Toxic Megacolon

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TOXIC MEGACOLON Daniel H. Present, MD

Toxic megacolon is a well-known and serious clinical entity usually identified as a complication of inflammatory bowel disease, especially ulcerative colitis. Although there have been several prior isolated reports of inflammation of the large bowel associated with colonic dilatation, Marshak and colleagues40 are credited with using the term toxic megacolon in describing the entity in detail. Because of its fulminant nature, the frequent need for surgery, and the potentially life-threatening complications associated with a high mortality, there has been great debate regarding the medical management and the appropriate time for surgical intervention. This article attempts to give the physician a practical and comprehensive clinical approach to the diagnosis and medical management of toxic megacolon as well as the indications for surgery. DEFINITION

Toxic megacolon is defined as a severe attack of colitis, seen in several inflammatory conditions involving the large bowel and accompanied by total or segmental dilatation of the colon. The two components of this entity must be present, that is, toxicity as well as the dilatation of the large intestine. There are multiple obstructing clinical conditions that can cause dilatation of the colon, such as colon cancer, fecal impaction, diverticulitis, and volvulus. In addition, dilatation of the colon can be seen in patients without obstruction secondary to ileus, Hirschsprung's disease, excessive narcotic ingestion, and Ogilvie's syndrome. Almost all of the above noted conditions do not have the associated toxicity that was originally described by Jalan and coworkers 28 as having at least three of the following: temperature of over 101 SF, tachycardia of 120 or From the Department of Medicine, Mt. Sinai School of Medicine, New York, New York MEDICAL CLINICS OF NORTH AMERICA VOLUME 77 • NUMBER 5 • SEPTEMBER 1993

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greater, leukocytosis with a white blood cell count over 10,500 and a hematocrit or hemoglobin reading less than 60%. In addition, Jalan noted that with progressive disease, patients would usually manifest at least one of the following: dehydration, mental changes, electrolyte disturbance, and hypotension. The combination of a toxic patient with dilatation of the colon confirms this serious and life threatening entity. INCIDENCE AND MORTALITY

The reported incidence of toxic megacolon complicating ulcerative colitis has great variability, ranging from 1.6% to 22%.17 In recent years, the incidence at most major institutions appears to be decreasing, possibly associated with earlier recognition of severe exacerbations or more intensive medical management. Also, approximately 50% of new cases of ulcerative colitis are presenting with more distal disease, limited to the rectum and sigmoid, and these patients would be less likely to develop toxic megacolon. Crohn's colitis, which was not well defined until the early 1960s, was originally thought not to develop into toxic megacolon. Although Hawk and Turnbull25 recognized cases of toxic megacolon complicating granulomatous disease, the first detailed case report was presented by Schachter and associates in 1967.58 A review of the patients in earlier large series of ulcerative colitis with toxic megacolon dearly demonstrates that Crohn's colitis was often not recognized because at least one or two patients had the latter type of disease. 41 The reported incidence of toxic megacolon in Crohn's disease has also been variable, ranging from 0% to 20%, with a probable frequency of 2% to 4%.22 It has been suggested that megacolon will be more likely to occur earlier in the course of Crohn's disease before there is significant fibrosis. It is also believed that the fibrosing nature of Crohn's disease as well as its segmental involvement would make it less likely than ulcerative colitis to develop into dilatation. Recent analysis of several series, however, has suggested that this is not so, with an incidence of 4.4% to 6.4%. In many large series, patients are referred from outside the institution for this complication, and a representative study at one such institution20 demonstrated a 6% incidence of toxic megacolon in ulcerative colitis and a 1.2% incidence in Crohn's disease with an overall incidence of 3.6% in inflammatory bowel disease. Despite the relatively low incidence of this complication, the morbidity and mortality can be high. Mortality rates in large series are variable, often depending on whether patients are treated medically or with early surgery. Mortality rates range from 0%47 to 45%.28 There have been several large reviews comparing mortality with either medical or surgical therapy. In a comprehensive review by Strauss and colleagues61 of 604 patients, medical mortality was 27% in 160 patients of whom 24% had perforated colons. The surgical mortality was 19.5% in 444 patients, occuring in 41.2% who had perforated and 8.8% in those who had surgery before a perforation. The overall mortality in these 604 patients

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from series dating from 1955 to 1975 was 19%. In contrast, recent series of medicaP2 and surgica146 therapy have reported no mortality. From the medical therapy point of view this decrease in mortality is probably related to earlier recognition, a more intensive and specific medical management regimen with a team approach, in which surgeons are involved earlier in the course of management. In the surgical series, the improved mortality is likely related to more experienced surgeons performing colectomy earlier with improved postoperative care (intensive care units, antibiotics, fluid and electrolyte balance). The controversies related to medical versus surgical therapy is discussed in greater detail later in this article. DIFFERENTIAL DIAGNOSIS

There are multiple underlying causes of toxic megacolon. The patient's present illness and history are the most crucial information required in managing a patient with this complication. If a patient is known to the treating physician and has had underlying inflammatory bowel disease, either ulcerative or Crohn's colitis, diagnostic studies and management are clear. On the other hand, if this is the patient's first presentation, a variety of other organic problems must be excluded before it can be concluded that this is the first attack of inflammatory bowel disease (Fig. 1). To compound the problem, it must be noted that approximately one third of attacks of toxic megacolon do occur during the initial episode of inflammatory bowel disease. If this is the initial contact with the patient, the important points to be elicited in the history that would suggest underlying inflammatory bowel disease are prior bouts of diarrhea, often lasting 1 week or longer, episodes of diarrhea with nausea and vomiting requiring admission to a hospital or emergency room for dehydration, a history of recurring episodes of what were thought to be attacks of appendicitis, recurrent and persistent rectal bleeding, and nocturnal diarrhea. Other more subtle clues, often not volunteered by the patient include the history of frequent oral aphthous ulcerations (seen in Crohn's disease), episcleritis, erythema nodosum, or arthritis involving larger joints such as the knee, ankle, and wrist. Also suggestive are recurrent episodes of significant weight loss without dieting or history of a persistently elevated sedimentation rate. In the acute phase of megacolon, abdominal physical findings are variable, but the findings that might lead a physician to the diagnosis of Crohn's disease include oral aphthous lesions, clubbing of the fingernails, and perianal fistula. Rectovaginal fistula can be seen with both ulcerative colitis and Crohn's disease. If the patient has a documented history of inflammatory bowel disease and has not seen the current treating physician, then it is important to confirm the patient's type of inflammatory bowel disease, Crohn's or ulcerative colitis. Therapy may be altered depending on the type of disease. The history of prior significant involvement of the small intestine documented on radiograph and

