44 Colon ischemia

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44 Colon ischemia

SETH E. PERSKYAND LAWRENCE J. BRANDT

Introduction

Colon ischemia (CI) is the most common form of gastrointestinal ischemia, accounting for more than 50% of all cases of such ischemic injuries [1].

Although colonic gangrene has been recognized for more than 100 years it was not until the 1950s and

1960s that milder forms of CI were described [2].

Today we recognize six patterns of CI: reversible colopathy, transient colitis, chronic ulcerating colitis, gangrene, stricture, and fulminant universal colitis.

While CI most often is idiopathic, some episodes can be linked to proven etiologies. CI commonly is misdiagnosed as inflammatory bowel disease (IBD);

however, clinicians must be able to differentiate these two causes of colitis, as their management and prognosis differ markedly. This chapter will discuss current knowledge of the etiologies, pathogenesis, presentations, and management of CI.

Incidence/etiology

Although CI is the most common form of gastrointestinal ischemia it remains largely under- diagnosed. Stated to be the cause of 1 in 2000 hospitalizations [3], its exact incidence remains u n k n o w n , since a large n u m b e r of cases go undetected; they are either subclinical in nature, mild and resolve spontaneously before patients present to a physician, or are misdiagnosed as infectious colitis or IBD [4]. While the incidence of IBD classically has been described as having a bimodal age distribution, most cases in the second peak actually are cases of CI rather than of new onset IBD [4, 5]. In one series [4], after reviewing the clinical, radiographic and patho- logic findings of patients who developed new-onset colitis after age 50, 75% of these cases were classified as definite CI, whereas only 15% of these cases were classified as definite ulcerative or Crohn's colitis. In the remaining 10% of cases a definitive diagnosis could not be established. Therefore, when encounter-

ing a patient over the age of 50 with new-onset colitis, CI is the most likely cause, and new-onset IBD should be considered only after carefully excluding CI.

CI aff'ects both sexes equally, and unlike IBD, which predominantly affects young patients, 90%) of sporadic cases of CI occur in patients over age 60.

Affected patients often have atherosclerotic vascular disease, although there is no close correlation between the severity of such changes and the occur- rence of CI. There are several recent small case series [6-8] that report a lesser proportion of cases in the elderly, with up to 34% of cases of CI occurring in patients below the age of 50 [7]. It is this subset of patients who are often misdiagnosed with IBD.

Unlike IBD, however, the vast majority of patients with CI improve spontaneously, i.e. with no or conservative therapy, whereas patients with IBD usually improve only after receiving definitive therapy with aminosalicylates or corticosteroids.

The proven etiologies of CI in the older population diff'er markedly from those in younger patients (Table 1). Most commonly, however, no etiology is found and it is believed that CI develops as a result of spontaneous episodes of local 'nonocclusive' ischemia, in association with small vessel atherosclerotic disease. Angiograms in affected patients rarely correlate with clinical disease, and only show age-related changes such as narrowing and tortousity of the inferior mesenteric artery and its branches [56]. Less commonly, systemic alterations in blood flow, such as hypoperfusion from underlying cardio- vascular disease, sepsis, hypovolemia, or inferior mesenteric artery (IMA) thrombosis, lead to CI.

Constipation and straining during bowel movements also have a deleterious, albeit transient, effect on colonic blood flow, and therefore may render the colon susceptible to ischemic injury.

There are two special clinical problems which have a significant association with CI. First, up to 10%) of patients undergoing elective abdominal aortic sur-

Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 799-810.

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Table 1. Characteristics of colon Ischemia in young vs. older subjects*

Younger patients Elderly patients

Identifiable causes

Idiopathic etiology associations

Course

Location

Differential diagnosis

(Approximately 40% of patients) Coagulopathies

Vasculitis Infections

Long-distance running

Medications: Oral contraceptives, pseudoephedrine, danazol, sumatriptan, psychotropic agents, cocaine, alosetron

Approximately 60% of cases

May be recurrent. Progression to chronic CI (i.e. chronic ulcerating colitis, stricture) unstudied Right side

Rectum IBD; infection

(Approximately 10% of patients) Aortic surgery

Cardiac failure/dysrhythmias Arterial embolus/thrombosis Shock

Medications: digoxin, psychotropic agents, flutamide, hormone replacement therapy

Approximately 90% of cases Distal obstructing lesions ( ~ 5%):

carcinoma, volvulus, constipation, fecal impaction; colonic stricture; diverticulitis Single episode. Progression to chronic CI (i.e.

