Pathophysiology of Mesenteric Ischemia

Pathophysiology of Mesenteric Ischemia

0039-6109/92 $0.00 + .20 INTESTINAL ISCHEMIA PATHOPHYSIOLOGY OF MESENTERIC ISCHEMIA Amit Patel, MO, Ronald N. Kaleya, MO, and Robert J. Sammartano, ...

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PATHOPHYSIOLOGY OF MESENTERIC ISCHEMIA Amit Patel, MO, Ronald N. Kaleya, MO, and Robert J. Sammartano, BS

It has long been recognized that the severity of ischemia-induced intestinal injury is inversely related to blood flow. 14 Ischemic injury to the intestinal mucosa occurs when the tissue is deprived of oxygen and other nutrients necessary to maintain cellular metabolism and integrity. Reduction of blood flow to the intestine may be a reflection of generalized poor systemic perfusion, as in shock or with a failing heart, or a result of local morphologic or functional changes of the splanchnic vasculature. Narrowing of the major mesenteric vessels, focal atheromatous emboli, vasculitis as a consequence of a systemic disease, or mesenteric vasoconstriction can lead to inadequate circulation at a cellular level. Whatever the cause, the results of intestinal ischemia are the same: a spectrum of injury ranging from completely reversible functional alterations to transmural hemorrhagic necrosis of portions or all of the bowel. GENERAL CONSIDERATIONS

Several factors contribute to ischemic injury of the bowel, including the state of the general circulation, the extent of collateral blood flow, the response of the mesenteric vasculature to autonomic stimuli, circulating vasoactive substances, local humoral factors, and the normal and abnormal products of cellular metabolism before and after reperfusion of the ischemic segment. In addition, the functional demands of From the Department of Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York




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the bowel, as dictated by motor, absorptive, and secretory activities; the intestinal microflora; and the rate of cellular turnover affect the extent and severity of intestinal injury. Because these factors are so diverse and cannot all be controlled in the experimental or clinical setting, investigation of the role of individual factors often does not reflect the full and profound pathophysiological consequences of intestinal ischemia.


The intestines are protected from ischemia to a great extent by their abundant collateral circulation. Communications between the celiac and superior and inferior mesenteric beds are numerous, and a general rule that has proved valid over many years is that at least two of these vessels must be compromised to produce symptomatic intestinal ischemia. Moreover, occlusion of two of the three vessels occurs frequently without evidence of ischemia, and total occlusion of all three vessels in an asymptomatic patient has been observed. Collateral pathways around occlusions of smaller arterial branches in the mesentery are provided for by the primary, secondary, and tertiary arcades in the small bowel and the marginal artery of Drummond, the central anastomotic artery, and the arc of Riolan in the colon. Within the bowel wall itself, there is a network of communicating submucosal vessels that can maintain the viability of short segments of intestine where the extramural arterial supply has been lost. The intestine responds to reductions in blood flow by redistributing flow to the various layers. In general, the intramural blood flow in regional ischemia redistributes to favor the mucosa, especially the superficial portion.": 28 Collateral pathways open immediately when a major vessel is occluded, in response to the fall in arterial pressure distal to the obstruction. Experimentally, occlusion of the superior mesenteric artery is followed, at least transiently, by an increase in celiac and inferior mesenteric arterial flows." Increased blood flow through this collateral circulation continues as long as the pressure in the vascular bed distal to the obstruction remains below the systemic pressure. Unless mesenteric vasoconstriction develops in these vascular beds, the blood flow is almost always sufficient to maintain intestinal viability. Vasoconstriction in the involved vascular bed elevates the pressure in the distal bed, causing a reduction in collateral flow and potentially compromising bowel viability. If the occlusion is removed and blood flow reconstituted, the arterial pressure in the previously obstructed bed returns to systemic levels, and flow through the collateral channels ceases. An acute decrease in perfusion pressure is compensated for by local regulatory mechanisms so that flow reduction is proportionately less than the reduction in perfusion pressure .16 This physiologic action, termed "autoregulation," is secondary to vasodilation of the resistant



