Nej M CPC 0900643

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
case records of the massachusetts general hospital

Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor
Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Christine C. Peters, Assistant Editor
Case 31-2009: A 26-Year-Old Man

with Abdominal Distention and Shock
Hasan B. Alam, M.D., Gregory L. Fricchione, M.D.,
Alexander S.R. Guimaraes, M.D., Ph.D., and Lawrence R. Zukerberg, M.D.
PR E SEN TAT ION OF C A SE

Dr. Jeffrey S. Ustin (Trauma, Emergency Surgery, and Surgical Critical Care): A 26year-old man was admitted to this hospital because of abdominal distention and
shock.
The patient had been well until the evening before admission, when mild abdominal pain developed, shortly after he had eaten five or six frankfurters. The pain
gradually increased overnight, and nausea developed the next day. In the evening
of the day of admission, his parents found him unresponsive, with coffee-grounds
material emanating from his mouth. They called emergency medical services. On
examination, he was obtunded, with agonal respirations. The trachea was intubated
without medications, and supplemental oxygen was administered by means of an
anesthesia bag attached to the endotracheal tube; the patient was transported to
another hospital. On examination in the emergency department, the femoral pulse
rate was 150 beats per minute, and the respiratory rate 24 breaths per minute; the
blood pressure could not be measured. Twenty-two minutes after arrival, during insertion of a central intravenous catheter, the patient became pulseless, and cardiopulmonary resuscitation (CPR) was begun. Within 12 minutes, the blood pressure
was 87/70 mm Hg and compressions were stopped. Screening of the urine for
toxins was negative. Laboratory-test results are shown in Tables 1 and 2. He began
to awaken, and fentanyl and vecuronium were administered. A nasogastric tube
was inserted, and brown material (200 to 300 ml) was aspirated. Levofloxacin and
metronidazole were administered intravenously. Computed tomography (CT) of the
abdomen and pelvis reportedly showed markedly dilated loops of bowel, without
free air or evidence of obstruction or volvulus, and CT scans of the chest and head
were normal.
Two hours 40 minutes after arrival, the patient was transferred to this hospital
by helicopter. The blood pressure during transfer ranged between 79 and 116 mm Hg
systolic and between 34 and 50 mm Hg diastolic, and the pulse was 125 beats per
minute. Four intravenous catheters were in place. The patient arrived at this hospital 47 minutes later.
The patients history was obtained from his family. The patient had had increas-
From the Departments of Surgery (H.B.A.),

Psychiatry (G.L.F.), Radiology (A.S.R.G.),
and Pathology (L.R.Z.), Massachusetts
General Hospital; and the Departments
of Surgery (H.B.A.), Psychiatry (G.L.F.),
Radiology (A.S.R.G.), and Pathology
(L.R.Z.), Harvard Medical School.
This article (10.1056/NEJMcpc0900643)
was updated on December 15, 2010, at
NEJM.org.
N Engl J Med 2009;361:1487-96.
Copyright 2009 Massachusetts Medical Society.
n engl j med 361;15 nejm.org october 8, 2009
The New England Journal of Medicine

Downloaded from nejm.org on November 1, 2015. For personal use only. No other uses without permission.
Copyright 2009 Massachusetts Medical Society. All rights reserved.
1487
The
of
m e dic i n e
Table 1. Hematologic and Chemical Laboratory Data.*

Reference Range, Adults,
This Hospital
Day of Admission,
Other Hospital
On Admission,
This Hospital
Hematocrit (%)
41.053.0 (men)
56.1
49.2
Hemoglobin (g/dl)
13.517.5 (men)
18.9
16.9
450011,000
17,500
20,600
Neutrophils
4070
66.4
63
Lymphocytes
2244
14.3
24
411
18.5
Variable
White-cell count (per mm3)

Differential count (%)
Monocytes
Eosinophils
08
0.6
Basophils
03
0.2
Band forms
010
150,000400,000
194,000
120,000
Activated partial-thromboplastin time (sec)
22.134.0
34.3
>150.0
Prothrombin time (sec)
10.313.2
16.7
29.6
<500
>1000
Platelet count (per mm3)
International normalized ratio

d-Dimer
1.59
(ng/ml)
Fibrinogen (mg/dl)
150400
Sodium (mmol/liter)
135145
Potassium (mmol/liter)
3.44.8
116
141
5.9
Chloride (mmol/liter)
100108
105
Carbon dioxide (mmol/liter)
23.031.9
825
32
Urea nitrogen (mg/dl)

