- Email: [email protected]
Toxic megacolon
SEMINAR
Seminar
Toxic megacolon
Sunil G Sheth, J Thomas LaMont First described in 1950, toxic megacolon is a potentially lethal complication of idiopathic inflammatory bowel disease or infectious colitis, characterised by total or segmental non-obstructive colonic dilatation of at least 6 cm associated with systemic toxicity.1,2 The crucial features of this disorder are that the dilatation results from inflammatory colitis and that it is accompanied by systemic manifestations or toxicity. Colonic dilatation also occurs in patients with congenital megacolon (Hirschsprung’s disease), idiopathic or acquired megacolon occurring with chronic constipation of any cause, and intestinal pseudo-obstruction, a manifestation of diffuse gastrointestinal dysmotility of various causes. These disorders are not accompanied by colitis or systemic toxicity and thus are fundamentally different from toxic megacolon with severe inflammatory or infectious colitis. The most widely used criteria for the clinical diagnosis of toxic megacolon were proposed by Jalan et al2 (panel 1).
Incidence No precise incidence rate for toxic megacolon is available. The lifetime risk of toxic megacolon in ulcerative colitis and Crohn’s disease was about 1–5%3 20 years ago but has gradually decreased because of earlier recognition and better management of severe colitis. Clinically symptomatic Clostridium difficile infection occurs in about 1% of all patients admitted to hospital, and a few of these may develop severe C difficile colitis with toxic megacolon.4,5
Aetiology Although most commonly recognised as a complication of inflammatory bowel disease, toxic megacolon may also complicate infectious colitis of diverse aetiology (panel 2), as well as ischaemic colitis, volvulus, diverticulitis, and obstructive colon cancer. Pseudomembranous colitis due to C difficile infection and acute severe colitis due to salmonella, shigella, or campylobacter infection are very rarely complicated by toxic dilatation. Fewer than 3% of patients with amoebic colitis have a fulminant clinical course, and a small fraction of these develop toxic megacolon. Among patients with HIV infection or AIDS, cytomegalovirus colitis is the principal cause of toxic megacolon and emergency laparotomy and usually occurs in the setting of disseminated cytomegalovirus infection. Lancet 1998; 351: 509–13 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA (S G Sheth MD, Prof J T LaMont MD) Correspondence to: Prof J Thomas LaMont (e-mail: [email protected])
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Panel 1: Diagnostic criteria for toxic megacolon Radiographic evidence of colonic distension At least three of the following: Fever >38°C (101·5°F) Heart rate >120/min Neutrophilic leucocytosis >10·5⫻109/L Anaemia In addition to the above, at least one of the following: Dehydration Altered consciousness Electrolyte disturbances Hypotension
Cytomegalovirus infection of the colon may also precipitate toxic megacolon in patients with inflammatory bowel disease. In one series, evidence of cytomegalovirus infection was found in the resected colons of six of 46 patients with ulcerative colitis.6 Five of these six patients but only two of the 40 patients without cytomegalovirus infection had toxic dilatation.6
Pathogenesis Several pathogenetic mechanisms probably contribute to the development of toxic megacolon in inflammatory bowel disease (figure). Whereas in typical ulcerative colitis the inflammatory response is limited to the mucosa, toxic megacolon is characterised by severe inflammation extending into the smooth-muscle layer, which paralyses the colonic smooth muscle and leads to dilatation. The extent of dilatation seems to be correlated with the depth of inflammation and ulceration. Damage to the myenteric plexus of the colon is not a consistent finding, and hypokalaemia and other electrolyte disturbances probably do not contribute to dilatation in most patients. Panel 2: Disorders associated with toxic megacolon Inflammatory Ulcerative colitis Crohn’s disease Infectious Bacterial C difficile pseudomembranous colitis Salmonella—typhoid and non-typhoid Shigella Campylobacter Yersinia Parasitic Entamoeba histolytica Cryptosporidium Viral Cytomegalovirus colitis Self-limited colitis (culture negative) Other Pseudomembranous colitis secondary to methotrexate therapy Kaposi’s sarcoma
509
SEMINAR
Lamina propria
Muscle layer
Serosa Epithelial cell
Lumen
NO LTB4
Nitric oxide (NO) released by neutrophils paralyses muscle cells, leading to dilatation
NO
Lymphocyte
Capillary
Colitis
Neutrophils invade mucosa, leading to crypt abscesses and diffuse colitis
Neutrophil
Macrophage
NO
Ulcerated mucosa
Necrotic epithelial cell
In toxic megacolon, neutrophils also invade the muscle layer and damage muscle cells directly by release of proteloytic enzymes, cytokines, leukotriene B4 (LTB4)
Systemic uptake of cytokines and other inflammatory mediators leads to fever, tachycardia, hypotension, &c
Mast cell
Smooth muscle cell
Fibroblast
Pathogenesis of toxic megacolon
Nitric oxide, a known inhibitor of smooth-muscle tone, may be involved in the pathogenesis of toxic megacolon. Nitric oxide is generated by macrophages and smooth-muscle cells in the inflamed colon. Mourelle and colleagues7 studied nitric oxide synthase in the colons of patients who underwent surgery for toxic megacolon, active pancolonic ulcerative colitis without toxic megacolon, and non-obstructive colonic neoplasm (controls). Both the amount and the activity of the inducible form of the enzyme were significantly increased in the muscular layer in toxic megacolon, particularly in the more dilated colonic segments. In animal studies, inducible nitric oxide synthase was decreased after bowel decontamination with oral nonabsorbable broad-spectrum antibiotics or administration of dexamethasone, both of which prevented experimental colonic dilatation.8 The diameter of the colon, contractility of the colonic muscle, and intracolonic pressure improved after pharmacological blockade with inhibitors of nitric oxide synthase, which suggests a possible treatment in patients with toxic megacolon.
Pathology The gross pathological features of toxic megacolon are similar in both ulcerative colitis and Crohn’s disease1 with pronounced dilatation of the colon, thinning of the bowel wall, and deep ulcers. The histological hallmark is acute inflammation in all the layers of the colon with varying degrees of myocyte degeneration, necrosis, and replacement by granulation tissue infiltrated by histiocytes, neutrophils, lymphocytes, and plasma cells. The muscle fibres are commonly shortened and rounded with aggregates of eosinophilic cytoplasm. The preservation of colonic submucosal and myenteric plexuses is a common feature9 and is evidence against a neuropathic process. In toxic megacolon secondary to C difficile, or rarely ischaemia, the characteristic pathological features include diffuse ulcerations, raised mucosal nodules, yellowish-white superficial plaques with normal intervening mucosa (typical pseudomembrane appearance), and extensive denudation. Similar features may be found in fulminant amoebic colitis in addition to the characteristic “wet510
blotting-paper” appearance of the involved bowel segments, punched-out ulcers, and presence of trophozoites in biopsy.