vessels downstream from the occlusion, largely in response to the release of local metabolites from the ischemic tissue. Some of this vasodilation also is attributable to relaxation of vascular smooth muscle in direct response to a decreased perfusion pressure." Autoregulation of flow can be maintained for only a brief period of time. The degree of reduction in blood flow that the bowel can tolerate without damage is remarkable. In one of our studies, mesenteric arterial flow was reduced by 75% for 12 hours, yet no morphologic changes could be identified by light microscopy, and there was normal distribution of Patent Blue V dye." One reason for these findings is that, given that only one fifth of the mesenteric capillaries are open at any time, and uptake of oxygen occurs only in these open capillaries, normal oxygen consumption clearly can be maintained with only 20% to 25% of normal blood flow. When intestinal blood flow is reduced, oxygen extraction is increased, allowing a fairly constant oxygen consumption over a wide range of blood flows. Additionally, the arteriovenous oxygen difference widens as a reflection of the enhanced oxygen extraction. However, below a critical level of blood flow, oxygen consumption falls precipitously because increased extraction can no longer compensate for the diminished blood flow. 10


There is an extensive network of vessels within the bowel wall arising from the vasa recta and vasa brevia on the mesenteric border of the bowel. These vessels give rise sequentially to the external muscular vascular plexus, then penetrate the muscular coat and form a rich submucosal plexus. This plexus is more extensive in the small bowel than in the colon and may make the small intestine more resistant to ischemia than the colon." A central arteriole originates from the submucosal plexus, loses its muscular coat, and arborizes into an extremely rich subepithelial capillary network within each individual villus. The flow through this redundant system is controlled by a network of resistance and capillary vessels, which in turn are affected by many functional, humoral, local, and neural influences. There are two primary mechanisms for the control of splanchnic vascular resistance. The first is neural, mediated by the autonomic nervous system. The second is humoral, consisting of a variety of circulating hormones, including catecholamines, vasoactive peptides, and inflammatory mediators such as histamine and the arachidonic acid metabolites. A number of pharmaceutical agents have either primary or secondary effects on the splanchnic vasculature, and many of these are splanchnic vasoconstrictors. In the clinical setting, use of these agents can cause splanchnic ischemia.


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The sympathetic nervous system, primarily by activation of the alpha-adrenergic receptors, is important for the maintenance of resting splanchnic arteriolar tone. Although circulating catecholamines also playa role, the primary mechanism of sympathetic control is neural. Particularly, stimulation of afferent adrenergic fibers releases norepinephrine from the nerve synapses supplying the smooth muscle of the precapillary resistance vessels. However, as seen elsewhere in the body," 18 reduction of blood flow is associated with disproportionate vasoconstriction in the postcapillary venous beds that comprise the capacitance vasculature." The combined effect of vasoconstriction of the arterial and venous beds cannot be predicted, but in the cat, even in instances where the overall blood flow is reduced by 50%, the blood flow to the villi is preserved at normal or near-normal levels. Within minutes of the initial vasoconstriction, blood flow rises to near-normal levels (autoregulatory escape). The exact nature of this response has not been elucidated, but it seems to be a generalized process inherent to all vascular smooth muscle. The most appealing explanation is the differential effects of the alpha- and beta-adrenergic stimuli. Betaadrenergic agonists cause vasodilation, whereas alpha-adrenergic agents cause vasospasm. The net alteration in intestinal blood flow produced by sympathetic stimulation cannot be predicted from experimental studies, because adrenergic stimuli also change bowel motility and wall tension, absorption, and secretion, all of which can have a pronounced effect on the regional and local blood flow. 21 Circulating catecholamines influence the splanchnic vasculature in a manner similar to norepinephrine released at local sympathetic nerve terminals, as discussed above. The major sympathetic response in circulatory shock is mediated by the neural pathway.

