REVIEWS

Mesenteric Ischemia – a Complex Disease Requiring an Interdisciplinary Approach. A Review of the Current Literature ANCA FLORIAN¹, RUXANDRA JURCUT¹,², IOANA LUPESCU²,³, M. GRASU²,³, M. CROITORU¹, CARMEN GINGHINĂ¹,² ¹Cardiology Department, “Prof. Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases ²“Carol Davila” University of Medicine and Pharmacy ³Radiology and Imaging Department, “Fundeni” Clinical Institute

Mesenteric ischemia is caused by a reduction in intestinal blood flow with potential catastrophic clinical consequences: sepsis, bowel infarction, and death. In the recent years, the incidence of mesenteric ischemia increased, now accounting for 0.1% of hospital admissions. Among the multiple factors responsible for this change is the heightened awareness for the diagnoses, the advanced mean age of the population and the increasing number of critically ill patients. Acute mesenteric ischemia is a potentially fatal vascular emergency, with overall mortality of 60–80%; prompt diagnosis and treatment are paramount. A high index of suspicion in the setting of a compatible history and physical examination serves as the cornerstone to early diagnosis of mesenteric ischemia. Restoration of intestinal blood flow, as rapidly as possible, is the main goal of treatment in patients with acute mesenteric ischemia. This may be achieved by medical means, endovascular procedures and by surgery. Chronic mesenteric ischemia is an uncommon process that occurs only when severe atherosclerotic narrowing of a major splanchnic vessel exists in association with occlusion of one or two of the remaining vessels. Its diagnosis is mainly based on the characteristic clinical picture, on the presence of an occlusive lesion in the splanchnic vessels and on the absence of other common causes of abdominal pain. The means available for mesenteric revascularization are the surgical techniques of flow restoration and the more recently developed percutaneous transluminal procedures. Key words: atherosclerosis, mesenteric ischemia, mesenteric thrombosis.

I. GENERAL CONSIDERATIONS

60% and continues to be a challenging diagnostic problem [1].

1.1. INTRODUCTION 1.2. ANATOMY OF THE INTESTINAL CIRCULATION

Mesenteric ischemia is caused by a reduction in intestinal blood flow with impaired tissue oxygenation and nutrient supply [1]. The clinical consequences can be catastrophic, including sepsis, bowel infarction, and death, making rapid diagnosis and treatment imperative [2]. In recent years, the incidence of mesenteric ischemia increased, now accounting for 0.1% of hospital admissions. Among the multiple factors responsible for this change is increased awareness for the diagnosis, advancing mean age of the population and the increasing number of critically ill patients. Despite advances in knowledge of pathophysiology, laboratory diagnosis and imaging techniques, acute intestinal ischemia is still associated with mortality rates of more than ROM. J. INTERN. MED., 2010, 48, 3, 207–222

Generally, the involved segment of ischemic intestine has a linear correspondence to the location and extent of vascular occlusion. Knowledge of the vascular anatomy is therefore crucial for the understanding of the pathophysiology, clinical presentation, and therapy of intestinal ischemia [1] (Fig. 1). The splanchnic circulation is characterized by a vast network of collateral blood vessels, linking the 3 major vessels together and with the extramesenteric circulation. The major collateral connections are: the junction of the superior and inferior pancreaticoduodenal arteries (linking the celiac axis and the superior mesenteric artery,

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SMA), the marginal artery of Drummond and the Riolan’s arch, between the middle colic and the left colic arteries (linking the superior mesenteric artery with the inferior mesenteric

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artery, IMA) and the collateralization between the inferior mesenteric artery and systemic circulation which occurs in the rectum (superior and middle rectal vessels) [3].

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Fig. 1. – Mesenteric arterial circulation. A. The superior mesenteric artery. B. The inferior mesenteric artery. Trajectory and branches. (Modified from [1]).

1.3. MESENTERIC PATHOPHYSIOLOGY

The key element of the mesenteric circulation physiology is the large capacity of the arteriolar bed to change its resistance in response to different stimuli (arterial hypotension, postprandial state) with wide fluctuations in splanchnic blood flow, which can range from 10 to 35% of cardiac output [6]. The numerous control mechanisms responsible for this variation can be classified as part of the intrinsic autoregulation, in response to acute reductions in perfusion pressure, and of the extrinsic control with neural and hormonal mechanisms [2]. These include the sympathetic nervous system, the renin-angiotensin axis and vasopressin, the later being used in portal hypertension variceal bleeding due to its vasoconstriction and venorelaxation effects [4]. Both the high adaptability of the vascular bed and the rich mesenteric collateral circulation have a protective effect against transitory ischemic injury. The mesenteric circulation is able to compensate an acute reduction of blood flow as high as 75% for

up to 12 hours. In return, a more prolonged reduction in the splanchnic blood flow generates vasoconstriction in the afferent bed, reducing also the collateral supply. The ischemic injury mechanism, consequence of the imbalance between oxygen and nutrient delivery and cellular metabolism requirements, is centered on a local inflammatory response. Increased production of reactive oxidants by both endothelial cells and leukocytes in postischemic tissues appears to be a key determinant of the injury to the microvasculature. Additionally, there is an imbalance between protective and proinflammatory mechanisms (reduced NO bioavailability). After flow restoration, the persistence of vasoconstriction along with ischemic tissue metabolites causes reperfusion injury [1][5]. 1.4. ACUTE MESENTERIC ISCHEMIA

Acute mesenteric ischemia syndrome comprises a group of physiopathological processes generated by the sudden onset of intestinal hypoperfusion, with severe consequences: bowel ischemia and necrosis [7].