chronic ulcerating colitis, stricture) uncommon Splenic flexure

Sigmoid colon

Infection; carcinoma; IBD less likely

*The presentation and clinical course is usually identical in both younger and older patients; this table merely emphasizes differences that may occasionally be seen.

gery develop CI. This is related to hypotension, intraoperative trauma to the colon, IMA loss during aneurysmectomy, or prolonged cross-clamp time. In the setting of emergent aortic surgery for repair of a ruptured abdominal aortic aneurysm, CI develops in up to 60% of cases. By assessing colonic perfusion intraoperatively with laser Doppler flowmetry [57, 58] and photoplethysmography [59], several investi- gators have been able to predict the development of postoperative CI. The intramural pH of the sigmoid colon before and after cross-clamping the aorta, as determined by tonometry, has also been used to predict postoperative CI [60]. Routine intraoperative reimplantation of the IMA to prevent postoperative CI has been advocated by one group [61], but is not routinely performed.

The second clinical problem associated with an increased risk of CI is colon obstruction. Approxi- mately 20% of older patients with CI have a distal and potentially obstructing lesion, such as carcinoma, stricture, fecal impaction, diverticulitis, or volvulus. CI probably develops from distension of the colon proximal to the obstructing lesion, which leads to increased intraluminal pressure and

decreased mucosal blood flow. Less commonly such lesions are within a segment of ischemic colon and, rarely, distal to it.

The causes of CI in younger persons are markedly different from those in elderly patients. Often these causes may not be immediately apparent to the clinician, and making a diagnosis of CI instead of new-onset IBD may be especially challenging. A well-described but rare cause of CI in young patients is mesenteric vasculitis. Such vasculidites include polyarteritis nodosa [31, 32], Takayasu's arteritis, or Buerger's disease [30], as well as systemic auto- immune disease, such as systemic lupus erythematosus (SLE) [27, 28] or Sjogren's syndrome [62].

Hypercoagulable states, such as protein S or C deficiency, antithrombin III deficiency, or activated protein C resistance (APCR, factor 5 Leiden) may also lead to CI in young patients. The anticoagulant actions of the protein C system are important in maintaining microvasculature patency [63]. Hetero- zygosity for APCR is present in approximately 5% of the general population, with affected individuals having an eight-fold risk of venous thrombotic disease [25]. For the rare individual with the homo-

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Seth E. Per sky and Lawrence J. Brandt 801 Table 2. Causes of colon ischemia

Non-latrogenic causes Iatrogenic causes

Non-occlusive ischemia Cardiac failure or dysrhythmias Shock

Obstructing colon carcinoma Volvulus

Strangulated hernia Arterial embolus

Inferior mesenteric artery thrombosis Cholesterol emboli [9,10]

Phlebosclerosis[11,12]

Pancreatitis [13,14]

Amyloid [ 1 0 , 1 5 - 1 7 ] Idiopathic dysautonomia [18]

Allergy [19, 20]

Trauma

Ruptured ectopic preganancy Long-distance running [21 ] Pit viper toxin [22]

Pheochromocytoma [23]

Kawasaki's disease [24]

Hematologic disorders Protein C and S deficiencies Sickle cell disease Antithrombin III deficiency Activated protein C resistance [25]

Prothrombin 2021OA mutations [26]

Vasculitis

Systemic lupus erythematosus [27-29]

Rheumatoid arthritis

Thromboangitis obliterans [30]

Periarteritis nodosa (hepatitis B) [31-32]

Takaysu's arteritis Infections

Escherichia co//0157:H7 [33, 34]

Angiostrongylus costaricensis Cytomegalovirus

Hepatitis B (polyarteritis nodosa) [31, 32]

Surgical

Aneurysmectomy Aortoiliac reconstruction Gynecologic operations Exchange transfusion Colonic bypass Lumbar aortography Colectomy with IMA ligation

Colonoscopy and barium enema [35, 36]

Medications Digitalis

Estrogens [25, 37, 38]

Danazol [39]

Progestins [40]

Gold compounds Psychotropic drugs [41 ] Pseudoephedrine [42]

Sumatriptan [43]

Cocaine [44]

Immunosuppressive agents [45]

NSAID [46]

Imipramine [47]

Methamphetamines [48, 49]

Vasopressin [50]

Ergot [51]

Oral hyperosmotic saline laxatives [52]

Interferon Alpha [53]

Glycerin enema [54]

Flutamide [55]

Alosetron

zygous defect for APCR tlie risk of tlirombosis increases 50-100-fold. Recently, a young woman with APCR was reported to develop ischemic colitis [25]; she was also taking oral contraceptives, another risk factor for ischemic colitis. Lastly, another hypercoagulable state is linked to genetic mutations in the prothrombin 20210 A allele, and bowel ischemia has recently been described in patients with this mutation [26]. In that report one of the two cases had CI.