Creatinine (mg/dl)
0.601.50
Estimated glomerular filtration rate

(ml/min/1.73 m2)
Glucose (mg/dl)
>60
70110
3.1
>10,000
132
8.0 (not hemolyzed)
104
13.7
31
3.0
2.86
27
29
144
164
Bilirubin (mg/dl)
Total
0.01.0
0.9
0.7
Direct
0.00.4
0.3
Total
6.08.3
3.4
Albumin
3.35.0
1.9
Protein (g/dl)
Phosphorus (mg/dl)
2.64.5
Magnesium (mg/dl)
1.72.4
Calcium (mg/dl)
8.510.5
Ionized calcium (mmol/liter)
1.141.30
Alkaline phosphatase (U/liter)
45115
3.2
6.2
1.11
48
1.00
120
Aspartate aminotransferase (U/liter)
1040
25
1081
Alanine aminotransferase (U/liter)
1055
30
1238
Lipase (U/dl)
1.36.0
Amylase (U/liter)
Creatine kinase (U/liter)
1488
9.9
3.8 (ref 1.73.0)
3100
60400 (men)
2.5
3.9
23
52
1100

case records of the massachusetts gener al hospital
Table 1. (Continued.)
This Hospital
Variable
Day of Admission,
Other Hospital
On Admission,
This Hospital
Troponin
Ultra troponin (ng/ml)
0.013 (ref 0.0000.780)
Troponin I
Negative
Troponin T (ng/ml)
0.000.09
Ammonia (mol/liter)
1248
Lactate (mmol/liter)
0.52.2
Ethanol (mg/dl)
Negative
<0.01
250
553
15.7
1 (ref 010)
* Ref denotes reference range. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert
the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert
the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to millimoles per liter, multiply by 0.4114. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for ionized calcium to milligrams per deciliter, divide by 0.250.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
ing abdominal distention during the past several

weeks. He had not had diarrhea. One month before admission, at the time of his annual physical examination, mild lymphocytosis and thrombocytopenia (platelet count, 123,000 per cubic
millimeter) had been noted. Urinalysis had been
normal. At follow-up testing performed 4 days
before admission, the platelet count was 132,000
per cubic millimeter; the white-cell and differential counts were normal. A diagnosis of paranoid
schizophrenia was made at the age of 16 years.
The patient had been poorly compliant with
medications in the past and had been an inpatient
at a psychiatric hospital for the past 3 years, staying at his parents home on the weekends, where
he was when he became ill. He had had fractures
of the fourth and fifth metacarpals of the right
hand in fights several years earlier and had been
bitten by a dog in the past. Medications included
clozapine (550 mg), valproic acid (2250 mg), and
glycopyrrolate (4 mg) orally at night. He had no
known allergies to medications. He smoked cigarettes and drank alcohol and did not use illicit
drugs. He was single, had completed the 11th
grade, had worked outdoors in the past, and was
currently unemployed. His brother also had schizophrenia. There was no family history of other
mental illness, diabetes mellitus, thyroid disease,
coronary artery disease, hypertension, gastrointestinal disease, or nephrolithiasis.
On examination, the patient was sedated, intubated, ventilated, and unresponsive to painful
stimuli. The blood pressure was 57/41 mm Hg,

the pulse 127 beats per minute, and the oxygen
saturation 97% while he was breathing 100%
oxygen. The pupils were round, 6 mm in diameter, and equal, and they reacted sluggishly to
light, with an absence of corneal reflexes. The
neck was supple, lung sounds were normal, and
no cardiac murmurs were heard. The abdomen
was rigid and distended, with tympany. The legs
were cold and pale, but the skin was not mottled.
The radial pulse was weakly palpable, and pedal
or femoral pulses were absent. Laboratory-test
results are shown in Tables 1 and 2. An electrocardiogram showed tachycardia (133 beats per
minute) that was thought to be of sinus origin,
right-axis deviation, and an intraventricular conduction defect. Intravenous fluids, norepinephrine, and phenylephrine were administered; the
blood pressure rose to 120/86 mm Hg. Vancomycin was added, and levofloxacin and metronidazole were continued.
Thirty minutes after the patients arrival at this
hospital, a procedure was performed.
DIFFER EN T I A L DI AGNOSIS
Dr. Hasan B. Alam: May we review the radiologic
studies?
Dr. Alexander S.R. Guimaraes: Contrast-enhanced
CT images of the abdomen and pelvis from the
other hospital (Fig. 1) show diffuse distention of
the entire colon. There is fecal material through-

1489
The
of
m e dic i n e
Table 2. Blood Gas Values.

This Hospital*
Variable
Day of Admission,
Other Hospital
On Admission,
This Hospital
1.00
1.00
<6.80
6.93
Fraction of inhaled oxygen