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Intestinal ischemia is a potentially fatal vascular emergency, with overall mortality of 60–80% [6]. 1. Etiology Based on its etiology, acute mesenteric ischemia can be categorized into 4 specific types,

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with some differences regarding predisposing factors, clinical picture and prognosis: mesenteric arterial embolism (50%), mesenteric arterial thrombosis (15–25%) (Table 1), nonocclusive mesenteric ischemia (NOMI) (20–30%) and mesenteric venous thrombosis (5%) [8].

Table I Predisposing factors for acute mesenteric ischemia (modified from [1][9]) Mechanism Arterial embolism (50% cases)

Arterial thrombosis (15–25%)

Nonocclusive mesenteric ischemia (20–30%)

Etiology Atrial fibrillation/flutter Myocardial infarction ± left ventricular aneurysm Infective endocarditis Mechanical valve prostheses Cardiomyopathies Valvular disease Cardiac catheterization and angiography Atherosclerosis, presence of atherosclerotic risk factors Age Low cardiac output Congestive heart failure Procoagulative status Vasculitis (including Takayasu arteritis) Aortic/superior mesenteric artery aneurysm/dissection (spontaneous or iatrogenic) Fibromuscular dysplasia Cardiogenic shock Hypovolemic shock Septic shock Low cardiac output Congestive heart failure Cardiac/Major abdominal surgery Dialysis Vasoconstricting agents: diuretics, alpha-adrenergic agonists, digoxin, cocaine, ergot derivatives

Acute mesenteric ischemia may also be observed, as a secondary process, in mechanical complications: strangulated hernia, intestinal intus-susception and volvulus, compression by tumors, aortic dissection, and trauma [7]. Mesenteric arterial embolism constitutes about 5% of peripheral emboli and is most frequently of cardiac origin. The SMA is anatomically susceptible to embolism because it has a large caliber and arises from the aorta at a narrow angle. About 15% of emboli impact at the origin of the SMA, whereas the majority lodge distally 3–10 cm in the tapered segment of the SMA, past the origin of the middle colic artery. The middle segment of the jejunum is most often involved in the ischemic process as it is most distant from the collateral circulation [2]. Table I. Mesenteric arterial thrombosis usually occurs as a superimposed phenomenon in patients with a

history of chronic intestinal ischemia from progressive atherosclerotic stenosis, usually at the origin of the arteries. Due to the rich collatera-lization, these patients typically tolerate major arterial obstructions and the often multivascular involvement makes revascularization complicated and risky (perioperative mortality of 70–100%) [6]. Nonocclusive mesenteric ischemia (NOMI) is due to mesenteric vasospasm, which can occur during periods of relatively low mesenteric flow, especially if there is underlying arterial atherosclerotic disease. The vasoconstriction is produced by sympathetic activity, possibly mediated by vasopressin and angiotensin. Moreover, mesenteric vasospasm may persist and perpetuate the ischemic injury even after correction of the precipitating event [1]. Because this condition frequently affects critically ill patients who have considerable comorbidities,

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the onset is often insidious and the mortality rates are high. With the increasing use of invasive monitoring in intensive care patients and with the use of vasodilators in heart failure the mortality rate in NOMI has declined [6]. Mesenteric venous thrombosis is the least common cause of mesenteric ischemia (5%) and is related to clotting disorders (primary or secondary) or to pathologic intra-abdominal conditions (Table II). Inherited hypercoagulable states are responsible for up to 75% of cases of mesenteric venous thrombosis. The most encountered disorder is the factor V Leiden mutation (20–40%), causing resistance to activated protein C. Thus, screening for thrombophilia must be taken into consideration in patients with mesenteric venous thrombosis [6].

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Intestinal ischemia following mesenteric venous thrombosis is due to the resistance in mesenteric venous blood flow which causes profound bowel wall edema, fluid efflux into the bowel lumen with resulting systemic hypotension and increase in blood viscosity. As a result, arterial flow is diminished, which ultimately leads to submucosal hemorrhage and bowel infarction [2]. The thrombi are usually palpable in the superior mesenteric vein. Involvement of the inferior mesenteric vein and, subsequently, of the large bowel is uncommon. The prognosis depends on the type of onset (acute versus chronic) and the extent of venous involvement. Patients with acute disease with involvement of the superior mesenteric or portal vein have a 30-day mortality approaching 30% [6].