There are a host of medications which may cause CI (see Table 2). Use of these medications may lead to ischemic injury via mesenteric vasoconstriction or thrombosis. The most commonly implicated medica-

tions have been oral contraceptive agents; in one study [37], 59% of younger individuals with reversible CI used these preparations. As mentioned above, patients with underlying hypercoagulable states who use oral contraceptive agents may be at a particularly increased risk for CI. Several other medications have recently been described in case reports to cause CI, including: sumatriptan [43], interferon-alpha [53], pseudoephedrine [42], non-steroidal anti-inflammatory agents [46], vasopressin [50], Danazol [39], imipramine [47], psychotropic agents [41], and digitalis. Several illicit drugs may also lead to CI, including cocaine [44] and methamphetamine [48, 49].

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Anatomy of colonic vasculature and pathogenesis of colon ischemia

Blood is supplied to the colon by the superior mesenteric artery (SM A), and the inferior mesenteric artery (IMA), which respectively carry blood to the proximal and distal parts of the colon. The SMA gives off the middle colic artery and then branches into: (a) the right colic artery, which supplies the distal ascending colon, hepatic flexure, and proximal half of the transverse colon; and (b) the ileocolic artery, which supplies the terminal ileum, cecum, and proximal ascending colon. The IMA, which is smaller than the SMA, branches into: (a) the left colic artery, which supplies the distal half of the transverse colon and the descending colon; (b) multiple sigmoid arteries, which supply the sigmoid colon; and (c) the superior rectal artery, which supplies the rectum.

The distal rectum is also supplied by the middle and inferior rectal arteries, which are branches of the internal iliac artery. Additionally, there are extensive collateral arteries between the SMA and the IMA, limiting the propensity of the colon to ischemic injury. These collateral vessels include: (a) the mar- ginal artery of Drummond, which is close to and parallels the wall of the intestine; (b) the central anastomotic artery, which is larger and more cen- trally placed; and (c) the arc of Riolan at the base of the mesentery. If either the SMA or IMA is occluded, a large collateral vessel, termed the 'meandering artery', may develop, representing a dilated central anastomotic artery or arc of Riolan. Resting blood flow to the colon is relatively low (8-44 ml/min per 100 g tissue) in comparison to other parts of the gastrointestinal tract [64], and colonic blood flow is even more diminished during functional motor activ- ity of the colon, e.g. bowel movements, making the colon uniquely susceptible to ischemia.

There are certain areas of the colon where collateral flow between the SMA and the IMA is crucial to maintain colonic integrity; these are the areas especially prone to ischemic injury. The most important of these 'watershed' areas is the splenic flexure, or Griffith's point, which has the highest propensity for CI, especially in individuals in whom the mar- ginal artery of Drummond is diminutive or absent.

The rectosigmoid junction, or the point of Sudeck, is another so-called watershed region. This region is dependent on anastomotic branches of the IMA and

the internal iliac artery, and CI may develop if these anastomotic branches are limited.

CI results from local hypoperfusion, with or without reperfusion injury. During hypoperfusion the involved colonic segment is deprived of important nutrients and oxygen; during extensive periods of hypoperfusion tissue hypoxia leads directly to cell death, with damage progressing outward from the mucosa to the serosa [65]. It has been shown that high levels of renin and angiotensin, which are elevated during periods of systemic hypotension, may exacerbate splanchnic vasospasm, leading to further colonic hypoperfusion and ischemia [66].