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Comprehensive history including information relating to travel, family history of IBD, other illnesses and current medications, and potential for HIV positivity

II No Prior History IBD Clinical evaluation for aphthous ulcers, clubbing, perianal disease Flexible sigmoidoscopy and biopsy HIV testing if indicated

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Stool culture Stool C. difficile

Stool 0," ood P""it, ObW"H" ,,,',,

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I

Prior History of IBD Review of prior colonoscopy and x-ray reports and films Limited flexible sigmoidoscopy and biopsy

Figure 1. Diagnostic evaluation for toxic megacolon. IBD = inflammatory bowel disease.

endoscopy, perianal fistula, or a biopsy specimen showing epithelioid granulomas are the only definitive ways to diagnose Crohn's disease. If none of these are present, endoscopic findings typical of Crohn's disease may be suggestive (skip lesions, cobblestoning, aphthous ulcerations) but cannot give a definitive diagnosis. Ulcerative colitis is suggested with a history of continuous rectal bleeding and a typical sigmoidoscopic or colonoscopic appearance of left-sided disease, but it must be noted that there are occasional cases of left-sided Crohn's that can be confusing. If the patient has no prior history of inflammatory bowel disease, other causes must be considered in which the vast majority are infectious in nature. Even if the patient has documented inflammatory bowel disease and has been quiescent for a long period of time, there still may be a superimposed infectious process. With this in mind, the recent history must be reviewed and in the least the treating physician must elicit whether the patient has been exposed to any infectious agent (travel, family members with similar symptoms, tainted food), has taken antibiotics within the recent month, or has a history of HIV positivity or other manifestations of AIDS. Also, a history of other illnesses that are being treated with medications that have the potential of producing colitis and megacolon should be elicited (examples would be psoriatic arthritis or rheumatoid arthritis treated with gold 35 or methotrexate2 ). Lymphomas may present with toxic megacolon. 69 A positive family his-

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tory of inflammatory bowel disease increases the likelihood that this is the patient's first attack of inflammatory bowel disease. In all patients who present with severe colitis and toxic megacolon, stool cultures should be performed to exclude infectious agents. Salmonella is an infrequent but not rare cause of colitis with toxic megacolon. In a large series26 Salmonella infection was found in 2 (3%) of 70 megacolon patients, whereas in most series of Salmonella colitis, toxic megacolon is uncommon. 56 The differential diagnosis is difficult and endoscopically the mucosa may be diffusely involved and appear like ulcerative colitis, whereas in others, segmental involvement suggests Crohn's disease?O Although colonoscopy is not considered the procedure of choice in deciding whether bacterial infection is the cause 6f colitis, a limited endoscopic examination is often performed in a new patient who presents with these symptoms. Experienced endoscopists may be able to suggest an infectious agent as with the presence of thick greenish pus or a yellow exudate that covers the mucosal surface without the presence of ulcerations. A rectal biopsy specimen evaluated by an experienced pathologist may be able to identify the histologic features that are typical for inflammatory bowel disease. 62 There are no definitive histologic characteristics that are diagnostic of acute colitis; however, this is suggestive when the biopsy sample lacks the specific patterns of inflammatory bowel disease. Salmonella may also be superimposed on inflammatory bowel disease and if suspected or confirmed, attempts should be made to avoid colonic resection because successful decompression has often occurred with intensive medical therapy. Toxic megacolon and colonic perforation due to Shigella dysentery is rare and is seen more often in neonates and infants, but there have been several case reports 67 associated with perforation and death. Although the endoscopic picture in Shigella more likely resembles ulcerative colitis, cultures are essential in making this diagnosis. Although Campylobacter is one of the most common causes of gastrointestinal infection seen in clinical practice, it has rarely been reported in the literature as causing toxic megacolon. 31 The diarrhea seen in Campylobacter is usually nonbloody and a definitive diagnosis is made on the basis of a positive stool or blood culture. Pathology usually shows a nonspecific enteritis. Endoscopic features have been reported as resembling either Crohn's disease or ulcerative colitis. Pseudomembranous colitis initially described in the 1800s and more recently found to result from a toxin producing strain of Clostridium difficile, has been associated with toxic megacolon. This entity has only occasionally been associated with antineoplastic chemotherapy8 and the vast majority of patients are secondary to the use of broad spectrum antibiotics. 63 Although some antibiotics such as clindamycin and lincocin are more often incriminated, the entities are associated with almost all antibiotics except vancomycin and aminoglycosides. l l Leukocytes are seen in the stool smear ~n 50% of cases but do not serve to distinguish pseudomembranous colitis from other entities. Endoscopy reveals diffuse ulcerations, raised mucosal nodules with typical pseudomembranes which appear as yellowish white plaques with normal intervening mu-

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cosa. The plaques may become confluent, with ultimate sloughing as the disease progresses. Histology shows polymorphonuclear leukocytes extending into the lamina propria but there is no evidence of deep layer destruction. There are often "epidemics" of pseudomembranous colitis seen in hospitals and communities. The mortality rate is high as with other causes of toxic megacolon, and the correct diagnosis is made with the finding of elevated C. difficile toxin titres or endoscopy. Early diagnosis is essential in trying to avoid surgical intervention or progression of the megacolon to perforation. There are only rare reports of acute amoebic colitis resulting in toxic dilatation and the more common finding is peritonitis secondary to a colonic perforation. 72 Mortality has been high in this complication of amoebiasis, perhaps due to delayed recognition. In a recent review!3 of approximately 2000 patients with AIDS followed over a 3-year period, 28 required emergency laparotomy. Toxic megacolon occurred in 5 of these patients and cytomegalovirus (CMV) was identified in 4 of the 5. Three of the toxic megacolon patients had underlying inflammatory bowel disease. Two other patients with inflammatory bowel disease had performation of the colon, one associated with CMV and one with Salmonella infection. The latter perforated patients were not identified as also having toxic megacolon. The authors reported a low mortality rate which they attributed to prior close liaison with these patients as well as a physician group with expertise in the management of AIDS. In patients who are HIV negative, CMV infection of the colon usually occurs in the presence of inflammatory bowel disease. In one series 12 of 46 patients who were resected with ulcerative coltitis, 6 were found to have CMV of which 5 had toxic megacolon. Of the remaining 40 patients without CMV, only 2 had toxic megacolon, suggesting that somehow CMV may predispose to the development of this complication. In addition, there has been a recent report of toxic megacolon occuring due to CMV without underlying inflammatory bowel disease. 49 Of interest is that the surgical specimen demonstrated damage limited only to the mucosa and submucosa and spared the muscularis propria and Auerbach's plexus. This finding raises questions as to the pathogenesis of CMV-induced toxic megacolon. PATHOGENESIS AND PREDISPOSING FACTORS