Clinical features Toxic megacolon is a complication of pancolitis rather than segmental disease, and affects male and female patients of all ages. Patients are at the highest risk of developing toxic megacolon early in their disease and some are affected at initial presentation.2 Up to 30% of patients develop dilatation within 3 months of diagnosis, and about 60% of cases occur within the first 3 years. Signs and symptoms of acute colitis, in many cases resistant to therapy, are typically present for a week or more before the onset of acute dilatation, often with severe bloody diarrhoea. Improvement of diarrhoea may herald the onset of megacolon. Triggering or predisposing factors are sometimes identified; these include hypokalaemia and use of opioids, anticholinergics, loperamide, psyllium seeds, and antidepressants. Barium enema or colonoscopy may cause distension that further impairs the blood supply to the colon wall and may increase mucosal uptake of bacterial products. Discontinuation or rapid tapering of corticosteroids, sulphasalazine, or mesalazine compounds may contribute to the development of megacolon. On physical examination the patient has altered consciousness, tachycardia, fever, postural hypotension, and abdominal distension and tenderness, with or without signs of local or general peritonitis. Large doses of steroids or analgesics and the impaired sensory perception may mask symptoms and signs of toxic megacolon.
Investigations Laboratory studies in toxic megacolon reveal anaemia related to blood loss and leucocytosis with a left shift except in patients with sepsis or AIDS, in whom neutropenia may supervene. Electrolyte disturbances are very common and multifactorial. The inflamed colon loses its capacity to reabsorb salt and water, and the rate of potassium excretion into the lumen is greatly increased because of inflammatory diarrhoea and steroid
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SEMINAR
Panel 3: Management of toxic megacolon General/supportive/medical management Monitoring in the intensive-care unit Bowel rest/nil by mouth; nasogastric tube Intravenous corticosteroids Intravenous broad-spectrum antibiotics Serial abdominal plain radiographs Aggressive fluid resuscitation and electrolyte repletion Daily complete blood counts and electrolytes Discontinuation of antimotility agents Blood transfusions for anaemia Total parental nutrition if required; early enteral feeding Repositioning manoeuvres Specific therapy for infectious agent identified Cytomegalovirus, C difficile, E histolytica Early surgical intervention for Progressive dilatation Worsening toxicity Failure of medical therapy Perforation, haemorrhage
use. Hypoalbuminaemia may not be a prominent feature in the early stages of the illness, but eventually in about 75% of patients albumin concentrations fall to below 30 g/L as a result of protein loss and decreased hepatic synthesis (due to chronic infection and malnutrition). Erythrocyte sedimentation rate and C-reactive protein concentrations are increased in most cases. Metabolic alkalosis secondary to volume depletion and potassium loss is associated with a poor prognosis.10 Plain abdominal radiography is crucial for diagnosis of megacolon and for following its course. The transverse or right colon is usually the most dilated, frequently to more than 6 cm, and sometimes up to 15 cm1 on films taken with the patient supine. Distension of the descending colon is less frequent and that of the sigmoid colon and rectum rare. Repositioning of the patient results in redistribution of air in the colon, causing variation in the location of the largest amounts of air; thus, the location of air is not as important as the degree of dilatation. Multiple air-fluid levels in the colon are common, and the normal colonic haustral pattern is either absent or severely disturbed. Deep mucosal ulcerations may appear as air-filled crevices between large pseudopolypoid projections extending into the colonic lumen. We emphasise that even though a maximum colonic diameter greater than 6 cm signifies megacolon, the overall clinical condition of the patient is more important in diagnosis of toxic megacolon than the absolute width of the dilated segment. Ultrasonography and computed tomography (CT) may aid overall management. High-resolution ultrasonography can be used to assess accurately the extent and activity of severe ulcerative colitis and response to therapy, and thus may help in the early detection of toxic megacolon.11 CT scan may occasionally be valuable in identifying the aetiology of megacolon. For example, in pseudomembranous colitis from C difficile infection, diffuse colonic thickening is a very sensitive (but not specific) finding. A CT scan may be especially useful in patients with AIDS who may have several intercurrent intra-abdominal processes.
Diagnosis The diagnosis of toxic megacolon must be considered in all patients presenting with abdominal distension and acute or chronic diarrhoea. Since there are several
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causes of toxic megacolon, the initial assessment should aim to establish the diagnosis of toxic megacolon as well as to identify the underlying aetiology so that specific therapeutic measures can be instituted. Clinical features that suggest inflammatory bowel disease as a cause of toxic megacolon include a preceding history of diarrhoea, bloody stools, abdominal pain, perianal disease, or extraintestinal manifestations such as arthritis, iritis, and skin or liver disease. Also important is a careful inquiry about recent travel, exposure to enteric pathogens, antibiotic or chemotherapy use, use of antimotility agents, and HIV/AIDS status. Limited endoscopy with biopsy may provide useful diagnostic information, particularly when there is a possibility of acute bacillary dysentery. Acute infectious colitis does not alter colonic crypt architecture, whereas inflammatory bowel disease is accompanied by diffusely abnormal crypt architecture, even if symptoms have been present for only 1 week.12 Cytomegalovirus colitis is characterised by the presence of inclusion bodies. A limited sigmoidoscopy may miss inclusion bodies, since ulcers may be found only in the ascending colon in up to 40% of cases. A full colonoscopy is extremely risky in patients with toxic megacolon and could easily lead to colonic perforation. In our opinion, colonoscopy should generally be avoided. However, the study by Alemayehu and Jarnerot13 suggested that colonoscopy was a safe procedure in patients with severe ulcerative colitis and helped in the decision on whether to operate.