Table II Predisposing factors for venous mesenteric thrombosis (modified from [1][2] and [9]) Mechanism Inherited procoagulative syndromes

Acquired procoagulative syndromes

Secondary to intra-abdominal processes

2. Clinical presentation Patients with acute mesenteric ischemia have been classically described as having rapid onset severe periumbilical abdominal pain, which is often out of proportion to findings on physical examination. Sudden abdominal pain with minimal abdominal signs accompanied by forceful bowel evacuation, nausea and vomiting, in a patient with risk factors for acute mesenteric ischemia should greatly heighten suspicion for the diagnosis [11]. The onset of symptoms may range from an acute one, with rapid deterioration, as in arterial embolism, to an insidious one, as in NOMI and mesenteric venous thrombosis. For example, patients suffering from a mesenteric arterial embolism present with abrupt

Etiology Factor V Leyden Activated protein C resistance – other mutations Prothrombin mutation Protein C, protein S, antithrombin III deficiency Antiphospolipidic syndrome Mieloproliferative disorders Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Polycythemia vera Sickle cell disease Portal hypertension Abdominal sepsis Abdominal trauma Pancreatitis Splenectomy Malignancy involving the portal territory

onset of severe abdominal pain sometimes associated with bloody diarrhea [15%]. In dramatic cases, dehydration from third-spacing of fluid, leading to mental confusion, tachycardia, tachypnea and circulatory failure dominates the clinical picture [6]. A typical patient with nonocclusive mesenteric ischemia is usually elderly, critically ill, with severe preexisting atherosclerotic disease and suffers an acute hemodynamic injury (such as myocardial infarction or congestive heart failure). This clinical picture along with the lack of history related information (frequently with preexisting cerebral damage, with sedation and invasive ventilation) postpone the diagnosis from hours to days. With the often necessary administration of medication such as digoxin and alpha adrenergic

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agonists, mesenteric hypoperfusion is often aggravated. Thus, nonocclusive mesenteric ischemia should be suspected in severe, hemodynamically unstable patients who are worsening, despite optimal therapy. Patients with mesenteric vein thrombosis typically search medical support late (1–2 weeks after onset) complaining of diffuse, nonspecific abdominal pain associated with anorexia and diarrhea. Fever, abdominal distention and hemocult positive stool samples are the most common findings. Bloody ascites and large fluid losses with third spacing may occur, leading to dehydration and hypotension and causing further propagation of thrombosis with the worsening of ischemia [6]. The final common pathway for all the specific causes of mesenteric ischemia is bowel infarction. When infarction occurs, the patient has peritoneal signs, hemodynamic instability and signs of sepsis with multiorgan failure [2]. As acute mesenteric ischemia may proceed to fatal intestinal infarction rapidly, prompt diagnosis and treatment are paramount. A high index of suspicion in the setting of a compatible history and physical examination serves as the cornerstone to early diagnosis of mesenteric ischemia. Survival is approximately 50% when diagnosis occurs within 24 hours after onset of symptoms, but it drops sharply to 30% or less when diagnosis is delayed [6]. 3. Laboratory studies Laboratory studies are nonspecific; while abnormal laboratory values may be helpful in supporting the suspicion of acute mesenteric ischemia, normal laboratory values do not exclude this diagnosis and do not justify delaying angiography when clinical suspicion exists. The most common laboratory abnormalities are hemoconcentration, leukocytosis, and metabolic acidosis, with high anion gap and lactate concentrations. High levels of serum amylase, aspartate aminotransferase, lactate dehydrogenase, and creatine phosphokinase are frequently observed at presentation, but none is sufficiently sensitive or specific to be diagnostic [6]. Normal D dimer levels may help to exclude mesenteric ischemia but elevated levels are less useful for its diagnosis [10]. Hyperphosphatemia and hyperkalemia are usually late signs and are frequently associated with bowel infarction [12].