Venous blood gas
pH
7.327.45
Partial pressure of carbon dioxide (mm Hg)
3550
88
66
Partial pressure of oxygen (mm Hg)
4090
52.7
63
Oxygen saturation (%)
52.8
Base excess (mmol/liter)
24.5
20.2
Arterial blood gas

pH
7.327.45
6.88
7.01
Partial pressure of carbon dioxide (mm Hg)
3542
77
63
Partial pressure of oxygen (mm Hg)
80100
381
281
Oxygen saturation (%)
99.5
Alveolararterial gradient
249
Base excess (mmol/liter)
20.5
16.7
* Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
out the colon and in the distal small bowel,

which is not distended. There is mild thickening
of the wall of the colon, and there is flattening
of the inferior vena cava, a finding that suggests
either increased abdominal pressure or low intravascular volume.
Dr. Alam: Abdominal distention is a common
finding that can occur in a variety of gastrointestinal, hepatobiliary, and pancreatic disorders.
The underlying causes can be categorized on the
basis of whether the distention is caused by gas
or fluid (Fig. 2). These categories are not mutually exclusive paralytic ileus or bowel obstruction may be associated with accumulation of
blood or ascites in the peritoneal cavity, and intestinal perforation can cause spillage of enteric
contents into the abdomen. In practice, the approach to the differential diagnosis is driven by
the physiological status of the patient and the
lethality of the underlying disease. If the patient
is stable (not in shock), imaging techniques, such
as CT, can be used to establish a diagnosis, where
as in an unstable patient such as this one, therapeutic interventions are urgently required, often
without an opportunity to use sophisticated diagnostic tests.
This patient has acute dilatation of the colon
in the absence of mechanical obstruction, a con1490
dition known as acute megacolon (Ogilvies syndrome). He also has thickening of the wall of the
colon, which suggests inflammation, and septic
shock with multiple organ failure; the combination of colonic distention (>6 cm in diameter)
associated with inflammation of the colon and
septic shock is known as toxic megacolon.1,2 In
a young patient, the most common cause of
toxic megacolon is inflammatory bowel disease,
which this patient did not have. The other leading cause often not associated with diarrhea
is colitis due to Clostridium difficile. However,
C. difficile colitis usually occurs in patients who
are taking multiple antibiotics again, not the
case in this patient.
In addition to colonic distention, shock, and
organ failure, this patient had a distended and
rigid abdomen and increased peak airway pressures. These findings are consistent with an
abdominal compartment syndrome, defined as
a sustained intraabdominal pressure above 20
mm Hg (with or without an abdominal perfusion
pressure below 60 mm Hg) that is associated with
organ dysfunction or failure.3,4 This condition is
being recognized with increasing frequency in
critically ill patients, including those with septic
shock,5 and has been identified as an independent predictor of death in such patients.6

in trauma patients that has been called the lethal

triad.7 These factors perpetuate one another,
A
creating a vicious cycle that is difficult to interrupt.8 Early development of coagulopathy is a
well-recognized marker of the severity of an injury, and its presence is associated with a significantly increased risk of death.9-11 In this critically ill patient with megacolon, an abdominal
compartment syndrome, and the lethal triad, no
further diagnostic evaluation was performed, and
he was taken directly to the operating room. At
laparotomy, we found massive distention of the
entire colon (maximum diameter, >15 cm), without evidence of perforation (Fig. 3). The rectum
and small bowel appeared to be hypoperfused
but viable, except for a small segment of terminal
ileum. We removed the entire colon and a small
segment of terminal ileum, leaving a segment of
rectum.
The patient had hypothermia, acidosis, and
diffuse bleeding during the operation, prompting
the surgical team to opt for a damage-control
strategy. The term damage control originated
in the U.S. Navy and referred to the ability of a
ship to absorb damage while continuing to perB
form its mission.12 Damage-control laparotomy
is widely practiced today in severely injured patients with trauma.13 The basic concept is to perform an abbreviated operation, focusing on controlling hemorrhage and contamination. This
initial operation is followed by a period of resuscitation in the intensive care unit (ICU) to reverse
the lethal triad of acidosis, hypothermia, and coagulopathy. The patients are taken back to the
operating room for a definitive operation once
the physiological disturbances have been correct
ed. Although used primarily for severely injured
patients, this approach is equally useful for other
critically ill patients who need an operation, such
Figure 1. CT Images of the Abdomen.
as this one.
Coronal (Panel A) and axial (Panel B) CT images show
After the terminal ileum and colon were rediffuse dilatation and mild thickening throughout the
moved,
we did not try to perform an anastomoRETAKE
1st
AUTHOR
Alam/Record
ICM
entire colon, without concomitant dilatation of the 2nd
REG F FIGURE 1a&b
sis
of
the
bowel, perform an ileostomy, or close
small bowel. Secondary findings include the presence
3rd
CASE
TITLE
the
abdominal
fascia. Instead, the stapled ends
Revised
of contrast
material filling the superior mesenteric arEMail
4-C
Line
of the bowel (ileum and rectum) were returned to
teryEnon
(Panel A, arrowhead) and
flattening
of theSIZE
inferior
ARTIST: mst
H/T
H/T
vena
cava (Panel B, arrowhead).
16p6
the abdomen, the fascia was left open to prevent
FILL
Combo
an increase in intraabdominal pressure, and a
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
temporary vacuum-assisted abdominal closure
Please check carefully.
was performed, involving the use of plastic sheets,
The Lethal
Triad and Damage-Control
towels, suction drains, and adhesive plastic dress
JOB: 36115
ISSUE: 10-8-09
Surgery
ing.14 The patient was then taken to the ICU for
Finally, this patient also had coagulopathy, acido- correction of his acidosis, coagulopathy, and hysis, and hypothermia an ominous trio of signs pothermia.