Treatment The main goal of treatment is to reduce the severity of colitis so as to restore normal colonic motility and to decrease the likelihood of perforation (panel 3). The initial treatment of toxic dilatation should be medical and obviates the need for surgery in about 50% of patients.1 However, a surgical consultation should be obtained on admission, and the patient should be assessed daily by both medical and surgical teams. The patient should be monitored in the intensive-care unit with frequent examinations by nursing and medical staff for signs of deterioration. Complete blood counts, electrolytes, and serial abdominal plain films are reviewed every 12 h initially, and then daily as the patient improves. Anaemia, dehydration, and electrolyte deficits, particularly hypokalaemia, may aggravate colonic dysmotility and should be aggressively treated. Total parental nutrition offers no proven benefit in terms of avoiding surgery or decreasing hospital stay in patients with ulcerative colitis,14 but is beneficial in decreasing the activity of Crohn’s disease and may be useful in patients who have long-standing nutritional depletion especially if they are likely to undergo surgery. The bowel should be completely rested, and a nasogastric tube (or long intestinal tube) should be placed initially to decompress the gastrointestinal tract. If the patient shows signs of improvement, enteral feeding is started since it may hasten mucosal healing and stimulate normal motility. All antimotility agents, narcotics, and anticholinergics should be discontinued. Patients should be given prophylaxis for both gastric stress ulcerations (intravenous H2-blockers) and deepvenous thrombosis (pneumatic compression stockings or low-dose subcutaneous heparin). Broad-spectrum antibiotics are recommended to reduce septic 511
SEMINAR
complications and in anticipation of peritonitis resulting from perforation. We recommend intravenous corticosteroids (hydrocortisone 100 mg or equivalent every 6–8 h or by continuous infusion) to all patients with toxic megacolon secondary to inflammatory bowel disease. Some physicians prefer to use methylprednisolone because of its lower sodium-retaining and potassium-wasting properties, and others prefer prednisolone because the parenteral dose is equal to the oral dose. Some authorities recommend corticotropin in patients who have not received steroids for at least 30 days, since it may be more beneficial than intravenous corticosteroids in the treatment of underlying ulcerative colitis.15 Sulphasalazine and mesalazine have no role in toxic megacolon and should be initiated only after the acute attack begins to resolve. In some patients, the acute flare may in fact coincide with the introduction of these drugs. Cyclosporin is useful in the treatment of severe colitis refractory to steroid therapy, but experience with this agent in toxic megacolon is limited. Some investigators recommend intermittent rolling manoeuvres16 or knee-elbow position17 to help redistribution of gas in the colon and decompression. These recommendations are based on the observation that when a patient is rolled from supine to prone position or adopts a knee-elbow position, gas rises to the distal colon and rectum and is more easily expelled. This technique may be especially useful when the toxicity is controlled but colonic dilatation persists. Medical therapy is successful when signs of toxicity are reduced, fluid and transfusion requirements decrease, abdominal and colonic dilatation begin to resolve, and the results of laboratory tests improve. Persistent fever after 48–72 h of steroid therapy should raise the possibility of local perforation or abscess. Free perforation, massive haemorrhage, increasing transfusion requirements, increasing signs of toxicity, and progression of colonic dilatation are indications for urgent operation. Most surgical studies recommend colectomy if after 48–72 h there is persistent colonic distension. However, some physicians recommend continuation of medical therapy up to 7 days if the patient seems to be clinically improving despite persistent megacolon without free perforation.16,18 Subtotal colectomy with end-ileostomy is the procedure of choice for urgent or emergency surgery, and causes less morbidity and mortality than single-stage proctocolectomy.19 Early surgery in patients without evidence of perforation results in much lower mortality (2–8%) than colectomy done after colonic perforation has occurred (40% or more).
In patients with toxic megacolon due to severe C difficile colitis, the first step is to stop the offending antibiotic and to give intravenous metronidazole plus oral vancomycin via a nasogastric tube. Colectomy is reserved for patients who do not respond within 48–72 h, or who show evidence of local perforation. A literature review of patients with toxic megacolon secondary to pseudomembranous colitis between 1968 and 1992 revealed an overall mortality of 31–35%, including 42% for surgically and 18% for medically treated patients.5 In two later studies, the overall mortality from severe C difficile colitis with toxic megacolon was 64–67%; mortality for surgically treated patients was 71–100%.4,5 In a series of six patients with acute abdomen secondary to C difficile colitis, decompression of dilated colons in two patients was achieved by colonoscopy, thus obviating the need for surgery.20 In patients with HIV infection or AIDS who develop toxic megacolon, limited endoscopy and imaging studies to search for treatable infectious and non-infectious causes is warranted. Those with cytomegalovirus colitis or pseudomembranous colitis respond poorly to medical therapy and many require emergency laparotomy with subtotal colectomy and ileostomy.21,22 Fulminant colitis during pregnancy, with or without toxic megacolon, is especially difficult to treat because the gravid uterus impairs a proper abdominal examination and diagnostic radiation poses hazards to the fetus.23 Moreover, disturbances during pregnancy mean that results for laboratory variables are unreliable; for example, haemoglobin and albumin concentrations fall, whereas erythrocyte sedimentation rate and Creactive protein concentrations rise. Intensive steroid therapy results in resolution of 75% of cases of fulminant colitis in pregnancy, with the remainder requiring urgent colectomy.
References
synthase in colonic smooth muscle from patients with toxic megacolon. Gastroenterology 1995; 109: 1497–502. 8 Mourelle M, Vilaseca J, Guarner F, et al. Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase. Am J Physiol 1996; 33: G425–30. 9 Norland CC, Kirsner JB. Toxic dilatation of the colon (toxic megacolon): etiology, treatment and prognosis in 42 patients. Medicine 1969; 48: 229–50. 10 Caprilli R, Vernia P, Colaneri O. Blood pH: a test for assessment of severity in proctocolitis. Gut 1976; 17: 763–69. 11 Arienti V, Campieri M, Boriani L, et al. Management of severe ulcerative colitis with the help of high resolution ultrasonography. Am J Gastroenterol 1996; 91: 2163–69. 12 Surawicz CM, Haggitt RC, Husseman M, et al. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology 1994; 107: 755–63.
1 2 3 4 5
6
7
Fazio VW. Toxic megacolon in ulcerative colitis and Crohn’s colitis. Clin Gastroenterol 1980; 9: 389–407. Jalan KN, Circus W, Cord WI, et al. An experience with ulcerative colitis: toxic dilatation in 55 cases. Gastroenterology 1969; 57: 68–82. Grieco MB, Bordan DL, Geiss MD, et al. Toxic megacolon complicating Crohn’s disease. Ann Surg 1980; 191: 75–80. Rubin MS, Bodenstein LE, Kent KC. Severe Clostridium difficile colitis. Dis Colon Rectum 1995; 38: 350–54. Trudel JL, Deschenes M, Mayrand S, et al. Toxic megacolon complicating pseudomembranous enterocolitis. Dis Colon Rectum 1995; 38: 1033–38. Cooper HS, Raffensper EC, Jonas L, et al. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilatation requiring colonic resection. Gastroenterology 1977; 72: 1253–56. Mourelle M, Casellas F, Guarner F, et al. Induction of nitric oxide
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Outcome Mortality rates in toxic megacolon are variable. Before 1976, the death rate in 604 cases of toxic megacolon was 27% for those treated medically and 19% in surgically treated patients.24 In later series, mortality rates have fallen to 0–2% in patients with inflammatory bowel disease, probably as a result of various factors, including early recognition of toxic megacolon, better intensive medical management, earlier surgical intervention, and better postoperative care. Variations in mortality rates are also related to the medical or surgical biases of the treating doctors.
