Toxic megacolon is the clinical term for an acute toxic colitis with dilatation of the colon. The dilatation can be either total or segmental. A more contemporary term for toxic megacolon is simply toxic colitis, because patients may develop toxicity without megacolon. For the purposes of this article, the term toxic megacolon (toxic colitis), or TM (TC), is used, but either toxicity or megacolon can occur exclusively of each other.[1]
The hallmarks of toxic megacolon (toxic colitis), a potentially lethal condition, are nonobstructive colonic dilatation larger than 6 cm and signs of systemic toxicity. TM (TC) was recognized by Marshak and Lester in 1950.[2] Jalan et al described the diagnostic criteria, which are as follows[3] (see Presentation and Workup):
TM (TC) was first thought to be a complication only of ulcerative colitis. In fact, TM (TC) may complicate any number of colitides, including inflammatory, ischemic, infectious, radiation, and pseudomembranous.[4, 5] Indeed, the incidence of TM (TC) is expected to increase due to the rising prevalence of pseudomembranous colitis (see the images below). (See Etiology.)
View Image | A 22-year-old man presented with abdominal pain, passage of blood and mucus per rectum, abdominal distention, fever, and disorientation. Findings from.... |
View Image | Gross pathology specimen from a case of pseudomembranous colitis demonstrating characteristic yellowish plaques. |
View Image | Computed tomography scan from a patient with pseudomembranous colitis demonstrating the classic accordion sign. |
Colonic dilatation may be present in other conditions, such as Hirschsprung disease,[6] idiopathic megacolon/chronic constipation, and intestinal pseudo-obstruction (Ogilvie syndrome). However, these patients do not develop signs of systemic toxicity and, therefore, do not fall into the category of having TM (TC) (see the image below). (See Etiology, Presentation, and Workup.)
View Image | A 72-year-old woman presented with vomiting and abdominal distention. The supine (right) and erect (left) plain abdominal radiographs show gross dilat.... |
The dreaded complication of TM (TC) is perforation, even in the absence of colonic dilatation. Numerous studies have demonstrated that classic physical signs of peritonitis are absent in the majority of patients with free perforation, possibly because of the effects of steroids. (See Prognosis and Presentation.)
Although the precise pathophysiology of toxic megacolon/colitis TM (TC) is unproven, several factors may contribute to its development and precipitation. In cases of uncomplicated colitis, the inflammatory response is confined to the mucosa. The microscopic hallmark of TM (TC) is inflammation extending beyond the mucosa into the smooth-muscle layers and serosa. Whereas the typical ulcerative colitis inflammatory response is limited to the mucosa, toxic megacolon is characterized by severe inflammation extending into the smooth muscle layer, thus paralyzing the colonic smooth muscle and leading to dilatation. The extent of dilatation seems to be correlated with the depth of inflammation and ulceration.[7]
Studies by Mourelle et al showed significantly increased amounts of inducible nitric oxide synthetase in the muscularis propria of patients with toxic megacolon, particularly in the more dilated colonic segments.[8, 9] Inflammation and upregulated nitric oxide synthetase are thought to increase local nitric oxide levels, which inhibits colonic smooth muscle and causes dilatation.[8, 9, 10]
As inflammation progresses into the smooth-muscle layers of the colon, nitric oxide and local inflammatory modulators appear to be involved in the pathogenesis of TM (TC). In toxic megacolon, neutrophils also invade the muscle layer and directly damage muscle cells by the release of proteolytic enzymes, cytokines, and leukotriene B4.[7] Systemic uptake of cytokines and other inflammatory mediators leads to fever, tachcardia, hypotension, and other signs of systemic toxicity. Nitric oxide is generated by inflammatory cells such as neutrophils and macrophages in the inflamed portions of the colon, inhibiting smooth-muscle tone and leading to colonic dilatation.
