7.1 Etiology

In contrast to mesenteric ischemia, where the cause of the disease is occlusion of major vessels, in nongangrenous ischemic bowel disease the hypo-oxygenation is caused by hypoperfusion of the gut wall microcirculation. Only occasionally is there secondary occlusion of intramural vessels. Many causes may precipitate this disorder. Hypoperfusion is most commonly caused by vascular diseases - e.g., collagen disease, vasculitis, diabetes, atherosclerosis - or by increased viscosity of the blood in sickle cell disease or polycythemia vera. Acute hypotension due to hemorrhage, myocardial infarct, congestive heart failure, sepsis or vasoconstricting drugs may precipitate local ischemia in patients who already have impaired local circulation. Because of an adequate collateral circulation, localization is usually segmental. The necrosis of the gut wall is rarely transmural, and as a result, peritonitis is a rare complication. In the small bowel nongangrenous ischemic bowel disease manifests as "focal segmental ischemia" and in the colon as "nongangrenous ischemic colitis." A list of the more common causes of nonocclusive ischemic bowel disease is provided in Table 1.

TABLE 1.  Causes of nonocclusive ischemic bowel disease

A. Acute diminution of intramural blood flow

1. Small vessel disease
Cholesterol embolus
Diabetes
Rheumatoid arthritis
Amyloidosis
Chronic radiation injury
Systemic vasculitis
Collagen diseases
Allergic granulomatosis
Behçet's syndrome

2. Nonocclusive hypoperfusion
Hypercoagulable states and increased viscosity
-Oral contraceptives
-Polycythemia vera
-Sickle cell disease
-Acute leukemia
-Antithrombin C disease
Shock
-Hemorrhage
-Hypovolemia
-Cardiopulmonary bypass
-Abdominal aortic reconstruction
-Sepsis
-Pancreatitis
-Anaphylaxis
-Cardiogenic shock
-Multiple organ dysfunction syndrome
Congestive heart failure
Portal hypertension
Medications
-Digitalis
-Diuretics
-Catecholamines
-Estrogens
-Nonsteroidal anti-inflammatory agents
-Neuroleptic agents
-Verapamil overdose
-Cocaine abuse
Long-distance running

B. Increased demand on marginal blood flow

1. Increased motility
Mass lesions
-Carcinoma
-Diverticular disease
Obstruction

2. Increased intraluminal pressure
Obstruction
Fecal impaction
Colonoscopy
Barium enema

C. Idiopathic (spontaneous)

Ischemia to short segments of the small bowel results in a variable clinical course that depends on the severity of the infarct. For short segment involvement there is usually appropriate collateral circulation, and thus the disease involves only the mucosa and submucosal tissues. Limited necrosis may heal completely. Ongoing repeated injury may cause chronic enteritis, almost indistinguishable from Crohn's disease. In some patients the necrotic ulcer may lead to late stricture formation. Occasionally the process may become transmural, resulting in peritonitis. Diagnosis is difficult, as the symptoms may be those of chronic recurrent abdominal pain, bowel obstruction or frank peritonitis. Unless there is complete spontaneous resolution, the treatment of strictures and persistent ulcers is usually surgical. The diagnosis is often made only on histology of the resected small bowel.

7.3.1 PATHOGENESIS

There are two major forms of colonic ischemia: gangrenous (transmural) and nongangrenous colitis (disease contained within the colonic wall). These are in fact two different diseases, with different etiologies and clinical courses, and require different approaches to their management. Gangrenous ischemic colitis is caused by obstruction of the major mesenteric vessels and is discussed in Section 4 (see Figure 1). Occasionally, transmural gangrene may develop when nongangrenous ischemic colitis slowly progresses to transmural necrosis. The recognition and management of this complication of the originally nongangrenous disease is crucial, and as discussed below, depends on careful ongoing observation of the patient with nongangrenous ischemic colitis.

