Tohoku J. Exp. Med., 2009, 218, 83-92 Ischemic 83 Review : Surging Waves of Update

Michael Stamatakos,1 Emmanuel Douzinas,2 Charikleia Stefanaki,1 Constantina Petropoulou,1 Helen Arampatzi,3 Constantinos Safioleas,1 George Giannopoulos,1 Constantinos Chatziconstantinou,4 Constantinos Xiromeritis5 and Michael Safioleas1

1Fourth Department of Surgery, Medical School, University of Athens, ATTIKON General Hospital, Athens, Greece 2Third Department of Critical Care, Medical School, Athens University, Eugenidion Hospital, Athens, Greece 3First Department of Obstetrics and Gynecology, Athens University Medical School, Alexandra Hospital, Athens, Greece 4Department of Radiology, General Hospital ‘St. Panteleimon’, Nikaia, Greece 5First Department of Surgery, University of Athens Medical School, Laikon Hospital, Athens, Greece

Ischemic colitis is the most common type of intestinal , and it represents the consequences of acute or, more commonly, chronic blockage of blood flow through arteries that supply the . Ischemic colitis is manifested through a continuum of injury and considered as an illness of the elderly. The incidence of ischemic colitis has been underestimated, because many mild cases may go unreported. Patients experience abdominal pain, usually, localized to the left side of the abdomen, along with tenderness and bloody . Severe ischemia may lead to bowel necrosis and perforation, which results in an acute abdomen and shock, frequently, being accompanied by lactic acidosis. Although computed tomography may have indicative findings, colonoscopy is the golden standard of diagnosis. Supportive care with intravenous fluids, optimization of hemodynamic status, avoidance of vasoconstrictive drugs, bowel rest, and empiric antibiotics will produce clinical improvement within 1 to 2 days in most patients. The condition resolves completely with conservative treatment, in most cases, but late diagnosis or severe ischemia can be associated with high rates of complications and death. However, when the interruption to the blood supply is more severe or more prolonged, the affected portion of the large intestine may have to be surgically removed. The present paper aims at bringing ischemic colitis up to date, by reviewing the current medical literature and extracting the contemporary data, about its presentation, diagnosis and treatment, which is of benefit to the readership, who may encounter this potentially fatal entity. ──── ischemic colitis; intestinal tract; atherosclerosis; colonic ischemia; colon. Tohoku J. Exp. Med., 2009, 218 (2), 83-92. © 2009 Tohoku University Medical Press

Ischemic colitis or more appropriately, increasing attention. Marston et al. (1966) classified this of the colon, has been known for up to 100 years. Early disease into 3 forms: transient, strictures, and gangrene. It concern equated this condition to colonic second- is defined as a “reversible condition caused by obstruction ary to accidental arterial ligation during surgical procedures. of blood flow in intestinal tract mucosa without apparent Shaw and Green (1953) reported an episode of infarction blockage of the main artery” (Marston et al. 1966). In gen- after inferior mesenteric artery ligation. Although it was eral, ischemic colitis is more common, in the elderly and its known that an occasional patient manifested a relatively prevalence increases with age, but it is also seen in younger benign process after such arterial ligation, it was not until patients (Brandt and Boley 2000). Its causes include vascu- 1963, when Boley et al. (1963) reported 5 patients with a lar factors, such as ischemia and embolus, intestinal factors disease labeled “reversible vascular occlusion of the colon” such as , and history thus providing emphasis upon the milder component of this of intestinal surgery (Pescatori et al. 2009), as well as problem. Marston et al. (1966) reported on 16 patients, who administration of drugs, such as antibiotics, appetite sup- manifested three stages of a spontaneous disease, which pressants (phentermine), chemotherapeutic agents (vinca they labeled ischemic colitis. Since that time, ischemic alkaloids and taxanes), constipation inducing medications, colitis or alternatively, colonic ischemia has drawn ever decongestants (pseudoephedrine), cardiac glucosides, Received March 5, 2009; revision accepted for publication April 2, 2009. Correspondence: Michael Stamatakos MD. Phd. Fourth Department of Surgery, Medical School, University of Athens, ATTIKON General Hospital, 153 Aigyptou, ANO GLYFADA, 16562, Athens, Greece. e-mail: [email protected]

83 84 M. Stamatakos et al. diuretics, ergot alkaloids, hormonal therapies, statins, illicit protected from ischemia to a great extent by an abundant drugs, immunosuppressive agents, laxatives, non-steroidal collateral blood supply; namely, the colon is nourished by anti-inflammatory drugs, psychotropic medications, sero- the superior mesenteric artery (SMA), the inferior mesen- tonin agonists/antagonists and vasopressors. Iatrogenic teric artery (IMA), and the branches of the internal iliac causes may result in ischemic colitis (Brandt and Boley arteries. The SMA gives rise to the middle colic, right colic, 1992; Champagne et al. 2007; Steele 2007). While surgery and ileocolic arteries, which supply the right colon and the is indicated for the gangrenous form of this disease, tran- right half of the transverse colon. The IMA branches into sient and structuring forms are often ameliorated by bowel the left colic, sigmoid, and superior rectal (hemorrhoidal) rest, fasting, and/or parenteral fluid administration. The arteries, which supply