Humoral Factors

The important vasoconstrictor peptides include angiotensin II and vasopressin. Vasopressin selectively affects the splanchnic resistance vasculature, and this response is disproportionately greater than that of the systemic circulation." This differential vasoconstriction is exploited in the use of vasopressin for the therapeutic control of gastrointestinal hemorrhage. Vasopressin is released as a result of systemic hypotension, and if the latter results from mesenteric ischemia, the vasopressin may exacerbate vasoconstriction in the splanchnic vessels. In a canine model of occlusive mesenteric ischemia, Bulkley et al demonstrated the preferential constriction of the ischemic segments of intestine by vasopressin. 12 Similarly, a differential vasoconstriction is seen in the response of



the splanchnic vasculature to angiotensin II. This is probably secondary to the greater number of angiotensin II receptors in the splanchnic vascular smooth muscle, as demonstrated by Gunther et a1. 20 Clinically, the splanchnic hypersensitivity to angiotensin II, which is generated by renin released from the hypotensive kidney during a low-flow state, may be a contributory mechanism underlying mesenteric ischemia. In an experimental cardiogenic shock model of nonocclusive mesenteric ischemia, disproportionate ischemia was found secondary to severe splanchnic vasospasm. This response was unaffected by blockade of the sympathetic nervous system but was abolished by inhibition of the renin-angiotensin axis. These hemodynamic changes correlated closely with plasma renin levels and could be reproduced, in the absence of shock, by the infusion of angiotensin II directly into the mesenteric vessels. In addition, the histologic intestinal damage resembles that seen with nonocclusive mesenteric ischemia."

Local Factors

Although many arachidonic acid metabolites cause splanchnic vasodilation, the prostaglandins PGF 2a , PGB 2 and PG02; the leukotrienes C 4 and 04; and some thromboxane analogues produce splanchnic vasoconstriction.P Blockade of prostaglandin synthesis with aspirin, indomethacin, or meclofenamate produces a decrease in the resting levels of splanchnic flow, suggesting that one or more of the arachidonic metabolites playa role in maintaining vasodilator tone. 17 Local factors that accompany ischemia have a potent vasodilatory effect on intestinal vessels. Hyperkalemia, hyperosmolarity of the blood, decreased local oxygen tension, adenosine released on breakdown of adenosine triphosphate, and a high concentration of carbon dioxide causing local acidosis will dilate resistance vessels and produce local hyperemia. Boley and associates" snowed in dogs that high intraluminal potassium concentrations cause an initial vasodilation followed by severe vasoconstriction, leading to local ischemia of the affected bowel segment. Subsequently, those investigators correlated these findings with the occurrence of small-bowel ulcers in patients receiving oral potassium chloride supplementation in tablet form." Gastrointestinal hormones, including cholecystokinin, gastric in~ hibitory peptide, glucagon, neurotensin, and secretin, have been studied for an effect on intestinal blood flow. To date, administration of these hormones in physiologic concentrations has shown no appreciable effect on intestinal blood flow. 27

Consequences of Bowel Function for Blood Flow

Motor activity, especially of the colon, where intraluminal pressures can exceed the systemic arterial pressure for short periods, can markedly


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reduce the overall blood flow. However, the accumulation of waste metabolites during the period of function can, concurrently, increase the local blood flow. The sum effect of these factors, again, cannot be predicted. With increased vascular permeability in the intestine caused by ischemia and reperfusion injury, accumulation of fluid in the bowel wall and lumen can cause distention, which may also impede blood flow, especially when the mesenteric perfusion pressure falls, as in occlusive mesenteric ischemia. Pharmacologic Effect of Exogenous Vasodilators on Blood Flow

Locally administered vasodilators such as papaverine prevent or reverse the persistent vasoconstriction following a drop in blood flow in the superior mesenteric artery. This observation suggested that intraarterial papaverine could be used clinically to treat vasoconstriction associated with the low-flow syndrome. Kukovetz and Poch showed that papaverine is a potent inhibitor of the enzyme phosphodiesterase, which is the major enzyme in the degradation of cyclic adenosine monophosphate (cAMP), which modulates vascular smooth-muscle relaxation." Inhibition of this enzyme potentiates the vasodilatory effect of cAMP by allowing it to accumulate rather than be metabolized by the phosphodiesterase. Other agents, such as prostaglandin £1 and glucagon, may also act via this pathway by increasing the formation of cAMP. 8 Mesenteric Vasoconstriction

