Fulminant Ulcerative Colitis Clarence K. W. Wong, MD, FRCPC† B. R. Yacyshyn, MD, FRCPC* Address *2E3.11, Walter MacKenzie Health Sciences Centre, 8440 112th St., Edmonton, Alberta, T6G 2B7, Canada. Email:
[email protected] †Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Current Treatment Options in Gastroenterology 2000, 3:217–226 Current Science Inc. ISSN 1092-8472 Copyright © 2000 by Current Science Inc.
Opinion statement • Fulminant ulcerative colitis necessitates immediate hospitalization. • Supportive therapy such as aggressive rehydration, restriction of oral intake, and consideration of parenteral nutrition should be initiated. • High-dose intravenous steroids should be started in almost all cases. • Antibiotics and cyclosporine should be considered, especially in disease refractory to steroid therapy. • Indications for surgery should always be kept in mind, and early involvement of the surgical team is always encouraged. • Avoidance of life-threatening complications such as toxic megacolon, hemorrhage, and perforation is the goal of any treatment for fulminant ulcerative colitis.
Introduction Improved understanding of the role of the immune system in inflammatory bowel disease (IBD) has had negligible impact on the management of one of its severest forms. Fulminant ulcerative colitis represents an acute, clinically dangerous manifestation of gut inflammation and bacteremia. Ulcerative colitis (UC) is a chronic recurrent inflammatory condition of the colonic mucosa. Intermittent flares often punctuate the clinical course, and affected areas can range from the rectosigmoid colon and left colon to the entire colon. Disease severity can also be variable, where chronically stable patients can suddenly present with acute and severe disease. Severe and fulminant colitis are two concerning developments of UC. Severe ulcerative colitis, as described by Truelove and Witts in 1955 [1], is defined
as six or more bowel movements per day, macroscopic blood in the stool, fever, tachycardia, anemia, abdominal tenderness, an increased erythrocyte sedimentation rate, and thumb printing on x-ray. Fulminant ulcerative colitis specifically refers to a patient with severe colitis who presents with toxic signs and symptoms [2••]. In these presentations, there are greater than ten bowel movements per day, blood is seen in all stools, transfusions are required, and there is bowel dilation on x-ray (usually over 8cm in mid-transverse colon) [1] (Fig. 1). Early recognition and treatment of severe and fulminant UC are imperative to avoid the emergent complications seen in these conditions. These include toxic megacolon, massive hemorrhage, and perforation. This review will discuss some of the new modalities that may ameliorate this dangerous presentation of UC.
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Inflammatory Bowel Disease Figure 1. A treatment algorithm for the management of fulminant ulcerative colitis. Abbreviations: intravenous (IV), ulcerative colitis (UC), total parenteral nutrition (TPN), white blood count (WBC).
Treatment Diet and lifestyle • Patients admitted with fulminant UC should have restricted oral intake. • Total parenteral therapy (TPN) is commonly used in fulminant UC patients, but has not been shown to be superior to bowel rest alone. TPN can be a useful adjunct in fulminant UC patients with severe nutritional depletion. • Smoking (nicotine) has been associated with lower rates of admission for patients with UC [3], but its use as a therapeutic modality should be discouraged due to its well-established health risks. • In the acute setting of fulminant UC, patients should also have restricted oral intake. With colonic dilation, nasogastric tube placement is required. Although parenteral nutrition has not been shown to be superior to bowel rest, it may be an important consideration in patients who are at high nutritional risk [4,5]. Nicotine therapy has no role in the acute treatment of fulminant UC.
Pharmacologic treatment • Glucocorticosteroids are the mainstay of therapy for fulminant UC. They should be administered early in the presentation.
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• Antibiotic therapy remains controversial. Despite lack of evidence regarding their efficacy, the empiric use of antibiotics is still encouraged. • Cyclosporine therapy has gradually increased, with more clinicians familiarizing themselves with the possible benefits and side effects. It appears to be a useful adjunct in steroid-refractory patients where surgical intervention appears imminent.