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SEMINAR 13 Alemayehu G, Jarnerot G. Colonoscopy during an attack of severe ulcerative colitis is a safe procedure and of great value in clinical decision making. Am J Gastroenterol 1991; 86: 187–90. 14 Dickinson RJ, Ashton MG, Axon ATR, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980; 79: 1199–204. 15 Meyers S, Sachar DB, Goldberg JD, et al. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis: a prospective, randomized, double-blinded clinical trial. Gastroenterology 1983; 85: 351–57. 16 Present DH, Wolfson D, Gelernt IM, et al. Medical decompression of toxic megacolon by “rolling”: a new technique of decompression with favorable long-term follow-up. J Clin Gastroenterol 1988; 10: 485–90. 17 Panos MZ, Wood MJ, Asquith P. Toxic megacolon: the knee-elbow position relieves bowel distension. Gut 1993; 34: 1726–27.
18 Caprilli R, Vernia P, Latella G, et al. Early recognition of toxic megacolon. J Clin Gastroenterol 1987; 9: 136–42. 19 Block GE, Moosa AR, Siminowitz D, et al. Emergency colectomy for inflammatory bowel disease. Surgery 1977; 82: 531–36. 20 Triadafilopoulos G, Hallstone AE. Acute abdomen as the first presentation of pseudomembranous colitis. Gastroenterology 1991; 101: 685–91. 21 Beaugerie L, Ngo Y, Goujard F, et al. Etiology and management of toxic megacolon in patients with human immunodeficiency virus infection. Gastroenterology 1994; 107: 858–63. 22 Davidson T, Allen-Mersh TG, Miles AJG, et al. Emergency laparotomy in patients with AIDS. Br J Surg 1991; 78: 924–26. 23 Boulton R, Hamilton M, Lewis A, et al. Fulminant ulcerative colitis in pregnancy. Am J Gastroenterol 1994; 89: 931–33. 24 Strauss RJ, Flint GW, Platt N, et al. The surgical management of toxic dilatation of the colon: a report of 28 cases and a review of the literature. Ann Surg 1976; 184: 682–88.
Further reading
megacolon complicating Clostridium difficile pseudomembranous colitis. Am J Gastroenterol 1988; 83: 304–07. Danovitch SH. Fulminant colitis and toxic megacolon. Gastroenterol Clin North Am 1989; 18: 73–82. Garrett JM, Sauer WG, Moertel CG. Colonic motility in ulcerative colitis after opiate administration. Gastroenterology 1967; 53: 93. Grand RJ, Ramakrishna J, Calenda KA. Inflammatory bowel disease in the pediatric patient. Gastroenterol Clin North Am 1995; 24: 613–32. Prantera C, Lorezetti R, Cerro P, et al. The plain film accurately estimates the extent of active ulcerative colitis. J Clin Gastroenterol 1991; 13: 231–34.
Epidemiology Farmer RG, Easley KA, Rankin GB. Clinical patterns in ulcerative colitis: disease location, progression and prognosis. Dig Dis Sci 1993; 38: 1137–46. Marshak RH, Lester LJ, Friedman AI. Megacolon: a complication of ulcerative colitis. Gastroenterology 1950; 16: 768–72. McInerney GT, Sauer WG, Baggenstoss AH, et al. Fulminating ulcerative colitis with marked colonic dilatation: a clinicopathologic study. Gastroenterology 1962; 42: 244–57.
Aetiology and pathogenesis Christianson K. Toxic megacolon complicating shigellosis. J R Coll Surg Edin 1987; 32: 109–10. Connolly GM, Gazzard BG. Toxic megacolon in cryptosporidiosis. Postgrad Med J 1987; 63: 1103–04. Gonzalez A, Vargas V, Guarner L, et al. Toxic megacolon in typhoid fever. Arch Intern Med 1985; 145: 2120. Kalkay MN, Ayanian ZS, Lehaf EA, et al. Campylobacter-induced toxic megacolon. Am J Gastroenterol 1983; 78: 557–59. Orloff J, Saito R, Lasky S, et al. Toxic megacolon in cytomegalovirus colitis. Am J Gastroenterol 1989; 84: 794–97. Snowden JA, Young MJ, Mckendrick MW. Dilatation of the colon complicating acute self-limited colitis. Q J Med 1994; 87: 55–62. Stuart RC, Leahy A, Cafferky M, et al. Yersinia enterocolitica infection and toxic megacolon. Br J Surg 1986; 73: 590. Velanovich V, Laporta AJ, Garrett WL, et al. Pseudomembranous colitis leading to toxic megacolon associated with antineoplastic therapy: report of a case and review of the literature. Dis Colon Rectum 1992; 35: 369–72. Wig JD, Talwar BL, Bushnurmath SR. Toxic dilatation complicating fulminant amoebic colitis. Br J Surg 1981; 68: 135–36.
Clinical features Atherton LD, Leib ES, Kaye MD. Toxic megacolon associated with methotrexate therapy. Gastroenterology 1984; 86: 1583–88. Brown CH, Ferrante WA, Davis WD. Toxic dilatation of the colon complicating pseudomembranous enterocolitis. Am J Dig Dis 1968; 13: 813–21. Burke GW, Wilson M, Mehrez I. Absence of diarrhea in toxic
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Diagnosis and treatment McIntyre PB, Powell-Tuck J, Wood SR, et al. Controlled trial of bowel rest in the treatment of severe acute colitis. Gut 1986; 27: 481–85. Morris JB, Zollinger RM, Stellato TA. Role of surgery in antibioticinduced pseudomembranous enterocolitis. Am J Surg 1990; 160: 535–39. Prantera C, Lorenzetti R. Severe ulcerative colitis: a personal point of view. Hepatogastroenterology 1989; 36: 240–03.
Outcome Dalton HR, Jewell DP. The management of severe ulcerative colitis. Ann Intern Med 1991; 23: 389–91. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis: part 3—complications. Gut 1964; 5: 1–22. Flatmark A, Fretheim B, Gjone E. Early colectomy in severe ulcerative colitis. Scand J Gastroenterol 1975; 10: 427–31. Grant CS, Dozois RR. Toxic megacolon: ultimate fate of patients after successful surgical management. Am J Surg 1984; 147: 106–10. Greenstein AJ, Kark AE, Dreiling DA. Crohn’s disease of the colon: III toxic dilatation of the colon in Crohn’s disease. Am J Gastroenterol 1975; 63: 117–28. Koudahl G, Kristensen M. Toxic megacolon in ulcerative colitis. Scand J Gastroenterol 1975; 10: 417–21. Lennard-Jones JE, Ritchie JK, Hidler W, et al. Assessment of severity in ulcerative colitis: a preliminary study. Gut 1975; 16: 579–84. Travis SPL, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 1996; 38: 905–10.