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4. Imagistic studies Plain abdominal radiograph is a nonspecific diagnostic tool, completely normal radiographic findings being reported in more than 25% of patients with mesenteric ischemia. As with the laboratory tests, the value of plain abdominal X-rays is in excluding other diagnoses, such as intestinal obstruction or perforated viscus. Subtle signs of acute mesenteric ischemia on plain abdominal radiographs include adynamic ileus and distended, air-filled loops of bowel, but these abnormalities are most commonly due to other causes such as pancreatitis, mechanical obstruction, or colonic pseudoobstruction. More specific radiographic findings occur in 25% of patients, usually those with advanced disease. These findings include mural thumb-printing resulting from edema or hemorrhage. In advanced stages of ischemia, pneumatosis of the bowel wall can be detected. Specifically, portal vein gas on abdominal radiography portends an extremely poor prognosis [13]. Intraluminal barium contrast evaluations are contraindicated because residual contrast can limit visualization of the mesenteric vasculature during the following diagnostic tests (i.e. CT and angiography) [6]. B-scan abdominal ultrasonography is widely practiced as the first diagnostic procedure in patients with acute abdominal pain, its main value being to exclude other underlying abdominal pathology (i.e. aortic aneurysms or dissection). In patients with acute mesenteric ischemia, ultrasonography may reveal a thickening (> 45 mm) of the bowel wall, signs of ileus with distended bowel loops and hypoperistalsis. In severe cases, ultrasound may show intraperitoneal fluid or even air in the portal vein as a sign of massive intestinal necrosis. In contrast to chronic intestinal ischemia, duplex ultrasonography of the abdomen is not an appropriate diagnostic tool for suspected acute intestinal ischemia [14]. Doppler-flow ultrasonography can visualize stenoses or occlusions in the celiac or superior mesenteric arteries (Sp 92–100%, Sb 70– 89%). However, the test is often technically limited by the presence of air-filled loops of distended bowel. In addition, its sensitivity is limited for detecting more distal emboli or for the assessment of NOMI [2]. Like two dimensional ultrasonography, computerized tomography (CT scan) of the abdomen is used as a first line diagnostic tool in patients with acute abdominal pain [14].

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Conventional (spiral) CT scan of the abdomen may show evidence of mesenteric atherosclerosis, arterial or venous thrombosis (Figs. 2 and 3), focal or segmental bowel wall thickening, dilated fluid-filled bowel loops, engorgement of mesenteric vessels and in later stages intestinal pneumatosis with portal venous gas and infarction of other viscera (Figs. 4 and 5). In studies, the

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sensitivity of CT with intravenous contrast for the diagnosis of mesenteric venous thrombosis was approximately 90% (failure to opacify the mesenteric veins); for this reason CT scan is considered the investigation of choice in these patients [2]. The intravenous use of non-ionic iodine contrast might compromise the subsequent mesenteric angiography [14].

Fig. 2. – CT Angiography images showing thrombosis in the proximal segment of the superior mesenteric artery and stenosis with partial thrombosis of the celiac axis (white arrows); calcified atheromas at the origins of the celiac axis and the superior mesenteric artery (black arrows). (a) Axial plane. (b) Sagittal plane reconstruction. With the courtesy of I G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

Fig. 3. – CT Angiography images, sagittal reconstruction, showing thrombosis in the middle segment of the superior mesenteric artery with poor distal opacifiation (arrows). With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

Fig. 4. – Spiral CT images showing circumferential calcified atheromas in the abdominal aorta and in the superior mesenteric artery (arrows); small bubbles of gas in the intestinal wall, pneumatosis intestinalis (arrow heads). With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

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Fig. 5. – Spiral CT images showing air in the portal space, situated peripherally, in the left hepatic lobe and in the fourth hepatic segment. With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

The increasing use of multislice technology, characterized by a high spatial resolution and a relatively non-invasive nature with short acquisition times, makes MDCT (multidetector CT) scan angiography a strong and serious competitor to established vascular imaging techniques [15]. Thus, MDCT angiography might outline the traditional diagnostic pathways (angiography) in patients in which an endovascular therapeutic procedure is not taken into consideration [16]. Magnetic resonance angiography (MRA) may represent a non invasive, non-radiating alternative to CT angiography, especially in patients with iodine allergy. Initial experience suggests MRA may be highly sensitive for the diagnosis of mesenteric venous thrombosis, although helical CT is still preferred because of its lower costs, wide availability and excellent sensitivity [17]. More data comparing these modalities to conventional angiography are needed, especially to understand whether these studies can accurately detect the presence of small thromboemboli, early, reversible ischemia, or nonocclusive ischemia. Angiography is still recommended if there is a strong clinical suspicion for these entities [18]. Selective mesenteric angiography is still considered by most authorities on vascular disorders of the bowel as the gold standard for the diagnosis of acute mesenteric ischemia. Its sensitivities in five of six studies have ranged between 90% and 100%; specificity was reported in two of these studies to be 100% [11]. Early and large implementation of angiography has been the major factor for the

decline in the mortality of patients with acute mesenteric ischemia over the past 30 years. Both antero-posterior and lateral views are needed for adequate visualization of the mesenteric vasculature (Fig. 6) [19]. There are some controversies related to the routine use of mesenteric angiography motivated by the technical difficulties in critically ill patients, by the relative high number of false-negatives in early stages, by its potential renal toxicity and, most important, by its limited availability in some countries. Mesenteric angiography can usually differentiate embolic from thrombotic arterial occlusions. Thrombotic disease usually involves the origin the SMA with complete lack of visualization of the artery’s origin and with delayed views showing prominent collateral vessels. Emboli usually lodge after the first major branch of the SMA. Mesenteric venous thrombosis is characterized by a generalized slowing of arterial flow (up to 20 seconds) in conjunction with lack of opacification of the corresponding mesenteric or portal venous outflow tracts. This is usually segmental, in contrast to NOMI, which is diffuse and shows normal venous runoff. In addition, NOMI characteristically shows narrowing and multiple irregularities of the major superior mesenteric artery tributaries, the “string of sausages” sign. Venous occlusion and NOMI may show contrast material refluxing back into the aorta on selective SMA angiography [20]. More controversial is the need for angiography in a patient with suspected acute mesenteric ischemia and signs of acute abdomen, usually indicating

