Nonocclusive Mesenteric Ischemia

Pathophysiology

NOMI was initially described as a postmortem small intestinal gangrene in patients without evidence of arterial or venous occlusive disease. Such observations formed the basis for the hypothesis that heart failure, peripheral hypoxemia, paradoxical splanchnic vasospasm, and reperfusion injury could all contribute to its development.

Mesenteric vasospasm, usually in the superior mesenteric artery (SMA) distribution, is a sine qua non of NOMI. It can result from excessive sympathetic activity during cardiogenic shock or hypovolemia, and it represents a homeostatic mechanism that attempts to maintain cardiac and cerebral perfusion at the expense of blood flow to the visceral and peripheral organs. Vasopressin and angiotensin are the likely neurohormonal mediators of this process. In experimental models, angiotensin-converting enzyme (ACE) inhibitors appear to prevent NOMI and are more effective than α-adrenergic agonists.

The intestinal circulation possesses extensive protective mechanisms to preserve oxygen delivery to tissues. Over a wide range of blood pressure, intestinal blood flow can be maintained as a result of an autoregulatory response mediated by local and systemic factors leading to arteriolar smooth muscle relaxation and vasodilation. Below a critical pressure of 40 mm Hg, oxygen consumption declines and ischemia ensues. Intestinal ischemia begins at the mucosal villus tip and over hours extends to the remainder of the mucosa, submucosa, and muscularis.

Although intestinal autoregulation can initially offset reductions in blood flow, this adaptive response is self-limited, lasting for only several hours. Vasospasm ensues and can persist even after optimal blood flow is restored and the initiating event is corrected. The exact mechanism of persistence of vasospasm is unknown, but it plays an important role in the development and maintenance of occlusive and nonocclusive mesenteric ischemia as well as reperfusion phenomena complicating mesenteric revascularization.

Digitalis, now rarely prescribed, has historically been associated with the development of NOMI. In early series of patients, digitalis use was noted in a majority of patients with this diagnosis. Digoxin preparations have been shown to induce experimental in vitro and in vivo vascular smooth muscle contraction. In the current era, vasoactive medications such as epinephrine, norepinephrine, and vasopressin have also been associated with the development of NOMI.

Studies of reperfusion injury after mesenteric ischemia can further delineate mechanisms relevant to NOMI. As a consequence of restoration of oxygenated blood flow to hypoxic tissues, release of reactive oxygen species can result in significant cellular membrane injury, increased capillary permeability, and connective tissue degradation. Subsequent failure of intestinal autoregulation and paradoxical vasoconstriction can ensue, resulting in tissue injury.

The degree of ischemia–reperfusion injury appears to be related to the frequency as well as duration of ischemic episodes. Clark and Gewertz demonstrated that two 15-minute periods of low flow followed by reperfusion resulted in more severe histologic injury than a singe 30-minute period of ischemia. NOMI results in an analogous scenario, where hypoperfusion may be partial and occasionally repetitive. Episodic reperfusion is thought to prime the ischemic tissue with leukocytes that are attracted to and produce reactive oxygen species. This concept is further supported by studies demonstrating attenuation of ischemia–reperfusion injury by reperfusion with leukopenic blood or blockade of endothelial cell surface receptors for leukocyte adherence. Reports of NOMI following elective mesenteric revascularization have associated this syndrome with reperfusion phenomena, further supporting reperfusion injury in the pathogenesis of NOMI.