Glucocorticosteroids Standard dosage Methylprednisolone: 30 mg every 12 hours; hydrocortisone 100 mg every 8 hours. Contraindications Viral/bacterial infections, Cushing’s syndrome, or acute psychoses. Main drug interactions Numerous interactions to multiple classes. Some key interactions include anticholinesterase drugs (myasthenic crisis), antidiabetic drugs (impaired glucose control), and diuretics (enhanced K+ loss). Main side effects Multiple organ systems can be affected. The system list includes musculoskeletal (myopathy, metabolic bone disease, osteonecrosis), neurological (psychoses), ophthalmic (cataracts), immunological (opportunistic infections), and endocrine (cushingoid state, impaired glucose tolerance). Glucocorticosteroids can mask/ induce intestinal perforation. Patients typically note weight gain, and have an increased appetite. In children, growth retardation is a major concern. Special points Patients admitted with severe or fulminant UC are started on parenteral corticosteroids as a mainstay of therapy. They are given along with fluid resuscitation, correction of electrolyte imbalances, and administration of antibiotics as indicated. Most patients admitted with fulminant UC have already failed maximal doses of oral corticosteroids (40–60 mg daily), oral aminosalicylate (4.8 g mesalamine daily), and topical therapy. Treatment should ensue for 7–10 days, with intravenous corticosteroids at the doses described above [6•]. Doses higher than these have not demonstrated further benefit [7]. Treating for longer than 10 days does not improve short- or long-term remission rates, and may actually be linked to increased colectomies [8]. Although uncommonly used now, intravenous adrenocorticotropic hormone (ACTH) has been given with efficacious results in those patients not previously on steroids [9,10]. The overall response in severe colitis has been debated, with reported ranges of 38% [11], 56% [12], and 85% [13]. In an analysis of five studies, remission was maintained in 54% to 69% [11]. Overall, corticosteroids remain the backbone of therapy in fulminant ulcerative colitis. Patients should be admitted and started at maximal doses, with close follow-up of the clinical course. As mentioned above, steroid therapy can mask severe complications such as colonic perforation, and close liaison with the surgical team is necessary if the patient does not improve clinically.
Antibiotics • Many antibiotics have been studied in the management of fulminant colitis. The premise that microbial agents may mitigate and perpetuate the immunoinflammatory process in IBD has made these drugs an ideal choice in empiric therapy [14]. There is no doubt regarding the danger of sepsis in the patient with fulminant UC. However, antibiotic effectiveness in preventing morbidity has been debated in multiple studies. • Multiple organisms have been implicated in exacerbating inflammatory bowel disease. The list includes Salmonella, Shigella, Campylobacter, Clostridium difficile, cytomegalovirus, and Listeria monocytogenes. The first four organisms are commonly screened for, and susceptible to, the regimens listed below. • Cytomegalovirus has been found to exacerbate ulcerative colitis, with a prevalence of 4.6% [15•]. It can even cause flares in patients who are not on long-term immunosuppression [16].
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Inflammatory Bowel Disease • L. monocytogenes is a ubiquitous, gram-positive anaerobe that can induce listeriosis. Patients presenting with this condition are often febrile, septic, and can go on to develop meningoencephalitis. Mortality has been reported as high as 13% to 34%. L. monocytogenes has recently been found in a case of fulminant ulcerative colitis [17]. Current treatment regimes with metronidazole or ciprofloxacin are ineffective against this organism. Thus, appropriate antibiotic coverage may need to be widened. Screening for an infectious agent should be one of the initial diagnostic maneuvers used to investigate the patient with fulminant UC. • Four antibiotics may be used for fulminant UC (Table 1).
