INTRODUCTION
Mesenteric ischemia disorders are precipitated by a circulation insufficiency event that deprives one or several abdominal organs of adequate respiration to meet metabolic demands. Although mesenteric ischemia occurs infrequently, the mortality rate is from 60% to 100%, depending on the source of obstruction[1]. Even with recent technological advancement, successful outcome is dependent upon a high index of suspicion and prompt management.
This spectrum of disorders can be roughly categorized by the acuity or chronicity of presentation. Acute mesenteric ischemia is further subdivided based on the etiology of the occlusion; embolic, thrombotic or nonocclusive. It has been estimated that one third of acute cases are caused by arterial embolism, one third caused by acute arterial thrombosis, and the remaining majority of acute cases are caused by a nonocclusive etiology, with a small proportion of cases from venous thrombotic etiology[2,3]. Chronic ischemic symptoms usually stem from longstanding atherosclerotic disease of two or more mesenteric vessels. This article will briefly review the pathophysiology and presentation of the various ischemic entities and review the current state of the art in diagnosis and treatment.
PATHOGENESIS AND PRESENTATION
The classic presentation of patients with embolic disease is of sudden catastrophic abdominal pain out of proportion to physical examination findings. Only one third of patients present with the classic triad of abdominal pain, fever and heme-positive stools. These patients often have a history of cardiac disease which might predispose to embolus formation (atrial fibrillation, ventricular aneurysm, mitral valve disease, etc.). If there is a thrombotic component to the acute event, a history of chronic abdominal pain and coexistent atherosclerotic disease can be elicited. Venous thrombosis of the visceral vessels can also precipitate an acute ischemic event. Compromised venous return leads to interstitial swelling in the bowel wall, with subsequent arterial flow impedance and eventual necrosis. Etiologic factors for venous thrombosis include portal hypertension, intrabdominal sepsis, cirrhosis, pancreatitis, malignancy and trauma. Less common causes of acute mesenteric ischemia include arteritis, ergot administration, aortic dissection with concomitant occlusion of visceral vessels, and iatrogenic causes related to cardiopulmonary shunting in cardiac surgery.
Patients who present with nonocclusive mesenteric ischemia do so in a clinical setting of extremely low-flow splanchnic circulation, usually in the presence of vasopressor use. No vascular occlusion is usually demonstrated because pulsatile blood flow is present in larger arteries[4]. Patients with severe cardiac failure are at risk for nonocclusive mesenteric ischemia from vasospasm related to elevated sympathetic activity or hypovolemia. Catecholamines and medications such as digitalis, by interfering with the autoregulation of mesenteric circulation, can also cause vasospasm.
The etiology of chronic ischemia is also multifactorial and many of the causes are similar to those listed for acute ischemia, but rarely from emboli. The most common cause of chronic intestinal ischemia is atherosclerotic occlusion or severe stenosis of the mesenteric arteries. A stenosis of > 50% is present in 18% of patients older than 65 years, but very few of these patients have symptoms[5]. Slow-growing obstructions are usually the source of this disease. Similar to acute disease, chronic nonatheromatous lesions which probably occur in a higher proportion in the visceral vessels include Takayasu’s arteritis, dysplastic lesions, and Buerger’s disease[6]. Chronic symptoms are caused by the gradual reduction in blood flow to the intestine. Since total blood flow to the intestine can vary from 20% when fasting to 35% after eating, symptoms occur with the demand for blood flow[7]. The three major gastrointestinal arteries that arise from the abdominal aorta are the celiac axis, the superior mesenteric artery (SMA), and the inferior mesenteric artery (IMA). Since collateral circulation is present at several levels, patients may be asymptomatic even with stenoses in several arteries. When SMA is occluded, the pancreaticoduodenal arteries supply blood via the hepatic and gastroduodenal arteries to the bowel, and when the celiac artery is also occluded, IMA supplies blood to the small bowel via the left colic branch. Frequently angiography will demonstrate a large meandering mesenteric artery, which is an important vessel in the collateral circulation from the inferior mesenteric artery. Symptoms usually occur if two or more vessels are occluded. Chronic mesenteric arterial ischemia typically causes postprandial abdominal pain and weight loss. As the obstructive process progresses, chronic dull pain ensues. Chronic venous occlusion causes vague abdominal pain or distention and usually does not infarct the bowel. Frequently, it is found incidentally on abdominal imaging.