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infarcted bowel. While laparotomy is considered the first choice, some investigators support early angiography in this setting. The reasons would be: diagnosis of acute mesenteric ischemia and its cause, the means to administer intra-arterial vasodilators for

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NOMI and as part of the therapy for occlusive disease, provision of a ‘‘roadmap’’ for revascularization procedures, and access for serial postoperative angiographic studies [11].

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Fig. 6. – Selective angiography images (left anterior oblique views) of the main abdominal aortic branches showing: (A) ostial subocclusion of the celiac axis; (B) ostial subocclusion of the superior mesenteric artery, with hepatic artery originating from the superior mesenteric artery; (C) severe ostial stenosis of the inferior mesenteric artery with opacification of the superior mesenteric artery through collateral vessels – Riolan’s arch. With the courtesy of M. Croitoru, of Cardiac Catheterization and Angiography Department, “Prof. Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases.

Urgent laparotomy is indicated for all the cases in which angiography is not rapidly available [11]. 5. Other tests Electrocardiography may reveal the presence of atrial fibrillation or myocardial necrosis as an embolic substrate. Echocardiography (transthoracic and transesophageal) may also reveal an intracardiac embolic source (left ventricular aneurysm, intracavitary thrombus, infective endocarditis, etc.). Colonoscopy has been used to diagnose ischemic colitis but may not have adequate sensitivity and specificity in detecting ischemic changes (rather than infarction). Peritoneal fluid analysis may yield abnormal results (elevated white blood cell counts and phosphate, lactate dehydrogenase, and lactate levels) in mesenteric ischemia, its role in the diagnosis of

acute mesenteric ischemia is neither well studied nor widely accepted [22]. Special laboratory tests, like serum alphaglutathione S-transferase and intestinal fatty acidbinding protein (I-FABP) are under evaluation [23][24]. II. TREATMENT 1. SUPPORTIVE THERAPY

In the setting of suspected acute mesenteric ischemia, aggressive hemodynamic monitoring along with active resuscitation and treatment of underlying condition are mandatory. Adequate hydration and measures taken to improve cardiac output (inotropes, rate control) are very important regarding the underlying mechanism of ischemia, but are most decisive in NOMI, in which they improve mesenteric vascular constriction [6].

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Initial management should also include initiation of parenteral broad spectrum antibiotics to prevent bacterial translocation generated by ischemia. Vasoconstricting agents and digitalis should be avoided if possible since they can exacerbate mesenteric ischemia. If vasopressors are required, dobutamine, low-dose dopamine, or milrinone are preferred since they have less of an effect on mesenteric perfusion compared with other vasopressor agents. Systemic anticoagulation should be administered to prevent thrombus formation or propagation unless patients are actively bleeding [25]. Analgesia is also very important, as intense pain can be a trigger for shock. 2. RESTORATION OF FLOW

Restoration of intestinal blood flow, as rapidly as possible, is the main goal of treatment in patients with acute mesenteric ischemia. This may be achieved by medical means, endovascular procedures and by surgery. The appropriate therapeutic algorithm depends on the etiology of ischemia, thus a rapid and accurate diagnosis is crucial. The traditional treatment of mesenteric arterial embolism has been early surgical laparotomy with catheter based embolectomy. Postoperative intraarterial administration of papaverine and heparin can attenuate associated vasospasm and prevent subsequent thrombosis [25]. A less well established approach is local infusion of thrombolytic therapy which has been successful in a number of reports [26–28]. The therapeutic decision should be taken depending on the presence or absence of peritoneal signs, on whether arterial occlusion is partial or complete, and on whether the location of the embolus is above the origin of the ileocolic artery or in more distal branches [1]. Data derived from small series of thrombolytic therapy in acute SMA occlusion reported that early treatment (8– 12 hours), absence of intestinal necrosis and distal emboli have the best odds for successful reperfusion [14]. A “second-look” laparotomy within the next 24 to 48 hours may be necessary to resect additional ischemic or gangrenous bowel. Surgical exploration is mandatory in patients who do not demonstrate clot lysis within four hours or develop evidence of progressive ischemia. Despite success in case series, the long-term reocclusion rate after thrombolytic therapy has not been well studied. Long-term management is aimed at the prevention of future embolic events, typically with the use of oral anticoagulation [29].

