad
spectrum antibiotics should be used, and initiation of oral
intake should wait until bowel function begins to return.
I

leus is not uncommon after perforated appendicitis and
diet should be advanced slowly.
Complications following appendectomy include wound
inf
ection, 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
t
he 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 Reading
Emil S, Laberge JM, Mikhail P, et al. Appendicitis in children: a
ten-year update of therapeutic recommendations. J Pediatr
Surg 2003;38:236–42.
J
ones 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.
S
tephen AE, Segev DL, Ryan DP, et al. The diagnosis of acute
a

ppendicits in a pediatric population. J Pediatr Surg
2003;38:367–71.
438 / Advanced Therapy in Gastroenterology and Liver Disease
439
CHAPTER 75
CONSTIPATION
ONKI CHEUNG,MD,AND ARNOLD WALD,MD
initiating evacuation, or a feeling of incomplete evacua-
tion. Physicians should therefore not rely only on the cri-
teria of defecation frequency when examining patients and
managing constipation.
It is important to identify treatable causes of constipa-
tion, which include many diseases and the side effects of
many drugs. If these are absent, functional constipation
should be considered.
The initial management of chronic constipation
includes educating the patient and correcting any mis-
conceptions as to the wide range of normal bowel habits.
Broad treatment principles include increasing fluid and
fiber intake, and reducing excessive or incorrect use of lax-
atives and cathartics. Taking advantage of normal post-
prandial increases in colonic motility, patients should
attempt to defecate after meals, particularly in the morn-
ing when colonic motor activity is highest. Most patients
will respond to these measures together with the judicious
use of laxatives. A summary of available laxatives is shown
in Table 75-1 followed by the approximate costs of the
common 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
Constipation
Laxatives Usual Adult Dose Onset of Action
*Bulk-forming laxatives
Bran 2–4 tablespoons qd 12 to 72 h
Methylcellulose 1 to 3 tbsp qd 12 to 72 h
Psyllium 1 to 3 tbsp qd 12 to 72 h
Calcium polycarbophil 2 to 4 tablets qid 24 to 48 h
*Osmotic agents
Polyethylene glycol 17 g in 240 mL water 24 to 48 h
Sorbitol 15 to 30 mL qd 24 to 48 h
Lactulose 15 to 30 mL qd 24 to 48 h
Saline laxatives
Magnesium sulfate
15 g qd
0.5 to 3 h
Magnesium citrate
200 mL qd
0.5 to 3 h
*Stimulant laxatives (oral)
Senna 2 to 4 tabs qd 6 to 12 h
Cascara
1 to 2 tabs qd
6 to 12 h
Bisacodyl

30 mg qd
6 to 10 h
*Prokinetic agents
Misopr
ostol
200–800 mcg qd
1 to 4 h
T
egaser
od
6 mg bid
1 to 4 h
Colchicine 0.6 mg tid 1 to 4 h
Suppositor
y
Bisacodyl
1 ever
y 2 to 3 days
0.25 to 1 h
Glycerine 1 every 2 to 3 days 0.25 to 1 h
Enemas
Tap water
500 mL
0.25 h
Phosphate 45 mL 0.25 h
Mineral oil retention 100 to 250 mL 0.25 h
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
the bottom.
TABLE 75-2. Approximate Costs of Commonly Used

Laxatives
Laxatives Monthly Costs
Osmotic agents
Polyethylene glycol $42 for 17 g qd
Sorbitol $18 for 30 mL qd
Lactulose $60 for 30 mL qd
Saline laxatives
Magnesium citrate $60 for 200 mL qd
Magnesium hydroxide $27 for 30 mL qd
Stimulant laxatives
Senna $3 to 6 for 2 to 4 tablets every 2 to 3 days
Cascara $2 to 4 for 1 to 2 tablets every 2 to 3 days
Bisacodyl $3 for 30 mg every 2 to 3 days
Prokinetic agents
Misoprostol $45 for 200 µg qd
Tegaserod $120 for 2 or 6 mg bid
Colchicine $18 for 0.6 mg tid
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.