Table 1. Antibiotics that can be used in fulminant ulcerative colitis Metronidazole, IV Vancomycin, oral Ciprofloxacin, oral or IV Tobramycin, oral or IV
Metronidazole Standard dosage 500 mg IV every 8 hours. Contraindications Hypersensitivity reactions. Care should be used in patients with active neurological disorders, blood dyscrasias, or hypothyroidism. Main drug interactions This drug can increase levels of phenytoin and lithium. Warfarin may be potentiated (prolonged prothrombin time). Disulfiram-like reactions occur with concurrent use of alcohol. Main side effects Mainly gastrointestinal (nausea, anorexia, discomfort). Others include peripheral neuropathies, confusion, and unpleasant metallic taste. Special points Metronidazole has been the most closely examined antibiotic in inflammatory bowel disease. Most studies have occurred with Crohn’s disease, where it has appeared to possess immunosuppressive properties. In UC, multiple trials with metronidazole have shown their benefit in maintenance therapy [18]. However, in severe colitis, metronidazole has not been shown to have any benefit [19,20]. In two studies, 78 patients were given metronidazole at 0.5 g every 8 hours intravenously, some with the addition of tobramycin. Clinical outcomes were found to be no different than with the placebo-treated group. Despite this data, metronidazole continues to be advocated as empiric intravenous therapy during fulminant colitis [6••,21,22•]. In the treatment of pouchitis, response to metronidazole has been favorable [23]. In a series of 104 consecutive patients requiring restorative proctocolectomy with ileal J-pouch anal anastomosis, 50% developed pouchitis over a 40-month follow-up period. However, 96% responded to metronidazole or ciprofloxacin [24]. In a small double-blind crossover study, metronidazole was found to be superior to placebo in chronic unremitting pouchitis [25]. Thus, although the only clear evidence for metronidazole administration lies in patients with pouchitis, it continues to be advocated as empiric therapy in fulminant UC.
Ciprofloxacin Standard dosage 400 mg IV every 12 hours; or 500–750 mg orally every 12 hours. Contraindications Hypersensitivity reactions. Safety in children has not been established. Main drug interactions Concomitant administration with theophylline has lead to severe adverse events (cardiac arrest, seizures). Prothrombin time can be increased in patients on warfarin. Main side effects Nausea and diarrhea. Special points Given the negative trials with metronidazole in acute UC, investigators have looked to different agents that may show benefit. The fluoroquinolones are a safe and effective class, effective against many of the organisms that may induce a UC flare. They have been shown to be in effective in cases of pouchitis [24]. Studies with Crohn’s disease and ciprofloxacin have been encouraging, and further trials in
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UC are now emerging. Two recent randomized double-blind control trials using ciprofloxacin in acute UC resulted in differing conclusions. Mantzaris et al. [26] conducted a trial on 70 UC patients, 33 of whom had moderately active disease. They were randomized to ciprofloxacin (250 mg b.i.d.) versus placebo. Additionally, all patients were treated with prednisolone, betamethasone enemas, and olsalazine. At the end of 2 weeks, 70.5% of the ciprofloxacin and 72% of the placebo group were in clinical remission. Thus, it was concluded that there was no additional benefit to adding ciprofloxacin as an adjunctive therapy. Turunen et al. [27] also conducted a double-blind, placebo-controlled study with ciprofloxacin in moderate to severe UC patients. Of 83 patients, 38 were randomized to receive 500–750 mg of ciprofloxacin twice a day, or placebo. All patients were on tapering doses of steroids and mesalamine. At 6 months, the treatment failure rate in the ciprofloxacin group was significantly less than in the placebo group (21% versus 44%). However, this trial has been questioned on some inconsistencies. There were more nonsmokers in the placebo group, dosage and route of steroids was not clearly outlined, and no mention was made of any immunomodulatory agents. Nevertheless, we await further randomized clinical trials to assess the usefulness of ciprofloxacin in fulminant UC.