Myenteric plexus involvement is not consistent and likely does not contribute to colonic dilatation. Hypokalemia and other electrolyte disturbances probably do not contribute to dilatation in most patients.[7]
Inflammatory causes of toxic megacolon (toxic colitis), or TM (TC), include the following:
Infectious causes of TM (TC) include:
In a murine model, spread of type 1 herpes simplex virus infection from the sensory nervous system to the autonomic ganglia of the colonic enteric nervous system has been associated with toxic megacolon and lethality, primarily via viral gene transcription, pathologic inflammatory responses, and neutrophil-mediated destruction of the enteric neurons.[19] The use of laxatives prevented lethality in the mice following genital HSV-1 infection.
TM (TC) may also be caused by:
Often, triggering or predisposing factors can be identified. Signs and symptoms of acute colitis may be present for as long as 1 week before dilatation develops. Although the risk of TM (TC) increases with the severity of colitis, rapid tapering or abrupt discontinuation of medications such as steroids, sulfasalazine, and 5-aminosalicylic acid may precipitate toxemia and dilatation.
Medications that negatively impact bowel motility also are implicated in the development of toxic megacolon. These include, but are not limited to, anticholinergics, antidepressants, loperamide, and opioids. Procedures such as barium enema or colonoscopy may cause distention, impair blood supply, or exacerbate a microperforation and cause subsequent toxemia.
A retrospective study by Tschudin-Sutter et al indicated that the incidence of TM (TC) is higher in pediatric patients with community–associated, rather than healthcare facility–associated, C difficile infection. The study involved 202 pediatric patients with C difficile infection, including 38 with community–associated infection, 144 with healthcare facility–associated infection, and 20 with an indeterminate source of infection. Compared with the healthcare facility–associated group, children with a community–associated infection had a higher rate not only of TM (TC) but also of toxic shock and recurrence. (They were less likely, however, to have comorbidities than were children with healthcare facility–associated infection.)[26]
The incidence of toxic megacolon (toxic colitis), or TM (TC), cited in the literature of depends on the etiology. The lifetime risk of TM (TC) in ulcerative colitis has been estimated to be 1-2.5%. In one series of 1236 patients admitted to the hospital over a 19-year period, toxic megacolon was present in 6% of patients, specifically 10% of ulcerative colitis admissions and 2.3% of Crohn disease admissions.[27]
TM (TC) has been reported to occur in approximately 5% of severe attacks of ulcerative colitis. In pseudomembranous colitis, toxic megacolon occurs in 0.4-3% of patients. This number is expected to increase in proportion to the increasing prevalence of pseudomembranous colitis, which is thought to be due to the increased use of broad-spectrum antibiotics.
In the United States, Jewish people are more prone to ulcerative colitis than are people who are not Jewish. In Israel, Ashkenazi Jewish people have a higher incidence of ulcerative colitis than do Sephardic Jewish people. No data exist regarding race and the incidence of TM (TC).
Regarding ulcerative colitis, most studies demonstrate that both sexes are affected equally.
Young adults (aged 20-40 y), primarily, are affected by ulcerative colitis, but this disease may present at any age. With TM (TC), no predilection appears to exist for any particular age group. All ages may be affected. Many individuals present with TM (TC) during their first flare. The mean duration of disease has been reported to be 3-5 years.
A few studies have shown that the prognosis is poor with medical management of toxic megacolon (toxic colitis), or TM (TC). A study by Grant and Dozois followed the clinical course and ultimate outcome in 38 patients with TM (TC) who were successfully treated nonoperatively.[28] Thirty-two patients had ulcerative colitis and 6 had Crohn disease, with complete follow-up ranging 3-22 years (average, 13 y). Eleven of 38 patients (29%) eventually suffered a second episode of fulminant acute colitis or recurrent TM (TC). Ultimately, a total of 18 patients (47%) underwent colon resection, which was performed on an emergency or urgent basis in 15 patients.[28]
The survival prognosis of TM (TC) should be excellent in the absence of perforation. Indeed, the mortality rates for TM (TC) have improved substantially over the past few decades, from 20% in 1976 to 4-5% currently. The decrease is a result of earlier recognition, intensive medical management, early surgical consultation, and improved surgical technique and postoperative care. If perforation occurs, the mortality rate is approximately 20%.