The exact cause of toxic megacolon is not well understood. Although the inflammatory changes in uncomplicated ulcerative colitis are confined to the mucosa, it appears that in toxic megacolon there is spread of the acute inflammation to the deeper layers of the colonic wall. This spread to the longitudinal muscle layers (and even the serosa) is considered one of the key factors in the development of toxic megacolon. Pathology shows severe inflammation with polymorphonuclear leukocyte infiltration, microabscesses, edema and necrosis, and this may result in paralysis of the colonic smooth muscle which then allows the colon to

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dilate and perhaps lose its propulsive contractions. Destruction of the myenteric plexus which is located between the longitudinal and circular muscle layers of the colon may be playing a role; however, some studies55 have found that the myenteric plexus was histologically intact, even in areas of significant dilatation and inflammation. Other reports have described destruction of Auerbach's plexus in patients with toxic megacolon, whereas obliteration of Meissner's plexus does not appear to be significant. In some studies,s the colonic dilatation has shown correlation with the depth of ulcerations into the deeper muscle layers. It is not unusual for this inflammatory process to proceed through the serosa and produce a free or sealed-off colonic perforation. The latter would depend on whether the perforation was intraperitoneal or extraperitoneal and the presence of omentum. This is significant at the time of surgery when manipulation may unseal these perforations, resulting in fecal contamination of the peritoneal cavity. Ulceration of the colon is often extensive and leaves large areas of denuded mucosa. The mucosa that remains, appears as isolated edematous islands. The mucosa normally functions as a barrier protecting the patient from toxic elements that may appear in the colonic lumen. Where severe colitis occurs, toxins and bacterial antigens may penetrate through the ulcerations and result in the release of inflammatory cytokines producing fever, leukocytosis, and if left untreated, shock. There have been reports of a number of triggering factors that seem to predispose to developing fulminant colitis or toxic megacolon. 18 In my experience, the most common is early discontinuation or marked decrease in dosages of therapeutic medications. This includes discontinuation of sulfasalazine or other 5-aminosalicyclic acid (5-ASA) agents when the patient is in a clinical but often not endoscopic remission, or premature rapid lowering of steroid medications often after an episode of severe colitis. Patients must be strongly cautioned not to discontinue sulfasalazine or 5-ASA drugs since these agents do provide prophylaxis against exacerbation. Others have noted the onset of toxic megacolon after having had a recent barium enema?3 In these cases, it is not certain whether the barium enema was responsible, perhaps by opening up a sealed off perforation, or what role the cleansing agent played in the development of toxic megacolon, perhaps by producing an electrolyte imbalance. Likewise, the performance of endoscopy to beyond 20 cm has been felt to be contraindicated because of the possibility of perforation or triggering toxic dilatation. A recent studi has suggested that colonos copy during an acute attack of colitis is safe and states that colonoscopy is of great value in deciding the timing of surgical intervention. This author has personally observed four cases of toxic megacolon triggered by extensive endoscopy and it is unlikely that the endoscopic findings would be a major final determinant in advising colectomy. Several drugs that have potent motility effects have been accused of inducing the developm~nt of toxic megacolon. These include narcotic antidiarrheals (deodorized tincture of opium, codeine, loperamide, diphenoxylate), anticholinergic agents as well as antidepressants with sig-

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nificant anticholinergic effects. The antimotility and anticholinergic properties may enhance the dilatation which is occuring secondary to inflammation or localized perforation. In several reports,48 introduction of narcotic agents anteceded the development of megacolon within a few days. It is prudent for the clinician to discontinue these symptomatic agents once the patient has demonstrated increasing bowel activity as well as systemic manifestations. Electrolyte abnormalities are implicated by many authors1o as predisposing to the development of toxic megacolon. Because potassium depletion may inhibit the motility of the colon, thereby producing a paralytic ileus, several authors have cited it as a major factor. Other authors64 feel that this type of electrolyte abnormality is very common in severe ulcerative colitis and is produced by massive losses of fluid through diarrhea as well as potassium depletion secondary to intravenous steroids. Whether this deficiency is a causative factor or just part of the syndrome, adequate potassium replacement is essential in all these patients with depleted amounts of potassium. A recently recognized and unusual trigger of severe colitis is the discontinuation of cigarette smoking. The mechanisms are uncertain and do not apply to patients with Crohn's disease. This author has seen one patient with toxic megacolon that developed soon after cessation of smoking. It has been suggested by several authors that steroids may allow deeper penetration of the inflammatory process into the bowel wall resulting in localized perforation and the possible development of toxic megacolon. 4 There is no clear cut evidence in the literature to support this speculation, and because corticosteroids are the drug of choice for fulminant colitis and toxic megacolon, delay in initiating this therapeutic agent is not warranted by the available information. CLINICAL AND RADIOGRAPHIC PRESENTATION

Patients with pre-existing inflammatory bowel disease are now the focus of this article because the literature provides comprehensive data regarding presentation of these patients. They will usually present in the midst of an attack of colitis, most often for 1 week or longer, having at least 6 bowel movements daily containing moderate amounts of blood and associated with crampy abdominal discomfort often relieved with the passage of stool. It must be noted that some patients with marked dilatation may present with only 1 to 2 bloody bowel movements daily. Patients also have constitutional symptoms, such as tachycardia, fever, lethargy, and occasionally hypotension. Pallor associated with anemia is common. Abdominal findings will vary greatly, often depending on whether the patient has been taking corticosteroids. The usual findings are those of abdominal distention, tenderness without rebound, especially along the colonic contour. In the presence of high-dose steroids, physical findings may be minimal to absent and the clinician must then rely on abdominal x-ray examination. Localized tenderness and rebound tender-