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Seminar
Toxic megacolon
Sunil G Sheth, J Thomas LaMont First described in 1950, toxic megacolon is a potentially lethal complication of idiopathic inflammatory bowel disease or infectious colitis, characterised by total or segmental non-obstructive colonic dilatation of at least 6 cm associated with systemic toxicity.1,2 The crucial features of this disorder are that the dilatation results from inflammatory colitis and that it is accompanied by systemic manifestations or toxicity. Colonic dilatation also occurs in patients with congenital megacolon (Hirschsprung’s disease), idiopathic or acquired megacolon occurring with chronic constipation of any cause, and intestinal pseudo-obstruction, a manifestation of diffuse gastrointestinal dysmotility of various causes. These disorders are not accompanied by colitis or systemic toxicity and thus are fundamentally different from toxic megacolon with severe inflammatory or infectious colitis. The most widely used criteria for the clinical diagnosis of toxic megacolon were proposed by Jalan et al2 (panel 1).
Incidence No precise incidence rate for toxic megacolon is available. The lifetime risk of toxic megacolon in ulcerative colitis and Crohn’s disease was about 1–5%3 20 years ago but has gradually decreased because of earlier recognition and better management of severe colitis. Clinically symptomatic Clostridium difficile infection occurs in about 1% of all patients admitted to hospital, and a few of these may develop severe C difficile colitis with toxic megacolon.4,5
Aetiology Although most commonly recognised as a complication of inflammatory bowel disease, toxic megacolon may also complicate infectious colitis of diverse aetiology (panel 2), as well as ischaemic colitis, volvulus, diverticulitis, and obstructive colon cancer. Pseudomembranous colitis due to C difficile infection and acute severe colitis due to salmonella, shigella, or campylobacter infection are very rarely complicated by toxic dilatation. Fewer than 3% of patients with amoebic colitis have a fulminant clinical course, and a small fraction of these develop toxic megacolon. Among patients with HIV infection or AIDS, cytomegalovirus colitis is the principal cause of toxic megacolon and emergency laparotomy and usually occurs in the setting of disseminated cytomegalovirus infection. Lancet 1998; 351: 509–13 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA (S G Sheth MD, Prof J T LaMont MD) Correspondence to: Prof J Thomas LaMont (e-mail: [email protected])
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Panel 1: Diagnostic criteria for toxic megacolon Radiographic evidence of colonic distension At least three of the following: Fever >38°C (101·5°F) Heart rate >120/min Neutrophilic leucocytosis >10·5⫻109/L Anaemia In addition to the above, at least one of the following: Dehydration Altered consciousness Electrolyte disturbances Hypotension
Cytomegalovirus infection of the colon may also precipitate toxic megacolon in patients with inflammatory bowel disease. In one series, evidence of cytomegalovirus infection was found in the resected colons of six of 46 patients with ulcerative colitis.6 Five of these six patients but only two of the 40 patients without cytomegalovirus infection had toxic dilatation.6
Pathogenesis Several pathogenetic mechanisms probably contribute to the development of toxic megacolon in inflammatory bowel disease (figure). Whereas in typical ulcerative colitis the inflammatory response is limited to the mucosa, toxic megacolon is characterised by severe inflammation extending into the smooth-muscle layer, which paralyses the colonic smooth muscle and leads to dilatation. The extent of dilatation seems to be correlated with the depth of inflammation and ulceration. Damage to the myenteric plexus of the colon is not a consistent finding, and hypokalaemia and other electrolyte disturbances probably do not contribute to dilatation in most patients. Panel 2: Disorders associated with toxic megacolon Inflammatory Ulcerative colitis Crohn’s disease Infectious Bacterial C difficile pseudomembranous colitis Salmonella—typhoid and non-typhoid Shigella Campylobacter Yersinia Parasitic Entamoeba histolytica Cryptosporidium Viral Cytomegalovirus colitis Self-limited colitis (culture negative) Other Pseudomembranous colitis secondary to methotrexate therapy Kaposi’s sarcoma
509
SEMINAR
Lamina propria
Muscle layer
Serosa Epithelial cell
Lumen
NO LTB4
Nitric oxide (NO) released by neutrophils paralyses muscle cells, leading to dilatation
NO
Lymphocyte
Capillary
Colitis
Neutrophils invade mucosa, leading to crypt abscesses and diffuse colitis
Neutrophil
Macrophage
NO
Ulcerated mucosa
Necrotic epithelial cell
In toxic megacolon, neutrophils also invade the muscle layer and damage muscle cells directly by release of proteloytic enzymes, cytokines, leukotriene B4 (LTB4)
Systemic uptake of cytokines and other inflammatory mediators leads to fever, tachycardia, hypotension, &c
Mast cell
Smooth muscle cell
Fibroblast
Pathogenesis of toxic megacolon
Nitric oxide, a known inhibitor of smooth-muscle tone, may be involved in the pathogenesis of toxic megacolon. Nitric oxide is generated by macrophages and smooth-muscle cells in the inflamed colon. Mourelle and colleagues7 studied nitric oxide synthase in the colons of patients who underwent surgery for toxic megacolon, active pancolonic ulcerative colitis without toxic megacolon, and non-obstructive colonic neoplasm (controls). Both the amount and the activity of the inducible form of the enzyme were significantly increased in the muscular layer in toxic megacolon, particularly in the more dilated colonic segments. In animal studies, inducible nitric oxide synthase was decreased after bowel decontamination with oral nonabsorbable broad-spectrum antibiotics or administration of dexamethasone, both of which prevented experimental colonic dilatation.8 The diameter of the colon, contractility of the colonic muscle, and intracolonic pressure improved after pharmacological blockade with inhibitors of nitric oxide synthase, which suggests a possible treatment in patients with toxic megacolon.
Pathology The gross pathological features of toxic megacolon are similar in both ulcerative colitis and Crohn’s disease1 with pronounced dilatation of the colon, thinning of the bowel wall, and deep ulcers. The histological hallmark is acute inflammation in all the layers of the colon with varying degrees of myocyte degeneration, necrosis, and replacement by granulation tissue infiltrated by histiocytes, neutrophils, lymphocytes, and plasma cells. The muscle fibres are commonly shortened and rounded with aggregates of eosinophilic cytoplasm. The preservation of colonic submucosal and myenteric plexuses is a common feature9 and is evidence against a neuropathic process. In toxic megacolon secondary to C difficile, or rarely ischaemia, the characteristic pathological features include diffuse ulcerations, raised mucosal nodules, yellowish-white superficial plaques with normal intervening mucosa (typical pseudomembrane appearance), and extensive denudation. Similar features may be found in fulminant amoebic colitis in addition to the characteristic “wet510
blotting-paper” appearance of the involved bowel segments, punched-out ulcers, and presence of trophozoites in biopsy.