the left half of the transverse colon to duration of fasting and fluid administration varies among proximal . The distal rectum is supplied by inferior individuals (Gandhi et al. 1996). Significant prolongation and middle rectal (hemorrhoidal) arteries, which are branch- of healing is sometimes observed, especially in patients es of the internal iliac artery. (Brandt and Boley 2000). with an ulcer. There is an extensive mesenteric collateral circulation that Ischemic colitis encompasses a number of clinical enti- provides substantial protection from ischemic insults. The ties, all with a final result of insufficient blood supply to a SMA and IMA communicate through the marginal artery of segment or the entire colon. This disease results in ischemic Drummond, which runs along the splenic flexure and the necrosis of a variable severity that can range from superfi- arc of Riolan. The marginal artery of Drummond is absent cial mucosal involvement to full-thickness transmural or underdeveloped in 5% of the population, placing the necrosis (Baixauli et al. 2003). Bowel ischemia is mainly a splenic flexure at particular risk of ischemia. If SMA or disease of old age, caused by atheroma of mesenteric ves- IMA is gradually occluded, the arc of Riolan or the central sels. Other causes include embolic disease, vasculitis, anastomotic artery may dilate to compensate and be termed fibromuscular hyperplasia, aortic aneurysm, blunt abdomi- the meandering artery. The IMA and the internal iliac arter- nal trauma, disseminated intravascular coagulation, irradia- ies communicate through the superior and middle/inferior tion, and hypovolemic or endotoxic shock. Occlusive mes- rectal (hemorrhoidal) arteries. The dual blood supply of the enteric infarction (embolus or thrombosis) has a 90% rectum from the mesenteric and iliac arteries makes it resis- mortality rate, whereas nonocclusive disease has a 10% tant to ischemia. However, certain areas are more vulnera- mortality rate. Venous infarction occurs in young patients, ble in some people. The marginal artery of Drummond, usually after abdominal surgery. Patients may present with which runs along the mesentery within 1 to 8 cm of the colicky abdominal pain, which becomes continuous. It may colon, is composed by the terminal portions of the branches be associated with vomiting, diarrhea, or rectal bleeding of the major vascular arcades. This artery can keep the left (Arnott et al. 1999). The colon is the most common site of colon viable when the inferior mesenteric artery is ligated gastrointestinal ischemia. Colonic ischemia is associated during rectosigmoidectomy. However, the anatomy is vastly with many precipitating factors and may be due to single- variable. For example, the marginal artery of Drummond is vessel occlusion or global hypoperfusion. The clinical occasionally tenuous at the splenic flexure, as described by manifestations are often subtle and vary, so a high level of Griffiths, and indeed is absent at this point in up to 5% of awareness is needed. Special consideration should be given patients (Griffiths 1956). It is poorly developed in the right on this disease, in the case of patients, who have recently colon in 50% of the population, explaining the occurrence undergone cardiac or aortic surgery (Parish et al. 1991). of right-sided colitis (Sonneland et al. 1958). One or more Clinical patterns vary from transient colitis to fulminant of the three branches of the superior mesenteric artery may ischemia with gangrene. Routine biochemical tests are be absent in up to 20% of people. Branches of the inferior helpful but nonspecific. It is of note that patients with isch- mesenteric artery may similarly be absent. emic colitis almost always are presented with lactic acido- On the other hand, 60% of people have an additional sis, especially in severe cases (Al Shammeri and Duerksen vessel, called the arch of Riolan or meandering mesenteric 2008). The diagnosis is usually made by history, examina- vessel, which provides communication between the left col- tion and endoscopy. The condition resolves completely ic and superior mesenteric arteries. The splenic flexure is a with conservative treatment in most cases, but late diagnosis “watershed” area between the areas supplied by the two or severe ischemia can be associated with high rates of main arteries. Sierocinski found that a 1-2 cm to 2-8 cm complications and death. Once ischemic colitis is diag- area of the splenic flexure was devoid of vasa recta, setting nosed, serial physical examinations and colonoscopies are this area predisposed to ischemia (Sierocinski 1975). There helpful for follow-up. Prompt surgery is required for severe is also a watershed area at Sudek’s point between the sig- episodes, when conservative measures fail, and for patients moid colon and the rectum, where the lowest sigmoid with chronic symptoms (Brandt and Boley 2000). branches usually join branches of the superior rectal artery. A third potential watershed area is the right colon, where the Pathogenesis marginal vessel is poorly developed in up to 50% of people An understanding of the blood supply to the colon is (Baixauli et al. 2003). Therefore, any portion of the bowel necessary when considering ischemic colitis. The colon is may be affected, but the sites most often affected are the Ischemic Colitis 85

