MESENTERIC ISCHEMIA 0039-6109/97 $0.00 + 2 0

NONOCCLUSIVE MESENTERIC ISCHEMIA

Hisham S. Bassiouny, MD

Acute mesenteric ischemia remains a major cause of intra-abdomi- nal catastrophe and mortality in the vascular patient population. Inter- ruption or diminution of blood flow to the small intestine and right colon principally results from mechanical obstruction of the superior mesenteric artery (SMA) by embolus or thrombosis or from primary splanchnic vasoconstriction, a clinical entity known as nonocclusive mes- enteric ischemia (NOMI).

It estimated that NOMI is the underlying cause in at least 20% to 30% of cases of acute mesenteric ischemia and, unfortunately, results in mortality in up to 70% of afflicted patients.2, 18* 30 This dismal prognosis is usually attributed to difficulty in antemortem diagnosis and an incom- plete understanding of its pathophysiologic mechanism. Furthermore, the clinical presentation of NOMI is frequently associated with other life-threatening disorders in patients sustained by advanced mechanical and pharmacologic life support. Liberal use of arteriography in patients suspected to have NOMI offers the best chance for early diagnosis and treatment prior to bowel infarction. The purpose of this article is to summarize the current knowledge of the pathophysiology of NOMI and discuss the diagnostic and treatment modalities that may enhance survival in these critically ill patients.

PATHOPHYSIOLOGY

NOMI was first described following postmortem examination of patients with small intestinal gangrene without evidence of arterial

From the Section of Vascular Surgery, Department of Surgery, University of Chicago, Chicago, Illinois

SURGICAL CLINICS OF NORTH AMERICA

VOLUME 77 * NUMBER 2 * APRIL 1997 319

320 BASSIOUNY

or venous occl~sion.~, l4 Subsequent reports by Cohen? Wilson and Qualheim,3l and Ende'O confirmed these findings in patients with severe cardiac failure. It was postulated that cardiac failure, peripheral hypox- emia, and paradoxical splanchnic vasospasm precipitate intestinal ische- mia. Investigation of the regulatory mechanisms of the mesenteric circu- lation has revealed that mesenteric vasoconstriction, intestinal hypoxia, and ischemia-reperfusion (IR) injury all may contribute to the develop- ment of NOMI.

Mesenteric vasospasm is a sine qua non of NOMI. It may be induced by excessive sympathetic activity during cardiogenic shock or hypovo- lemia and represents a homeostatic mechanism that attempts to maintain cardiac and cerebral perfusion at the expense of the splanchnic and peripheral circulations. Experimental work by Bailey et al,' and later expanded by McNeill et a1,2l indicates that the putative neurohormonal mediators of mesenteric vasoconstriction in response to low cardiac output and hemorrhage are vasopressin and angiotensin. With pro- longed or intermittent periods of vasoconstriction, adequate blood flow may be maintained with declining perfusion pressures until a finite autoregulatory limit is reached. This adaptive response is effected by local arteriolar smooth muscle relaxation and va~odilatation.~~, 27 In addi- tion, the intestine is capable of increasing oxygen extraction with re- duced intestinal blood flow. Experimentally, maximal extraction is reached at a critical pressure of 40 mm Hg, beyond which oxygen consumption declines and ischemia ensues.22 Ultrastructural damage is first observed at the villous tip and proceeds to the deeper mucosa, submucosa, and muscularis within a few hours. Initially, the bowel appears pale, then cyanotic with loss of peristaltic activity, and then frankly gangrenous and necrotic.

Once set in motion, mesenteric vasospasm may persist even after correction of the precipitating event. Autoregulatory vasodilatation and increased collateral flow may help to offset initial reductions in blood flow, but, after several hours, the autoregulatory capacity is e~ceeded.~ The exact mechanism behind the persistence of vasospasm is unknown, but it frequently may respond to direct intra-arterial papaverine infu- sion. This phenomenon of persistent prolonged vasoconstriction plays an important role in the development and maintenance of occlusive and nonocclusive intestinal ischemia and also may complicate mesenteric revascularization."

The use of digitalis has been noted in the majority of patients presenting with NOMI. Digoxin preparations have been shown experi- mentally to alter mesenteric vasoreactivity by stimulating arterial and venous smooth muscle cell contraction in vitro and in vivoZ3 and may enhance mesenteric arteriolar vasoconstriction in the setting of acute venous hyperten~ion.'~

Reperfusion of ischemic intestine may be complicated by IR injury, which occurs as a consequence of restoration of oxygenated blood to hypoxic tissue maintained on anaerobic metabolism. During critical is- chemia, ATP levels are depleted, generating large amounts of adenosine,

NONOCCLUSNE MESENTERIC ISCHEMIA 321

a precursor of hypoxanthine. Concomitantly, xanthine dehydrogenase is converted to xanthine oxidase, which reacts with intracellular hypoxan- thine to produce uric acid and toxic oxygen free radi~a1s.I~ These free radicals induce significant cellular membrane injury, increasing capillary permeability and connective tissue degradation. The degree of IR injury appears to be related to the frequency as well as the duration of the ischemic episodes. For example, Clark and Gewertzs demonstrated that two short 15-minute periods of low flow followed by reperfusion re- sulted in a more severe histologic injury than a single 30-minute period of ischemia. In NOMI, a similar scenario exists; hypoperfusion may be partial and, occasionally, repetitive. It is thought that episodic reperfu- sion primes the ischemic tissue with leukocytes that are attracted to and produce free radi~a1s.I~ This concept is substantiated by recent experimental evidence that IR injury may be attenuated by reperfusion with leukopenic blood or by blockade of endothelial cell surface recep- tors for leukocyte adherence.20, 24 The application of these novel ap- proaches in human NOMI awaits further study.