1491
The
of
m e dic i n e
Abdominal distention and shock
Fluid
Ascites
Infected ascites
Acute liver failure
Gas
Blood
Aortic-aneurysm leak
Solid-organ bleeding
(spleen or liver)
Mesenteric bleeding
Extraluminal cause
(bowel perforation)
Intraluminal causes
Obstructive
Volvulus
Tumors
Stricture
Nonobstructive
Motility disorders
Inflammation
Infection
Ischemia
Figure 2. Differential Diagnosis of Abdominal

Distention and Shock.
1st
RETAKE
AUTHOR: Alam
ICM
2nd categories of causes, along
The flow diagram is not an all-inclusive list
of causes
FIGURE:
2 of 3but instead shows the common
REG F
3rd
with examples of each.
CASE
EMail
Enon
ARTIST: ts
Early, Goal-Directed Resuscitation
Line
H/T
Combo
4-C
H/T
Revised
SIZE
33p9
The wall was thin, ranging from 0.3 to less than

Early, goal-directed resuscitation has
been
shown
cm has
in thickness,
and was red and dusky, withFigure has been redrawn 0.1
and type
been reset.
carefully.
to lower the mortality rate among patientsPlease
withcheckout
evidence of perforation. A 50-cm-long segsepsis and shock.15-17 For optimal results, the re- ment of distal ileum had a wall thickness of apJOB: 36115
ISSUE: 10-08-09
suscitation protocol must be initiated as soon as proximately 0.3 cm.
a diagnosis of shock is made, not delayed until
On histological examination, the colonic muadmission to the ICU. This concept is at the core cosa showed coagulative necrosis with hemorof evidence-based recommendations for the resus- rhage, loss of crypts, and basal regeneration of
citation of patients with sepsis.18 Early, goal- the remaining crypts, features that are consisdirected resuscitation was begun when this pa- tent with ischemic damage (Fig. 3). The necrosis
tient arrived in the emergency department and and hemorrhage were confined to the mucosa,
continued throughout the operation and during without involvement of the submucosa or musthe next few days.
cularis. The segment of ileum showed similar
mucosal changes. There was no evidence of
acute inflammation, pseudomembranes, or vasDr . H a s a n B . A l a ms Di agnosis
cular thrombi. These features are consistent with
Acute or toxic megacolon of unknown cause.
the diagnosis of acute megacolon (Ogilvies syndrome).
Pathol o gic a l Discussion
Acute megacolon (Ogilvies syndrome)
Dr. Lawrence R. Zukerberg: The removed segment of Acute megacolon that occurs in association with
colon was dilated, ranging from 15 to 18 cm in underlying inflammation, such as inflammatory
diameter, and filled with bloody fecal material. bowel disease or C. difficile disease, is known as
1492