Despite adequate collateral pathways in most cases, acute interruption or diminution of blood flow in the mesenteric circulation caused by emboli or hypotension can result in intestinal ischemia secondary to persistent vasospasm. A decrease in flow in the superior mesenteric artery initially produces local vascular responses that tend to maintain intestinal blood flow, but if the diminished flow is prolonged, active vasoconstriction develops, which may persist even after the primary cause of the decreased flow is corrected. In 1948, Laufman furnished experimental evidence that persistent vasoconstriction follows superior mesenteric artery occlusion by embolus or thrombosis." He described "residual vasospasm" in precapillary arteries after the release of occlusion in the mesenteric circulation. Prolonged vasoconstriction associated with emboli occurring in the absence of shock and persisting even after embolectomy has been reported by Boley et al. 4 Moreover, Martin and his associates found that intravenously administered papaverine dilated "reflex vasospasm" in collateral vessels, which occurred proximal to and in response to an arterial occlusion.:"



Boley and associates" have shown that after an acute 50% reduction in blood flow in the superior mesenteric artery of anesthetized dogs, the arterial pressure in the peripheral mesenteric arteries fell to 49% of mean control values. When the flow was maintained at 50% of normal, the mesenteric arterial pressure returned to control values in 1 to 6 hours, while the celiac flow, which had initially increased, fell to control levels. The greater fall in mesenteric pressure suggests lowered resistance or vasodilation, but Selkurt et al have demonstrated that changes in active resistance cannot be deduced when pressure and flow are changing in the same direction. 31 The increased vascular resistance caused by vasoconstriction ultimately resulted in decreased collateral perfusion through the celiac system. If the occluder was removed from the superior mesenteric artery as soon as the mesenteric arterial pressure rose to control values, the flow through the superior mesenteric artery immediately returned to normal. However, if the occlusion was maintained for 30 to 240 minutes after the mesenteric arterial pressure had returned to control levels, the flow in the superior mesenteric artery did not return to normal. Rather, it remained at 30% to 50% of control values because of persistent arterial vasoconstriction despite the removal of the occlusion. This decreased flow continued for as long as 5 hours of observation. In this manner, mesenteric vasoconstriction plays a significant role in the development of ischemia in both acute occlusive and nonocclusive arterial forms of mesenteric ischemia. When papaverine was infused during the 50% flow restriction, the mesenteric arterial pressure remained low, and increased celiac flow persisted throughout 4 hours of observation. The flow in the superior mesenteric artery returned to normal on release of the obstruction. On the basis of these observations, the use of intra-arterial papaverine infusions is recommended in the management of both the occlusive and nonocclusive forms of acute mesenteric ischemia. Intra-arterial papaverine is also recommended for some patients with acute mesenteric venous thrombosis, which has been shown experimentally to cause arterial spasm." The presumption that the bowel injury occurs during the period of diminished cardiac output or hypotension and that correction of these problems returns the mesenteric blood flow to normal does not explain adequately the operative findings of persistent bowel ischemia when no arterial or venous obstruction is found and cardiac function has been optimized. The onset of abdominal signs and symptoms caused by intestinal ischemia may actually begin after the correction of the primary systemic problems in patients with nonocclusive mesenteric ischemia. This paradox can be explained by the experimental observations that an episode of low mesenteric flow, as short as 2 hours in duration, can produce mesenteric ischemia as a result of persistent vasoconstriction, and this ischemia may continue after the correction of the initiating problem. Bulkley et aP2 questioned the salutary effect of papaverine in occlusive mesenteric ischemia based on experimental studies in isolated intestinal loops. Their experiments showed that papaverine adminis-


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tered intravenously during a brief period of occlusion actually caused an adjacent nonischemic segment to steal blood flow from the ischemic segment. This was postulated to result from vasodilation of the adjacent normal vascular bed in the presence of an already maximally vasodilated ischemic segment. These experimental findings are contradicted by the very clear morphologic, roentgenologic, and clinical benefits of papaverine in nonocclusive and occlusive mesenteric ischemia, suggesting that the findings were a result of the design of the experimental model rather than a clinically significant finding. In fact, because Bulkley and his associates made their observations immediately and for just 15 minutes after acute occlusion, it is not surprising but entirely predictable that-because they were looking at the initial and early hemodynamic responses-they found no evidence of vasoconstriction and that vasodilators did not appear beneficial.