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ness may suggest impending perforation and generalized tenderness with guarding and rebound tenderness strongly indicates a free perforation. After the diagnosis of toxic megacolon is confirmed, percussion of the abdomen becomes an important physical diagnostic modality. Large amounts of intestinal gas in the transverse colon can often be suspected by tympany found in the mid and left upper quadrants of the abdomen. When no tympany is present the x-ray findings usually show no major distention. Likewise, percussion of the right upper quadrant demonstrating loss of hepatic dullness may be the first clinical evidence of a perforation complicating toxic megacolon. The crucial study in diagnosing and managing toxic megacolon is the abdominal x-ray. The most prominent feature is colonic dilatation. The upper limit of normal for the width of the transverse colon is approximately 6 cm. In Fazio's series,18 the mean diameter of the colon was 9.2 cm (range, 5.8-16 cm) and when perforation was noted the mean diameter was 9.1 cm. In Norland and Kirsner's series,48 the mean diameter was 8.8 cm (range, 6-15 cm). Truelove and Marks 64 suggest, and the author agrees, that when evaluating the patient it is often best not to rely on the exact measurement of the transverse colon but rather the overall clinical condition of the patient. It is important to note that although the transverse colon appears to be the portion with greatest involvement this is not accurate. Patients with toxic megacolon are seriously ill and often stay in bed continually with the head of the bed elevated and in a supine position. Because the transverse colon is the most anterior of all colonic segments, air will tend to accumulate in this segment. If the patient is moved into the prone position, the colonic air column will redistribute, filling other segments of the boweP4 This has important therapeutic implications to be discussed later. Dilatation of the colon in and of itself may be a nonspecific finding and there are several other radiographic criteria for the diagnosis of inflammatory changes. Of great significance is the contour of the bowel wall in which the normal haustral pattern is either absent or markedly edematous.23 The contour will appear scalloped and nodular with polypoid projections noted along the margins. Correlating with the pathology, pseudopolyps, or areas of residual mucosal islands sitting on denuded mucosal surfaces will appear as no dularity seen throughout the air column. Radiolucent linear ulcerations are occasionally noted and are believed to reflect submucosal accumulations of gas and are representative of deep ulcerations with undermining. It is believed that these lucencies may be a forerunner of perforation which will be demonstrated on abdominal radiographs by the presence of free air in the peritoneal cavity. The air may track and produce subcutaneous emphysema and pneumomediastinum with and without pneumoperitoneum. Pneumomediastinum may be present when the perforation occurs into the retroperitoneal area. When a patient presents with a severe attack of inflammatory bowel disease from whatever origin, abdominal x-rays are essential. A full obstructive series, including prone, supine, and upright films must be performed. Early findings such as an increase in small intestinal gas appear to be somewhat predictive of those patients who may go on to

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develop toxic megacolon as well as those patients who are more likely to respond to medical therapy. In a series7 of 69 patients with fulminant colitis, of the 31 with increased small intestinal gas, 7 went on to develop toxic megacolon (Fig. 2). In the remaining 38 patients who did not have increased small intestinal gas, megacolon was not observed. In another series9 of 75 patients an increased degree of small intestinal distention was associated with the need for surgical intervention. Likewise, a continuous thin air column noted in the descending or transverse colon and occuring in the presence of clinical toxicity is a sign of impending toxic megacolon, and treatment must be initiated immediately. In the author's experience, the initiation of treatment when small bowel gas is present and a small column of air is noted will prevent the vast majority of patients from developing a full-blown toxic megacolon. There is little need for ultrasonography and CAT scanning in the diagnosis and management of toxic megacolon. An endoscopic examination is often considered in the presence of fulminant colitis or megacolon. It is only needed in patients who are presenting for the first time with colitis and in whom it may be of some help in differential diagnosis (that is, infectious colitis versus Crohn's

Figure 2. Early toxic megacolon demonstrating a dilating colon with the classic radiographic features as well as a marked increase in small intestinal gas. This patient was subsequently decompressed with the passage of a long intestinal tube and rolling technique.

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versus ulcerative colitis). If performed, the scope should not be passed above 20 cm, nor should air be insufflated. Full colonoscopy should not be performed in the face of a severe attack of colitis because the plain abdominal film appears to give an accurate estimate of the extent of involvement. In a recent studtl of 97 ulcerative colitis patients, slightly over 80% were correctly classified as to the extent of involvement by a plain abdominal film. This technique was particularly accurate in total colitis which is the most common extent of involvement associated with toxic megacolon. Laboratory studies are essential in the management of patients with toxic megacolon and should be performed on presentation and every 24 to 48 hours thereafter. The studies should include a complete blood count with differential, serum electrolytes, chemistries including albumin levels and sedimentation rate. A leukocytosis with a left shift is invariably present and a markedly high leukocyte count may suggest perforation. It must be noted that the white blood cell count will be elevated once steroids have been administered and sequential testing is essential in clinical decision-making. Hemoglobin and hematocrit levels will invariably show anemia and repeat studies will indicate when the anemia has reached levels that will require transfusion. Electrolyte studies are of great value as to the need for replacing fluids, salt and potassium, the latter of which is markedly decreased when using high dose steroids. Several centers have used serum electrolyte and pH values in predicting the outcome.6 A poor prognosis is suggested by alkalosis which can be measured with arterial pH samples. In addition, 24-hour measurements of stool have noted a poor prognosis associated with increased fecal weight and with a lowered fecal potassium/sodium ratio. Serum albumin levels are usually low and sequential monitoring can be used as an indication for nutritional replacement. Although some centers have used IIIIN-Ieukocyte testing to evaluate extent and severity of activity, it is the author's personal experience that it is of little help in diagnosis and management. The author's personal experience suggests that erythrocyte sedimentation rate closely parallels the clinical course in the vast majority of patients with fulminant colitis and toxic megacolon. This simple test should be performed on a daily basis. Intensive laboratory monitoring of the patient is of utmost importance in therapeutic decision-making (Table 1).