In contrast to the rarity of nonocclusive ischemia of the small bowel is the relative frequency of local vascular hypoperfusion of the colon. The cause of this relative frequency may be related to the following factors: In comparison to the small intestine, the colon receives less blood, has fewer vascular collaterals, has susceptible "watershed areas" and possesses an ongoing forceful motor activity. Elevated intramural pressure during increased motility in patients with constipation, diverticular disease and cancer of the colon may lead to diminished gut wall blood flow. Similarly, distention with air during colonoscopy or barium enema may temporarily reduce blood flow to the colon. The large bowel also has a different neuroendocrine control. Evidence in our laboratory has indicated that the vessels of the canine colon respond more vigorously to hypotension than those of the small intestine and that contrary to the latter, in the colon the major local vasoconstrictory substance is angiotensin.

The classic clinical presentation is characterized by a sudden onset of severe crampy abdominal pain, diarrhea mixed with bright red blood, and occasionally melena. Physical examination may reveal a distended abdomen. Bowel sounds are present and there are no signs of peritoneal involvement. The patient is usually elderly and may show signs of one of the associated diseases such as hypotension, congestive heart failure and atherosclerosis. Under specific conditions, nongangrenous ischemic colitis can also occur in the young. This is often due to iatrogenic or patient-induced causes such as contraceptive medication, nonsteroidal anti-inflammatory agents, cocaine abuse, verapamil overdose, etc. (for details see Table 1). In the elderly, the specific event that precipitated the attack occasionally cannot be determined. The early clinical presentation may be so similar to that of infectious colitis, ulcerative colitis, Crohn's colitis and pseudomembranous colitis that the diagnosis can be established only by exclusion of infection, including Clostridium difficile, and by demonstrating the classic radiographic (Figure 5 and Figure 6) and/or colonoscopic (Figure 7) findings of ischemic colitis. Because large vessels are never involved, angiography has no place in the diagnosis of nongangrenous ischemic colitis.

Radiographic and colonoscopic investigations have to be carried out within 24-48 hours of the onset of the disease, as the typical findings tend to disappear and are rapidly replaced by nonspecific signs. The first radiologic examination should be an abdominal survey film (Figure 5), which may demonstrate the classic intramural hemorrhage-induced thumb-printing in an air-filled segment of the colon. This finding, however, may not always be diagnostic, because occasionally it can be mimicked by mucosal and submucosal edema caused by severe inflammatory processes. Colonic involvement is usually segmental in ischemic colitis. Although any part of the colon may be affected, the "watershed" areas of the splenic flexure and of the recto-sigmoid junction are most commonly involved. Thumb-printing can be demonstrated by barium enema (Figure 6), but differentiation between edema and submucosal hemorrhage can be done only by colonoscopy, where hemorrhage can be recognized as large dark red submucosal blebs (Figure 7). Because distention of the colon with air may compress intramural blood vessels and thus further decrease blood flow, barium enema and colonoscopy must be carried out carefully with minimal air insufflation. After 24-48 hours, the hemorrhage resolves and the mucosa becomes necrotic. If colonoscopy is done at this stage, the endoscopist may be unable to differentiate the necrosis and ulcerations resulting from ischemic colitis from those caused by Crohn's disease or pseudomembranous enterocolitis. The pathologist reviewing biopsies taken a few days after the onset of the disease may have similar difficulties. Not infrequently, only time will tell whether the patient has inflammatory bowel disease (IBD) or ischemia. It is not impossible that some elderly patients with what is thought to be late-onset IBD or young women on contraceptive medication who are thought to have Crohn's are actually suffering from ischemic colitis.

The disease can progress in four different ways (Figure 1). Mild disease may resolve spontaneously. In patients with involvement of only small segments, the symptoms and physical findings subside within 24-48 hours and complete resolution can occur within two to three weeks. In some, the disease does not resolve and may progress to ongoing or recurrent chronic colitis. As the pathological response of colonic tissue to chronic injury is restricted to a very few modalities, such as infiltration with leukocytes, crypt abscess, hemorrhage, necrosis, ulceration and regeneration of crypts, the pathologist may also have difficulty in differentiating ongoing ischemic colitis from Crohn's disease. Hemosiderin, a sign of previous bleeding, is often considered a typical manifestation of ischemic colitis (Figure 8). Unfortunately, this finding is not restricted to ischemic colonic disease, as it can be found in any type of colitis, including IBD, if hemorrhage has occurred sometime in the past.