Intestinal ischemia induces a spectrum of injury, from subtle changes in capillary permeability to transmural necrosis, and the final outcome is dependent on local as well as systemic factors. There are basically two separate factors responsible for the subsequent damage. Hypoxia is the initial insult and is followed by reperfusion injury when some flow is re-established. As the injury progresses and homeostatic changes occur, one region may be experiencing hypoxic injury while another is undergoing reperfusion. The changes that occur when intestine is deprived of an adequate blood supply are both metabolic and morphologic. Brown et al" noted some ultrastructural changes within 10 minutes and at 30 minutes found extensive changes including accumulation of fluid between cells and the basement membranes. The tips of the villi then begin to slough, and a membrane of necrotic epithelium, fibrin, inflammatory cells, and bacteria accumulates. Later, edema appears, followed by bleeding into the submucosa. Cellular death progresses from the lumen outward until there is transmural necrosis of the entire bowel wall. 1, 14 The exact nature of the cellular processes responsible for the changes is not clear, but numerous pathways have been implicated. An important consequence of ischemic bowel disorders is enhanced transcapillary filtration, interstitial edema, and, ultimately, the net movement of fluid into the lumen of the bowel. Comparison of vascular permeability in control intestinal preparations and preparations subjected to 1 hour of ischemia with and without subsequent reperfusion clearly indicated that both ischemia and reperfusion increase vascular permeability. 19 Several endogenous substances, including oxygen free radicals, platelet-activating factor, arachidonic acid metabolites, and bacterial endotoxins, have been implicated in the pathogenesis of intestinal ischemia. These substances are released during small bowel ischemia,



and they are felt to be important mediators of the ischemic injury. There is a rapidly growing body of evidence that oxygen radicals such as superoxide, hydrogen peroxide, and hydroxyl radical mediate the cellular injury produced by reperfusion of ischemic intestine and other tissue. (see article by Zimmerman and Granger elsewhere in this issue.)


Although the primary function of the small intestinal mucosa is the absorption of nutrients, it also is an important barrier to luminal bacteria and their toxins. Recent studies have documented that the barrier function of the intestinal mucosa is deranged in experimental animals subjected to ischemia. Changes in mucosal permeability induced by ischemia and reperfusion have been studied by measuring either the clearance from blood to the intestinal lumen of various agents or the translocation of luminal bacteria to mesenteric lymph nodes. Several investigators have shown that complete ischemia followed by reperfusion leads to a marked increase in gut mucosal permeability .15,26 Chui et al showed that the morphologic changes and the magnitude of the increment in mucosal permeability are directly related to the extent and duration of the ischemic insult." It appears that oxygen uptake must be reduced to less than 50% of control values for ischemiareperfusion to increase mucosal permeability." The precise mechanism for ischemic and ischemic-reperfusion injuries has yet to be elucidated, but sepsis is the principal clinical consequence of the increased vascular permeability and bacterial translocation. PATHOPHYSIOLOGIC RESPONSE TO ACUTE MESENTERIC ISCHEMIA

The pathophysiologic response to reduced intestinal blood flow is complicated, and the consequences of mesenteric ischemia are only now being fully appreciated. On occlusion of the superior mesenteric artery, there is initially a marked increase in bowel activity. This increase in motor function results in rapid bowel evacuation and increases the oxygen demands of the affected intestine. Shortly thereafter, bowel motility ceases either as a result of the massive sympathetic response to mesenteric ischemia or as a consequence of local factors associated with the ischemia itself. Within hours, the bowel becomes hemorrhagic and edematous as the capillary integrity is compromised. Intramural hydrostatic pressure rises with increased edema and hemorrhage. In normal bowel, this increased intramural pressure is usually well tolerated, but as perfusion pressure to the edematous bowel decreases, the edema can further compromise an already marginal blood flow. In addition, bacterial utilization of a marginally adequate intestinal oxygen