Table 1. Causes of mesenteric ischemia. CAUSES COMMENTS Hypoperfusion Heart failure or prolonged shock of any etiology Embolic occlusion Atherosclerosis Arterial thrombosis Venous thrombosis Vasculitis Large-vessel vasculitis: Takayasu arteritis and giant cell arteritis. Medium-vessel vasculitis: polyarteritis nodosa and Kawasaki syndrome. Small-vessel vasculitis: microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, Henoch-Schönlein syndrome, systemic lupus erythematosus, rheumatoid vasculitis and Behçet disease. Thromboangiitis obliterans Disseminated intravascular coagulation Hypercoagulable states Sickle cell disease Aortic dissection Aortoiliac surgery ischemia This can be developed if the inferior mesenteric artery (IMA) is sacrificed during an abdominal aortic surgery dissection IMA sacrifice This artery may be sacrificed during colonic resection, although most patients tolerate ligation of the IMA because the collateral circulation is adequate. Translumbar aortography Cardiac surgery Liver transplantation Particularly from an incarcerated or Colonic carcinoma Trauma Drugs Vasoconstrictors (eg, digitalis), norepinephrine, pseudoephedrine, ergot alkaloids, oral contraceptives, estrogens, various diuretics, antihypertensive medications, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, alosetron, paclitaxel, meloxicam, cocaine, and amphetamine abuse may be involved. Corrosive injury This usually affects the proximal gut, but in rare cases, it may cause penetrating injury of the transverse colon Bowel infections Necrotizing Radiation injury Large-bowel ischemia In rare cases, this may result from vascular steal syndrome. An example is occlusion of the femoral or iliac artery. The lower extremity involved is supplied by a hypertrophied IMA and hemorrhoidal arteries, with reversed flow in the internal iliac artery. Arteriovenous fistula between This is an unusual cause of mesenteric ischemia. Patients with this condition also have portal the mesenteric artery and veins hypertension. sigmoid colon, ascending colon and splenic flexure. In sys- Ischemic colitis can be described as an inflammatory temic low-flow states, the right colon is most often disease of the colon due to diminished blood flow, leading involved, while localized nonocclusive ischemia affects to bowel wall ischemia and a secondary inflammation. watershed areas, such as the splenic flexure and the sigmoi- Most of the classifications of in the liter- do-rectal junction (Guttormson and Bubrick 1989). ature are based on the major causative factors. Two mecha- Ligation or occlusion of the inferior mesenteric artery pro- nisms may cause bowel ischemia: The first and most com- duces changes of the sigmoid colon, although changes may mon is diminished bowel perfusion, due to low cardiac be more extensive, if other vessels have been previously output, often seen in patients with cardiac disease or in cas- occluded. Ischemic colitis isolated to the right colon is of- es of prolonged shock of any etiology. The second mecha- ten a manifestation of acute ischemia, which may have a nism is occlusive disease of the vascular supply to the bow- more fulminant course. Right-sided ischemic colitis el, due to atheroma, thrombosis, or embolism in which the accounts for 8% to 46% of cases (Landreneau and Fry collateral circulation is not adequate to maintain bowel 1990). The small bowel alone, the colon alone, or occasion- integrity. Regardless of the mechanism, the disease follows ally both may sustain a hypoxic injury from a variety of the same course. Depending on the cause and severity of causes. Collectively, all these gut hypoxic injuries are des- the impairment of the bowel blood supply, the morphologic ignated by the term mesenteric ischemia. pattern can be arbitrarily subdivided into 3 groups: (1) 86 M. Stamatakos et al. transmural infarction, (2) mural infarction, when the injury cases, minute intramural thrombi are found, and whether extends from the mucosa into the muscularis and (3) muco- these are the cause or effect of the ischemic injury is not sal infarction, when ischemic damage is confined to the clear. The affected bowel loops may appear dark red or mucosa (Fisher and Fry 1987). The etiology of mesenteric purple as a result of luminal hemorrhage, but serosal hemor- ischemia is summarized in Table 1 (Stamatakos et al. 2008). rhage, necrosis, or inflammatory exudates, are absent. The mucosa appears hemorrhagic, edematous, and thickened, Transmural infarction with superficial ulceration (Stamatakos et al. 2008). Histo- Transmural infarction usually occurs in the small bow- logic analysis may show vascular dilatation associated with el because it is entirely dependent on the mesenteric blood a few extravasated red cells and hemorrhagic necrosis with- supply, whereas the large bowel is near the posterior in the superficial layers of the mucosa. However, this abdominal wall, whose vesicles contribute in creating a col- necrosis may extend into submucosa and the superficial lay- lateral blood supply and venous drainage for the large bow- ers of the muscularis. In the colon, bacterial contamination el. Transmural infarction frequently involves a long seg- may produce superimposed pseudomembranous inflamma- ment of bowel, although in rare cases, skip lesions occur. tion. The combination of necrosis and bacterial invasion Transmural infarction is usually the result of thrombosis or develops when the mucosal barrier becomes defective. embolism of the superior mesenteric artery (SMA), which Thus, the morphologic changes seen in ischemic colitis may may only affect the small bowel (approximately one half of resemble those of pseudomembranous colitides or other the mesenteric ischemia). Mesenteric venous thrombosis is inflammatory and/or infective processes (Hwang and another cause; this may involve both the small bowel and Schwartz 2001). the large bowel. Colonic infarction tends to