toxic megacolon.19,20 In the absence of colonic

inflammation, the diagnosis is acute megacolon,
also known as Ogilvies syndrome. Because of the
absence of evidence of colitis, the diagnosis of
toxic megacolon can be ruled out in this case.
Although the mucosal necrosis has features of
ischemic necrosis, the absence of transmural necrosis or distribution according to a pattern of
arterial or venous supply makes a primary vascular cause unlikely.
The cause of the ischemic necrosis in massive
ly dilated intestinal segments is related to Pascals principle and Laplacess law. Pascals principle states that the pressure within a cylindrical
structure is the same, regardless of whether the
structure is dilated, and Laplaces law states that
the wall tension of a cylinder is equal to the pressure within the cylinder multiplied by the radius.
Therefore, a dilated intestinal segment has a
greater wall tension than a nondilated segment;
if the dilatation and tension are sufficiently great,
blood flow may be obstructed and ischemia of
the bowel will occur.
Acute megacolon develops because of abnormal intestinal motility. Normal colonic motility
requires integration of myogenic, neural, and hormonal influences. The enteric nervous system21
is independent but is connected to the central
nervous system by sympathetic and parasympathetic nerves. The targets of the enteric neurons
are muscle cells, secretory cells, endocrine cells,
microvasculature, and inflammatory cells. The
neurons in the enteric plexuses are stimulated by
a food bolus, which both distends the gut and
stimulates the mucosal surface, leading to the
release of factors that stimulate interneurons.
The stimulated interneurons transmit excitatory
signals proximally, which cause contraction and
inhibitory signals distally, and these in turn cause
relaxation. These signals are transmitted by the
neurotransmitters acetylcholine and serotonin,
among others.
This patient was taking clozapine, a drug that
has both anticholinergic and antiserotonergic
properties, which can cause severe gastrointestinal motility problems, including massive colonic
dilatation and acute megacolon.22-24 Pathological
features of reported cases are similar to those
seen in this case, with involvement of the right
side or the entire colon and ischemic mucosal
Figure 3. Ileocolectomy Specimen.

A gross photograph of the resected colon (Panel A)
shows massive distention. Blood and fecal material with1st
AUTHOR
ICMlumen
in the
causedAlam/Record
black discoloration ofRETAKE
the colonic
2nd
FIGURE 3a&b of the colonic wall (Panel B,
wall.REG
A Fphotomicrograph
3rd
CASE
TITLE
hematoxylin
and eosin) shows mucosal ischemic
Revised neEMailwith loss of most crypts,
crosis,
mucosal hemorLine and 4-C
SIZE
EnonwithARTIST:
H/T BasalH/T
rhage,
red cellsmst
and fibrin.
regeneration
is
16p6
FILL
Combo
evident
within the crypts (inset,
hematoxylin and eosin).
Figure has been redrawn and type has been reset.
Please check carefully.
necrosis, which may be associated with perforation ifJOB:

the 36115
diameter of the colon
exceeds
12 cm.
ISSUE:
10-8-09
Dr. Nancy Lee Harris (Pathology): Dr. Fricchione,
can you comment on the likelihood that this patients acute megacolon was due to clozapine?
Clozapine-induced gastrointestinal
hypomotility
Dr. Gregory L. Fricchione: This mans psychiatric illness is marked by an early onset (at the age of 16
years), inpatient commitment in the state-hospital
system for 3 years, and trials of many antipsy-

1493
The
chotic medications, suggesting treatment-resistant chronic schizophrenia. Most recently, he had

been treated with clozapine (550 mg per day),
valproate (2250 mg per day), and glycopyrrolate
(4 mg per day).
Since the 1950s, drugs that antagonize the
dopamine D2 receptors, such as chlorpromazine,
other phenothiazines, and butyrophenones such
as haloperidol so-called typical antipsychotic
agents have been important in the management of schizophrenia.25 However, although they
are effective antipsychotic agents, their dopaminereceptor antagonism also leads to extrapyramidal side effects, prompting a search for alternative antipsychotic approaches.26,27 Clozapine is a
dibenzodiazepine compound with antiserotonergic properties and a relatively low affinity for D2;
in 1958, it became the first of a class of atypical
antipsychotic agents characterized by reduced
extrapyramidal side effects. There are now five
other atypical antipsychotic agents in this category: risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.
Although it was an effective antipsychotic
agent, clozapine was found in some patients to
cause neutropenia (3%) and agranulocytosis
(0.8%) and was taken off the market in 1975.25
However, it was later shown to be more effective
than chlorpromazine for the treatment of resistant schizophrenia28 and to reduce the mortality
rate by decreasing the suicide rate. This led to its
reintroduction as a nonfirst-line treatment, with
required hematologic monitoring of white cells
and the absolute neutrophil count. Clozapine can
also have other side effects besides neutropenia
and agranulocytosis, including delirium, seizures,
cardiomyopathy, myocarditis, venous thrombo
embolism, hypersalivation, weight gain, the meta
bolic syndrome, sedation, hypotension, and tachy
cardia. Constipation is very common, occurring
in 14 to 60% of patients.23
Recently, a syndrome of clozapine-induced
gastrointestinal hypomotility was described,23
with an estimated prevalence of 0.3% and a mortality rate of 27.5%. Risk factors include high
doses of clozapine; increased clozapine plasma
levels due to medical illness, fever, or coadministration of the cytochrome P-450 inhibitors fluoxetine and fluvoxamine; concomitant use of anticholinergic medications or other hypomotility
inducers such as opiates; and a history of gastrointestinal disease and bowel surgery. Obesity, a
low-fiber diet, dehydration, hypersalivation, and
1494
of
m e dic i n e
diaphoresis may lower the threshold for constipation and its more serious outcomes.23
This patients clozapine dose was 550 mg per
day higher than the mean dose in the reported
cases of clozapine-induced gastrointestinal hypo
motility (428 mg per day) and higher than the
dose for those who died (535 mg per day). Our
patient was also receiving an anticholinergic
medication (glycopyrrolate), presumably for clozapine-induced hypersalivation, and was also taking valproate, which can cause a minor increase
in clozapine metabolites.29 We do not know exactly how long the patient had been taking clozapine, but it was at least several months and
possibly more than a year. In the reported cases,
20% of cases of clozapine-induced gastrointestinal hypomotility developed within 1 month after
the start of treatment with clozapine, 36% with
in 4 months, and more than 50% within the
first year.
Serious complications usually develop in patients with clozapine-induced gastrointestinal hypomotility between 6 hours and 4 weeks after
initial reports of problems. This patient had abdominal distention for several weeks and then
acute symptoms on the evening before admission.
Patients with schizophrenia may have a higher
pain threshold than other patients, as well as difficulty in expressing pain.30 Psychotropic medications themselves may cause sedation and antinociception. A combination of these factors
may delay the diagnosis, as they probably did in
this case.
Before clozapine is administered, preexisting
constipation should be treated, and education
about diet, food intake, dehydration, and exercise should be provided. Regular weekly screening during the first 4 months of clozapine treatment is advised, with attention to constipation,
a change in bowel habits, and abdominal girth.23
This case, in which gastrointestinal complications developed at least several months after the
start of treatment with clozapine, suggests that
the screening period should probably be extend
ed. Avoidance of concomitant medications that
can cause constipation, such as opiates and anti
cholinergic medications, is recommended. The
gradual development of abdominal distention in
this patient, in the context of the administration
of clozapine and glycopyrrolate, should have
prompted consideration of discontinuation of
these medications. This case highlights the morbidity and mortality associated with clozapine-