During relatively short periods of hypoperfusion, however, most of ischemic damage results from subsequent reperfusion injury. In one study [67], the injury observed after 3 h of hypoperfusion and 1 h of reperfusion was more severe than that observed after 4 h of isolated hypoperfusion. There are extensive data showing that, during reperfusion, there is mucosal neutrophil accumulation, with release of reactive oxygen metabolites by activated neutrophils as part of the inflammatory process [64]. In an equine model of CI [68], one group of horses was subjected to 6 h of hypoperfusion, and another group to 3 h of hypoperfusion followed by 3 h of reperfusion. Con- centrations of neutrophils within the mucosa were significantly higher during reperfusion as compared with the corresponding times in the group subjected to prolonged hypoperfusion. The reactive oxygen metabolites released from activated neutrophils are derived from molecular oxygen, and mediate both mucosal damage and disruption of microvascular integrity. Reactive oxygen metabolites cause perox- idation of lipids, thereby disrupting cell membranes and destroying cell compartmentation, resulting in cell lysis. Reactive oxygen metabolites also alter nucleotide function, and damage cellular proteins and enzymes. These effects ultimately lead to impaired cellular function or necrosis.

Several reactive oxygen metabolites are released during reperfusion injury (Table 3). First, the univalent reduction of oxygen produces the superoxide anion radical, O2. The cellular toxicity associated with superoxide is usually attributed to its role as a precursor to more reactive oxygen species, such as hydrogen peroxide (H2O2) and the hydroxyl radical (OH), which is formed via the Haber-Weiss reaction (O2 + H2O2). The Haber-Weiss reaction is acceler- ated by the presence of transition metals, such as iron, which are present in high concentrations in intestinal mucosa. Hypochlorous acid (HOCl) is

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Seth E. Persky and Lawrence J. Brandt

Table 3. Xanthine oxidase pathway for induction of Ischemia

In Non-Ischemic Tissue:

803

Hypoxanthine + R^O + N A D

During Tissue Ischemia:

Hypoxanthine + HjO + 2O2

XDH

1+ *-

xo

Xanthine + 2O2 + H2O xo

Xanthine + NADH + H+

Xanthine +

Uric Acid + Reactive Oxygen Metabolite Production:

Univalent reduction of oxygen *• O2

H2O2

divalent reduction or dismutation

O.

Haber-Weiss Reaction

0 / + HP,

H2O2 (Hydrogen Peroxide Radical) - -OH (HydroxylRadical)

another potent oxidizing agent formed from the reaction of H2O2 with CI" and H"^ when activated neutrophils secrete the enzyme myeloperoxidase (MPO). In animal models of reperfusion injury, treatment with antioxidants, such as superoxide dismutase (SOD), catalase, and dimethyl sulfoxide (DMSO), as well as with iron chelators, such as desferoxamine, has been shown to attenuate reperfusion injury by suppressing the formation of these reactive oxygen metabolites [8, 69, 70]; such agents have not been tested clinically in CI.

In addition to their direct cytotoxic effects, reactive oxygen metabolites also initiate the production and release of leukocyte chemoattractants, such as leukotriene B4 and platelet-activating factor (PAF), which increase polymorphonuclear leukocyte migra- tion, leading to further oxidant production [71, 72].

Activated neutrophils also release a variety of

enzymes, such as collagenase and elastase, that can directly injure mucosa and the microvasculature.

Reactive oxygen metabolites are also formed by the oxidant-producing enzyme, xanthine oxidase (XO). In ischemic tissue XO has the ability to generate O^ and H2O2 during the oxidation of xanthine and hypoxanthine. Normally, i.e. in non- ischemic tissue, XO does not produce reactive oxygen metabolites, as it uses NAD"^ instead of O2 as an electron-acceptor. During tissue ischemia, however, due to a proteolytic conversion in the enzyme, XO uses O2 as an electron-acceptor, generating reactive oxygen metabolites. The XO inhibitor, allopurinol, has been shown to attenuate both the epithelial cell necrosis and the increased microvascular permeability observed after reperfusion of the rat small intestine [73], but this agent has not been tested in the clinical setting.

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Clinical presentation

The clinical presentation of CI varies with the underlying cause, extent of vascular obstruction, and presence or absence of comorbity. The spectrum of CI is wide (Table 4), and includes reversible colopathy, transient colitis, chronic ulcerating colitis, gangrene, stricture, and fulminant universal colitis.

Most patients with CI present with the acute onset of mild, crampy, left lower quadrant pain, followed by the urge to defecate. These symptoms are followed over the next 24 h by the passage of bright red or maroon blood mixed with diarrheal stool. In one study of 47 patients, 87% had abdominal pain, 68%

had diarrhea, and 38% had nausea and vomiting [74].