occur in 2 watershed territories; (1) the splenic flexure, which is the Epidemiology watershed territory between the SMA and IMA blood sup- No reliable demographic data describe the incidence of ply, and (2) the distal sigmoid colon, which forms the ischemic colitis, worldwide. The incidence is thought to be watershed area between the IMA and hypogastric artery underestimated, because many mild cases may remain unre- supply. Regardless of the pathogenesis, the infracted bowel ported since they are of mild and transient nature. More- always appears hemorrhagic. Early in the course of the dis- over, many cases are misdiagnosed as inflammatory bowel ease, the bowel appears intensely congested and dusky or disease or infectious colitis (Green and Tendler 2005). In purple red in color, with foci of subserosal and submucosal contrast, the incidence in patients undergoing abdominal ecchymoses. As the disease progresses, the bowel wall aortic reconstructive procedures has been studied. Hunter appears edematous, thickened, rubbery, and hemorrhagic. and Guernsey reported that as many as 10% of such patients The lumen of the bowel may contain mucus or frank blood. have some degree of ischemic colitis (Hunter and Guernsey Arterial occlusion usually results in a sharply defined border 1988). With population aging, the incidence of ischemic between the infracted bowel and the normal vascularized colitis is expected to present a further increase. Ischemic bowel, whereas in venous thrombosis, the boundary colitis is the most common type of ischemic disease affect- between infracted bowel is ill - defined with no clear demar- ing the and accounts for 50% of cases. cation between viable and nonviable bowel. Microscopy No data suggest that the worldwide incidence or prevalence reveals suffusion of the bowel wall, which tends to mask the of ischemic colitis differ between countries. Mortality and underlying ischemic necrosis. Later in the course of the morbidity depend on the cause and comorbidities such as disease, inflammatory infiltration of the bowel wall and underlying cardiac disease, vasculitides, among others. In a ulceration ensue. Bacterial contamination is often present, study, it was found that approximately 90% of cases of and bowel perforation may occur within 3-4 days. Arterial ischemic colitis occur in elderly patients, as well as younger occlusion may be difficult to demonstrate histologically, patients (Binns and Isaacson 1978). The prognosis of isch- particularly if ischemia is the result of spasm or a low perfu- emic colitis is more favorable than that of other forms of sion state superimposed on atheromatous disease. mesenteric ischemia. A transient ischemic episode resolves usually within 1-3 months without sequelae. With signifi- Mucosal and Mural infarction cant ischemic injury, long strictures may follow and cause Mucosal and mural infarction is an ischemic injury that mechanical problems such as bowel obstruction. More is confined to the inner layers of the intestinal wall. It is severe ischemic trauma may cause bowel gangrene and per- usually the result of hypoperfusion rather than occlusive foration, but this is a rare phenomenon. In a series of 150 disease. The hypoxic injury may extend deeply, but the patients with colonic ischemia, Brandt et al. (1981) reported serosa is usually spared. Shock and cardiac failure are that 44.7% had reversible disease, 18.7% had persistent major causative factors. Many patients with this condition colitis, 12.7% had ischemic stricture and 18.7% had gan- have also received vasoconstricting drugs such as digitalis grene or perforation. In 5.3%, follow-up was insufficient. or norepinephrine. This type of injury may involve any part No racial or ethnic predilection for ischemic colitis is of the gut and is usually patchy and segmental, unlike trans- reported. The male-to-female ratio in ischemic colitis is mural infarction, which involves long segments. In some approximately 1 : 1. It is already established by the afore- Ischemic Colitis 87 mentioned that ischemic colitis is a disease of the elderly. It can be present without leukocytosis (Versteeg and Broders is rarely seen in those younger than 60 years. According to 1979; Kaleya and Boley 1995). If acute ischemia leads to Brandt and Boley (2000) and to Fisher and Fry (1987), the infarction, then fever, neutrophilia, and a metabolic acidosis average patient age at diagnosis is 70 years. Younger may be present. Severe ischemia may lead to elevated lev- patients can develop ischemic colitis. Most published els of lactate, inorganic phosphate, and alkaline phospha- descriptions have been case reports or small case series. tase. Unfortunately, these are all unreliable indicators for Etiologic factors have included sickle cell disease, other diagnosis and are poor predictors of the presence of isch- vasculopathies or coagulopathies, disease induced by drugs emic colitis (Kurland et al. 1992). Although ischemic coli- (eg, cocaine, oral contraceptives), or long-distance running tis can be classified as a separate entity on the basis of its (Brandt et al. 1981; Fisher and Fry 1987). clinical, radiologic and anatomic features, it is often con- fused with other colonic disorders. In the acute stage of Presentation and clinical features ischemic colitis, differential diagnosis includes other types Once blood flow drops below a critical threshold, isch- of inflammatory bowel disease (eg, Crohn’s disease, ulcer- emia occurs, with consequences dependent on the individu- ative colitis), colonic injury induced by nonsteroidal anti- al’s ability to respond by increasing flow. Ischemia