Adequate intestinal perfusion can usually be maintained at near normotensive blood pressures when only one artery is involved, and under these circumstances mesenteric ischemia rarely occurs. When multiple severe occlusions are present, acute intestinal ischemia occurs from the critical reduction in the blood flow. Severe symptoms and possible infarction of the intestines can occur. The bowel becomes ischemic when the intestinal blood pressure falls below 40 mmHg[7].
At the cellular level, ischemia causes mitochondrial dysfunction, loss of ion transfer regulation and intracellular acidosis. Changes in membrane permeability and release of free radicals and degradative enzymes lead to cell death and tissue necrosis. Experimental models in rats have demonstrated mucosal injury and bacterial translocation within 2 h of a 30 min hypovolemic, hypotensive episode[8].
DIAGNOSTIC MODALITIES
Over the last decade, duplex ultrasonography has shown promising results in the diagnosis of chronic mesenteric ischemia. Multiple studies, using angiography as a standard reference, have found that duplex ultrasonography is an accurate screening test for proximal stenosis or occlusion. End diastolic velocity greater than 45 cm/s or peak systolic velocity greater than 275 cm/s portends high specificity for SMA stenosis[9-11]. However, these findings must be correlated with a clinical scenario and angiographic findings. In addition, duplex exams are limited in quality by patient body habitus, overlying bowel gas, patient compliance, and operator dependence[12].
Magnetic resonance angiography, although initially criticized for limitations in resolution and oversensitivity, is being investigated for diagnosis of mesenteric ischemia. Recent studies show a disease specificity of 95%[13]. Li et al[14], used magnetic resonance oximetry to evaluate the percentage of oxygenated hemoglobin in the preprandial and postprandial SMA in patients with chronic ischemic symptoms. Compared to asymptomatic atherosclerotic patients, this study showed a statistically significant increase in oxygen extraction and a decrease in oxygenated hemoglobin in the mesenteric ischemia group. Combined with magnetic resonance angiography, oximetry may hold promise as a powerful diagnostic modality. Selective mesenteric angiography is considered to be the gold standard for the diagnosis of acute arterial occlusion. Abrupt cutoff of the SMA with the absence of collateral circulation is diagnostic with virtually 100% sensitivity in acute embolic occlusion[15]. The more important outcome of arterial catheterization in this era however, as discussed below, will be the development of endovascular therapy.
While imaging of the visceral vessels and involved organs are essential to determine severity of disease, physiologic or biochemical means of detection, both for diagnosis and as a predictor of behavior, do not exist. Serum lactate, an established marker of cell hypoxia, has been shown to have a sensitivity of 96% in patients with mesenteric ischemia[16]. However, lactic acidosis is often a late finding in the diagnostic pathway with concomitant shock, bowel necrosis and circulatory collapse. In this regard, several areas of research should be mentioned. Small animal models have shown that tachyarrythmias detected by electrophysiologic sensors of the bowel wall are sensitive indicators of visceral hypoperfusion. Seidel showed that transabdominally placed superconducting quantum interference devices can accurately detect small bowel electrical rhythms in situ. Moreover, in this animal model of SMA occlusion, the ischemic intestine exhibited decreased electrical activity which was detected with a sensitivity and specificity of 94% and 100%, respectively. This noninvasive modality stands to be validated with future work[17,18].