CLINICAL PRESENTATION

It is estimated that acute mesenteric ischemia is responsible for 1: lOOO of all hospital admissions. NOMI comprises about 20% of such cases.3 The incidence of NOMI may be declining, despite an aging of the population, because of the widespread use of systemic vasodilators in cardiac intensive care, including calcium channel blockers and ni- trates. These agents improve cardiac hemodynamics and help prevent mesenteric vasospasm. The clinical diagnosis of NOMI requires a high index of suspicion in elderly patients with any of the following risk factors: acute myocardial infarction with shock; congestive heart failure; dysrhythmia; hypovolemia from burns, sepsis, pancreatitis, and hemor- rhagic shock; and the administration of splanchnic vasoconstrictors such as a-adrenergic agents and digitalis. Early diagnosis, prior to bowel infarction and peritonitis, is the most important variable that predicts improved survival.

Abdominal pain out of proportion to physical findings is a cardinal symptom in patients with acute mesenteric insufficiency and is com- monly manifest after embolic or thrombotic occlusion of the SMA. In NOMI, however, it is absent in 20% to 25% of cases.16 When present, the pain is usually severe but may vary in intensity, character, and location. In the absence of pain, unexplained abdominal distention and gastroin- testinal bleeding may be the earliest signs of ischemia and impending intestinal infarction. Fever, diarrhea, nausea and vomiting, and dimin- ished bowel sounds are other common but nonspecific manifestations. Diffuse or localized abdominal tenderness, rebound, and rigidity are ominous signs and usually herald transmural bowel infarction and peri- tonitis.

322 BASSIOUNY

DIAGNOSIS

Hematologic and serologic abnormalities are frequently detected during the course of acute mesenteric insufficiency but, unfortunately, are nonspecific. Leukocytosis of 15,000 cells/mm3 or more with a left shift, along with hemoconcentration due to extracellular fluid loss into the bowel and peritoneal cavity, is commonly d~cumented.~ Other nota- ble abnormalities include elevated amylase levels in the serum or perito- neal fluid and hyperph~sphatemia.'~ Metabolic acidosis and a rise in the serum glutamic-oxaloacetic transaminase, lactate dehydrogenase, or creatine phosphokinase occur late in the course of intestinal ischemia and often signify nonreversible ischemia or infarction.

Plain abdominal radiography is useful in excluding other causes of abdominal pain such as perforated viscus or bowel obstruction. A nor- mal plain film in a patient with pain out of proportion to physical findings is suggestive of early acute mesenteric ischemia and should prompt consideration of diagnostic arteriography. Abnormal findings on plain film suggesting mesenteric ischemia such as ileus, bowel wall edema, thumbprinting, a gasless abdomen, or intramural or portal air appear late in the course of NOMI and are suggestive of transmural infarction. Furthermore, positive findings on plain films are present in only 20% to 60% of cases.29

If technically feasible, duplex ultrasonographic examination may provide information regarding the patency of the origin and proximal segment of the SMA and aid in differentiating between occlusive and nonocclusive mesenteric ischemia. Visualization of the primary or sec- ondary branches of the SMA is difficult, if not impossible, thereby limiting this technique for the evaluation of pathology distal to the SMA origin. However, detection of superior mesenteric vein and portal venous thrombi may be possible.

Definitive diagnosis of NOMI requires expeditious arteriographic study of the aorta and mesenteric vessels. The study is invaluable in the assessment of mesenteric vasospasm and in determining other causes of acute mesenteric ischemia. If time allows, arteriography should be considered even when a decision to explore the patient has been made, in order to help formulate the most appropriate intraoperative strategy. Oral contrast studies should be avoided if arteriography is contemplated in patients suspected of having NOMI.

Siegelman et a12* have described four reliable arteriographic criteria for the diagnosis of mesenteric vasospasm: (1) narrowing of the origins of multiple branches of the SMA, (2) alternate dilatation and narrowing of the intestinal branches, the "string-of-sausages" sign (Fig. l), (3) spasm of the mesenteric arcades, and (4) impaired filling of the intramu- ral vessels. Anteroposterior and lateral views are essential for complete arteriographic evaluation to visualize the collateral arcades and origins of the major visceral vessels and exclude other causes of mesenteric ischemia. The absence of collateralization is suggestive of an acute pro- cess. Embolic occlusion of the SMA usually occurs at its origin or major

NONOCCLUSIVE MESENTERIC ISCHEMIA 323

Figure 1. Selective angiograrn of a aorto- celiac and SMA bypass graft 6 days fol- lowing revascularization. On resuming oral intake, the patient complained of abdomi- nal pain, prompting diagnostic arteriogra- phy. Note the severe vasospasm in the branches of the SMA. (From Gewertz BL, Zarins CK: Postoperative vasospasrn after antegrade mesenteric revascularization: A report of three cases. J Vasc Surg 4:382- 385, 1991 ; with permission.)

proximal branches (middle colic and ileocolic) with visualization of some collateral flow. Sluggish arterial flow without an occlusive lesion and nonopacification of the mesenteric and portal veins in the venous phase are suggestive of mesenteric venous thrombosis.