is, then, inflammatory drugs, pseudomembranous colitis, and various manifested as a spectrum of findings varying from transient kinds of infectious colitides. Endoscopic biopsy may be intramural and submucosal hemorrhage and edema to gan- instrumental in differentiating ischemic colitis from idio- grene. Ischemic colitis may present in two major clinical pathic and infectious colitides. Moreover, patterns: gangrenous (15%-20% of cases) and nongangre- the sharp demarcation between viable and necrotic colonic nous (80%-85%). In the nongangrenous form, lesions may mucosa seen in endoscopy is a strong indicator of ischemia. develop that are transient and reversible, or that progress to In the chronic stage, the stricture of ischemic colitis must be chronic and irreversible strictures (10%-15%) or chronic distinguished from that of diverticular disease, carcinoma of segmental colitis (20%-25%) (Gandhi et al. 1996). The pat- the colon, and inflammatory bowel disease. Particular cau- tern of clinical presentation depends on the cause (Table 2), tion should be exercised when the rectum is included in the the extent of vascular obstruction, the speed of ischemic ischemic insult. Differentiating ischemic from ulcerative insult, the degree of collateralization, and comorbidity con- colitis can be extremely difficult. Moreover, ischemic and ditions. In most cases, there is no identifiable initiating fac- idiopathic ulcerative colitis may coexist (Brandt and Boley tor, though a recent history of cardiac or vascular surgery, 1992). Differentials include adrenal adenoma, adrenocorti- major systemic illness, or myocardial event may be present cal carcinoma, adrenal hemorrhage and adrenal metastases (Parish et al. 1991; Longo et al. 1992; Arnott et al. 1999; (Korobkin 2000). Fitzgerald et al. 2000). Up to 20% of patients may have associated colonic pathology, such as cancer. Mild to mod- Diagnosis erate abdominal pain is present in about 60% of cases, is The diagnosis of ischemic colitis depends on early and generally abrupt in onset, and is usually described as repeated evaluation of the patient in conjunction with bio- cramps. Patients often have an urgent desire to defecate. chemical, radiological, and endoscopic assessment. The The pain may be associated with diarrhea, frequently fol- radiologic findings in ischemic colitis are nonspecific and lowed within 12 to 24 hours by mild bleeding. The blood may be seen in other inflammatory disorders of the colon. may be bright red or maroon and is mixed with the stool. A reliable diagnosis of ischemic colitis can be made only The bleeding is not copious-profuse bleeding should sug- when radiologic findings are correlated with the patient’s gest another diagnosis. Clinical examination may reveal clinical image (Gourley and Gering 2005). When sudden mild to moderate tenderness over the ischemic segment. If thromboembolism occurs, patients experience abdominal peritoneal signs develop, they are manifested late in the pain localized at the left side of the abdomen, along with course of the condition and are often very subtle. The white tenderness and bloody diarrhea. Severe ischemia may lead cell count is generally raised, but significant ischemic injury to bowel necrosis and perforation resulting in an acute

Table 2. Etiologic factors. Idiopathic — Colonic obstruction — Shock — Medications Digitalis, diuretics, NSAF, catecholamines, estrogens, danazol, gold, neuroleptics Major vascular occlusion Mesenteric ischemia, trauma Small vessel disease Diabetes mellitus, vasculitis, rheumatic disease, radiation injury Hematologic disorders Deficiencies, sickle-cell disease Cocaine abuse Long distance running 88 M. Stamatakos et al. abdomen and shock. The patient’s signs and symptoms diagnosis of intestinal ischemia. CT is often used, as the generally resolve within several days. In some cases, a initial diagnostic test, when assessing patients with nonspe- bowel stricture may be developed and cause bowel obstruc- cific abdominal pain. It suggests the diagnosis and location tion. Rarely, chronic ischemic colitis may occur, causing or exclude other serious medical conditions and therefore rectal pain and incontinence. Plain abdominal radiography narrow the differential diagnosis possibilities and illustrate is usually an initial examination undertaken in most cases the complications. Intrinsic colonic abnormalities cannot be involving acute abdominal problems. However, it is a use- used to diagnose or predict the development of infarction ful examination for excluding colon infarction (Scholz (Balthazar et al. 1999). In non-transmural ischemic colitis, 1993). Plain radiographic imaging reveals dilatation of a the initial bowel-wall thickening, thumbprinting and perico- part of the colon, in early stages of the disease. When both lonic stranding, with or without peritoneal fluid, can be seen the small bowel and the large bowel are affected by isch- on CT images. In these cases, CT usually demonstrates the emic injury, the small bowel may become dilated with double halo or target sign. After reperfusion of the ischemic thickening of the valvulae conniventes. Over time, the bowel wall, the sign may be produced by edema in the sub- haustra become thickened and edematous, and it contains a mucosa and appear as low attenuation or by hemorrhage and large amount of secretions. With further edema, the haus- appear as high attenuation. If there is total vascular occlu- tral markings disappear completely, and the colon acquires sion without reperfusion (infarction), the colonic wall a hoselike appearance. Localized pneumatosis coli may be remains thin and