GENERAL MEDICAL MANAGEMENT

The confirmed diagnosis of toxic megacolon is considered by many as an indication for surgical intervention within 48 to 72 hours if there is no improvement with medical therapy. There appears to be little data to support a specific timing for surgical intervention since there are few well-defined clinical trials using standardized therapeutic regimens. It

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Table 1. MONITORING THE PATIENT WITH TOXIC MEGACOLON

1. Physical examination daily by both medical and surgical team to include evaluation for abdominal tenderness and rebound tenderness as well as percussion for distention and loss of hepatic dullness. 2. Recording of vital signs at least four times daily and more often if deterioration is noted. 3. Recording of number and character of bowel movements to include the presence or absence of blood, liquid versus solid stool. Optional if available: measurement of stool weight and electrolytes. 4. Blood studies every 24 to 48 hours to include complete blood count, sedimentation rate, serum electrolytes, serum albumin, and other chemistries. Optional: arterial pH. 5. Daily obstructive series.

must be noted, however, that the best results in decompression associated with low mortality have been obtained in those centers with specialist experience and where an early specific intensive medical regimen has been instituted.3D Recently, there has been some progress published in reviews attempting to define the specific therapeutic modalities being used in the management of fulminant colitis and toxic megacolon. 24 • 53 The following recommendations identify specifics to be used by the physician who is managing toxic megacolon (Table 2). The first management rule when faced with a patient who presents seriously ill with colitis, is hospitalization followed by consultation with an experienced surgeon. Because surgical intervention is required in many patients, a team approach must be adopted in which the patient is seen by both the medical and surgical teams once or twice daily. In addition, the monitoring outlined previously should be instituted immediately (see Table 1). Table 2. MEDICAL MANAGEMENT OF TOXIC MEGACOLON

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Hospitalization and consultation with surgeon Monitoring by medical and surgical team 1 to 2 or more times daily Intravenous fluid and electrolyte replacement Blood transfusion if needed Avoidance of narcotics. antidiarrheals, and anticholinergics No oral food or liquids with intravenous nutritional support Total parenteral nutrition only for Crohn's disease or in patients with long-term depletion. Passage of a long intestinal tube with placement in radiology department Daily obstructive series Rolling technique every 2 to 3 hours for 15 minutes Intravenous administration by continuous infusion of hydrocortisone 300 mg, or ACTH, 120 U (if the patient has not been on prior steroid therapy) Triple antibiotic therapy (aminoglycoside, metronidazole, ampicillin) administered intravenously If no improvement in 7 to 10 days, consider intravenous cyclosporine, 4 mg/kg per day Surgical intervention for free perforation, massive bleeding, progressive deterioration despite intensive therapy, or failure to respond to steroid therapy after 10 days A compassionate nursing and medical team, providing emotional support for the patient and family with possible hospital visitation by support teams from the Crohn's and Colitis Foundation of America

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There must be adequate administration of fluids and electrolytes and dehydration should be corrected. In addition, electrolyte abnormalities should be treated, especially potassium and magnesium depletion which may impair smooth muscle functioning. The patient should be transfused if the anemia is significant (hemoglobin less than 9 g/ dL). Medications for symptomatic relief such as narcotics, anticholinergics and antidiarrheals must not be administered because they may prolong the toxic megacolon. Narcotic analgesics should be avoided since they mask clinical signs and may worsen distention. The discomfort of toxic megacolon and fulminant colitis is related to the disease and the abdominal distention and when treated adequately with decompression does not require narcotics. If patients are taking antidepressants with anticholinergic activity they should be discontinued. Minor tranquilizers may be administered for anxiety or when steroids are resulting in significant emotional side effects. Oral fluids and food are discontinued and nutrition is administered intravenously. There is no evidence to support the use of total parenteral nutrition in the treatment of either fulminant ulcerative colitis or toxic megacolon complicating ulcerative colitis.15, 44 Studies demonstrate that total parenteral nutrition does not avoid surgical intervention nor shorten the duration of time spent in the hospital. When the megacolon is decompressed and the patient shows a marked decrease in the signs of severe toxicity, it is my experience that there is an advantage to early feeding in terms of supplying the essential nutrients to the colonic mucosa. This applies primarily to ulcerative colitis, whereas in Crohn's disease there are reports of total parenteral nutrition playing a distinct therapeutic role in decreasing clinical activity.45 Parenteral nutrition should only be used in toxic megacolon if the patient has been nutritionally depleted for long periods of time and surgery appears likely.

SPECIFIC MEDICAL THERAPY

As has been noted, patients who are going to, or have developed toxic megacolon appear to have an increased accumulation of intestinal gas, which when extensive predicts an increased requirement for surgery?' 9 Although some studies suggest that passage of a nasogastric tube is advisable (in some or all patients), it is the author's personal experience and others that the passage of a long intestinal tube is more effective in decompression of the megacolon. 27,52 It is advised that soon after the tube is passed, the patient should be transferred to the x-ray department where fluoroscopic positioning will allow easier passage of the mercury weight into the duodenum, thereby resulting in more rapid removal of small intestine liquid and air. In addition, as has been described previously, air tends to accumulate preferentially in the transverse colon because the patient assumes the supine position while lying in bed. If the patient is allowed to main-

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tain this position, distention will continue to increase and suggest to both internist and surgeon that surgery should be performed earlier. Great success has been demonstrated with a rolling technique in which the bed is flattened and the patient rolls over into a prone position for approximately 10-15 minutes every 2 to 3 hours. Lying in this position allows the redistribution of colonic air as described by Kramer and Wittenberg,34 and the patient is then encouraged to pass flatus in this position. Only on occasion is a thin, soft rubber catheter inserted into the rectum when the patient feels he or she cannot release air and liquid in that position. A consecutive series of 19 patients52 showed decompression in all 19 when this rolling technique was instituted in addition to the other therapeutic modalities. There are also patients in whom toxicity is controlled with medications and in whom megacolon persists. In these patients the rolling technique is especially important because surgery is usually not required if the inflammatory process has been brought under control. There have been scattered case reports3 of decompression of toxic megacolon by placement of an indwelling colonic tube via colonoscope. Although many clinicians feel colonoscopy is safe during an attack of megacolon, I believe the passage of a long tube and the rolling technique will provide the same result without the added risk of endoscopy. There has been controversy regarding the role of steroids in the management of toxic megacolon. 42 Because steroids have shown efficacy in active ulcerative colitis65 as well as in active Crohn's disease,59 the argument becomes moot because most patients will have had steroid therapy initiated in order to suppress the active inflammatory process before the toxic megacolon develops. Although there are no controlled trials to show the corticosteroids are useful in treating patients with toxic megacolon, they cannot be discontinued when this complication arises or the patient will be at risk for adrenal insufficiency. It has also been strongly suggested that the risk of colonic perforation is no greater when steroids are administered. 48 For those patients who have been on prior steroid therapy, hydrocortisone is administered in a standard dose of 100 mg every 6 to 8 hours (or methylprednisolone, 6 to 15 mg every 6 hours). A pilot study57 to demonstrate the efficacy of higher dose methylprednisolone (1 g daily) was in fact less successful than the use of intermittent methylprednisolone in lower doses. Although no controlled trial has been completed comparing intravenous steroids administered continuously versus bolus administration, it is the author's personal experience that continuous administration is more effective. In an uncontrolled manner we have seen a number of patients respond when switched to continuous hydrocortisone after having failed pulse therapy. In a single controlled trial,43 adrenocorticotropic (ACTH) administered by continuous infusion, 40 U every 8 hours, was shown to be more effective than intravenous hydrocortisone (100 mg every 8 hours) if the patient had not been receiving prior steroid therapy. If the patient has toxic megacolon and has not received prior steroid therapy, ACTH should be considered. Although topical steroids in the form of hydrocortisone enemas were initially used in patients with fulminant and severe colitis they have been mentioned rarely in the treatment of toxic megacolon and

