Toxic megacolon is a serious disease. Complications include sepsis, septic shock, multi-organ failure, GI bleeding, colon perforation, and death. The mortality rate is about 20%, and slightly higher (in the range of 35–60%) with fulminant C. difficile colitis. A white blood cell count higher than 50 K and lactate higher than 5 are predictors of mortality. Depending on the extent of operative intervention, wound infection, staple line dehiscence, and ostomy complications are the main perioperative risks in patients undergoing surgical therapy.

Successful management of toxic megacolon requires a multi-disciplinary approach from medical and surgical teams. Early surgical consultation is crucial, though an aggressive initial attempt at medical management is appropriate. Typically, these patients should be admitted to an intensive care unit. Bowel rest, nasogastric decompression, resuscitation, and electrolyte repletion are key starting points. Frequent serial abdominal examinations, laboratory studies, and radiographs are used to follow their clinical course. Broad spectrum antibiotics are initiated to reduce septic complications. If there is a history of inflammatory bowel disease, high-dose hydrocortisone can be given and does not result in higher risk of perforation. If C. difficile is present, discontinuing the offending antibiotic and administering rectal vancomycin (500 mg in 100 mL saline as retention enema every 6 h) as the oral route (500 mg four times daily) may be ineffective in most patients and with intravenous metronidazole (500 mg three times daily) is appropriate. Any antimotility agents, anticholinergics, and opiates should also be discontinued. Medical therapy is successful in 50–75% of patients.