Gastrointestinal blood loss is not of hemodynamic significance. If there is hemodynamic instability, or if significant blood loss requiring transfusion occurs, other diagnoses should be considered. Approxi- mately 10% have only subclincal disease and present later with constipation or obstruction secondary to stricture formation. The elderly may also present with altered levels of consciousness. Prior to the onset of symptoms the vast majority of patients with CI feel well. CI, however, may also develop shortly after a major cardiac event, such as a myocardial infarction or new-onset atrial fibrillation, or during hemodialysis-associated hypotension; these patients have higher mortality than do patients without these precipitating factors. In several reports [7, 75], approximately 30% of CI cases occurred immediately following such episodes of systemic hypotension. Unfortunately, even with classic presentations, the diagnosis is often overlooked. In one series [7], CI

Table 4. Types and approximate incidences of colon ischemia

Type Incidence (%)

Reversible colonopathy Transient colitis Chronic ulcerating colitis Stricture

Gangrene

Fulminant universal colitis

3 0 - 4 0 1 5 - 2 0 20-25 10-15 15-20

<5

was initially considered only in 17% of patients ultimately diagnosed with CI.

Physical examination usually reveals mild to moderate tenderness over the involved segment of bowel. Low-grade fever is present in a minority of patients. In more severe cases patients may also have abdominal distension from an ileus. Approximately 15-20% of patients present with peritoneal signs from colonic perforation. The vast majority of patients, however, look well at presentation. Labora- tory analysis may show a mild leukocytosis, which may parallel the extent of injury. The hematocrit is usually at the patient's baseline since blood loss is minimal, and hemoconcentration from fluid losses is not severe.

Any segment of the colon may be aff'ected by ischemia' however, the 'watershed' areas of the sigmoid colon and splenic flexure are most commonly involved (Fig. 1). In the largest series to date, ischemia isolated to the right colon was seen in 8% of patients, ischemia isolated to the rectum in 6%, and segmental ischemia proximal to the splenic flexure was seen in 12%.

Figure 1. Ischemia of the colon: patterns of involvement in 250 cases.

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Seth E. Per sky and Lawrence J. Brandt 805 Specific etiologies tend to involve specific areas of

the colon. Systemic low flow states usually produce CI of the ascending colon as a result of vasoconstriction within the distribution of the SMA. Sponta- neous non-occlusive ischemic injury usually involves the watershed areas of the left colon. Colon ischemia after abdominal aortic surgery typically involves the descending colon, due to operative IMA injury.

Ischemia isolated to the rectum accounts for only 3 - 6% of all cases of CI [1, 76], and is seen in patients with aorto-iliac atherosclerotic disease; in up to half of these cases ischemia is preceded by a super- imposed hemodynamic event, leading to systemic hypotension. In this situation severe atherosclerotic disease combined with hypotension compromises the collateral blood supply to the rectum. The length of aff'ected bowel also varies with the cause of ischemia. Atheromatous emboli involve short segments, whereas non-occlusive injuries involve longer portions of colon.

The diagnosis of CI depends on prompt clinical suspicion, followed by appropriate laboratory, roentgenographic, and colonoscopic studies. Using these studies other causes of colitis (e.g. infections, IBD), can be excluded, as can other diagnoses that are often considered, such as diverticulitis and colon carcinoma. A thorough stool analysis for potential causes of infectious colitis should be performed.

Stool should be cultured for common pathogens, such as Salmonella, Shigella, and Campylobacter, as well as for E. coli 0157:H7. In one study [34], immunohistologic staining for E. coli 0157:H7 was performed in a retrospective manner on archived colonic biopsy specimens from 24 patients with various colitides. Biopsies from 27.3% of patients initially diagnosed with CI were found to stain positively for E. coli 0157:H7 antigens, thereby impHcating an infectious etiology for some cases of CI previously considered to be idiopathic in origin. If there is concomitant hemolysis or renal failure, thereby increasing the clinical suspicion for this infection, immunohistochemical staining may be performed on biopsy specimens if stool cultures for E. coli 0157:H7 were not obtained at the time of the presentation.