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Treatment of patients with acute mesenteric artery thrombosis is mainly surgical [2]. Surgical thrombectomy alone is unlikely to be successful in the long term, due to the persistence of thrombogenic atherosclerotic plaques, so it has to be accompanied by a revascularization method (arterial reconstruction, bypass or endovascular stenting). In patients without peritoneal signs, having angiographic evidence of good collateral blood flow, observation while on heparin anticoagulation may be justified. The use of aspirin in the perioperative period has not been well evaluated, but it may be justified in this setting if the risk of progressive ischemia appears to be greater than the risk of bleeding. After recovery, antiplatelet agents such as aspirin may reduce the risk of recurrent mesenteric ischemia [30]. Treatment of the underlying shock state is the most important initial step in treating nonocclusive intestinal ischemia [14]. Thus, the management of NOMI is essentially pharmacological and is achieved by local selective infusion of vasodilators into the superior mesenteric artery (papaverine, tolazoline, nitroglycerin, glucagon, prostaglandin E and isoproterenol) [31]. The greatest clinical experience is with papaverine, which is administered as a continuous infusion. This approach has resulted in a reduction in mortality rates from 70%–90% to 50%–55% during the last two decades. Subsequent management is dictated by the patient’s clinical response to vasodilator therapy, ranging from repeated angiography (after 30 minutes and every 24 hours) for evaluation of vasospasm and the decision to stop papaverine infusion, to immediate laparotomy if signs of acute abdomen develop or the patient condition is worsening [32]. Standard initial treatment for acute mesenteric venous thrombosis consists in heparin anticoagulation. Anticoagulation with heparin can be given even in patients who have gastrointestinal bleeding if the bleeding risk is considered to be outweighed by the risk of intestinal infarction. Intraarterial infusion of papaverine during angiography to relief the concomitant arterial spasm is also an option. Thrombolytic therapy has not a clear indication in superior mesenteric vein thrombosis and should be considered experimental. Prevention of recurrent venous thrombosis with oral anticoagulation is indicated for at least six

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months; a longer duration may be warranted if a thrombophilic state has been identified [33]. 3. NECROTIC TISSUE RESECTION AND SECONDLOOK LAPAROTOMY

Differentiation between viable and nonviable, necrotic bowel tissue is done by exploratory laparotomy. The moment of intervention depends on the clinical condition of the patient, on the presence of peritoneal signs and on the mechanism of the ischemic injury. Fluoresceine or the Wood lamp may help for a better delineation of the necrotic tissue. If a revascularization procedure is intended and resection of necrotic tissue is not imminent, it is recommended to evaluate viability after the flow restoration. After that, efforts should be made in order to minimize the reperfusion injury by administrating vasodilatators and agents with free radicals neutralizing effect (allopurinol, angiotensin converting inhibitors). A second-look laparotomy (after 24–48 hours) is recommended, even after successful primary intervention, because the intraoperative assessment of bowel viability is often inaccurate, and few reliable signs are available to detect persistent ischemia or developing infarction in the postoperative period [34]. The rationale for this second look is based in part on the frequent occurrence of vasospasm after revascularization. Second-look laparoscopy has been advocated as a substitute for second-look laparotomy, but the reliability of this approach remains unproved [35][36]. III. PROGNOSIS

Perioperative mortality in patients undergoing revascularization for acute mesenteric ischemia ranges from 44% to 90% [37]. Published data on long-term results after successful revascularization are few, and in general, prognosis is not as favorable as that for patients with chronic mesenteric ischemia. The most important prognostic factor is the early diagnosis. Recurrence is not uncommon, and it carries a poor prognosis. The small proportion of patients that survives massive bowel resection usually develop short-gut syndrome, requiring long-term total parenteral alimentation or small-bowel transplantation.

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Chronic mesenteric ischemia Chronic mesenteric ischemia (intestinal angina) is a clinical syndrome characterized by recurrent abdominal pain and weight loss as a result of repeated transient episodes of insufficient intestinal blood flow, usually related with the increased metabolic demand associated with digestion. Intestinal angina is an uncommon process that occurs only when severe atherosclerotic narrowing of a major splanchnic vessel exists in association with occlusion of one or two of the remaining vessels [1]. Approximately 90% of the patients complaining of intestinal angina have at least 2 out of 3 major mesenteric vessels occluded and 50% of them have critical stenosis in all the 3 vessels. This is because the very efficient collateral circulatory network in the small bowel and colon can successfully overcome the single occlusion of a major vessel. Chronic mesenteric ischemia is seen in middle-aged and elderly people, predominantly in women (3:2) with multiple cardiovascular risk factors and atherosclerotic involvement of other territories: coronary artery disease, peripheral artery disease, cerebrovascular disease (over 50% of patients). 3.1. DIAGNOSIS