In the case of ulcerative colitis, a proctocolectomy cures patients of the disease. In the case of Crohn disease, proctocolectomy does not necessarily cure the patient, because Crohn disease can occur in any portion of the gastrointestinal tract.
With the use of tumor necrosis factor (TNF)-alpha inhibitors, it is hoped that more cases can be managed medically in future. More studies are needed.
Educating the patient about toxic megacolon (toxic colitis), or TM (TC), is crucial. First, educate the patient about the causes of the disease. The most common cause of TM (TC) is inflammatory bowel disease. However, with the rising incidence of C difficile, pseudomembranous colitis must always be considered, even in patients with inflammatory bowel disease. Educate the patient about ulcerative colitis, Crohn disease, and indeterminate colitis.
The patient should be clearly informed that, if an operation is required for this acute problem, an ostomy likely will be the procedure needed, regardless of the cause.
Secondly, educate the patient about the operation. Patients require at least a temporary, and possibly a permanent, ostomy. Most patients require a thoughtful, compassionate discussion regarding this aspect of their treatment. The psychological aspects of dealing with an ostomy can be extremely difficult.
Finally, educate patients so that they understand that this disease is a process that may require several months to overcome if an operation is needed and that a 2- or 3-stage procedure is usually required.
Patients with toxic megacolon (toxic colitis), or TM (TC), typically have signs and symptoms of acute colitis that may be refractory to treatment. Common complaints include diarrhea, abdominal pain, rectal bleeding, tenesmus, vomiting, and fever. The patient may already have a diagnosis of inflammatory bowel disease or another cause of colitis, although in some patients, TM (TC) may be the initial presentation of inflammatory bowel disease.
A careful history may reveal recent travel, antibiotic use, chemotherapy, or immunosuppression. Patients are usually very ill, with the toxic definition including some or all of the following symptoms:
The diagnostic criteria developed by Jalan et al may be helpful to guide the history of patient suspected of having toxic megacolon (toxic colitis). They are as follows[3] :
The vital signs in a patient with toxic megacolon (toxic colitis), or TM (TC) generally reveal tachycardia and fever. If the condition is severe, the patient may be hypotensive or tachypneic.
In inflammatory colitides (ie, ulcerative colitis, Crohn colitis), physical findings may be minimal, because high-dose steroids are routinely used; however, the abdomen maybe distended, and bowel sounds are usually decreased. Signs of perforation may also be masked by high-dose steroids, as in inflammatory bowel disease. With toxemia, patients may be obtunded.
Peritoneal signs may indicate perforation. They include the following:
The form of megacolon usually associated with ulcerative colitis is defined by a transverse colon that is 6cm or more in diameter, with loss of haustration.
Patients with toxic megacolon (toxic colitis), or TM (TC), may develop leukocytosis with a left shift. Patients can also present with leukemoid reaction. Additionally, bloody diarrhea results in anemia.
Although the presence of an increased white blood cell count contributes to the diagnosis of TM (TC)—and most investigators believe that the absence of a high white blood cell count makes defining a disease as toxic megacolon difficult—an abnormally low count, or even a white blood cell count that is within normal limits, does not rule out toxic megacolon. This is because in immunosuppressed or extremely toxic patients, the white blood cell count actually may be normal or low.
Electrolyte disturbances are very common in TM (TC) secondary to inflammatory diarrhea, steroid use, and ongoing gastrointestinal losses. The inflamed colon is unable to reabsorb salt and water.
A coagulation panel should be ordered in the event that surgery is required. A nutrition panel, in accordance with the physician's practice, is helpful in determining treatment (eg, albumin vs prealbumin) and in assessing nutritional status.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are usually elevated. Although these findings may support the diagnosis of TM (TC), they are not specific.