D
IETARY FIBER
Dietary 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 lo
w 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 flatulence
a
re 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 hard
impactions. 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 in
patients who fail to respond to or are intolerant of bulk
or osmotic agents. These agents alter intestinal electrolyte
transport and increase intestinal motor activity. They may
be used intermittently or chronically when patients fail to
respond adequately to bulk or osmotic laxatives. Some
physicians recommend that they be taken for no longer
than 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 are
the
y asso
ciated with colorectal or other cancers. Stimulant
laxatives often cause superficial damage to surface epithe-
lial cells, but this is of no functional significance and is
reversible when laxatives are discontinued. A reasonable
regimen is to use stimulant laxatives when no spontaneous
bowel movement occurs after 48 or 72 hours. They may be
used alone or combined with bulk or osmotic laxatives.
Major side effects occur only with excessive and prolonged
abuse, 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
f
ormed 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-
c
oloration of melanosis coli occurs throughout the colon
and is more prominent in the proximal colon. Withdrawal
of laxatives is normally accompanied by resolution of pig-
me
ntation after many months.
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
d
uration
o
f action may be
o
ccasionally 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.
Teg ase rod (Zelnorm) is a
partial 5-HT
4
agonist 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
µ
g
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
p
r
egnant 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
t
o 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
I
n
s
low transit constipation (STC),
t

here is a failure to move
luminal contents through the proximal colon. This may be
associated with dietary factors, such as severe caloric defi-
ciency, with medications that alter motility or with certain
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 enteric
nerves, such as decreased volume of interstitial cells of Cajal
and reduction of myenteric neural elements. We usually
start with colon cleansing using enemas with or without
mineral oil. If these are unsuccessful, a water-soluble con-
trast enema (Gastrografin or Hypaque) administered under
fluoroscopy 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 osmotic
agent with stimulant laxatives every 2 to 3 days if there are
no spontaneous bowel movements. Other agents such as
misoprostol or tegaserod may be tried if the patient
responds suboptimally to osmotic and stimulant laxatives.
If a patient with disabling symptoms from STC is unre-
sponsive to medical therapy, surgery may be considered.
The most common operation recommended is subtotal
colectomy with ileorectal anastomosis for which overall
success 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 debilitating

diarrhea after surgery, as have others. Because of this expe-
rience, we emphasize the importance of careful patient
selection. The following four criteria should be met before
s
urg
ery is undertaken: (1) chronic, severe, and disabling
symptoms from constipation that are unresponsive to
medical therapy, (2) slow colonic transit of the inertia pat-
tern, (3) no evidence of intestinal pseudo-obstruction by
radiologic and manometric studies, and (4) normal
anorectal function. Diagnostic studies to rule out pelvic
floor dysfunction are critically important, as subtotal colec-
tomy with ileorectal anastomosis is unlikely to help if the
latter is not corrected. Another reported surgical approach
is antegrade colonic enema, although we use it very infre-
quently. For patients who have impaired continence mech-
anisms, an ileostomy is a viable option.We are reluctant to
recommend subtotal colectomy in patients when pain is a
significant component of their complaint, because it can-
not b
e assumed that it will relieve pain.
Outlet Dysfunction Constipation
In outlet dysfunction constipation, the primary failure is
an inability to adequately evacuate contents from the rec-
t
um. This may be due to failure of coordinated relaxation
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
b
iofeedback 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. Most
patients with megarectum can be treated conservatively with
enemas or suppositories. We rarely consider proctocolec-

tomy with an ileoanal pouch and only if anorectal conti-
n
ence 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 Figure
75-1), and biofeedback therapy should be offered. Failure
of conservative therapy may lead to proctocolectomy with
ileal pouch anal anastomosis or end ileostomy for those
with untreatable anorectal dysfunction.
Normal Transit Constipation
Constipated patients with normal colon transit and nor-
mal anorectal function often misperceive bowel frequency
and exhibit increased psychological distress. It is impor-
tant to reassure these patients that there is no evidence of
abnormal function of the colon or rectum. Patients should
be educated to increase fluid and fiber intake, take advan-
tage of gastrocolonic responses, and avoid excessive use
of laxatives. We often screen these patients for underlying
anxiety, depression or other psychological distress using a
previously validated psychological symptom form, the
SCL-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 CTS
Abnormal ARM
Slow CTS

Abnormal ARM
Slow CTS
Normal 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
No improvement