3.1.1. Clinical presentation Clinical manifestations are related to the limited ability of the celiac artery or SMA to supply increased blood flow in response to metabolic demands after a meal, mainly because of atherosclerotic vascular lesions. Alternatively, it has been suggested that a steal phenomenon from the intestinal to the gastric circulation occurs when food reaches the stomach [38]. Patients classically complain of dull, postprandial epigastric pain, usually within the first hour after eating. The pain can be of variable intensity and location, and may occasionally radiate to the back. The severity of the pain is increased after larger meals with high fat content. Frequently, patients experience weight loss (80%), due to the development of a food aversion and approximately one-third of them have nausea, vomiting, and early satiety [39]. Physical findings are non-specific: weight loss with signs of malnutrition, sometimes abdominal

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tenderness without rebound during an episode of severe pain and indirect signs of atherosclerotic vascular disease (diminished peripheral pulses, carotid or femoral bruits, or stigmata of past stroke). The diagnosis is mainly based on the characteristic clinical picture, on the presence of an occlusive lesion in the splanchnic vessels documented by angiography and on the absence of other common causes of abdominal pain. In most cases, patients undergo an extensive workup for obscure chronic abdominal pain, including routine laboratory evaluation, plain abdominal radiographs, upper and lower GI endoscopy, small bowel barium series, and ultrasonography or abdominal CT [1]. 3.1.2. Imagistic studies Plain abdominal radiograph may suggest the diagnosis by showing calcification of the mesenteric vessels. Duplex ultrasonography of the mesenteric vessels is a useful initial test for supporting the clinical diagnosis of chronic intestinal ischemia. This test is technically difficult but can be accomplished in more than 85% of subjects in the elective setting. The test has an overall accuracy of approximately 90% for detection of greater than 70% diameter stenoses or occlusions of the celiac

Fig. 7. – CT Angiography images – maximum intensity projection (MIP) reformatation – showing short ostial stenosis of the celiac axis and stenosis of the superior mesenteric artery, approximately 1 cm below its origin. With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

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and superior mesenteric arteries when performed in highly experienced laboratories [14][38][40]. Angiography is recommended if the results of noninvasive testing are equivocal or if they suggest that intervention is required (establishing the feasibility of revascularization). In order to better appreciate the lesions, acquisition must also take biplanar views [41]. Along with direct signs of stenoses, indirect ones may also suggest the diagnosis, like the presence of an enlarged arch of Riolan for proximal mesenteric arterial obstruction [14]. MDCT and CT angiography allow an extensive and nonivasive evaluation of mesenteric lesions (Fig. 7). Visualisation of the collateral vessels (Riolan‘s arch, pancreatico-duodenal arch) and of the change in caliber of the ischemic bowel loops (stenotic) may help the diagnosis [42]. Magnetic resonance angiography (gadoliniumenhanced MRA) is highly sensitive for detecting stenoses at or near the origin of the SMA or the celiac artery (Figs. 8 and 9); however, the technique is much less reliable for detecting more distal lesions. The usefulness of these techniques is currently limited by the high costs and the need for significant expertise. At present, MRA should be considered experimental as a diagnostic tool for chronic mesenteric ischemia [38].

Fig. 8. – MR Angiography images – MIP reformatation – showing short severe stenosis of the superior mesenteric artery (arrow). With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

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Fig. 9. – MR Angiography images, MIP reformatation, showing multiple atherosclerotic lesions in the superior mesenteric artery (arrow). With the courtesy of I.G. Lupescu, M. Grasu, Radiology and Imaging Department, Fundeni Clinical Institute.

3.2. TREATMENT

3.2.1. Medical therapy The goal of therapy for chronic mesenteric ischemia is revascularization. Taking into account the increased risk for thrombotic events with mesenteric infarction in these patients, medical therapy alone is indicated only when the surgical risk is prohibitive and the percutaneous revascularization is not feasible. On the other hand, all the patients, except for the ones with contraindications, must receive drugs addressed to the pathologic substrate, atherosclerosis, i.e. statins and antithrombotic therapy. Oral anticoagulation may also be associated. Analgetics and intravenous nitrates can be used for temporary pain control [38]. 3.2.2. Mesenteric revascularization The means available for mesenteric revascularization are the surgical techniques of flow restoration and the more recently developed percutaneous transluminal procedures: mesenteric angioplasty with or without stenting. The goals of these interventions are to relieve symptoms, to improve nutrition and to prevent mesenteric infarction [1].

Mesenteric revascularization should be considered in patients with intestinal angina (symptomatic chronic mesenteric ischemia), with documented critical stenoses in at least 1 of 3 major mesenteric vessels and in which other causes for chronic abdominal pain have been excluded. Also, revascularization may be considered in asymptomatic patients who are submitted to aortic reconstruction for aortoiliac occlusive disease and in whom significant mesenteric occlusion is present, because they have an increased risk of mesenteric infarction after surgery [14]. The indication for surgery in asymptomatic patients in the absence of a need for aortic reconstruction is not clear. It has been proposed by some authors that surgery should be considered in such patients when three-vessel ischemia is documented because of the high risk of developing ischemic symptoms or death [43]. Complete revascularization has been recommended by many surgeons, but several authors have recently proposed that bypass grafting of the superior mesenteric artery alone is an effective and durable procedure for treatment of intestinal ischemia [44]. For many years, surgical revascularization has been the treatment of choice for chronic mesenteric ischemia. The techniques used include