unenhancing, associated with dilatation of apparent. Eventual tubular narrowing and stricturing the lumen. In these cases, CT may demonstrate a thrombus appears over a long segment. Even if the initial radiograph- in the corresponding mesenteric vessel. If ischemia is trans- ic findings may be normal in colonic ischemia, it is an mural, strictures may form. Occasionally, a toxic invaluable procedure in the differential diagnosis of an develops. Pneumatosis and/or gas in the mesenteric veins acute abdomen (Scholz 1993). Barium enema results are are ominous signs, when associated with bowel wall thicken- abnormal in 90% of patients with ischemic colitis. Barium ing and are due to bowel infarction. Pneumatosis coli or enema examination during the acute stage of a vascular pneumatosis intestinalis can be diagnosed by demonstrating insult demonstrates spasm associated with thickening and air bubbles in the colonic or intestinal wall. The gas bubbles blunting of the mucosal folds. Multiple mucosal scalloping are arranged in a linear trend and are best visualized with the or thumbprinting are seen along the contours of the bowel. window settings for bone or lung (Jones et al. 1982; Seen en face, the thumbprints appear as polypoid filling Balthazar et al. 1999; Barkhausen et al. 1999; Horton et al. defects. With further progression of mucosal edema, the 2000; Horton and Fishman 2001; Wiesner and Willi 2001; folds become thickened and ill-defined. Intraluminal secre- Thoeni and Cello 2006). MRI is mostly useful for magnetic tions are increased. Ulcerations are frequently observed in resonance angiography, particularly in individuals with pathologic specimens of the diseased bowel segment. With compromised renal function. Moreover, it has been shown diffuse ulceration, the mucosa may be completely effaced. that the sensitivity of MRI in the detection of bowel isch- Ulcers may be seen as a serrated mucosa. Deep ulcers are a emia is comparable to that of CT and it has the added late finding. advantage of not using ionizing radiation. It may be useful In the healing phase when fibrosis sets in, associated in depicting bowel-wall changes and in demonstrating mes- flattening and rigidity of the intestinal wall may be enteric vascular abnormalities. As with CT, the additional observed. The antimesenteric border of the colon becomes use of contrast enhancement allows an assessment of the pleated because of scarring, and they may appear as saccu- dynamic changes in the bowel wall (Ha et al. 1998). MRI lations or pseudodiverticula. With a continuing fibrotic pro- has significant problems in depicting small thromboembo- cess, the affected segment of the large bowel acquires a lism in small mesenteric vessels (Li et al. 1994). tubular shape with smooth contours and a concentric lumen. Ultrasonography is a noninvasive technique that may The final outcome is usually a long stricture with proximal provide useful information, particularly in investigating bowel dilatation. Nonetheless, when a stricture develops, it chronic mesenteric ischemia. It is unlikely, though, to be is shorter than the original length of the ischemic segment, definite in excluding a diagnose of mesenteric ischemia. It as seen radiologically. The stricture formation in ischemic is undebatable, though, that absence of blood flow in the colonic disease is smooth and tapering, with a concentric ischemic colon on Doppler sonography is a better predictor lumen and without shouldering or contour defects. Saccu- of an unfavorable outcome than early clinical and laboratory lations are common in ischemic colitis, but skip lesions are findings (Danse et al. 2000). Bowel gas frequently prevents rare. Barium enema should be avoided in cases where there the visualization of changes in colon, which are usually par- is a suspicion of gangrene or perforation. Barium enema, ticularly marked around the splenic flexure. In the initial also, makes the later use of angiography or endoscopy more stages, the ischemic bowel may show increased peristalsis, difficult because of residual contrast agent Iida( et al. 1986; which is at that time reduced. The bowel wall becomes Yao et al. 2000). CT is the single best diagnostic modality thickened, and nodular and intramural hemorrhage and ede- after the plain radiography, because it can exclude many ma give rise to areas of reduced echogenicity. Gas may also other causes of abdominal pain and can also establish the be detected in the portal vein; this is a poor prognostic sign. Ischemic Colitis 89

Color flow Doppler sonography is effective in demonstrat- et al. 1988), tonometry (Schiedler et al. 1987) and sampling ing flow disturbances associated with tortuosity and stenosis of inferior mesenteric blood (Delaney et al. 1999). None of at the origin of the celiac axis. The potential for collateral- these, however, is established in clinical practice at this ization between the celiac axis, SMA, and IMA is remark- time. Serum D-lactate, a bacterial product that translocates able. As a result, the peak systolic in the celiac axis may be across the ischemic intestinal wall, appears to be signifi- lower or much higher than expected when concomitant cantly elevated in patients with acute mesenteric ischemia SMA occlusion is present. This variation may result in the (Murray et al. 1994) and has been used to help prediction of overestimation or underestimation of the extent of ischemic ischemic colitis after repair of a ruptured abdominal aortic disease. Images may demonstrate absent or barely visible aneurysm (Poeze et al. 1998). Intestinal fatty acid-binding color flow, absent arterial signals, and thickened