Radiologic evaluation is performed commonly in the initial assessment of patients with CI. Whereas these examinations provide information regarding location and severity of disease, they are neither sufficiently sensitive nor specific in most situations to diagnose CI definitively. Plain films of the abdo- men are important initially, and findings suggestive

of CI may be identified in 30% of patients [77];

colonic thumbprinting, which represents submucosal hemorrhage and edema, may be seen; an ileus or colonic pseudo-obstruction may be present, and toxic megacolon has been described [78]. In severe cases pneumatosis coli, intraperitoneal air, or both, may be seen. In addition to the above findings, computerized tomography scanning may reveal segmental colonic thickening with narrowing of the colonic lumen, and may demonstrate mild to moderate amounts of free intraperitoneal fluid; portal venous gas may also be seen in advanced cases.

Rarely, patients with CI may have intrahepatic abscess formation [79]. Unfortunately, none of these findings is specific for CI. Recently, scintigraphic imaging with technectium-99m was reported to localize a segment of CI [80]. Nuclear imaging with indium-111 has also been described in the literature 6[81, 82]. These tests, however, are expensive, lack specificity, and are not routinely used to diagnose CI.

If CI is suspected, and the patient has no signs of peritonitis, colonoscopy or the combination of sigmoidoscopy and a gentle barium enema should be performed within 48 h of the onset of symptoms.

Evaluation should be performed early, because submucosal hemorrhages are resorbed and mucosal abnormalities may improve quickly. Barium enema was the first method used to diagnose CI, and has a reported sensitivity of 60-80% [83, 84]. Thumbprint- ing, segmental longitudinal ulcers, and mucosal abnormalities are delineated well by barium enema.

Barium enema is also a useful technique for the evaluation of strictures, which may develop after an acute episode of CI. Colonoscopy, however, provides a better assessment of mucosal abnormalities than does barium enema [84], is the procedure of choice in the acute and chronic setting, and is safe if performed carefully [84]. Colonoscopic evaluation may demonstrate submucosal hemorrhagic nodules, which are the equivalent of radiologic thumbprinting. Such nodules are blue or red; however, black nodules may also be seen, and indicate colonic gangrene. Colonic ulcerations exhibit a spectrum ranging from small aphthae to large, wide, parallel longitudinal ulcers, known as 'bearclaw' ulcers. In the mildest form of CI, i.e. reversible colopathy, submucosal hemorrhages are resorbed quickly, and mucosal ulceration is not seen on colonoscopy. In cases of transient colitis the mucosa covering submucosal hemorrhages breaks down, blood is exuded into the lumen, and erythema, edema, ulceration, and mucosal friability are seen on colonoscopy. Mural spasm and

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luminal narrowing may also be present. Occasion- ally, pseudomembranes are observed, mimicking Clostridium difficile colitis. If the inflammatory response to ischemia is vigorous there may be a heaping-up of the mucosa and submucosa, which may mimic a stricturing or polypoid neoplasm.

Morphologic changes after an ischemic insult vary with the duration and severity of the injury. Repeat colonoscopy or barium enema 1 week after the initial study should reflect evolution of the injury, either by demonstrating normalization of the colonic mucosa or replacement of submucosal hemorrhagic nodules with a transient segmental ulcerative colitis. Over time, in cases of more severe injury, granulation tissue replaces the mucosa and submucosa. Persis- tence of submucosal nodules on follow-up examination should suggest another diagnosis, such as carcinoma, lymphoma, IBD, or amyloidosis. Although colonoscopy can only survey the mucosal aspect of the colon, future studies with endoscopic ultrasound may help assist with diagnosis, and perhaps help predict prognosis by evaluating the entire thickness of the colonic wall [85].

Colonoscopy also aflbrds the clinician an oppor- tunity to biopsy affected as well as normal-appearing mucosa. In the early stages of CI the biopsies are usually non-specific. As in other forms of acute colitis, cryptitis, crypt abscesses, and an acute inflammatory infiltrate may be present, and usually do not help in differential diagnosis. Additionally there may be fibrin thrombi in submucosal capil- laries, submucosal hemorrhage, vascular conges- tion, loss of normal crypt architecture, an absence of surface epithelial cells, and mucin depletion.

Although the use of biopsies in the diagnosis of CI is limited because of the superficial and often non- specific nature of the small specimens, findings that are diagnostic of CI on histologic analysis are mucosal gangrene and the presence of ghost cells.

Biopsy is also important to exclude other entities, such as IBD. In the presence of pseudomembranes, histologic evidence of hyalinization of the lamina propria, presence of atrophic-appearing micro- crypts, full-thickness mucosal necrosis, and lamina propria hemorrhage are more suggestive of CI than of C. difficile colitis [86].