induced gastrointestinal hypomotility and the reason, a motion for temporary guardianship,
importance of screening.
accompanied by a medical certificate, and a
Rogers guardianship were filed 12 weeks into
this hospitalization and received court approval
Discussion of M a nagemen t
at approximately week 15. A Rogers guardianDr. Harris: I would like to ask Drs. Ustin and Fer- ship supplements regular guardianship when it
nandez-Robles, who cared for this patient on the is deemed necessary for safety reasons to give
Surgical and Psychiatry services, respectively, to psychiatric medications against a patients will.
tell us how the patients care was managed and The patients father is the current Rogers guardhow he is doing.
ian and legal guardian. Six months after the
Dr. Ustin: The patient required many additional patients admission, the temporary guardianship
operations, including resection of ischemic ileum, that we filed for was extended by 90 days, because
creation of an ileostomy, delayed abdominal clo- he was still on our psychiatric unit.
sure, drainage of an intraabdominal hematoma,
This has been a very challenging case for us.
and placement of a tracheostomy tube. He had Clozapine is reserved for cases in which several
profound multisystem organ failure with septic trials of antipsychotic agents have been unsucshock, a peak lactate level of 24 mmol per liter, cessful, and it was the one medication that
liver failure with a total bilirubin level of 44 mg seemed to control this patients psychosis. Severe
per deciliter (752 mol per liter), renal failure clozapine-induced gastrointestinal hypomotility
requiring 2 months of renal-replacement thera- developed, but after his colon was removed, we
py, and respiratory failure requiring 2 months of thought it would be safe to offer him this drug
mechanical ventilation. Approximately 1 week again. Unfortunately, he refuses to take it beinto his hospitalization, he had received 55 units cause it had caused acute megacolon. Although
of packed red cells, 70 units of platelets, and 134 his father could order it under the terms of the
units of fresh-frozen plasma for severe coagu Rogers guardianship, he has declined to do so.
lopathy and bleeding. Because of gastrointesti- We first started a trial of olanzapine (10 to 20 mg
nal dysfunction and the short-gut syndrome, he daily for 17 weeks), with insufficient response.
required parenteral nutrition. Pulmonary mucor We then switched to risperidone, and the dose was
mycosis and heparin-induced thrombocytopenia increased to 8 mg per day, which is the higher
developed and required placement of an inferior end of the therapeutic dosage range. Most revena cava filter during the postoperative period. cently, aripiprazole (5 mg) was added. Within the
Ultimately, after 4 months on the surgical past month, he also received a trial of ziprasiservice, the patients renal and kidney function done because of a persistently irritable mood, but
returned to normal and he was weaned from the it was discontinued because it was ineffective.
ventilator and transitioned to tube feeding and
During the patients stay in the psychiatric
then to an oral diet. He was ambulatory and unit, additional medical problems were addressed:
gaining weight and was transferred to the psychi tachycardia, anemia, renal failure, hypercalcemia,
atry service for management of schizophrenia.
and physical deconditioning. His medical condiDr. Carlos Fernandez-Robles (Psychiatry): When I tion stabilized, and he became independent in
saw this patient for the first time, he was still in activities of daily living. He continued to display
the ICU, intubated and sedated and not requir- guarded, paranoid behavior and did not acknowling antipsychotic medications. Once his medical edge that he had any psychiatric condition. An
condition stabilized, treatment with olanzapine oral, dissolving preparation of risperidone (Risper(10 mg per day) was begun; while he was in the dal M-Tabs) was required, to prevent him from
ICU, he received all required doses of this medi- spitting out the medication. He was transferred to
cation, and his psychosis was well controlled. a state hospital after a total of 6 months in this
After his transfer to the regular surgical ward, hospital. Three months later, he was discharged
he began refusing psychiatric medications, and to a halfway house. His psychiatric symptoms
his psychiatric problems recurred.
are reasonably well controlled with risperidone
His behavior was oppositional, and he refused and oxcarbazepine. The colostomy was reversed
essential medications and procedures, including 6 months after discharge, 13 months after his
the administration of intravenous fluids. For this initial admission to this hospital.