Pathology in cases of TM (TC) demonstrates acute inflammation involving all layers of the colon. Variable amounts of necrosis and degeneration are present. Infiltration by inflammatory cells (neutrophils, macrophages, and lymphocytes) is noted. The myenteric and submucosal plexuses are usually preserved.
Plain abdominal radiographs are essential for the diagnosis and management of toxic megacolon (toxic colitis), or TM (TC). Repeated abdominal plain films are necessary to evaluate the efficacy and progress of treatment.
Radiographic findings include the following:
Comparison with old baseline films, if these are available, is helpful. Avoid barium studies in a patient who is severely toxic; the potential for perforation is considerable.
Maconi et al found intestinal ultrasonography potentially to be a diagnostic test for toxic megacolon.[29] The investigators demonstrated similar findings in 4 cases. The findings, including the following, need further evaluation by more studies:
A computed tomography (CT) scan should probably be obtained in patients for whom the diagnosis of toxic megacolon (toxic colitis), or TM (TC), is being considered. A CT scan may identify a local or contained perforation.
If the diagnosis remains unclear or the cause of toxicity is thought to be an abscess, a CT scan may be helpful. There is little literature on the role of CT scanning in TM (TC), but additional studies may help to further define the role of this imaging modality in diagnosing and deriving a prognosis for TM (TC). (See the image below.)
View Image | Computed tomography scan from a patient with pseudomembranous colitis demonstrating the classic accordion sign. |
If the diagnosis of toxic megacolon (toxic colitis), or TM (TC), is in doubt and the patient's condition is not toxic or unstable, endoscopy may be attempted by appropriately trained personnel.
Endoscopy may take the form of flexible sigmoidoscopy or colonoscopy. If clinical concern of TM (TC) exists, the examination should not progress beyond sigmoidoscopy, if at all. The scope should be advanced only as far as is needed for diagnosis. Air insufflation should be a minimal.
According to some experts, colonoscopy is generally justified only if the patient has no or minimal inflammation of the sigmoid or rectum. Perforation is an obvious potential complication of this approach.
Communicating with the patient and the patient's family at all times is imperative. Toxic megacolon (toxic colitis), or TM (TC), can be fatal, and clear lines of communication are essential.
Treatment of TM (TC) includes 3 main goals: (1) reduce colonic distention to prevent perforation, (2) correct fluid and electrolyte disturbances, and (3) treat toxemia and precipitating factors. Careful and frequent monitoring of the patient is required, and, initially, CBCs, electrolytes, and abdominal radiographs should be checked every 12 hours. If the patient is malnourished, consider parenteral nutrition.
During the initial resuscitation, fluid replacement, electrolyte repletion, and transfusion should be aggressive. Broad-spectrum intravenous (IV) antibiotics with coverage equivalent to ampicillin, gentamicin, and metronidazole should be initiated. All medications that may affect colonic motility—including narcotics, antidiarrheals, and anticholinergic agents—must be stopped.
The patient with TM (TC) should be put on bowel rest, and a nasogastric tube (NGT) or long intestinal tube should be placed to assist with gastrointestinal decompression. Long suction tubes may be more helpful for colonic decompression, but they should be placed into the ileum under fluoroscopic guidance.
The patient should be started on IV steroids. IV hydrocortisone is necessary for patients who are taking corticosteroids or who have been recently treated with corticosteroids.
It is important to recognize that although symptomatic improvement may correspond to improvement in the disease process, this is not always the case. Cessation of bowel movements may indicate worsening of the patient's condition. Including repeated abdominal plain films in the evaluation of the clinical picture remains essential.
Any possible triggers for TM (TC) should be stopped, including narcotics, antidiarrheals, and anticholinergics.