Clinical features Toxic megacolon is a complication of pancolitis rather than segmental disease, and affects male and female patients of all ages. Patients are at the highest risk of developing toxic megacolon early in their disease and some are affected at initial presentation.2 Up to 30% of patients develop dilatation within 3 months of diagnosis, and about 60% of cases occur within the first 3 years. Signs and symptoms of acute colitis, in many cases resistant to therapy, are typically present for a week or more before the onset of acute dilatation, often with severe bloody diarrhoea. Improvement of diarrhoea may herald the onset of megacolon. Triggering or predisposing factors are sometimes identified; these include hypokalaemia and use of opioids, anticholinergics, loperamide, psyllium seeds, and antidepressants. Barium enema or colonoscopy may cause distension that further impairs the blood supply to the colon wall and may increase mucosal uptake of bacterial products. Discontinuation or rapid tapering of corticosteroids, sulphasalazine, or mesalazine compounds may contribute to the development of megacolon. On physical examination the patient has altered consciousness, tachycardia, fever, postural hypotension, and abdominal distension and tenderness, with or without signs of local or general peritonitis. Large doses of steroids or analgesics and the impaired sensory perception may mask symptoms and signs of toxic megacolon.
Investigations Laboratory studies in toxic megacolon reveal anaemia related to blood loss and leucocytosis with a left shift except in patients with sepsis or AIDS, in whom neutropenia may supervene. Electrolyte disturbances are very common and multifactorial. The inflamed colon loses its capacity to reabsorb salt and water, and the rate of potassium excretion into the lumen is greatly increased because of inflammatory diarrhoea and steroid
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Panel 3: Management of toxic megacolon General/supportive/medical management Monitoring in the intensive-care unit Bowel rest/nil by mouth; nasogastric tube Intravenous corticosteroids Intravenous broad-spectrum antibiotics Serial abdominal plain radiographs Aggressive fluid resuscitation and electrolyte repletion Daily complete blood counts and electrolytes Discontinuation of antimotility agents Blood transfusions for anaemia Total parental nutrition if required; early enteral feeding Repositioning manoeuvres Specific therapy for infectious agent identified Cytomegalovirus, C difficile, E histolytica Early surgical intervention for Progressive dilatation Worsening toxicity Failure of medical therapy Perforation, haemorrhage
use. Hypoalbuminaemia may not be a prominent feature in the early stages of the illness, but eventually in about 75% of patients albumin concentrations fall to below 30 g/L as a result of protein loss and decreased hepatic synthesis (due to chronic infection and malnutrition). Erythrocyte sedimentation rate and C-reactive protein concentrations are increased in most cases. Metabolic alkalosis secondary to volume depletion and potassium loss is associated with a poor prognosis.10 Plain abdominal radiography is crucial for diagnosis of megacolon and for following its course. The transverse or right colon is usually the most dilated, frequently to more than 6 cm, and sometimes up to 15 cm1 on films taken with the patient supine. Distension of the descending colon is less frequent and that of the sigmoid colon and rectum rare. Repositioning of the patient results in redistribution of air in the colon, causing variation in the location of the largest amounts of air; thus, the location of air is not as important as the degree of dilatation. Multiple air-fluid levels in the colon are common, and the normal colonic haustral pattern is either absent or severely disturbed. Deep mucosal ulcerations may appear as air-filled crevices between large pseudopolypoid projections extending into the colonic lumen. We emphasise that even though a maximum colonic diameter greater than 6 cm signifies megacolon, the overall clinical condition of the patient is more important in diagnosis of toxic megacolon than the absolute width of the dilated segment. Ultrasonography and computed tomography (CT) may aid overall management. High-resolution ultrasonography can be used to assess accurately the extent and activity of severe ulcerative colitis and response to therapy, and thus may help in the early detection of toxic megacolon.11 CT scan may occasionally be valuable in identifying the aetiology of megacolon. For example, in pseudomembranous colitis from C difficile infection, diffuse colonic thickening is a very sensitive (but not specific) finding. A CT scan may be especially useful in patients with AIDS who may have several intercurrent intra-abdominal processes.
Diagnosis The diagnosis of toxic megacolon must be considered in all patients presenting with abdominal distension and acute or chronic diarrhoea. Since there are several
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causes of toxic megacolon, the initial assessment should aim to establish the diagnosis of toxic megacolon as well as to identify the underlying aetiology so that specific therapeutic measures can be instituted. Clinical features that suggest inflammatory bowel disease as a cause of toxic megacolon include a preceding history of diarrhoea, bloody stools, abdominal pain, perianal disease, or extraintestinal manifestations such as arthritis, iritis, and skin or liver disease. Also important is a careful inquiry about recent travel, exposure to enteric pathogens, antibiotic or chemotherapy use, use of antimotility agents, and HIV/AIDS status. Limited endoscopy with biopsy may provide useful diagnostic information, particularly when there is a possibility of acute bacillary dysentery. Acute infectious colitis does not alter colonic crypt architecture, whereas inflammatory bowel disease is accompanied by diffusely abnormal crypt architecture, even if symptoms have been present for only 1 week.12 Cytomegalovirus colitis is characterised by the presence of inclusion bodies. A limited sigmoidoscopy may miss inclusion bodies, since ulcers may be found only in the ascending colon in up to 40% of cases. A full colonoscopy is extremely risky in patients with toxic megacolon and could easily lead to colonic perforation. In our opinion, colonoscopy should generally be avoided. However, the study by Alemayehu and Jarnerot13 suggested that colonoscopy was a safe procedure in patients with severe ulcerative colitis and helped in the decision on whether to operate.