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there are no controlled trials to confirm efficacy. It is our experience that topical treatment of the rectal mucosa tends to quiet bowel symptoms such as urgency, frequency and the degree of bleeding; however, patients with megacolon have difficulty retaining this medication and we recommend that they be started only after the colon has been decompressed. Although Truelove and Jewell66 administered intravenous antibiotics as part of their regimen in the treatment of severe attacks of ulcerative colitis, controlled trials with metronidazole8 and vancomycin16 have shown no efficacy. Because the ulcerated mucosa of the colon may lend itself to invasion by enteric organisms resulting in systemic bacteremia and because of the high risk for perforation and the frequent finding of microperforations in the surgically resected specimens, I recommend administering triple antibiotics to indude an aminoglycoside, metronidazole, and ampicillin (which covers enterococci) in all patients with toxic megacolon. With increased availability of third-generational cephalosporins, these may be substituted for broad spectrum coverage. An advantage of administering metronidazole is that it is also effective in Crohn's disease, amoebiasis, and where there may be a secondary C. difficile superimposed colitis. It should be noted at this time that after toxicity has abated and the megacolon is decompressed, if diarrhea is persisting, stools should be rechecked for the C. difficile toxin. Sulfasalazine and the newer oral 5-ASA agents are not started if the patient is taking nothing by mouth. There is no indication for initiation of these drugs in the severely ill patient; however, when the patient has recovered, toxicity has abated and the patient is being fed, these agents should be re-added if they were being taken before the megacolon episode. Although 6-mercaptopurine and azathioprine have shown efficacy in controlled trials in both ulcerative colitis and Crohn's disease,54 they are not used in patients with toxic megacolon because they are slow in onset of action (mean response time 3.1 months). A preliminary report36 noted that intravenous cydosporine (4 mg/kg per day) was effective in severe active ulcerative colitis patients who had failed to respond to 10 days of intravenous steroids. Further follow-up showed a response rate of over 80% in 32 patients. 37 A recent double blind controlled triaP8 has been completed and has confirmed these findings. Although cydosporine therapy has not been used in toxic megacolon, once the megacolon patient is decompressed this immunosuppressive should be considered. The authors have noted no significant toxicity during the short-term cydosporine administration, nor was surgery more complicated in patients who failed to respond to this therapy. In this era of high-technology treatment, it is important to have a compassionate medical, surgical, and nursing team that can provide emotional support for a patient who is fearful of undergoing surgery and requiring a stoma. The patient should be provided with frequent updates as to the progress.and as to the therapeutic options both medically and surgically. It may also be helpful to have hospital visitation from educated lay members of the Crohn's and Colitis Foundation of America. 60

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MEDICAL AND SURGICAL OUTCOME

As was noted earlier, there is significant variation in mortality in both medical and surgical series. The outcome of management and the decision regarding surgical intervention may be related to several factors including the experience of the treating physician; whether the primary managing physician is an internist, gastroenterologist, or surgeon; and often recent experiences with similar cases of megacolon. There is absolute agreement that free perforation is an indication for surgery. Massive hemorrhage, although unusual, is also an indication for colectomy. A consensus group30 found that any patient who requires more than 6 to 8 U of blood in the first 48 hours and is still actively bleeding should undergo colectomy. The same group states that urgent colectomy is required for colons that remain dilated after 24 to 48 hours of intravenous corticosteroids. This is contrasted to the experience of Katzka and coworkers,32 who treated patients for up to 7 days if no free perforation had occurred and if the patient was improving clinically. In over half their patients the colons were salvaged with no mortality. In the author's personal experience,52 19 of 19 patients (100%) were decompressed within 1 to 13 days (mean, 4.9 days). Mortality occurred in 2 (10.5%), both of whom were decompressed within 5 days. One patient died from a pulmonary embolus and the other secondary to sepsis. It should be noted that death from pulmonary embolus is one of the major causes of mortality in toxic megacolon patients, whether treated medically or surgically.33 Outcome analogies can be drawn from the reviews of the medical management of severe ulcerative colitis. In one large series29 of 158 patients, the remission rate in the severe group was only 55.7%, and if the entire colon was involved, 53% had a colectomy within 3 weeks. Relapse rate is also high in this group, occuring in 38% during the first year of remission. This study does not mention toxic megacolon. The long-term follow-up of the medically treated Katzka series32 shows that of 12 patients who underwent successful medical therapy 9 did not require colectomy and are either in remission or have mild symptoms. In my personal medical series,52 13 of 19 patients (68%) are either completely well or minimally symptomatic with a mean followup of 6.5 years. None of the patients are requiring steroids. Patients with Crohn's disease are likely to fare better than patients with ulcerative colitis during and after megacolon because they are probably less likely to experience perforated colon. In our own personal experience, 100% of Crohn's patients are well for a long-term period, although several have required 6mercaptopurine to obtain remission. The medical experience is contrasted with several surgical series such as the Mayo Clinic 19 experience which had a complete follow-up of 38 patients who had responded to conventional medical therapy. Of the 38, 47% ultimately required colonic resection, and only 32% of the original group achieved satisfactory long-term clinical remission. In the series by Greenstein and associates,2° 6 of 14 successful medical responders had a satisfactory long-term clinical response. In Fazio's18 series of seven