Vancomycin Standard dosage 125 mg to 500 mg orally every 6 hours. Contraindications Hypersensitivity. Main drug interactions Poorly absorbed when given orally. Can have an additive effect with intravenous vancomycin. Main side effects Most reactions reported occur with the intravenous form. These include an anaphylaxis-like reaction, nephrotoxicity and ototoxicity. Special points Oral vancomycin can be beneficial in certain presentations of fulminant colitis. In those patients positive for Clostridium difficile toxin, vancomycin has been beneficial in providing symptomatic improvement. However, treatment does not always affect the underlying UC [28]. Trnka and LaMont [29] treated five UC patients who suffered frequent relapses. They were all C. difficile toxin positive, and responded within 2 weeks to oral therapy. A double-blind prospective trial of oral vancomycin versus placebo was conducted in C. difficile toxin negative idiopathic colitis patients. Of the 40 patients, 33 had UC and were treated for 7 days with vancomycin or placebo. No significant differences in clinical outcome were noted, although there was a trend toward decreased surgery in the treatment group [30]. Thus, vancomycin use in C. difficile-negative fulminant UC cannot be recommended as a routine therapy. However, these trials highlight the importance of testing for treatable infectious agents, even in fulminant UC.
Tobramycin Standard dosage 1 mg/kg every 8 hours, intravenous or oral. Contraindications Hypersensitivity to this drug or other aminoglycosides. Main drug interactions Care should be taken when given with other drugs that have neurotoxic or nephrotoxic effects. Concurrent use with diuretics may enhance ototoxicity. Main side effects Nephrotoxicity and neurotoxicity (vestibular and auditory). Special points Dosage should be adjusted to creatinine clearance, and can be adjusted according to serum trough levels. An aminoglycoside with excellent activity against gram negative organisms would appear to be an ideal candidate in treating fulminant UC. Taken orally, it may also avoid some of the adverse effects that hamper prolonged intravenous therapy. Two initial studies gave support to tobramycin therapy. In a large randomized, double-blind placebo controlled trial, 84 patients with acute UC were given oral tobramycin as an adjunct to steroid therapy for one week. Compared with 43% in the placebo group, 74% of the tobramycin group achieved symptomatic remission. Histologic improvement was also significant. A follow-up [31] study examined the maintenance of remission after 1 week of therapy. The tobramycin group appeared to have less treatment failures in the short term, but the benefit
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Inflammatory Bowel Disease was no different than placebo by 1 year [32]. Mantzaris et al. [19] randomized 39 patients with severe UC to a combination of intravenous tobramycin and metronidazole versus placebo. All patients were treated with parenteral nutrition, intravenous hydrocortisone (100 mg q.i.d.) and hydrocortisone enemas (100 mg b.i.d.). Seven patients in each group did not improve, and required emergent colectomy. Thus, this study showed no benefit with an antibiotic combination. More studies are needed with tobramycin before it can be recommended in fulminant UC. As well, the route of administration may be critical as the positive studies looked at an oral route whereas the negative study used the intravenous route.
Immunosuppressants Cyclosporine A (CyA) Standard dosage 2–4 mg/kg/day, intravenous infusion. Contraindications Hypersensitivity to cyclosporine. Caution is given in treating patients with psoriasis, rheumatoid arthritis, and renal dysfunction. Main drug interactions Numerous drug interactions can increase or decrease serum concentrations of CyA. Of note, ketoconazole, corticosteroids, and calcium channel blockers increase CyA levels while phenytoin, carbamazepine an octreotide can lower CyA serum levels. The addition of NSAIDs, ciprofloxacin or amphotericin B to CyA can lead to nephrotoxicity. Main side effects Hypertension, hypertrichosis, gingival hyperplasia, nausea, vomiting, and paresthesias. Special points In rare cases, CyA can cause anemia, thrombocytopenia, hepatic dysfunction and renal dysfunction. There have been case reports of malignancies, in particular the lymphoproliferative disorders. Dosage can be adjusted according to serum measurements. Taken at trough times, the initial levels of CyA during acute therapy should run between 200–400 