Recently, plasma D-dimer has been suggested as an early marker of acute ischemia. In animal studies D-dimer has been shown to correlate with the onset of ischemia and it functions as a time sensitive indicator of disease progression[19,20]. Similarly, the enzyme alcohol dehydrogenase has been identified as a potentially sensitive indicator of bowel ischemia as opposed to generalized systemic hypoperfusion[21]. Glutathione S-transferase, a detoxifying cytosolic enzyme, is also a substance of interest. It is released with cell membrane damage and several isoforms have been correlated with bowel specificity. This enzyme has also been shown to exhibit a time and duration specific detectable increase with progressive tissue ischemia[22].
Computed tomography (CT) is a fast, widely available noninvasive modality that has improved enormously in recent years. In 2000, the American Gastrointestinal Association concluded that CT was of limited use in the diagnosis of acute mesenteric ischemia, except in patients suspected of having superior mesenteric vein thrombosis[15]. Since then, multidetector row computed tomography has emerged as the gold standard for evaluation of mesenteric ischemia. In one prospective series, the positive and negative predictive values in a series of 291 patients were found to be 90% and 98%, respectively[23]. In another prospective series of 62 patients evaluated for mesenteric ischemia with multidetector CT and mesenteric angiography, the sensitivity and specificity was found to be 96% and 94%, respectively[24].
TREATMENT OPTIONS
Management of mesenteric ischemia clearly depends on the nature, acuity and severity of disease. Early intervention involves resection of nonviable bowel, restoration of blood flow to the ischemic intestine and supportive care. In the acute thromboembolic event, operative embolectomy has been the traditional procedure with reasonable short and long term outcomes. Surgical revascularization for visceral ischemia due to an occluded SMA was first described by Shaw et al[25] in 1958, in which they reported two successful cases of mesenteric thromboendarterectomy. For chronic occlusive disease, when revascularization is considered, single-vessel bypass to the superior mesenteric artery has been very successful, even in patients with multiple-vessel occlusions. Cunningham et al, reported an 86% symptom-free rate at 5 years after surgical revascularization[26]. In one study, the operative procedure had a perioperative mortality rate of 3%, a 5-year survival rate of 61%, and a 9-year assisted primary graft patency of 79%[27]. Those who advocate multiple vessel revascularization suggest that there is a higher incidence of graft failure and recurrence of symptoms after single-vessel revascularization. At the Mayo Clinic, the 5-year graft patency rates have been 90%, 54%, and 0% with three-vessel, two-vessel, and one-vessel bypasses respectively[28].
Antegrade aortoceliac bypass and transaortic endarterectomy have been successful for poor-risk patients, and are usually adequate for multiple outflows. Antegrade mesenteric bypass grafts from the distal thoracic aorta have also been associated with low mortality and morbidity rates[29]. Antegrade bypass from the supraceliac aorta can reduce kinking, compression, turbulence, and thrombosis, but has been associated with renal ischemia and can be technically challenging. Retrograde bypass from the infrarenal aorta or iliac artery is technically easier and avoids renal ischemia, but has been related to lower inflow and graft kinking. Revascularization of the superior mesenteric artery and celiac axis has been used to minimize the recurrence of symptoms and organ infarction if one graft fails[30]. Graft failure has been reported to be higher in males[31]. While most patients with chronic venous mesenteric ischemia can be treated with anticoagulation therapy, the source of the thrombus must be determined and treated.
Since the first reports of percutaneous transluminal angioplasty of the visceral vessels in 1980, endovascular therapy for atherosclerotic disease has rapidly expanded in both scope and indication in the last ten years. In both the acute and chronic presentation of intestinal ischemia, endoluminal therapy has emerged as a main, if not first-line therapy. Symptom relief with implantation of stents in the proximal celiac artery has been reported[32,33]. In addition, the thrombosis rate of mesenteric prostheses has been reduced from 18% to 1% with the addition of antiplatelet therapy.