1495
A NAT OMIC A L DI AGNOSIS

Acute megacolon (Ogilvies syndrome), with extensive mucosal ischemic necrosis, due to clozapineinduced gastrointestinal hypomotility.
This case was presented at Surgical Grand Rounds, November

20, 2008.
Dr. Guimaraes reports receiving grant support from AstraZeneca.
No other potential conflict of interest relevant to this article was
reported.
We thank Drs. Jeffrey S. Ustin and Carlos Fernandez-Robles
for assistance in preparing the case presentation.
references
1. Berman L, Carling T, Fitzgerald TN,
et al. Defining surgical therapy for pseudo

membranous colitis with toxic mega
colon. J Clin Gastroenterol 2008;42:476-80.
2. Gan SI, Beck PL. A new look at toxic
megacolon: an update and review of incidence, etiology, pathogenesis, and management. Am J Gastroenterol 2003;98:
2363-71.
3. World Society of the Abdominal Compartment Syndrome. WSACS consensus
guidelines summary. (Accessed September 11, 2009, at http://www.wsacs.org/
consensus_summary.php.)
4. Malbrain ML, Deeren D, De Potter TJ.
Intra-abdominal hypertension in the critically ill: it is time to pay attention. Curr
Opin Crit Care 2005;11:156-71.
5. Regueira T, Bruhn A, Hasbun P, et al.
Intra-abdominal hypertension: incidence
and association with organ dysfunction
during early septic shock. J Crit Care 2008;
23:461-7.
6. Malbrain ML, Chiumello D, Pelosi P,
et al. Incidence and prognosis of intra
abdominal hypertension in a mixed population of critically ill patients: a multiplecenter epidemiological study. Crit Care
Med 2005;33:315-22.
7. Tieu BH, Holcomb JB, Schreiber MA.
Coagulopathy: its pathophysiology and
treatment in the injured patient. World J
Surg 2007;31:1055-64.
8. Dirkmann D, Hanke AA, Gorlinger K,
Peters J. Hypothermia and acidosis synergistically impair coagulation in human
whole blood. Anesth Analg 2008;106:162732.
9. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute
traumatic coagulopathy: initiated by hypo
perfusion: modulated through the protein
C pathway? Ann Surg 2007;245:812-8.
10. Maegele M, Lefering R, Yucel N, et al.
Early coagulopathy in multiple injury: an
analysis from the German Trauma Registry on 8724 patients. Injury 2007;38:298304.
11. Niles SE, McLaughlin DF, Perkins JG,
et al. Increased mortality associated with
the early coagulopathy of trauma in combat casualties. J Trauma 2008;64:1459-63.
12. Rotondo MF, Schwab CW, McGonigal
MD, et al. Damage control: an approach
for improved survival in exsanguinating
penetrating abdominal injury. J Trauma
1993;35:375-83.
13. Lee JC, Peitzman AB. Damage-control
laparotomy. Curr Opin Crit Care 2006;12:
346-50.
14. Maerz L, Kaplan LJ. Abdominal compartment syndrome. Crit Care Med 2008;
36:Suppl:S212-S215.
15. Rivers E, Nguyen B, Havstad S, et al.
Early goal-directed therapy in the treatment of severe sepsis and septic shock.
N Engl J Med 2001;345:1368-77.
16. Sebat F, Johnson D, Musthafa AA, et al.
A multidisciplinary community hospital
program for early and rapid resuscitation
of shock in nontrauma patients. Chest
2005;127:1729-43.
17. Shapiro NI, Howell MD, Talmor D, et
al. Implementation and outcomes of the
Multiple Urgent Sepsis Therapies (MUST)
protocol. Crit Care Med 2006;34:1025-32.
18. Dellinger RP, Levy MM, Carlet JM, et
al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit
Care Med 2008;36:296-327.
19. Bharucha AE, Phillips SF. Megacolon:
acute, toxic, and chronic. Curr Treat Options Gastroenterol 1999;2:517-23.
20. Hanauer SB, Wald A. Acute and chronic megacolon. Curr Treat Options Gastroenterol 2007;10:237-47.
21. Goyal RK, Hirano I. The enteric nervous system. N Engl J Med 1996;334:110615.
22. Leong QM, Wong KS, Koh DC. Necro-
tising colitis related to clozapine? A rare