ng/mL. Lichtiger and Present [33] first described administration of CyA during acute flares of ulcerative colitis in 1990. Since then, it has continued to be investigated as an alternative to surgical intervention, and is often seen as “rescue” therapy. CyA should be considered in severe and fulminant cases of UC refractory to glucocorticosteroid therapy. The first study of CyA therapy in acute UC boasted a positive response in 80% of patients [34]. Stack [35] recently found that in his series, 91% of patients in the short term, and 53% over the follow-up period of 39 months avoided colectomy. The high response rate of CyA has recently been refuted by a number of studies. A retrospective analysis of 216 patients with severe ulcerative colitis over 6 years revealed a low remission rate on IV CyA (56%), which later fell to 40% during follow-up [36]. In a study of 30 Irish patients with acute UC, only 53% responded to IV CyA. Although no research to date completely explains the varied response to treatment with CyA, our lab recently reported the expression of ATP-cassette binding protein (ABC) pump named P-glycoprotein 170 (P-gp) in IBD patients [37]. One of the many proposed functions of P-gp is the transport of drugs and toxins, which includes CyA. Our work showed that Crohn’s patient lymphocytes express high levels of P-gp consistent with lack of efficacy of CyA in this disease. Interestingly, UC patient lymphocytes expressed significantly lower, yet quite varied levels of P-gp compared to Crohn’s patient samples. This observation may help explain the varied patient response to CyA and also the varied clinical trial data reported. Given the multiple adverse effects and possible drug interactions with CyA, different modalities have emerged to improve remission rates. Oral microemulsion preparations of CyA (Neoral) that improve bioavailability have been used in maintenance after acute flares of UC, and as first-line therapy. In an open-label trial of Neoral versus the traditional IV CyA followed by an oral encapsulated CyA, all patients on Neoral had a short-term response (3 months). In addition, 17% of patients receiving IV CyA had a major toxic reaction, compared with none in the Neoral group [38]. Oral CyA has been used effectively in children with fulminant
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UC. Nearly 80% of children achieved clinical remission on an oral dose of 4.6–9.6 mg/kg/day in the short term. However, only 28% avoided colectomy over the follow-up period of 5 years [39]. Another method of improving long-term remission after CyA therapy for fulminant UC is the addition of immunomodulating medications. Maintenance therapy with 6-mercaptopurine (6-MP) was prescribed for 16 of 22 patients who responded to IV CyA. Along with tapering steroids and sulphasalazine, 6-MP at 1 mg/kg/day helped maintain clinical remission in 75% of patients after 1 year of follow-up [40]. Azathioprine (AZA) at 2.5 mg/kg/day given to IV CyA responders also maintained remission of 78% of patients at 1 year [41]. Cohen et al. [41] found similar responses to 6-MP/AZA in their 5-year retrospective analysis of patients treated for severe UC flares. In their group of 36 IV CyA responders, 80% of patients who were maintained with 6-MP/AZA avoided colectomy at 5.5 years. In the management of the fulminant UC patients, steroid therapy should be first-line therapy. However, there is increasing evidence that CyA should be attempted in steroid refractory patients. A recent poll of clinicians has found that over 50% have used CyA in fulminant disease. The use of newer preparations with higher bioavailability, and supplementation with immunomodulating drugs appears to hold promise in treating fulminant UC [42,43].
Endoscopic therapy • Endoscopy is appropriate as an investigational aid if the diagnosis is in question. However, it should be avoided if possible, and should not delay surgery where the indications are clear. • In severe colitis, endoscopy of the colon may assist in confirming the etiology and ensuring that the proper pathway of therapy is followed. Avoidance of endoscopy when possible is important in fulminant UC, due to possible exacerbation of fulminant colitis. Coincident insufflation of the colon during the procedure may worsen dilatation, and increase the risk of perforation.
Surgery • The surgical procedure of choice in fulminant UC is a subtotal colectomy with ileostomy. • Absolute indications for surgery include perforation and massive hemorrhage. • Proceed to surgery prior to colonic perforation.