Once ischemic colitis has become chronic, it may resolve, relapse or progress to deeper intramural inflammation and necrosis. In severe disease the patient may exhibit toxic symptoms with chills, fever, severe bloody diarrhea and abdominal distention with diminished bowel sounds. The patient may develop leukocytosis, anemia, elevated platelet count and electrolyte disturbances. If the necrosis does not progress further, the process will heal first with granulation tissue, which is replaced by fibrous tissue, scarring and finally a stricture. In some instances the disease progresses to toxic megacolon, and if the intramural necrosis becomes transmural, acute peritonitis will ensue. This progression may take only a few hours or several days to develop, and as the patient must be surgically treated well before peritonitis develops, this process must be detected early by careful, sometimes hourly, follow-up of the patient.

Infectious enteropathies, IBD and other precipitating causes such as diverticulitis, cancer, etc. have to be detected and appropriately treated. Therapy for ischemic colitis can be considered under the following three categories: (1) nonspecific supportive therapy, (2) specific medical treatment and (3) surgical therapy.

Nonspecific supportive therapy. Fluid and electrolyte balance must be carefully maintained. Oral intake should be restricted according to the severity of disease. Well-nourished patients can be maintained for a few days without specific nutritional support, except for what they receive in intravenous solutions. Severely undernourished patients may require enteral nutrition, or if this is poorly tolerated, total parenteral nutrition (TPN). Bleeding is rarely severe enough to require blood transfusion, but if anemia is present it may have to be corrected even in elderly patients with poor cardiovascular reserve. This requires careful balancing, so that an already precariously maintained circulation is not overloaded. Usually, the patient will request medication to relieve diarrhea and abdominal pain. However, the use of analgesics, antispasmodic or antidiarrheal agents is contraindicated, because they may lead to an inert bowel, which may result in a toxic megacolon.

As the patient improves, a low-residue diet may be slowly started. If this is not well tolerated, enteric feeding may be required. However, in some patients the diarrhea and abdominal pain may become worse on enteric nutrition. This may be overcome with the use of an iso-osmotic product, dilution of the solution and constant slow administration over 24 hours.

Patients have to be carefully followed to detect deterioration, as they may progress to toxic megacolon or perforation. In patients who show signs of deterioration, the use of antibiotics may be justified. If there is further progression and the patient develops increasing peritoneal signs, surgery becomes imperative, even in an elderly patient who appears to be a poor surgical risk.

Specific medical treatment. There is no need for specific therapy for mild self-limiting disease. For chronic ongoing disease there is no proven specific therapy and no experimental data exist to assess the usefulness of any of the drugs utilized in IBD. Because of the relatively low incidence of ischemic colitis, up to now it has not been possible to design a valid prospective double-blind study to assess the efficacy of these drugs. However, patients with long-standing progressive disease have been treated with variable results using 5-aminosalicylic acid (5-ASA) by oral and/or (depending on the location of the disease) rectal administration. For patients who do not respond to 5-ASA, a trial with oral or local steroids may be attempted. There is no experience with metronidazole or immunosuppressive agents. In contrast to acute mesenteric arterial occlusion, there is no evidence in nongangrenous ischemic colitis that vasodilators (papaverine, ACE inhibitors, nitrites, etc.) are useful. By the time the patient is seen the intramural ischemic injury has already occurred and vasodilators cannot reverse the pathological changes. Treatment of heart disease, change of digitalis to other medication, discontinuation of estrogens, management of diabetes, recognition and treatment of vasculitis, polycythemia, etc., may not necessarily alter the outcome of already established chronic disease, but may prevent future recurrences.

Surgical therapy. Indications for immediate surgery are toxic megacolon and transmural necrosis leading to peritoneal signs. Usually within six months after onset of the disease a considerable number of patients with severe ischemic colitis will develop strictures. They present with symptoms of partial obstruction. One should attempt colonoscopic dilation, but if this fails stricturoplasty or surgical resection may be necessary.