but life threatening side effect. World J
Emerg Surg 2007;2:21.
23. Palmer SE, McLean RM, Ellis PM,
Harrison-Woolrych M. Life-threatening
clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin
Psychiatry 2008;69:759-68.
24. Townsend G, Curtis D. Case report:
rapidly fatal bowel ischaemia on cloza
pine treatment. BMC Psychiatry 2006;6:
43.
25. Goff DC, Freudenreich O, Henderson
DC. Antipsychotic drugs. In: Stern TA,
Rosenbaum JF, Fava M, Biederman J,
Rauch SL, eds. Comprehensive clinical
psychiatry. Philadelphia: Mosby Elsevier,
2008:577-94.
26. Carlsson A, Lindqvist M. Effect of
chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol
Toxicol (Copenh) 1963;20:140-4.
27. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical
and pharmacological potencies of antischizophrenic drugs. Science 1976;192:
481-3.
28. Kane J, Honigfeld G, Singer J, Meltzer
H. Clozapine for the treatment-resistant
schizophrenic: a double-blind comparison
with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.
29. Centorrino F, Baldessarini RJ, Kando
J, et al. Serum concentrations of clozapine
and its major metabolites: effects of co
treatment with fluoxetine or valproate.
Am J Psychiatry 1994;151:123-5.
30. Singh MK, Giles LL, Nasrallah HA.
Pain insensitivity in schizophrenia: trait
or state marker? J Psychiatr Pract 2006;12:
90-102.
Copyright 2009 Massachusetts Medical Society.
Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.
1496


Nej M CPC 0900643

Hochgeladen von

Dokumentinformationen

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Nej M CPC 0900643

Hochgeladen von

Copyright:

Verfügbare Formate

The

case records of the massachusetts general hospital

Case 31-2009: A 26-Year-Old Man

PR E SEN TAT ION OF C A SE

From the Departments of Surgery (H.B.A.),

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

Table 1. Hematologic and Chemical Laboratory Data.*

White-cell count (per mm3)

Activated partial-thromboplastin time (sec)

Prothrombin time (sec)

Platelet count (per mm3)

International normalized ratio

Carbon dioxide (mmol/liter)

Urea nitrogen (mg/dl)

Estimated glomerular filtration rate

Ionized calcium (mmol/liter)

Alkaline phosphatase (U/liter)

Aspartate aminotransferase (U/liter)

Alanine aminotransferase (U/liter)

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

case records of the massachusetts gener al hospital

0.013 (ref 0.0000.780)

ing abdominal distention during the past several

stimuli. The blood pressure was 57/41 mm Hg,

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

Table 2. Blood Gas Values.

Fraction of inhaled oxygen

Partial pressure of carbon dioxide (mm Hg)

Partial pressure of oxygen (mm Hg)

Oxygen saturation (%)

Base excess (mmol/liter)

Arterial blood gas

Partial pressure of carbon dioxide (mm Hg)

Partial pressure of oxygen (mm Hg)

Oxygen saturation (%)

Base excess (mmol/liter)

out the colon and in the distal small bowel,

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

case records of the massachusetts gener al hospital

in trauma patients that has been called the lethal

The New England Journal of Medicine

Abdominal distention and shock

Figure 2. Differential Diagnosis of Abdominal

Early, Goal-Directed Resuscitation

The wall was thin, ranging from 0.3 to less than

Pathol o gic a l Discussion

Acute megacolon (Ogilvies syndrome)

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

case records of the massachusetts gener al hospital

toxic megacolon.19,20 In the absence of colonic

Figure 3. Ileocolectomy Specimen.

necrosis, which may be associated with perforation ifJOB:

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

chotic medications, suggesting treatment-resistant chronic schizophrenia. Most recently, he had

n engl j med 361;15 nejm.org october 8, 2009

The New England Journal of Medicine

case records of the massachusetts gener al hospital