Subtotal colectomy with ileostomy Standard procedure Surgery is the procedure of choice in fulminant colitis. Preservation of the rectum is important, but in cases of fulminant colitis, surgical options may be limited by the medical instability of the patient. In this case, the most expeditious operation is usually the most prudent, specifically colectomy without proctectomy. In cases that are less severe, the distal segment can be exteriorized, left open as a mucous fistula, or converted into a Hartmann-type stump. An ileostomy should be constructed via Brooke’s method or a Kock’s pouch. Contraindications None. Complications Stoma revisions, small-bowel obstruction, bladder dysfunction, and sexual dysfunction. Special points It is estimated that half of all chronic UC patients will undergo surgery within the first 10 years of diagnosis [44]. Some of these cases (25%) present as fulminant UC that requires urgent surgical intervention [45]. While an elective procedure is always preferred, fulminant UC often necessitates emergent surgical treatment due to the imminent and potentially life-threatening complications.
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Inflammatory Bowel Disease There are no trials comparing medical versus surgical therapy in fulminant UC. However, prolonged medical therapy in toxic megacolon eventually resulted in unsatisfactory outcomes in those who initially responded [46]. The development of guidelines regarding the optimal timing for surgical intervention has been difficult. However, there are certain indications that require immediate surgical intervention (Table 2) [44].
Table 2. Indications for surgical intervention in ulcerative colitis [44] Massive hemorrhage Toxic megacolon with impending/frank perforation Fulminant disease refractory to medical therapy Obstruction from stricture Suspicion of colonic cancer Intractable disease One such indication is the suspicion of colonic perforation. Perforation has been found in only 4% of acute presentations. However, the risk is as high as 20% in a clinically severe attack with pancolitis [44]. A summary of studies has found that mortality can be reduced by four- to tenfold if colonic perforation can be avoided [47]. Proctocolectomies in the urgent setting should be avoided. Given an already acute situation, the additional of further complications such as hemorrhage, contamination, sepsis, and nerve damage is unwarranted [48]. The morbidity rate for an emergent proctocolectomy has been found to be as high as 40%, versus 20% for elective cases [49]. Continent ileostomy or ileoanal anastomosis should not typically be performed at the time of the initial operation for fulminant colitis.
Emerging therapies • Leukocytapheresis may preclude surgical intervention and decrease steroid dose. • A large body of interest in Japan is focused upon the role of leukocytapheresis in the treatment of IBD. This aspect of IBD therapy is interesting in that it represents one approach to the therapy of IBD by removing the source of inflammation, that being T-cells from the circulation of patients. Early experiments revealed benefit in UC patients treated with this method [50]. Sasaki et al. [50] found that six of nine steroid refractory patients with severe UC responded to this therapy. Another researcher also found that 34 of 37 patients with acute UC responded to the therapy. • In a prospective, randomized trial of 83 UC patients, Sawada et al. [51] compared leukocytapheresis to escalating steroid dose as adjunctive therapies. They found leukocytapheresis to be significantly effective versus steroids, and noted a decrease in steroid dose administered to the leukocytapheresis group. Side effects have been reported as not serious [52]. Thus, there is promising early data that leukocytapheresis may reduce the need for surgery and lower steroid dose. However, its practicality and cost effectiveness requires further study.