bowel-wall protein has also been shown to be elevated in patients with loops. Doppler techniques are particularly useful for inves- mesenteric infarction (Fried et al. 1991). Alpha-glutathione tigating chronic mesenteric ischemia. Limitations of S-transferase (alpha-GST) belongs to a family of enzymes Doppler analysis of celiac artery and SMA ischemia include involved in the detoxification of a range of toxic and foreign that (1) the great potential for collateralization in the compounds within the cell. It has been reported as a marker splanchnic vessels may make an assessment of a single- of ischemia (Calman et al. 1958), an isolated rise in alpha- vessel stenosis difficult, (2) the risk of error increases when GST indicated segmental ischemia, while massive elevation the angle of insonation is greater than 60° and (3) careful with coincident elevation of transaminase levels suggested a placement of the sample volume is crucial (Teefey et al. global, hypoperfusional, nonocclusive type of ischemia. 1996; Dirkx and Gerscovich 1998). More recently, scintigraphic methods have been used in the Angiography has a limited role in cases of colonic diagnosis of ischemic colitis. In-111 or Tc-99m labeled leu- ischemia, but it may be invaluable in a few specific indica- kocyte scintigraphy has been studied and demonstrated suc- tions, such as arteriovenous fistulas and vascular steal syn- cessful imaging of bowel infarction, yet the localization drome. It usually has no role in the evaluation and manage- mechanism still remains unclear. It is suggested that the ment of ischemic colitis, because at the time of symptom presence of polymorphonuclear leukocytes in the inflamma- onset, colon blood flow has returned to normal. Damage tory response to tissue ischemia, as a result of reperfusion from hypoperfusion is often at the arteriolar level, whereas injury may play the primary role (Stathaki et al. 2008). Tc- mesenteric vessels and arcades are patent. There are two 99m (V) DMSA is a low-molecular weight complex that exceptions where angiography may have some utility: when has been used successfully in the scintigraphic diagnosis of acute mesenteric ischemia is considered and cannot be inflammation (Lee et al. 1998). But, in conclusion, data clearly distinguished from ischemic colitis by clinical pre- suggest that Tc-99m (V) DMSA has no possible role in the sentation, or when there is isolated involvement of the right detection and diagnosis of ischemic colitis (Stathaki et al. side of the colon, suggesting superior mesenteric artery 2008). occlusion (Kaufman et al. 1977; Clark and Gallant 1984; Boos 1992; Cikrit et al. 1996; Yao et al. 2000; Kirkpatrick Treatment et al. 2003). Most cases of ischemic colitis do not underline any Colonoscopy, although invasive, is the most sensitive identifiable cause. However, a high index of suspicion is diagnostic test for ischemic colitis. Significant mucosal required in patients with abdominal pain, diarrhea, rectal changes can be seen, and biopsies can be taken when neces- bleeding, and abdominal tenderness who have a possible sary, especially when investigating chronic patterns of precipitating cause. Serial physical examinations and colonic ischemia. Extreme care is needed during colonos- repeated endoscopy may be required for the diagnosis and copy, particularly in patients with acute colonic ischemia. ongoing management (Church 1995). If the physical exam- Frank necrosis is manifested by black bowel wall, and this ination does not suggest gangrene or perforation, the patient is an indication to stop the colonoscopy procedure and pro- is treated expectantly. Very mild cases can be managed on ceed with laparotomy. Hemorrhagic nodules suggest less an outpatient basis with liquid diet, close observation, and severe ischemia and are seen early in the course, as they are antibiotics. For inpatients, a combination of intravenous rather transient. Nonspecific findings include superficial fluids and bowel rest is recommended to reduce intestinal ulceration, mucosal friability, edema, erythema and luminal oxygen requirements. Parenteral nutrition should be con- narrowing (Habu et al. 1996). As changes in the color of sidered for patients who do not respond immediately and the mucosa may reflect the severity of ischemia, viability of those who are poor candidates for surgery (Brandt and the colon, and prognosis, Church (1995) has proposed a Boley 2000) as they may need prolonged bowel rest. management algorithm based on findings at colonoscopy. Broad-spectrum antibiotics have been recommended by Bowel ischemia has always been difficult to be accu- many authors, as there is experimental evidence that this rately evaluated during surgery (Horgan and Gorey 1992); reduces the length and severity of bowel damage (Brandt hence, new intraoperative tests and ways of using currently and Boley 1992). It is critically important to maximize available diagnostic modalities are under investigation. intestinal perfusion. Therefore, digitalis and other vaso- These include intraoperative photoplethysmography (Ouriel pressors are withdrawn or minimized, if possible, and cardi- 90 M. Stamatakos et al. ac output is maximized by adequate fluid resuscitation may have to be permanent. In one series, 75% of patients (Binns and Isaacson 1978; Kim and Gewertz 1987). who underwent resection and stoma formation for segmen- Steroids have no role in the treatment of acute ischemia, tal involvement of the colon were able to have their stomas and they only serve in masking the development of perito- closed, versus only a third of patients with total colonic neal signs and delay a