During colonoscopy or barium enema, it is important to avoid overdistension of the colon, because colonic blood flow is diminished at intraluminal pressures greater than 30 mmHg. Additionally, at this pressure, blood is shunted from the mucosa to the serosa, exacerbating ischemic injury. In a dog

model [87] a 22-72% decrease in colonic blood flow persisted even after release of distension. Insufflation of carbon dioxide rather than room air during colonoscopy may reduce this potential complication of overdistension, as carbon dioxide increases colonic blood flow during colonic distension, and it is rapidly absorbed from the intestine, thus decreas- ing post-procedure colonic distension [88]. Another key to limiting complications during colonoscopy in patients with CI is to limit intubation to only the aff'ected region, and not continue proximal to affected bowel because of the risk of perforation. If clinically indicated, the segment of the colon proximal to the ischemic segment should be surveyed only after the acute episode of ischemia has resolved.

Angiography is rarely of any benefit in the evaluation of CI, because colonic blood flow has usually returned to normal by the time patients become symptomatic and, as mentioned earlier, anatomic abnormalities in the mesenteric circulation rarely explain the cause for CI. Therefore, angiography should not be used routinely in the evaluation of patients with CI. If, however, the clinical presentation is more consistent with acute mesenteric ischemia (e.g. the patient has severe abdominal pain), angiography plays an important role in the diff'eren- tial diagnosis. In a minority of patients with isolated right-sided colon ischemia, angiography may play a role in documenting and treating SM A disease, since such patients may be at risk for concomitant or subsequent small bowel ischemia. If the clinical presentation is confusing, and it is unclear whether the patient has CI or acute mesenteric ischemia, an alternative approach to differentiate the two is by administering an 'air' enema. Air can be instilled by a hand bulb or during sigmoidoscopy, and is followed by fluoroscopy. Submucosal hemorrhage and edema are seen as relative radiodensities against the column of air. If thumbprinting is isolated to the right colon, angiography is warranted to confirm SMA disease;

defects confined to the left colon do not warrant angiographic evaluation.

Therapy and prognosis

Once the diagnosis of CI is confirmed, initial management is largely supportive (Fig. 2). Any drug potentially implicated in the ischemic episode should be discontinued, and the patient's cardiac status should be optimized. Marked colonic distension, if present, should be treated with rectal tube decom-

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Seth E. Per sky and Lawrence J. Brandt 807

Resection of Involved Bowel

Diagnosis By Colonoscopy

IV Fluids, Anilbiotics NPO for 48-^72 hrs Maximize Cardiac Output

Avoid Vasopressors Continued Diarrhea Bleeding >24wks

Stable or Improving

Consider Repeat BE or Colonoscopy After 1 -2 weeks

Segmental Colitis Normal Symptomatic

Recurrent Fever or Sepsis

Figure 2. Algorithm for management of colon Ischemia.

Asymptomatic Observe

pression. Vasopressors should be avoided. The patient should be placed on bowel rest, and given intravenous fluids. Broad-spectrum antibiotics should be administered to cover anaerobic bowel flora, as several animal studies have demonstrated that the concentration of luminal anaerobic bacteria increases after ischemic injury to the bowel [89-91], largely due to their proliferation in an ischemia- induced hypoxic e n v i r o n m e n t . Additionally, ischemic injury disrupts the mucosal barrier, allow- ing for bacterial translocation and portal bacteremia. Metronidazole has been shown to prolong survival in rats subjected to mesenteric ischemia [91], and its use is recommended in patients with CI.

In only two patients short-chain fatty acid enemas have been reported to speed healing in CI [92]. A large-scale, randomized trial is needed to validate the eflicacy of this therapy. Infusions of splanchnic vasodilators, such as papaverine or prostaglandin El, have been shown to increase colonic blood flow in experimental models of CI [93], but are not used

clinically in the management of CI, since blood flow has returned to normal by the onset of symptoms, and vasodilators do not improve outcome.

Unfortunately it is impossible to predict the outcome of an ischemic insult from the initial clinical, radiologic, and colonoscopic findings. Patients who initially look well may deteriorate quickly, despite the results of initial studies. With conservative or even no medical therapy, however, patients with reversible colopathy or transient ischemic colitis will have a complete clinical and endoscopic recovery. Fortu- nately these patients encompass approximately 60- 70% of all cases of CI. Symptoms improve over 3-4 days, and complete endoscopic regression of colitis ensues over 4-6 weeks. Only 5% of patients with complete healing will have a subsequent recurrence of CI. Complete endoscopic regression of colitis may take up to 6 months, but during this time patients are often asymptomatic. These patients may require repeat colonoscopic examination to document healing or development of a stricture or chronic colitis.