If no improvement
If no improvement
If no
improvement
FIGURE 75-1. Diagnostic and treatment algorithm for severe constipation.
Constipation / 443
Constipation with IBS
I
n 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. Initial
disimpaction with colon cleansing is necessary for success-
ful long term management.We prefer to institute a low fiber
diet together with daily PEG solution to minimize stool and
g
as 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 respond
poorly 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 diverting
ileostomy or ileoanal anastomosis may be considered. For
megacolon with normal anorectal function, an ileorectal
anastomosis may be appropriate whereas in megarectum

with normal colon, a coloanal anastomosis, diverting
colostomy, or Duhamel procedure may be effective.
Supplemental Reading
Locke 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.
444
CHAPTER 76
MANAGEMENT OF ABDOMINAL WALL
DEFECTS
KURTIS A. CAMPBELL,MD,AND ANTHONY P. TUFARO, MD, DDS
Complex abdominal wall defects can occur both acutely
and as a delayed consequence of surgery or injury. Acute

defects may be the result of trauma, tumor excision, wound
dehiscence and evisceration, necrotizing fasciitis, or some
other intra-abdominal catastrophe. The acute complex defect
may be divided into two types: (1) unstable and (2) stable.
Those with unstable abdominal contents are those where
urgent 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 manage-
ment of these acute defects is more esoteric to the nonsurgeon
and will not be discussed further in this chapter.
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 relation to previous
chest 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 rearrangement
and advancement. The presence of previous incisions can
have a substantial impact on the blood supply to both the
skin and soft tissue and the myofascial components of the
abdominal wall. The extent of the fascial defect is also vitally
important and is likely best determined by a combination
of physical examination and radiographic imaging, partic-
ularly computed tomography or magnetic resonance imag-
ing. In the setting of an open wound, cultures of the wound
can guide antibiotic use both in the preoperative period and
after surgery. In patients who have undergone previous

tumor excision within the abdomen or abdominal wall, tis-
sue biopsy within the confines of a complex wound would
be important to rule out tumor recurrence.
The overall stability of the skin and soft tissue in the set-
ting of a complex abdominal wall defect can also be clas-
sifie
d as stable (type I) or type II, indicating absence or
instability of the skin and soft tissue coverage overlying the
myofascial defect (Mathes et al, 2000). As previously dis-
cusse
d, the perfusion of both the soft tissue and the myofas-
cia can have a significant impact on reconstruction, and,
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
o
f GI pathology, including enterocutaneous fistula, inflam-
matory bowel disease, other inflammatory 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
(F
r
anklin 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. The
classic use of these materials is either as an inset patch or
a
s reinforcement of a primary tissue repair of myofascia.
Placement of these materials can be done extrafascial or
above the fascia, extraperitoneal and subfascial, or
intraperitoneal. This too continues to be a much-debated
topic. 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. The

source of the tissue can be regional musculofascial flaps
most commonly represented by rectus abdominis advance-
ment, which can be achieved using one of several plastic
surgery 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 sub-
ject in the ongoing debates of prosthetic material versus
primary tissue repair and laparoscopic versus open tech-
niques. In these defects the laparoscopic repair can occur
by using a transabdominal preperitoneal approach or a
totally 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 appro-
priate methodology continues to be debated but likely
involves the following two important concepts: (1) surgeon
e
xp
erience and (2) whether the planned procedure repre-
sents repair of a recurrence (Neumayer et al, 2004)
Summary
In conclusion durable reconstruction of a complex abdom-
inal wall defect requires a complete evaluation of the defect
and optimal preparation of the patient along with thought-
ful surgical planning. Certainly a multidisciplinary
approach is ideal and more times than not should likely