possible necessary laparotomy. involvement (Longo et al. 1997). As a group, patients who Likewise, oral cathartics and bowel preparations should not require surgery are more critically ill, and the associated be given because of the risk of precipitating colonic perfo- mortality rate is 30% to 60% (Binns and Issacson 1978; ration or toxic dilation of the colon (Gandhi et al. 1996). Brandt and Boley 1992). As far as total parenteral nutrition Persistent unexplained or pyrexia increases concern is concerned, if a patient who would otherwise require sur- about infarction of the bowel. Assuming there is no full- gery has a concurrent or recent myocardial infarction or thickness ischemia on the initial endoscopy, repeated endos- major medical contraindications to surgery, a trial of long- copy should be regularly performed until the ischemic term parenteral nutrition and intravenous antibiotics may be changes improve or until there is a change in the clinical considered as an alternative, but less-than ideal, form of condition, which mandates other investigations or laparoto- treatment. my. The clinical course of chronic ischemic colitis is About 20% of patients with acute ischemic colitis reversible in about half of the cases. In about two thirds of require surgery. Indications include ongoing sepsis refrac- patients with a reversible injury, the symptoms resolve in 24 tory to medical management, signs of peritoneal irritation, to 48 hours, and endoscopic and radiographic investigations diarrhea and bleeding lasting more than 10 to 14 days, evi- confirm healing within 2 weeks. In severe but reversible dence of on imaging, endoscopic evi- injury (eg, in segmental ulcerative colitis), the colon may dence of full-thickness ischemia, or protein-losing enteropa- take 1 to 6 months to heal (Brandt and Boley 1992). In the thy that goes on longer than 2 weeks (Boley 1990). Without other third of cases, however, the damage is too severe to surgery, the risk of perforation is high. At laparotomy, the heal, leading to chronic segmental colitis or strictures. In diagnosis is confirmed and the involved segment of the such cases, the patient may have persistent diarrhea, rectal colon is resected. It is crucial to check for the viability of bleeding, protein-losing , or repeated episodes the mucosal margins of the resected specimen, as the serosal of sepsis, which may lead to perforation. Gangrene occurs surface of the bowel may look surprisingly well-perfu- in about 15% of patients and requires laparotomy within sed. Some authors have reported the use of intraoperative hours. Others (20%-25%) develop chronic segmental ulcer- techniques to exclude colonic ischemia, such as Doppler ating colitis, while about 10% subsequently develop stric- ultrasonography, intraoperative colonoscopy with laser tures. Fulminant pancolitis due to ischemia is rare, occur- Doppler, intraoperative photoplethysmography, oxygen ring in only 1%. Total colonic ischemia without rectal electrodes, pulse oximetry of transcolonic oxygen satura- involvement occurs in up to 18%, and this requires surgery tion, and intravenous fluorescein for determination of viabil- in all cases; the mortality rate is 75%, even with surgery ity (Maupin et al. 1989; Bergman et al. 1992). Many of (Longo et al. 1997). Endoscopy may suggest segmental these studies were evaluated at the time of aortic surgery in colitis. Biopsy specimens of bullae show submucosal hem- an effort to predict the development of ischemia (Schiedler orrhage and edema, while intervening areas reveal nonspe- et al. 1987; Ouriel et al. 1988; Horgan and Gorey 1992; cific inflammation. Venous congestion, mucus depletion Delaney et al. 1999). Generally, surgery involves colecto- and injury of the crypt’s architecture and surface epithelial my with end-colostomy or ileostomy, leaving the distal cells are also common. However, the diagnosis is not bowel, as a Hartmann stump or a mucous fistula, if poor always easy and chronic ischemic colitis can easily be mis- perfusion of the distal bowel end precludes oversewing. taken for inflammatory bowel disease. Intestinal ischemia-reperfusion leads to circulatory shock of Compounding the difficulty, pseudopolyposis may be the area, involved. Although, intravascular volume deple- present in patients with ischemic colitis. Patients may also tion is considered to be the main mechanism for the circula- develop ischemic strictures, which are classically smoother tory derangement, the pathophysiology of this type of shock than neoplastic strictures; however, differentiation is not and of the distant organ dysfunction is still not completely always easy and resection may be required, both for treat- comprehended. Douzinas et al. (2003) have reported that ment of symptoms and to obtain a definitive histopathologic reducing arterial oxygen content during reperfusion follow- diagnosis. Mildly symptomatic chronic disease frequently ing splanchnic ischemia may provide a possible strategy to responds to supportive management. In contrast to acute control the development of oxidative injury induced by ischemia, chronic ischemia may respond to topical steroid ischemia-reperfusion. Hypoxemic reperfusion represents an preparations. Resectional surgery is generally reserved for intervention that, when applied after ischemia and early patients for whom conservative supportive therapy fails and reperfusion, may attenuate the triggering of a multifactorial for those with recurrent episodes of colitis or with symp- cascade leading to the production of various reactive prod- tomatic strictures. 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