Thrombolytic therapy in the management of intestinal ischemia was first reported in 1979 with the successful application of intraarterial streptokinase in the SMA[34]. In those patients with ostial or short segment occlusion of the SMA and celiac artery, recanalization with or without concomitant fibrinolysis (depending on acuity and presence of thrombus) has been shown to have promising initial results[35]. In many centers, intracatheter fibrinolysis with or without embolus retrieval is the initial treatment for SMA thromboembolism[36-38]. With the increase in percutaneous approaches to therapy, concern has arisen regarding the durability of treatment. Hallisey et al, reported a 75% primary patency rate at a mean follow up of 2.3 years[39]. Matsumura et al, reported a 29% recurrence rate with endovascular treatment within 1 year of treatment[40]. It has been suggested that in selected patients, surgery should be the treatment of choice, because it provides better long-term primary patency[41-43].
When the results of open surgery are compared to those of percutaneous angioplasty and stenting, there is a higher incidence of recurrent symptoms after percutaneous angioplasty[44]. In a recent retrospective review, the Dartmouth group noted an increased rate of restenosis and reintervention in the stent group versus an historical control surgical group. However, despite reintervention, 93% were symptom-free at last follow-up with a significantly smaller periprocedural mortality rate compared to open surgical patients. In addition, the authors pointed out that in one case, stent placement allowed sufficient nutritional optimization as to allow a previously poor risk patient to tolerate a definitive open procedure[45]. Clearly, there may be a role for minimally invasive therapy in high risk patients. With the accumulating experience in high volume endovascular centers, emerging prospective data may be able to more adequately analyze outcome data between the two treatment modalities.
In the subset of patients who suffer from nonocclusive ischemia, intraarterial vasodilator therapy has been largely responsible for the decrease in mortality from 70% in the 1980’s to 50%-55% during the last decade[46]. Papaverine, the most common agent in practice today, is a nonaddictive opium derivative extracted from the poppy plant. It functions as a phosphodiesterase inhibitor and is usually infused directly into the SMA at a rate of 30 to 60 mg/h. The resultant accumulation of cyclic adenosine monophosphate acts to relax vascular smooth muscle. Recent work has shown that iloprost, a synthetic carbacyclin derivative of epoprostenol may improve SMA flow in a hypotensive porcine model. Iloprost, a potent inhibitor of platelet aggregation and powerful fibrinolytic agent, increases flow with no appreciable change in mean arterial pressure and cardiac output. This suggests a possible role for prostacyclin analogues in the treatment of nonocclusive ischemia[47].
Investigational therapy in the treatment of mesenteric ischemia has focused on pharmacologic strategies to treat mesenteric ischemia. These include renin-angiotensin blockers and free radical inhibitors. The renin-angiotensin axis has been shown in a porcine model to play a prominent role in vasoconstriction. In this model, blockade of this signal pathway was able to prevent the ischemic injury from induced splanchnic vasoconstriction[48]. These findings imply that hemodynamic forces of nonocclusive ischemia are mediated, at least in part, by the renin-angiotensin axis.
The dual-hit hypothesis of ischemic injury is comprised of the initial hypoxic episode and then the subsequent reperfusion injury after reestablishment of forward flow. There is significant data to suggest that reactive oxygen metabolites such as superoxide, hydrogen peroxide, and hydroxyl radicals mediate ischemic injury. These substances are thought to activate phospholipase A2, which leads to chemotaxis and leukocyte-mediated vessel injury[49]. In this regard, inhibition of xanthine oxidase by allopurinol has been shown to attenuate the epithelial cell damage during reperfusion[50]. Similarly, pretreatment with superoxide dismutase and dimethyl sulfoxide attenuates reperfusion injury in animal models[51-53]. However, since most of these therapies require pretreatment to be effective, it is difficult to foresee clinical applicability at this time.
In conclusion, mesenteric ischemia, a spectrum of disorders with multiple etiologies still carries significant morbidity and mortality. Despite advances in both diagnosis and treatment, prompt diagnosis and supportive care remain critical for successful outcome. New imaging techniques, endovascular therapy and emerging research may improve our approach to this deadly condition.
S- Editor Pan BR E- Editor Bi L