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patients that were treated successfully at the Cleveland Clinics, only two were well and five subsequently required colectomy. As was noted, these variations are probably related to the medical and surgical biases of the treating physicians. The author's experience with the use of immunosuppressives,54 which are instituted in many of these patients after they have recovered and left the hospital, may account for the long-term success rate. In our more recent cyclosporine experience in those patients who had already failed to respond to 10 days of intravenous steroid therapy, we have noted over an 80% acute response rate and our long-term follow-up demonstrates that approximately 60% of the original group are well and are not requiring either cyclosporine or steroids. Finally, many physicians and especially surgeons, are inclined towards surgery because of the current availability of the newer alternative procedures in ulcerative colitis. There had been prior great debate on the procedure of choice, comparing total proctocolectomy with ileostomy and subtotal colectomy and ileostomy leaving the rectal segment. A review of several large series71 showed that total proctocolectomy seemed to have a lesser mortality; however, if ileoanal anastomosis with proximal pouch is to be performed, the rectal segment must be left in place and used with later surgery. The concept of the ileoanal anastomosis with proximal pouch as a "cure" for ulcerative colitis must be carefully analyzed. The failure rate with this procedure is approximately 5% at major centers50 and pouchitis is now being noted with increasing frequency. The incidence in 734 patients with a mean followup of 41 months was 61%.39 This was also accompanied by other extraintestinal manifestations in some of the patients with pouchitis. Pouchitis appears to respond to metronidazole but some patients may go on to chronic pouchitis and require more intensive medication. Whether pouchitis will worsen over the years or continue to respond to antibiotics is unknown as it must be pointed out that ileoanal anastomosis with proximal pouch has only been utilized for 13 years. Chronic inflammatory changes in these pouches may potentially be associated with an increased risk for carcinoma. 14 The long-term management of inflammatory bowel disease patients once having had an episode of toxic megacolon should be individualized, taking into account both the newer medical and surgical alternatives. In summary, I have attempted to provide a comprehensive look at all aspects of toxic megacolon, emphasizing the differential diagnosis as well as controversies regarding medical versus surgical management. Because most individual physicians "fortunately" see only a rare case of toxic megacolon, it is hoped that this article will be of some help in returning these seriously ill patients to a state of good health. References 1. Alemyehu G, Jamerot G: Colonoscopy during an attack of severe ulcerative colitis is a

safe procedure and of great value in clinical deCision-making. Am J Gastroenterol 86:187-190,1991

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2. Atherton LD, Leib ES, Kaye MD: Toxic megacolon associated with methotrexate therapy. Gastroenterology 86:1583-1588,1984 3. Banez AV, Yamanish IF, Crans CA: Endoscopic colonic decompression of toxic megacolon: Placement of colonic tube and steroid colon clysis. Am J Gastroenterol 82:692694, 1987 4. Binder H: Steroids and toxic megacolon. Gastroenterology 76:888-889,1979 5. Bucknell NA, Williams GT, Bartram Cl, et al: Depth of ulceration in ulcerative colitis. Gastroenterology 79:19-25, 1980 6. Caprilli R, Frieri G, Latella G, et al: Fecal excretion of bicarbonate in ulcerative colitis. Digestion 38:136-142,1986 7. Caprilli R, Vernia P, Latella G, et al: Early recognition of toxic megacolon. J Clin GastroenteroI9:160-164,1987 8. Chap man RW, Selby WS, Jewell DP: Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 27:1210-1212,1986 9. Chew CN, Nolan DJ, Jewell DP: Small bowel gas in ulcerative colitis. Gut 32:1535-1537, 1991 10. Cohn EM, Copit P, Tumen JH: Ulcerative colitis with hypopotassemia. Gastroenterology 30:950-957, 1956 11. Cone JB, Wetzel W: Toxic megacolon secondary to pseudomembranous colitis. Dis Colon Rectum 25:478-482,1982 12. Cooper HS, Raffensper EC, Jonas L, et al: Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilatation requiring colonic resection. Gastroenterology 72:1253-1256, 1977 13. Davidson T, Allen-Mersh TG, Miles AJG, et al: Emergency laparotomy in patients with AIDS. Br J Surg 78:924-926, 1991 14. Devand DP, Rajan N, Rao R, et al: Carcinoma of the rectal pouch following restorative proctocolectomy. Dis Colon Rectum 35:257-260,1992 15. Dickinson RJ, Ashton MG, Axon A TR, et al: Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 79:1199-1204,1980 16. Dickinson RJ, O'Connor HJ, Tinder I, et al: Double blind controlled trial of oral vancomycin as adjunctive therapy in acute exacerbations of ulcerative colitis. Gut 26:13801384, 1985 17. Edwards FC, Truelove Se: The course and prognosis of ulcerative colitis. Part 3 Complications. Gut 5:1-22,1964 18. Fazio VW: Toxic megacolon in ulcerative colitis and Crohn's colitis. Clin Gastroenterol 9:389-407, 1980 19. Grant CS, Dozois RH.: Toxic megacolon: Ultimate fate of patients after successful surgical management. Am J Surg 147:106-110, 1984 20. Greenstein AJ, Kark AE, Dreiling DA: Crohn's disease of the colon. Ill. Toxic dilatation of the colon in Crohn's disease. Am J GastroenteroI63:117-128, 1975 21. Greenstein AJ, Sachar DB, Gibas A, et al: Outcome of toxic dilatation in ulcerative colitis and Crohn's colitis. J Clin GastroenteroI7:137-144, 1985 22. Grieco MB, Bordan DL, Geiss MD, et al: Toxic megacolon complicating Crohn's disease. Ann Surg 191:75-80, 1980 23. Halpert RD: Toxic dilatation of the colon. Radiol Clin North Am 25:147-154,1987 24. Hanan IM, Hanauer SB: Fulminant colitis in toxic megacolon. Journal of Intensive Care Medicine 3:164-170, 1988 25. Hawk WA, Turnbull RB Jr: Granulomatous colitis, pathogenetic concepts. Gastroenterology 51:802-805, 1966 26. Heppel J, Farkouh E, Dube 5, et al: Toxic megacolon. Dis Colon Rectum 29:789-792, 1986 27. Huizenga KA: Medical treatment and prognosis of some local complications of chronic ulcerative colitis and Crohn's disease. In Kirsner JB, Shorter JG (eds): Inflammatory Bowel Disease. Philadelphia, Lea and Febiger, 1975, pp 301-305 28. Jalan KN, Circus W, Cord WI, et al: An experience with ulcerative colitis: Toxic dilation in 55 cases. Gastroenterology 57:68-82,1969 29. Jarnerot G, Rolny P, Sandberg-Gertzen H: Intensive intravenous treatment of ulcerative colitis. Gastroenterology 89:1005-1013,1985