Rolling techniques (knee-elbow and prone) may be performed to assist in redistribution of colonic gas and decompression.[30, 31]
Some reports indicate that cyclosporine A may be beneficial in the treatment TM (TC) or of severe ulcerative colitis, with data suggesting that cyclosporine may provide an initial response rate of as high as 80%. After a variable follow-up period, the durable response rate decreases to approximately 40%.
Although further studies are needed, cyclosporine therapy may obviate the need for urgent colectomy, allowing an elective subtotal colectomy or proctocolectomy to be performed under more controlled circumstances.[32]
However, cyclosporine also has significant adverse effects, including immunosuppression and opportunistic infections, hypertension, renal toxicity, and neurologic complications.
Some experimental therapies under study may help patients with TM (TC) to avoid surgery. A case report showed that the use of infliximab, an anti–TNF-alpha monoclonal antibody, was successful in the treatment of TM (TC) in a patient whose condition failed to respond to usual treatment and who refused surgery.[33, 34]
Leukocytapheresis (LCAP) has been reported to be effective against TM (TC). A series of 6 patients whose conditions had failed to improve after treatment with antibiotics and high-dose steroids were enrolled in a study.[35] In 4 cases, the TM (TC) resolved by the morning after initiation of treatment with LCAP. In 2 patients, the TM (TC) resolved approximately 40 hours later. Improvement continued in 4 of the 6 patients.[35]
Hyperbaric oxygen has also been reported to be of use in the treatment of TM (TC),[36] but further studies are needed to confirm these results.
Shetler et al demonstrated that colonoscopic decompression and intracolonic vancomycin administration in the management of severe, acute, pseudomembranous colitis associated with ileus and TM (TC) is feasible, safe, and effective in approximately 57-71% of cases.[37]
Tacrolimus was successfully used in 1 case study in a patient with steroid-refractory ulcerative colitis complicated by TM (TC). Further studies are needed to validate the use.[38]
Intravenous immune globulin (IVIG) may potentially be a last-line adjunct therapy in patients with severe complicated, refractory C difficile infection (eg, shock, ileus, megacolon), taking into account the possibility of adverse effects.[39]
Consultation with a gastroenterologist and surgeon is required in cases of TM (TC). Depending on the health-care setting, consultations a nutritionist and an infectious disease specialist may also be needed.
Patients with TM (TC) should primarily be at bed rest.
Early surgical consultation is essential for cases of toxic megacolon (toxic colitis), or TM (TC). Indications for urgent operative intervention include free perforation, massive hemorrhage (6-8U packed red blood cells), increasing toxicity, and progression of colonic dilatation. Most authors recommend colectomy if persistent dilatation is present or if no improvement is observed on maximal medical therapy after 24-72 hours.
The rationale for early intervention is based on a 5-fold increase in mortality after free perforation. The mortality rate for nonperforated, acute toxic colitis is about 4%; if perforation occurs, the mortality is approximately 20%. Significant independent predictors of mortality include Mannheim peritonitis index (MPI) class II and American Society of Anesthesiologists (ASA) classes 4-5.[40]
Some physicians provide up to 7 days of medical therapy if the patient demonstrates clinical improvement despite persistent colonic dilatation. The authors recommend a strategy of early surgical intervention to minimize the incidence of colonic perforation. If no improvement occurs over 48-72 hours with medical therapy, perform surgical resection.
Whether to perform a total proctocolectomy or a subtotal colectomy with the rectum left behind is debated.[41, 42] The preference in the literature is to perform a subtotal colectomy; this is due to the following reasons:
Performing a total proctocolectomy in a patient who is acutely ill and toxic and on high-dose steroids increases the risk of complications, morbidity, and mortality.
Terminate the resection at the sacral promontory, and perform either a mucus fistula or a stapled rectal stump. If a stapled rectal stump is performed, keeping a rectal tube in place for 2-3 days may reduce the incidence of rectal stump blowout.