Treatment The main goal of treatment is to reduce the severity of colitis so as to restore normal colonic motility and to decrease the likelihood of perforation (panel 3). The initial treatment of toxic dilatation should be medical and obviates the need for surgery in about 50% of patients.1 However, a surgical consultation should be obtained on admission, and the patient should be assessed daily by both medical and surgical teams. The patient should be monitored in the intensive-care unit with frequent examinations by nursing and medical staff for signs of deterioration. Complete blood counts, electrolytes, and serial abdominal plain films are reviewed every 12 h initially, and then daily as the patient improves. Anaemia, dehydration, and electrolyte deficits, particularly hypokalaemia, may aggravate colonic dysmotility and should be aggressively treated. Total parental nutrition offers no proven benefit in terms of avoiding surgery or decreasing hospital stay in patients with ulcerative colitis,14 but is beneficial in decreasing the activity of Crohn’s disease and may be useful in patients who have long-standing nutritional depletion especially if they are likely to undergo surgery. The bowel should be completely rested, and a nasogastric tube (or long intestinal tube) should be placed initially to decompress the gastrointestinal tract. If the patient shows signs of improvement, enteral feeding is started since it may hasten mucosal healing and stimulate normal motility. All antimotility agents, narcotics, and anticholinergics should be discontinued. Patients should be given prophylaxis for both gastric stress ulcerations (intravenous H2-blockers) and deepvenous thrombosis (pneumatic compression stockings or low-dose subcutaneous heparin). Broad-spectrum antibiotics are recommended to reduce septic 511
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complications and in anticipation of peritonitis resulting from perforation. We recommend intravenous corticosteroids (hydrocortisone 100 mg or equivalent every 6–8 h or by continuous infusion) to all patients with toxic megacolon secondary to inflammatory bowel disease. Some physicians prefer to use methylprednisolone because of its lower sodium-retaining and potassium-wasting properties, and others prefer prednisolone because the parenteral dose is equal to the oral dose. Some authorities recommend corticotropin in patients who have not received steroids for at least 30 days, since it may be more beneficial than intravenous corticosteroids in the treatment of underlying ulcerative colitis.15 Sulphasalazine and mesalazine have no role in toxic megacolon and should be initiated only after the acute attack begins to resolve. In some patients, the acute flare may in fact coincide with the introduction of these drugs. Cyclosporin is useful in the treatment of severe colitis refractory to steroid therapy, but experience with this agent in toxic megacolon is limited. Some investigators recommend intermittent rolling manoeuvres16 or knee-elbow position17 to help redistribution of gas in the colon and decompression. These recommendations are based on the observation that when a patient is rolled from supine to prone position or adopts a knee-elbow position, gas rises to the distal colon and rectum and is more easily expelled. This technique may be especially useful when the toxicity is controlled but colonic dilatation persists. Medical therapy is successful when signs of toxicity are reduced, fluid and transfusion requirements decrease, abdominal and colonic dilatation begin to resolve, and the results of laboratory tests improve. Persistent fever after 48–72 h of steroid therapy should raise the possibility of local perforation or abscess. Free perforation, massive haemorrhage, increasing transfusion requirements, increasing signs of toxicity, and progression of colonic dilatation are indications for urgent operation. Most surgical studies recommend colectomy if after 48–72 h there is persistent colonic distension. However, some physicians recommend continuation of medical therapy up to 7 days if the patient seems to be clinically improving despite persistent megacolon without free perforation.16,18 Subtotal colectomy with end-ileostomy is the procedure of choice for urgent or emergency surgery, and causes less morbidity and mortality than single-stage proctocolectomy.19 Early surgery in patients without evidence of perforation results in much lower mortality (2–8%) than colectomy done after colonic perforation has occurred (40% or more).
In patients with toxic megacolon due to severe C difficile colitis, the first step is to stop the offending antibiotic and to give intravenous metronidazole plus oral vancomycin via a nasogastric tube. Colectomy is reserved for patients who do not respond within 48–72 h, or who show evidence of local perforation. A literature review of patients with toxic megacolon secondary to pseudomembranous colitis between 1968 and 1992 revealed an overall mortality of 31–35%, including 42% for surgically and 18% for medically treated patients.5 In two later studies, the overall mortality from severe C difficile colitis with toxic megacolon was 64–67%; mortality for surgically treated patients was 71–100%.4,5 In a series of six patients with acute abdomen secondary to C difficile colitis, decompression of dilated colons in two patients was achieved by colonoscopy, thus obviating the need for surgery.20 In patients with HIV infection or AIDS who develop toxic megacolon, limited endoscopy and imaging studies to search for treatable infectious and non-infectious causes is warranted. Those with cytomegalovirus colitis or pseudomembranous colitis respond poorly to medical therapy and many require emergency laparotomy with subtotal colectomy and ileostomy.21,22 Fulminant colitis during pregnancy, with or without toxic megacolon, is especially difficult to treat because the gravid uterus impairs a proper abdominal examination and diagnostic radiation poses hazards to the fetus.23 Moreover, disturbances during pregnancy mean that results for laboratory variables are unreliable; for example, haemoglobin and albumin concentrations fall, whereas erythrocyte sedimentation rate and Creactive protein concentrations rise. Intensive steroid therapy results in resolution of 75% of cases of fulminant colitis in pregnancy, with the remainder requiring urgent colectomy.
References
synthase in colonic smooth muscle from patients with toxic megacolon. Gastroenterology 1995; 109: 1497–502. 8 Mourelle M, Vilaseca J, Guarner F, et al. Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase. Am J Physiol 1996; 33: G425–30. 9 Norland CC, Kirsner JB. Toxic dilatation of the colon (toxic megacolon): etiology, treatment and prognosis in 42 patients. Medicine 1969; 48: 229–50. 10 Caprilli R, Vernia P, Colaneri O. Blood pH: a test for assessment of severity in proctocolitis. Gut 1976; 17: 763–69. 11 Arienti V, Campieri M, Boriani L, et al. Management of severe ulcerative colitis with the help of high resolution ultrasonography. Am J Gastroenterol 1996; 91: 2163–69. 12 Surawicz CM, Haggitt RC, Husseman M, et al. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology 1994; 107: 755–63.
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Fazio VW. Toxic megacolon in ulcerative colitis and Crohn’s colitis. Clin Gastroenterol 1980; 9: 389–407. Jalan KN, Circus W, Cord WI, et al. An experience with ulcerative colitis: toxic dilatation in 55 cases. Gastroenterology 1969; 57: 68–82. Grieco MB, Bordan DL, Geiss MD, et al. Toxic megacolon complicating Crohn’s disease. Ann Surg 1980; 191: 75–80. Rubin MS, Bodenstein LE, Kent KC. Severe Clostridium difficile colitis. Dis Colon Rectum 1995; 38: 350–54. Trudel JL, Deschenes M, Mayrand S, et al. Toxic megacolon complicating pseudomembranous enterocolitis. Dis Colon Rectum 1995; 38: 1033–38. Cooper HS, Raffensper EC, Jonas L, et al. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilatation requiring colonic resection. Gastroenterology 1977; 72: 1253–56. Mourelle M, Casellas F, Guarner F, et al. Induction of nitric oxide
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Outcome Mortality rates in toxic megacolon are variable. Before 1976, the death rate in 604 cases of toxic megacolon was 27% for those treated medically and 19% in surgically treated patients.24 In later series, mortality rates have fallen to 0–2% in patients with inflammatory bowel disease, probably as a result of various factors, including early recognition of toxic megacolon, better intensive medical management, earlier surgical intervention, and better postoperative care. Variations in mortality rates are also related to the medical or surgical biases of the treating doctors.