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supply and production of toxic metabolites may exacerbate the ischemic injury. The shift of intravascular volume into the bowel wall causes severe hemoconcentration and hypovolemic shock. Vasoactive mediators and bacterial endotoxins are released from the ischemic bowel into the peritoneal cavity and absorbed into the general circulation, causing a variety of physiological effects such as cardiac depression, septic shock, and acute renal failure. These effects may contribute to the death of the patient even before there is complete necrosis of the bowel wall. FUTURE CONSIDERATIONS

The local and systemic pathophysiological effects of mesenteric ischemia are slowly being elucidated. With increased understanding of the mediators of persistent vasoconstriction and cellular injury, pharmacologic agents such as selective mesenteric vasodilators, angiotensin II antagonists, prostaglandin inhibitors, and free radical scavengers may ameliorate the injury and improve patient survival.

References 1. Ahren C, Haglund U: Mucosal lesions in the small intestine of the cat during low flow. Acta Physiol Scand 88:1-9, 1973 2. Bailey RW, Bulkley GB, Hamilton SR, et al: Protection of the small intestine from nonocclusive mesenteric ischemic injury due to cardiogenic shock. Am J Surg 153:108116, 1987 3. Banks RO, Gallavan RH, Zinner MJ, et al: Vasoactive agents in control of the mesenteric circulation. Fed Proc 44:2743-2749, 1985 4. Boley SJ, Brandt LJ, Veith FJ: Ischemic disease of the intestine. Curr Probl Surg 15:185, 1978 5. Boley SJ, Allen AC, Shultz L, et al: Potassium induced lesions of the small bowel 1. JAMA 193:997-1000, 1965 6. Boley SJ, Shultz L, Krieger H, et al: Experimental evaluation of thiazides and potassium as a cause of small bowel ulcers. JAMA 192:763-766, 1965 7. Boley SJ, Regan JA, Tunick PA, et al: Persistent vasoconstriction: A major factor in nonocclusive mesenteric ischemia. Curr Topics Surg Res 3:425-430, 1971 8. Boorstein JM, Dacey LJ, Cronenwett JL: Pharmacologic treatment of occlusive mesenteric ischemia. J Sci Res 44:555-560, 1988 9. Brown RA, Chui C, Scott HJ, et al: Ultrastructural changes in the canine ileal mucosal cell after mesenteric artery occlusion. Arch Surg 101:290, 1970 10. Bulkley GB, Kvietys PR, Perry MA, et al: Effects of cardiac tamponade on colonic hemodynamics and oxygen uptake. Am J Physiol 244:G605-G612, 1983 11. Bulkley GB, Kvietys PR, Parks DA, et al: Relationship of blood flow and oxygen consumption to ischemic injury in the canine small intestine. Gastroenterology 89:852-857, 1985 12. Bulkley GB, Womack WA, Downey JM, et al: Collateral blood flow in segmental intestinal ischemia: Effects of vasoactive agents. Surgery 100:157-165, 1986 13. Chapnick BM, Feigen LP, et al: Differential effects of prostaglandins in the mesenteric vasculature bed. Am J Physiol 235:H326-H332, 1978 14. Chiu CJ, McArdle AH, Brown R, et al: Intestinal mucosal lesions in low flow states I: A morphological, hemodynamic and metabolic reappraisal. Arch Surg 101:478-483, 1970 15. Crissinger KD, Granger ON: Mucosal injury induced by ischemia and reperfusion in


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Address reprint requests to Ronald N. Kaleya, MD Department of Surgery Albert Einstein College of Medicine Montefiore Medical Center 111 East 210th Street Bronx, NY 10467