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30. Jewell DP, Caprilli R, Mortensen N, et al: Indications and timing of surgery for severe ulcerative colitis. Gastroenterol Int 4:161-164,1991 31. Kalkay MN, Ayanian ZS, Lehaf EA, et al: Campylobacter induced toxic megacolon. Am J Gastroenterol 78:557-559,1983 32. Katzka I, Katz S, Morris E: Management of toxic megacolon: The significance of early recognition and medical management. J Clin Gastroenterol1:307-311, 1979 33. Koudahl G, Kristensen M: Toxic megacolon in ulcerative colitis. Scand J Gastroenterol 10:417-421,1975 34. Kramer P, Wittenberg J: Colonic gas distribution in toxic megacolon. Gastroenterology 80:433-437, 1981 35. Lee FY, Lin HY, Pan S: Gold-induced fulminant colitis in a patient with psoriatic arthritis. J Clin Gastroenterol10:116-117, 1988 36. Lichtiger S, Present DH: Preliminary report: Cyclosporine in treatment of severe active ulcerative colitis. Lancet 2:16-19,1990 37. Lichtiger S: Cyclosporine therapy in inflammatory bowel disease. Open label experience. Mount Sinai Journal of Medicine 57:315-319,1990 38. Lichtiger S, Present DH, Kornbluth A, et al: A placebo controlled double blind randomized trial of cyclosporine in severe steroid refractory ulcerative colitis. Submitted for publication, 1993 39. Lbhmuller JC, Pemberton JH, Dozois RR, et al: Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch anal anastomosis. Ann Surg 211:622-629,1990 40. Marshak RH, Lester LJ, Friedman AI: Megacolon. A complication of ulcerative colitis. Gastroenterology 16:768-772, 1950 41. Marshak RH, Korelitz BI, Klein SH, et al: Toxic dilatation of the colon in the course of ulcerative colitis. Gastroenterology 38:165-180, 1960 42. Meyers S, Janowitz HD: The place of steroids in the therapy of toxic megacolon. Gastroenterology 75:729-731, 1978 43. Meyers S, Sachar DB, Goldberg JD, et al: Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. Gastroenterology 85:251-357,1983 44. McIntyre PB, Powell-Tuck J, Wood SR, et al: Controlled trial of bowel rest in the treatment of severe acute colitis. Gut 27:481-485, 1986 45. Muller JM, Keller HW, Erasin H: Total parenteral nutrition as the sole therapy in Crohn's disease: A prospective study. Br J Surg 70:40-43, 1983 46. Mungas JE, Mooja AR, Block GE: Treatment of toxic megacolon. Surg Clin North Am 56:95-102,1976 47. Neschis M, Siegelman SS, Parker JG: Diagnosis and management of the megacolon of ulcerative colitis. Gastroenterology 55:251-259,1968 48. Norland Cc, Kirsner JB: Toxic dilatation of colon (toxic megacolon): Etiology, treatment and prognosis in 42 patients. Medicine 48:229-250,1969 49. Orloff JJ, Saito R, Lasky S, et al: Toxic megacolon in cytomegalovirus colitis. Am J GastroenteroI84:794-797,1989 50. Pemberton JH, Kelly KA, Beart RW, et al: Ileal pouch - anal anastomosis for chronic ulcerative colitis: Long term results. Ann Surg 206:504-513,1987 51. Prantera C, Lorenzetti R, Cerro P, et al: The plain abdominal film accurately estimates extent of active ulcerative colitis. J Clin Gastroenterol13:231-234, 1991 52. Present DH, Wolfson D, Gelernt IM, et al: Medical decompression of toxic megacolon by "rolling." A new technique of decompression with favorable long term followup. J Clin Gastroenterol10:485-490, 1988 53. Present DH: Fulminant colitis. Semin Gastrointest Dis 2:107-114,1991 54. Present DH: 6-mercaptopurine and other immunosuppressive agents in the treatment of Crohn's disease and ulcerative colitis. Clin Gastroenterol North Am 18:57-72, 1989 55. Prohaska JV, Greer D, Ryan JF: Acute dilatation of the colon in ulcerative colitis. Arch Surg 89:24-30, 1964 56. Radsel-Medvescek A, Zargi R, Acko M, et al: Colonic involvement in salmonellosis. Lancet 1:601-602, 1977 57. Rosenberg W, Ireland A, Je~ell DP: High dose methylprednisolone in the treatment of active ulcerative colitis. J Clin GastroenteroI12:40-41, 1990 58. Schachter H, Goldstein MJ, Kirsner JB: Toxic dilatation complicating Crohn's disease of the colon. Gastroenterology 5:136-140,1967

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59. Shephard HA, Barr GO, Jewell DP: Use of an intravenous steroid regimen in the treatment of acute Crohn's disease. J Clin GastroenteroI8:154-159, 1986 60. Steiner-Grossman P, Banks PA, Present OH: The New People, Not Patients. A Sourcebook for Living With Inflammatory Bowel Disease. Dubuque, lA, Kendall Hunt Publishing Company, Crohn's and Colitis Foundation of America, Inc., 1992 61. Strauss RI, Flint GW, Platt N, et al: Surgical management of toxic dilatation of the colon: A report of 28 cases and a review of the literature. Ann Surg 184:682-688, 1976 62. Surawicz CM, Belic C: Rectal biopsy helps to distinguish acute self limited colitis from idiopathic inflammatory bowel disease. Gastroenterology 86:104-113,1984 63. Tedesco FJ: Pseudomembranous colitis: Pathogenesis and therapy. Med Clin North Am 66:655-664, 1982 64. Truelove SC, Marks CG: Toxic megacolon Part 1. Pathogenesis, diagnosis and treatment. Clin Gastroenterol10:107-117, 1981 65. Truelove Se, Witt LJ: Cortisone in ulcerative colitis. Final report on a therapeutic trial. Br Med J 2:1041-1048, 1955 66. Truelove Se, Jewell DP: Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1:1067-1070, 1974 67. Upadhyay AK, Neely JAC: Toxic megacolon and perforation caused by Shigella. Br J Surg 76:1217, 1989 68. Velano·vich V, Laporta AI, Garrett WL, et al: Pseudomembranous colitis leading to toxic megacolon associated with anti-neoplastic therapy: Report of a case and review of the literature. Dis Colon Rectum 35:369-372, 1992 69. Wagonfield JB, Baker AL, Reed JS, et al: Acute dilation of the colon in malignant lymphoma. Gastroenterology 70:264-267, 1976 70. Waye JD: Endoscopy in inflammatory bowel disease: Indications and differential diagnosis. Med Clin North Am 74:51-65, 1990 71. White JG, Farmer RG: What to do when toxic megacolon complicates inflammatory colitis. Journal of Critical Illness 2:37-46, 1987 72. Wig JD, Talmar BL, Bushnurmath SR: Toxic dilatation complicating fulminant amoebic colitis. Br J Surg 68:135-136,1981

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