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SEMINAR 13 Alemayehu G, Jarnerot G. Colonoscopy during an attack of severe ulcerative colitis is a safe procedure and of great value in clinical decision making. Am J Gastroenterol 1991; 86: 187–90. 14 Dickinson RJ, Ashton MG, Axon ATR, et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980; 79: 1199–204. 15 Meyers S, Sachar DB, Goldberg JD, et al. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis: a prospective, randomized, double-blinded clinical trial. Gastroenterology 1983; 85: 351–57. 16 Present DH, Wolfson D, Gelernt IM, et al. Medical decompression of toxic megacolon by “rolling”: a new technique of decompression with favorable long-term follow-up. J Clin Gastroenterol 1988; 10: 485–90. 17 Panos MZ, Wood MJ, Asquith P. Toxic megacolon: the knee-elbow position relieves bowel distension. Gut 1993; 34: 1726–27.
18 Caprilli R, Vernia P, Latella G, et al. Early recognition of toxic megacolon. J Clin Gastroenterol 1987; 9: 136–42. 19 Block GE, Moosa AR, Siminowitz D, et al. Emergency colectomy for inflammatory bowel disease. Surgery 1977; 82: 531–36. 20 Triadafilopoulos G, Hallstone AE. Acute abdomen as the first presentation of pseudomembranous colitis. Gastroenterology 1991; 101: 685–91. 21 Beaugerie L, Ngo Y, Goujard F, et al. Etiology and management of toxic megacolon in patients with human immunodeficiency virus infection. Gastroenterology 1994; 107: 858–63. 22 Davidson T, Allen-Mersh TG, Miles AJG, et al. Emergency laparotomy in patients with AIDS. Br J Surg 1991; 78: 924–26. 23 Boulton R, Hamilton M, Lewis A, et al. Fulminant ulcerative colitis in pregnancy. Am J Gastroenterol 1994; 89: 931–33. 24 Strauss RJ, Flint GW, Platt N, et al. The surgical management of toxic dilatation of the colon: a report of 28 cases and a review of the literature. Ann Surg 1976; 184: 682–88.
Further reading
megacolon complicating Clostridium difficile pseudomembranous colitis. Am J Gastroenterol 1988; 83: 304–07. Danovitch SH. Fulminant colitis and toxic megacolon. Gastroenterol Clin North Am 1989; 18: 73–82. Garrett JM, Sauer WG, Moertel CG. Colonic motility in ulcerative colitis after opiate administration. Gastroenterology 1967; 53: 93. Grand RJ, Ramakrishna J, Calenda KA. Inflammatory bowel disease in the pediatric patient. Gastroenterol Clin North Am 1995; 24: 613–32. Prantera C, Lorezetti R, Cerro P, et al. The plain film accurately estimates the extent of active ulcerative colitis. J Clin Gastroenterol 1991; 13: 231–34.
Epidemiology Farmer RG, Easley KA, Rankin GB. Clinical patterns in ulcerative colitis: disease location, progression and prognosis. Dig Dis Sci 1993; 38: 1137–46. Marshak RH, Lester LJ, Friedman AI. Megacolon: a complication of ulcerative colitis. Gastroenterology 1950; 16: 768–72. McInerney GT, Sauer WG, Baggenstoss AH, et al. Fulminating ulcerative colitis with marked colonic dilatation: a clinicopathologic study. Gastroenterology 1962; 42: 244–57.
Aetiology and pathogenesis Christianson K. Toxic megacolon complicating shigellosis. J R Coll Surg Edin 1987; 32: 109–10. Connolly GM, Gazzard BG. Toxic megacolon in cryptosporidiosis. Postgrad Med J 1987; 63: 1103–04. Gonzalez A, Vargas V, Guarner L, et al. Toxic megacolon in typhoid fever. Arch Intern Med 1985; 145: 2120. Kalkay MN, Ayanian ZS, Lehaf EA, et al. Campylobacter-induced toxic megacolon. Am J Gastroenterol 1983; 78: 557–59. Orloff J, Saito R, Lasky S, et al. Toxic megacolon in cytomegalovirus colitis. Am J Gastroenterol 1989; 84: 794–97. Snowden JA, Young MJ, Mckendrick MW. Dilatation of the colon complicating acute self-limited colitis. Q J Med 1994; 87: 55–62. Stuart RC, Leahy A, Cafferky M, et al. Yersinia enterocolitica infection and toxic megacolon. Br J Surg 1986; 73: 590. Velanovich V, Laporta AJ, Garrett WL, et al. Pseudomembranous colitis leading to toxic megacolon associated with antineoplastic therapy: report of a case and review of the literature. Dis Colon Rectum 1992; 35: 369–72. Wig JD, Talwar BL, Bushnurmath SR. Toxic dilatation complicating fulminant amoebic colitis. Br J Surg 1981; 68: 135–36.
Clinical features Atherton LD, Leib ES, Kaye MD. Toxic megacolon associated with methotrexate therapy. Gastroenterology 1984; 86: 1583–88. Brown CH, Ferrante WA, Davis WD. Toxic dilatation of the colon complicating pseudomembranous enterocolitis. Am J Dig Dis 1968; 13: 813–21. Burke GW, Wilson M, Mehrez I. Absence of diarrhea in toxic
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Diagnosis and treatment McIntyre PB, Powell-Tuck J, Wood SR, et al. Controlled trial of bowel rest in the treatment of severe acute colitis. Gut 1986; 27: 481–85. Morris JB, Zollinger RM, Stellato TA. Role of surgery in antibioticinduced pseudomembranous enterocolitis. Am J Surg 1990; 160: 535–39. Prantera C, Lorenzetti R. Severe ulcerative colitis: a personal point of view. Hepatogastroenterology 1989; 36: 240–03.
Outcome Dalton HR, Jewell DP. The management of severe ulcerative colitis. Ann Intern Med 1991; 23: 389–91. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis: part 3—complications. Gut 1964; 5: 1–22. Flatmark A, Fretheim B, Gjone E. Early colectomy in severe ulcerative colitis. Scand J Gastroenterol 1975; 10: 427–31. Grant CS, Dozois RR. Toxic megacolon: ultimate fate of patients after successful surgical management. Am J Surg 1984; 147: 106–10. Greenstein AJ, Kark AE, Dreiling DA. Crohn’s disease of the colon: III toxic dilatation of the colon in Crohn’s disease. Am J Gastroenterol 1975; 63: 117–28. Koudahl G, Kristensen M. Toxic megacolon in ulcerative colitis. Scand J Gastroenterol 1975; 10: 417–21. Lennard-Jones JE, Ritchie JK, Hidler W, et al. Assessment of severity in ulcerative colitis: a preliminary study. Gut 1975; 16: 579–84. Travis SPL, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 1996; 38: 905–10.
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