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Continued symptoms or protein-losing colopathy for more than 2-3 weeks is worrisome and is best treated by resection of the involved segment of colon. The extent of the resection should be guided by the distribution of disease as revealed by preoperative studies, rather than by the appearance of the serosal surface of the colon at the time of operation, because if the injury is not transmural, mucosal injury may be extensive despite a normal-appearing serosa.

Approximately 15% of patients with CI will develop full-thickness colonic gangrene during their initial presentation. These patients require resection of the involved colonic segment. Several alarm symptoms and signs that warrant prompt surgical intervention include severe pain or bleeding, persistent or increasing fevers, presence of rebound, involuntary guarding, or distension on abdominal examination. After segmental resection, symptoms improve and prognosis is excellent if perforation did not occur. If perforation is present at the time of surgery the patient's overall prognosis depends on his or her underlying age and comorbid status, as well as the timing of surgery and the ability to control concomitant sepsis.

One recent study identified two factors which may be predictive of a more severe colitis; an increased need for surgical resection and a higher mortality rate [94]. These factors were: chronic renal failure requiring hemodialysis, and ischemia involving the right colon. In that study up to 82% of hemodialysis patients with CI developed isolated right-sided ischemia [94], likely attributed to repeated episodes of systemic hypotension in the hemodialysis sessions.

As mentioned earlier, isolated right colonic involvement may indicate compromised SMA blood flow, warranting early angiography and surgical explora- tion due to the increased risk of more severe disease.

Approximately 20% of patients with CI will develop a chronic ulcerating ischemic colitis, manifest by continued symptoms of abdominal pain, diarrhea, fevers, or hematochezia. They may also have a protein-losing colopathy with resultant hypoalbuminemia. Differentiation from Crohn's colitis may be difficult on follow-up barium enema or colonoscopy; in both of these entities chronic ulceration, erythema, friable mucosa, edema and blunted vasculature may be seen. Mucosal nodular- ity may also be present in both conditions, and p s e u d o p o l y p o s i s h a s b e e n d e s c r i b e d as a consequence of chronic ulcerating colitis [95]. How- ever, patients with a non-healing segment of chronic ulcerating ischemic colitis do not respond to

corticosteroid therapy or other traditional therapies for IBD. Additionally, repeat biopsies from areas of chronic ulcerating ischemic colitis may show gland- ular dropout with associated ghost cells, as well as an increased deposition of mucosal and submucosal fibrous tissue. These biopsy findings are quite different from those seen in IBD, in which branching of glands and granulomata are commonly seen.

Patients with symptomatic chronic ulcerating ischemic colitis may benefit from a segmental resection; after resection, recurrence is rare.

Lastly, approximately 10% of patients develop a stricture after an acute episode of colon ischemia.

Strictures develop as a consequence of damage to the muscularis propria and its replacement with fibrous tissue. These patients may not present during the acute episode of ischemia, but develop constipation or colonic obstruction weeks to months later.

Patients with ischemic strictures can be observed if asymptomatic, since some strictures will regress in 12-24 months with no specific therapy. Symptoms from strictures, such as worsening constipation, usually do not respond to laxative therapy. While gentle use of bulk laxatives may dilate strictures, they may be hazardous if used in a zealous fashion.

Endoscopic dilation may be attempted if the stricture is short, although there are no data on the efficacy of this approach. Most symptomatic strictures should be surgically resected.

Summary

CI is the most common cause of mesenteric ischemia, and encompasses a wide clinical spectrum from mild, reversible disease to life-threatening colonic gangrene. While most commonly seen in elderly patients, younger patients are also at risk, especially if an underlying risk factor such as vasculitis, hyper- coagulability, or certain medication use such as oral contraceptives, pseudoephedrine, cocaine, or ergot, is present. Colonoscopic evaluation is critical in the evaluation of patients with CI, although it must be kept in mind that CI may mimic or be mimicked by other entities, such as IBD or carcinoma. Conserva- tive management usually leads to a full clinical recovery, although several subsets of patients may require segmental resection. Clinicians should always consider CI in the differential diagnosis of acute colitis, especially in elderly patients.

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Seth E. Persky and Lawrence J. Brandt 809

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