include gastroenterology involvement, particularly in those
patients who present with GI co-morbidities complicating
their abdominal wall defect and its reconstruction.
Supplemental Reading
Amid PK, Shulman AG, Lichtenstein IL. Open “tension-free”
r
e
pair o
f
inguinal hernias: the Lichtenstein technique. Eur J
S
urg 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
F
lum DR, Horvath K, Koespell T. Have outcomes of incisional
hernia repair improved with time?: a population-based
analysis. Ann Surg 2003;237:129–35.
Franklin ME Jr, Gonzalez JJ Jr, Glass JL, Manjarrez A.
L
aparoscopic ventral and incisional hernia repair: an 11-year
e
xperience. 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.
M
athes 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.
N
eumayer 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
w
all wound. In: Cameron JL, Evers BM, Fong Y, et al, editors.
A
dvances 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
h
ernia after repair of wound dehiscence: incidence and risk
factors. Am Surg 2004;70:281–6.
447
CHAPTER 77
LEFT-SIDED ULCERATIVE COLITIS AND
ULCERATIVE PROCTITIS
PHILIP B. MINER JR,MD
disease has yet to be explained. Physiologic differences exist
between the right and left sides of the colon with the dom-
inant luminal substrate for oxidative phosphorylation
being glutamine in the right colon and butyrate in the left
colon. In addition, there are differences in the distribution
of inflammatory cells in the right and left colon, which may
provide insight into the abrupt cessation of inflammation

at the line of disease demarcation. We histologically eval-
uated the “line of demarcation” in an attempt to under-
stand the aggressive and protective balance occurring at
the inflammatory interface. Much to our surprise, there
were numerous
mast cells on the normal side of the line
of demarcation and in the terminal ileum of patients with
well-defined left-sided UC. Evolving understanding of the
role 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 mast
cells has been ignored because they have always been given
a pathobiologic role in human physiology. The interaction
between the mast cell and the eosinophil has important
implications for IBD. The inflammatory response is depen-
dent on eosinophilic chemoattractant factor released by
the mast cell. The mast cell also modulates the effect of
eosinophil function and engulfs major basic protein, which
limits tissue injury.
From a practical perspective, the advent of videoen-
doscopy permits frequent assessment of the degree of
mucosal inflammation and response to therapy as well as
providing an opportunity to histologically evaluate a biopsy
of the mucosa. Endoscopic examination is essential to the
management of UC because it permits the assessment of
the severity and extent of mucosal inflammation. Biopsies
are easily obtainable and play an important role in distin-
guishing the severity and nature of the inflammation. In
left-sided UC, the laboratory evaluation is often normal
and the only method to assess disease severity is history,

physical examination, and videoendoscopy with biopsy.
During the initial evaluation, laboratory assessment is
esse
ntial in order to exclude a treatable infectious cause
of colitis and to assess the immunologic pressure on the
patient 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 evaluating 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 mysterious 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.
IMPORTANCE OF HISTOLOGY
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”).
E
OSINOPHILS
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 of
which is the presence of Intracellular Adhesion Molecule
(ICAM-1), which not only traffics the eosinophils to the
i
nflammatory site, but also is required for eosinophils acti-
vation. The importance of eosinophils in the activation of
disease may be determined by examination of the biopsy or
by stool studies. In the biopsy, the number of eosinophils
gives an estimation of the intensity of the inflammatory
response, but the presence of eosinophils in crypt abscesses
or mucosal migration of eosinophils indicates sufficient
immunologic pressure to force the eosinophils into the

intestinal lumen. These histologic findings identify activated
eosinophils. Eosinophils in the stool indicate migration of
eosinophils. Charcot-Layden crystals, which are related to
the intracellular products of the eosinophil, reflect proba-
ble eosinophil-induced tissue injury and suggest the need
for aggressive treatment of the increased number of
eosinophils.
Anorectal Physiology in Health and with
Inflammation
The complex physiology of the anorectum is adversely
influenced by inflammation with increased sensitivity to
sensation and an amplification of muscular responses stim-
ulated by stool in the rectum. Tenesmus is the sensation of
incomplete evacuation of the rectum or nonproductive
straining to defecate. It occurs when rectal contraction is
accompanied by internal anal sphincter relaxation. In the
presence of inflammation, there is sensitivity to lower than
normal volumes of balloon distention and exaggerated
relaxation of the internal anal sphincter (IAS). The sensa-
tions accompanying this response are perceived rectal full-
ness,
urg
ency to defecate and a sense of incomplete
evacuation. Occasionally, tenesmus continues when visi-
ble inflammation is no longer present. When this occurs,
treatment for microscopic inflammation or pharmacologic
manipulation of rectal contractility and IAS relaxation
improves these symptoms. In addition to the influence of
rectal 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 when
Lennard-Jones described proximal constipation in patients
with left-sided UC. Recent studies demonstrate inhibition
of stool movement proximal to the line of demarcation of
disease. 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-
v
idual relapses may not be identifiable. The four most com-
mon reasons patients relapse are the following:
Left-Sided Ulcerative Colitis and Ulcerative Proctitis / 449
1. A change in medication
2. Seasonal variation
3. Infection
4. Nonsteroidal anti-inflammatory drugs (NSAIDs).
C
hanges 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
m

