1st Article Flashcards
A 26- year-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 patient’s history was obtained from his family.
The patient had had increasing 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 patient’s arrival at this hospital, a procedure was performed.
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 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, whereas 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 condition known as acute megacolon (Ogilvie’s 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
The Lethal Triad and Damage-Control Surgery Finally, this patient also had coagulopathy, acidosis, and hypothermia —
an ominous trio of signs in trauma patients that has been called the “lethal triad.”7
These factors perpetuate one another, 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 perform 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 corrected.
Although used primarily for severely injured patients, this approach is equally useful for other critically ill patients who need an operation, such as this one.
After the terminal ileum and colon were removed, we did not try
to perform an anastomosis of the bowel, perform an ileostomy, or close the abdominal fascia.
Instead, the stapled ends of the bowel (ileum and rectum) were returned to the abdomen, the fascia was left open to prevent an increase in intraabdominal pressure, and a temporary vacuum-assisted abdominal closure was performed, involving the use of plastic sheets, towels, suction drains, and adhesive plastic dressing.14
The patient was then taken to the ICU for correction of his acidosis, coagulopathy, and hypothermia.
Early, Goal-Directed Resuscitation Early, goal-directed resuscitation has been shown to lower the mortality rate among patients with sepsis and shock.15-17
For optimal results, the resuscitation protocol must be initiated as soon as a diagnosis of shock is made, not delayed until admission to the ICU.
This concept is at the core of evidence-based recommendations for the resuscitation of patients with sepsis.18
Early, goal directed resuscitation was begun when this patient arrived in the emergency department and continued throughout the operation and during the next few days. Dr . H a s a n B . A l a m’s Di agnosis Acute or toxic megacolon of unknown cause.
Pathol o gic a l Discussion Dr. Lawrence R. Zukerberg: The removed segment of colon was dilated, ranging from 15 to 18 cm in diameter, and filled with bloody fecal material.
The wall was thin, ranging from 0.3 to less than 0.1 cm in thickness, and was red and dusky,
without evidence of perforation.
A 50-cm-long segment of distal ileum had a wall thickness of approximately 0.3 cm.
On histological examination, the colonic mucosa showed coagulative necrosis with hemorrhage, loss of crypts, and basal regeneration of the remaining crypts, features that are consistent with ischemic damage (Fig. 3).
The necrosis and hemorrhage were confined to the mucosa, without involvement of the submucosa or muscularis.
The segment of ileum showed similar mucosal changes.
There was no evidence of acute inflammation, pseudomembranes, or vascular thrombi.
–> These features are consistent with the diagnosis of acute megacolon (Ogilvie’s syndrome).
Clozapine-induced gastrointestinal hypomotility Dr. Gregory L. Fricchione: This man’s 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-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 non–first-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 thromboembolism, hypersalivation, weight gain, the metabolic syndrome, sedation, hypotension, and tachycardia. 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 diaphoresis may lower the threshold for constipation and its more serious outcomes.23 This patient’s clozapine dose was 550 mg per day — higher than the mean dose in the reported cases of clozapine-induced gastrointestinal hypomotility (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% within 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 extended.
Avoidance of concomitant medications that can cause constipation, such as opiates and anticholinergic 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 importance of screening.
Discussion of M a nagemen t Dr. Harris: I would like to ask Drs. Ustin and Fernandez-Robles, who cared for this patient on the Surgical and Psychiatry services, respectively, to tell us how the patient’s care was managed and how he is doing.
Dr. Ustin: The patient required many additional operations, including resection of ischemic ileum, creation of an ileostomy, delayed abdominal closure, drainage of an intraabdominal hematoma, and placement of a tracheostomy tube.
He had profound multisystem organ failure with septic shock, a peak lactate level of 24 mmol per liter, liver failure with a total bilirubin level of 44 mg per deciliter (752 μmol per liter), renal failure requiring 2 months of renal-replacement therapy, and respiratory failure requiring 2 months of mechanical ventilation.
Approximately 1 week into his hospitalization, he had received 55 units of packed red cells, 70 units of platelets, and 134 units of fresh-frozen plasma for severe coagulopathy and bleeding.
Because of gastrointestinal dysfunction and the short-gut syndrome, he required parenteral nutrition.
Pulmonary mucormycosis and heparin-induced thrombocytopenia developed and required placement of an inferior vena cava filter during the postoperative period.
Ultimately, after 4 months on the surgical service, the patient’s renal and kidney function returned to normal and he was weaned from the ventilator and transitioned to tube feeding and then to an oral diet.
He was ambulatory and gaining weight and was transferred to the psychiatry service for management of schizophrenia.
Dr. Carlos Fernandez-Robles (Psychiatry): When I saw this patient for the first time, he was still in the ICU, intubated and sedated and not requiring antipsychotic medications.
Once his medical condition stabilized, treatment with olanzapine (10 mg per day) was begun; while he was in the ICU, he received all required doses of this medication, and his psychosis was well controlled.
After his transfer to the regular surgical ward, he began refusing psychiatric medications, and his psychiatric problems recurred. His behavior was oppositional, and he refused essential medications and procedures, including the administration of intravenous fluids. For this reason, a motion for temporary guardianship, accompanied by a medical certificate, and a Rogers guardianship were filed 12 weeks into this hospitalization and received court approval at approximately week 15.
A Rogers guardianship supplements regular guardianship when it is deemed necessary for safety reasons to give psychiatric medications against a patient’s will. The patient’s father is the current Rogers guardian and legal guardian. Six months after the patient’s admission, the temporary guardianship that we filed for was extended by 90 days, because he was still on our psychiatric unit. This has been a very challenging case for us. Clozapine is reserved for cases in which several trials of antipsychotic agents have been unsuccessful, and it was the one medication that seemed to control this patient’s psychosis.
Severe clozapine-induced gastrointestinal hypomotility developed, but after his colon was removed, we thought it would be safe to offer him this drug again.
Unfortunately, he refuses to take it because it had caused acute megacolon. Although his father could order it under the terms of the Rogers guardianship, he has declined to do so.
We first started a trial of olanzapine (10 to 20 mg daily for 17 weeks), with insufficient response. We then switched to risperidone, and the dose was increased to 8 mg per day, which is the higher end of the therapeutic dosage range. Most recently, aripiprazole (5 mg) was added. Within the past month, he also received a trial of ziprasidone because of a persistently irritable mood, but it was discontinued because it was ineffective. During the patient’s stay in the psychiatric unit, additional medical problems were addressed: tachycardia, anemia, renal failure, hypercalcemia, and physical deconditioning. His medical condition stabilized, and he became independent in activities of daily living. He continued to display guarded, paranoid behavior and did not acknowledge that he had any psychiatric condition. An oral, dissolving preparation of risperidone (Risperdal M-Tabs) was required, to prevent him from spitting out the medication. He was transferred to a state hospital after a total of 6 months in this hospital. Three months later, he was discharged to a halfway house. His psychiatric symptoms are reasonably well controlled with risperidone and oxcarbazepine. The colostomy was reversed 6 months after discharge, 13 months after his initial admission to this hospital.
A NAT OMIC A L DI AGNOSIS Acute megacolon (Ogilvie’s 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.