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References and Recommended Reading Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance Truelove SC, Witts LJ: Cortisone in ulcerative colitis: final report on a therapeutic trial. BMJ 1955, 2:1041-1048. 2.•• Swan NC, Geoghegan JG, O'Donoghue DP, et al.: Fulminant colitis in inflammatory bowel disease: detailed pathologic and clinical analysis. Dis Colon Rectum 1998, 41:1511-1515. A good corellation of clinical and pathological findings in fulminant UC. 3. Boyko EJ, Koepsell TD, Perera DR, Inui TS: Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 1987, 316:707-710. 4. Dickinson RJ, Ashton MG, Axon AT, et al.: Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980, 79:1199-1204. 5. McIntyre PB, Powell-Tuck J, Wood SR, et al.: Controlled trial of bowel rest in the treatment of severe acute colitis. Gut 1986, 27:481-485. 6.• Kornbluth A, Sachar DB: Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997, 92:204-211. A current guideline to practice. 7. Rosenberg W, Ireland A, Jewell DP: High-dose methylprednisolone in the treatment of active ulcerative colitis. J Clin Gastroenterol 1990, 12:40-41. 8. Meyers S, Lerer PK, Feuer EJ, et al.: Predicting the outcome of corticoid therapy for acute ulcerative colitis. Results of a prospective, randomized, doubleblind clinical trial. J Clin Gastroenterol 1987, 9:50-54. 9. Meyers S, Sachar DB, Goldberg JD, Janowitz HD: Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, double-blind clinical trial. Gastroenterology 1983, 85:351-357. 10. Kaplan HP, Portnoy B, Binder HJ, et al.: A controlled evaluation of intravenous adrenocorticotropic hormone and hydrocortisone in the treatment of acute colitis. Gastroenterology 1975, 69:91-95. 11. Kornbluth A, Marion JF, Salomon P, Janowitz HD: How effective is current medical therapy for severe ulcerative and Crohn's colitis? An analytic review of selected trials. J Clin Gastroenterol 1995, 20:280-284. 12. Jarnerot G, Rolny P, Sandberg-Gertzen H: Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985, 89:1005-1013. 13. Travis SP, Farrant JM, Ricketts C, et al.: Predicting outcome in severe ulcerative colitis. Gut 1996, 38:905-910. 14. Gitnick G: Antibiotics and inflammatory bowel diseases. Gastroenterol Clin North Am 1989, 18:51-56. 1.
15.• Kaufman HS, Kahn AC, Iacobuzio-Donahue C, et al.: Cytomegaloviral enterocolitis: clinical associations and outcome. Dis Colon Rectum 1999, 42:24-30. A disease to think about in the differential diagnosis of fulminant UC. 16. Loftus EV Jr, Alexander GL, Carpenter HA: Cytomegalovirus as an exacerbating factor in ulcerative colitis. J Clin Gastroenterol 1994, 19:306-309. 17. Chiba M, Fukushima T, Koganei K, et al.: Listeria monocytogenes in the colon in a case of fulminant ulcerative colitis. Scand J Gastroenterol 1998, 33:778-782. 18. Gilat T, Leichtman G, Delpre G, et al.: A comparison of metronidazole and sulfasalazine in the maintenance of remission in patients with ulcerative colitis. J Clin Gastroenterol 1989, 11:392-395. 19. Mantzaris GJ, Hatzis A, Kontogiannis P, Triadaphyllou G: Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am J Gastroenterol 1994, 89:43-46. 20. Chapman RW, Selby WS, Jewell DP: Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986, 27:1210-1212. 21. Marion JF, Present DH: The modern medical management of acute, severe ulcerative colitis. Eur J Gastroenterol Hepatol 1997, 9:831-835. 22.• Hanauer SB: Review articles: Drug therapy: Inflammatory Bowel Disease. N Engl J Med 1996, 334:841-848. A good review. 23. Sandborn WJ: Pouchitis following ileal pouch-anal anastomosis: definition, pathogenesis, and treatment [comments]. Gastroenterology 1994, 107:1856-1860. 24. Hurst RD, Molinari M, Chung TP, et al.: Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg 1996, 131:497-502. 25. Madden MV, McIntyre AS, Nicholls RJ: Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci 1994, 39:1193-1196. 26. Mantzaris GJ, Archavlis E, Christoforidis P, et al.: A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am J Gastroenterol 1997, 92:454-456. 27. Turunen UM, Farkkila MA, Hakala K, et al.: Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study [comments]. Gastroenterology 1998, 115:1072-1078. 28. Lee DK, Cooper BT, Barbezat GO: Clostridium difficile toxin in chronic idiopathic colitis. N Z Med J 1986, 99:620-622. 29. Trnka YM, Lamont JT: Clostridium difficile colitis. Adv Intern Med 1984, 29:85-107.
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