Because the surgical treatment of TM (TC) requires an ostomy, the patient must give clear, informed consent. In addition, discussing the implications of an ostomy with the patient and the patient's family is helpful. Also, it is important to tell the patient that surgical treatment may be staged such that reoperation is required in the future.
Start the patient on antibiotics to cover the colonic bacterial flora. Any number of antibiotics that primarily cover gram-negative and anaerobic bacteria can be administered. In addition, begin the administration of steroids. Either hydrocortisone 100 mg IV piggyback (IVPB) every 6 hours or methylprednisolone 60 mg IVPB every 24 hours is acceptable. The latter has greater relative anti-inflammatory potency and less relative mineralocorticoid potency.
As previously mentioned, some reports indicate that cyclosporine A may be effective against toxic megacolon (toxic colitis), or TM (TC), and severe ulcerative colitis. However, cyclosporine has significant adverse effects, including immunosuppression and opportunistic infections, hypertension, renal toxicity, and neurologic complications.
Clinical Context: Hydrocortisone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Clinical Context: Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids also modify the body's immune response to diverse stimuli.
Clinical Context: Cyclosporine is used in acute, severe ulcerative colitis that is refractory to IV corticosteroids. An 11-amino acid cyclic peptide and a natural product of fungi, it acts on T-cell replication and activity.
Cyclosporine is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.
Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin-2 and the subsequent recruitment of activated T cells.
Cyclosporine has about 30% bioavailability, but there is marked interindividual variability. This agent specifically inhibits T-lymphocyte function, with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 hours of antigenic exposure.
Cyclosporine suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, graft-vs-host disease) for a variety of organs.
Immunosuppressant agents inhibit immune reactions resulting from diverse stimuli.
Clinical Context: Infliximab neutralizes the cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. Mix in 250 mL normal saline for infusion over 2 hours. It must be used with a low-protein-binding filter (1.2 µm or less).
Immunomodulatory agents regulate immune reactions that are responsible for inflammation.
A 22-year-old man presented with abdominal pain, passage of blood and mucus per rectum, abdominal distention, fever, and disorientation. Findings from sigmoidoscopy confirmed ulcerative colitis. Abdominal radiographs obtained 2 days apart show mucosal edema and worsening of the distention in the transverse colon. The patient's clinical condition deteriorated over the next 36 hours despite steroid and antibiotic therapy, and the patient had to undergo a total colectomy and ileostomy.
A 72-year-old woman presented with vomiting and abdominal distention. The supine (right) and erect (left) plain abdominal radiographs show gross dilatation of the colon with multiple air-fluid levels. On further questioning, the patient revealed that she was taking diuretics for hypertension. Blood biochemical tests revealed markedly lowered potassium levels. After potassium replacement therapy, the patient's pseudo-obstruction completely resolved.
A 22-year-old man presented with abdominal pain, passage of blood and mucus per rectum, abdominal distention, fever, and disorientation. Findings from sigmoidoscopy confirmed ulcerative colitis. Abdominal radiographs obtained 2 days apart show mucosal edema and worsening of the distention in the transverse colon. The patient's clinical condition deteriorated over the next 36 hours despite steroid and antibiotic therapy, and the patient had to undergo a total colectomy and ileostomy.
A 22-year-old man presented with abdominal pain, passage of blood and mucus per rectum, abdominal distention, fever, and disorientation. Findings from sigmoidoscopy confirmed ulcerative colitis. Abdominal radiographs obtained 2 days apart show mucosal edema and worsening of the distention in the transverse colon. The patient's clinical condition deteriorated over the next 36 hours despite steroid and antibiotic therapy, and the patient had to undergo a total colectomy and ileostomy.
A 72-year-old woman presented with vomiting and abdominal distention. The supine (right) and erect (left) plain abdominal radiographs show gross dilatation of the colon with multiple air-fluid levels. On further questioning, the patient revealed that she was taking diuretics for hypertension. Blood biochemical tests revealed markedly lowered potassium levels. After potassium replacement therapy, the patient's pseudo-obstruction completely resolved.