ucosa. 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 col-
itis manifest by edematous and often ulcerated mucosal
which appears similar to Crohn’s colitis. In a careful exam-
ination of patients with indisputable mesalamine sensitiv-
i
ty, we were unable to identify a serologic marker or
histologic findings unique to mesalamine toxicity. If
mesalamine sensitivity is suspected, discontinue the
mesalamine drug for 72 hours. If symptomatic improve-
ment occurs, this withdrawal trial supports mesalamine sen-
sitivity. The different efficacies of the various 5-ASA
products are discussed in the chapter on UC (see Chapter
78, “Ulcerative Colitis).
For patients with left-sided UC, maintaining remission
with mesalamine follows the guidelines that have been
established for UC. Mesalamine should be continued with
at least one-half of the dose required to establish a remis-
sion, or more if the initial attacks were prolonged or severe.
We have successfully used 1 g mesalamine enemas and
every other day 4 g enemas to maintain remission in
patients with left-sided UC. The data is more ambiguous
in patients with ulcerative proctitis. Primary therapy with
mesalamine suppositories is favored. The direct rectal

application 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 with
oral medications. Because the rectum effectively moves a
liquid enema out of the rectum and into the proximal sig-
moid and descending colon, the concentration of
mesalamine delivered to the rectum with a suppository
may be higher than the dose provided by a 4 g mesalamine
enema. In these patients, I treat to obtain remission and
then taper the mesalamine and wait for a symptomatic
relapse. Each relapse should be treated and if the interval
between relapses is short, then continuous maintenance is
recommended.*
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 expr
ession of interleukin-2 receptors
Inhibit tumor necrosis factor upregulation
*Edit
o
r’

s Note: This is a realistic approach since proctitis is so vari-
ab
le 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.
450 / Advanced Therapy in Gastroenterology and Liver Disease
Glucocorticoids
T
he 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.
R

OLE OF EOSINOPHILS IN RELAPSES
Seasonal or infectious relapses can be linked to high num-
bers of eosinophils by identifying increased numbers 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
e
very 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/BECLOMETHASONE
Early 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 release
form for CD (Entocort EC, AstraZeneca LP, Wilmington,
DE). The theoretical advantage of budesonide revolves
around the efficient first pass hepatic clearance of this
steroid from the portal blood. This should decrease the sys-
temic availability of the steroid and permit local steroid
suppression of the disease without systemic toxicity. It is
unfortunate that further studies were not conducted with
topical rectal budesonide, however, approximately 15%
of the blood flow from the distal colon escapes the portal
system 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 left-
sided UC. The same principle of high first pass clearance
resulted in few systemic side effects (Campieri et al, 2003).
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 concerns
about the toxicity of these drugs has become less of an issue
than the toxicity of chronic steroid use. The experience in
patients with CD led to the management of pancolitis with
6-MP/AZA. Success with UC management has permitted
the expansion of the patients suitable for treatment to those
with relatively refractory left-sided UC. I begin with 50 mg
6-MP and increase the dose to as high as 2 mg/kg in 25 mg
increments until there is control of the disease or emerging
toxicity. Most of the toxicity occurs in the first few months
of treatment and blood tests are followed carefully for
leukopenia, hepatitis, and pancreatitis.
Methotrexate (MTX) (25 mg intramuscularly [IM] once
a week) may also be used to induce remission, but many
responsive patients have only a short period before a MTX-
resistant relapse occurs. Once symptomatic control is
achieved, the dose may be lowered to 15 mg IM a week. A
return to 25 mg for a symptomatic recurrence can be help-
ful. The cautions advocated by the American Rheumatologic
Association regarding the emergence of liver disease after a
lifetime cumulative dose of 1500 mg should be applied to
patients receiving MTX, although this seems to be less of an
issue with once weekly IM MTX. Studies are in progress to
d
etermine 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 use
f
or this indication at this time.