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antegrade and retrograde bypass grafting, transaortic mesenteric endarterectomy and aortic reimplantation of the superior mesenteric artery. Perioperative mortality ranges from 0–11% but up to 50% in patients with acute on- chronic symptoms [45]. Primary graft patency rates at five years ranged from 57 to 69%, and 5-year survival rates ranged from 63 to 77% [46][47]. Advancing age, cardiac disease, hypertension and additional occlusive

A

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disease influence overall mortality, and concomitant aortic replacement, renal disease, and complete revascularization are associated with high postoperative morbidity rates [48]. Percutaneous transluminal angioplasty (Fig. 10), with or without stenting, has become an alternative to surgery for the many patients who are poor surgical candidates and for the patients in whom the diagnosis remains uncertain. Despite

B

Fig. 10. – Selective angiography images (left anterior oblique views) of superior mesenteric artery angioplasty showing: (A) the angioplasty balloon fully inflated in the proximal segment of the SMA; (B) contrast injection after the procedure – the metal stent and no residual stenosis. With the courtesy of M. Croitoru, of Cardiac Catheterization and Angiography Department, “Prof. Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases.

limited published experience, most authors have reported success rates of greater than 80%, defined as residual stenoses of less than 50%. Relief of abdominal pain has been achieved in 75–100% patients and half of the patients experienced weight gain. Long term follow-up indicates clinical remission in approximately 80% of patients at two to three years. Restenosis and recurrent symptoms occur in 17–50% of patients within the first year, making the limited durability of the procedure its greatest limitation (49–53). There have been no

large, randomized, controlled trials comparing angioplasty, with or without stenting and surgical revascularization. As a general approach, based on current data, surgical revascularization is the method of choice for patients with low surgical risk, while percutaneous angioplasty is preferred for high risk patients [54]. Surgery rather than angioplasty is indicated for suspected bowel necrosis. In patients who survive surgical revascularization, the prognosis is excellent; 5-year

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survival rates approach 80%, and most patients become free from symptoms, gain weight, and resume normal eating habits. In summary, both acute and chronic mesenteric ischemia are challenging medical problems in which a strong clinical suspicion remains the key to early diagnosis. On the one hand, in the acute case, an aggressive approach should be adopted because the outcome crucially depends on rapid

14

diagnosis and treatment, on the other hand, in chronic cases, the therapeutic decision should be carefully made, balancing risks and benefits, considering that patients have often severe comorbidities. With better understanding of the pathogenesis of mesenteric ischemia syndromes and the availability of a range of diagnostic and interventional techniques and adjuvant pharmacotherapy, an improved outcome can be achieved.

Ischemia mezenterică reprezintă un spectru de entităţi clinice care au ca mecanism comun alterarea aportului sangvin intestinal şi mezenteric cu consecinţe potenţial fatale: infarct mezenteric, sepsis şi chiar deces. Incidenţa globală a ischemiei mezenterice se află în creştere, aceasta fiind responsabilă de 0.1% din motivele de internare în spital; printre factorii răspunzători se numără: sporirea suspiciunii diagnostice, îmbătrânirea populaţiei şi creşterea prevalenţei pacienţilor critici. Ischemia mezenterică acută reprezintă o urgenţă vasculară reală, cu potenţial fatal şi cu o mortalitate de până la 80%. Diagnosticul precoce şi tratamentul corect sunt esenţiale, bazându-se pe un index înalt de suspiciune clinică alături de prezenţa unor date de anamneză şi examen clinic compatibile. Obiectivul principal în tratamentul ischemiei mezenterice acute este restabilirea cât mai rapidă a fluxului sangvin mezenteric. Aceasta se poate realiza prin măsuri medicale, intervenţionale şi chirurgicale. Ischemia mezenterică cronică este un sindrom cu prevalenţă relativ joasă, descriindu-se la pacienţii cu leziuni aterosclerotice severe ale vaselor splahnice, cu multiple ocluzii ale trunchiurilor principale. Diagnosticul ischemiei mezenterice cronice este în principal unul clinic, dublat de excluderea altor cauze de durere abdominală cronică şi de certificarea imagistică a existenţei unor leziuni aterosclerotice critice mezenterice. Opţiunile terapeutice de revascularizare in ischemia mezenterică cronică sunt tehnicile chirurgicale de restabilire a fluxului şi, dezvoltată mai recent, angioplastia mezenterică percutană cu sau fără implantare de stent. Corresponding author: Ruxandra Jurcuţ Department of Cardiology, “Prof Dr. C.C. Iliescu” Institute of Emergency for Cardiovascular Diseases, Şos. Fundeni No. 258, 022322 Bucharest, Romania E-mail: [email protected]

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