Laparoscopic evaluation may be helpful in excluding other causes of peritonitis.26 The role of this modality in the diagnosis of NOMI is limited to examination of the serosal surface and thus is helpful only in advanced cases when transmural infarction has occurred.

MANAGEMENT

Successful outcome in patients with NOMI is predicated upon the liberal use of mesenteric arteriography in patients at risk, prior to the onset of intestinal infarction. It is imperative to expeditiously manage precipitating cardiac events and maintain hemodynamic stability prior to diagnostic evaluation and definitive therapy. As indicated previously, vasoconstrictors, including digitalis preparations and a-adrenergic ago- nists, should be avoided and are preferably replaced by vasodilators that diminish cardiac preload and afterload.

Management of NOMI is essentially pharmacologic and is readily achieved by selective infusion of papaverine into the SMA. An effective treatment algorithm was previously described by Boley and his colleag~es.~, Once the angiographic diagnosis of NOMI is made and other causes of acute abdomen are excluded, intra-arterial papaverine is initiated at a dose of 30 to 60 mg/hr. Subsequent management is dictated

324 BASSIOUNY

by the patient's clinical response to vasodilator therapy. If peritoneal signs resolve, arteriography is repeated after a 30-minute saline infusion to document relief of vasospasm. Papaverine infusion should be contin- ued for at least 24 hours thereafter. It is advisable to repeat arteriography prior to discontinuation of therapy unless precluded by the risk of contrast-induced nephropathy. Certain precautions specific to the use of intra-arterial papaverine are noteworthy. The patient's hemodynamic status should be carefully monitored, as significant hypotension can result if the indwelling catheter migrates into the aorta and papaverine is infused into the peripheral circulation. In this event, the papaverine infusion should be substituted with saline and the position of the cathe- ter confirmed with plain film. Finally, heparin sodium should not be simultaneously infused owing to its chemical incompatibility with pa- paverine.

If the peritoneal signs fail to resolve with papaverine infusion and evidence exists of mounting leukocytosis, gastrointestinal bleeding, or free or intramural air, immediate celiotomy is indicated. Papaverine infusion is continued during celiotomy and postoperatively. The aim of operation is to (1) assess bowel viability, (2) resect obviously infarcted bowel segments, and (3) determine whether a second-look procedure at 24 hours is necessary. Nonviable bowel is dull gray or black in color, edematous, distended, and lacking in peristaltic activity and Doppler flow along the antimesenteric border. Although clinical assessment of intestinal viability is usually accurate, more objective methods are occa- sionally required, including the use of intraoperative Doppler ultraso- n ~ g r a p h y ~ ~ or fluorescin injection and inspection with Wood's lamp.'*

Intestinal continuity is restored after entrectomy if the margins are unequivocally viable; otherwise exteriorization is advised. Decision for a second-look procedure at 24 hours is made at the time of the initial celiotomy. If marginally viable intestinal segments are allowed to re- main, the decision to re-explore should be upheld irrespective of clinical improvement in the immediate postoperative period.

Intraoperatively, peritoneal lavage with warm saline and main- taining the ambient operating room temperature at or above 75°F help maintain normal core body temperature and alleviate vasospasm. Papav- erine infusion is continued until bowel viability is confirmed during the second-look procedure or until repeat angiography demonstrates relief of vasospasm. Systemic anticoagulation is unnecessary in patients with NOMI unless there is associated angiographic evidence of thromboem- bolism. In all patients with acute mesenteric insufficiency, broad-spec- trum antibiotics are administered to minimize septic complications re- lated to bacterial translocation and peritonitis.

SUMMARY AND CONCLUSION

NOMI remains a challenging clinical entity that demands a height- ened index of suspicion and an aggressive diagnostic and treatment

NONOCCLUSIVE MESENTERIC ISCHEMIA 325

strategy in order to avoid the untoward sequela of short bowel syn- drome and to achieve survival. Early arteriographic diagnosis and prompt institution of vasodilator therapy have proven successful in reducing the high (70% to 90%) mortality rate observed through the 1980s to 50% to 55% during the last decade. Continued investigations into the pathophysiologic mechanisms underlying splanchnic vasospasm and intestinal IR injury will, it is hoped, add more alternate and effective therapies to the current armamentarium.

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Hisham S. Bassiouny, MD Section of Vascular Surgery

University of Chicago MC5028

5841 South Maryland Avenue Chicago, IL 60637