Mesenteric ischemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

The factors that regulate the intestinal blood flow play a vital role in the development of mesenteric ischemia. Mucosa of the intestines has a high metabolic activity and accordingly a high blood flow requirement. The majority of blood supply of the intestine comes from the superior mesenteric artery, with a collateral blood supply from superior and inferior pancreaticoduodenal arteries (branches of the celiac artery) as well as the inferior mesenteric artery. The splanchnic circulation (arteries supplying the viscera) receives 15-35% of the cardiac output, making it sensitive to the effects of decreased perfusion. Mesenteric ischemia occurs when intestinal blood supply is compromised by more than 50% of the original blood flow without activation of adaptive responses. This can lead to disruption of mucosal barrier, allowing the release of bacterial toxins (present in the intestinal lumen) and vasoactive mediators which ultimately lead to complete necrosis (cell death) of the intestinal mucosa. This can further progress to depression in myocardial activity, sepsis, multiorgan failure, and without prompt intervention, even death.

Pathophysiology

Pathogenesis

• Intestinal mucosal damage occurs in response to ischemic insult.
• In response to providing protection from ischemia, mesenteric vessels undergo intrinsic autoregulation, which is an adaptive response to ischemia.
• In order to compensate for the ischemia, there is vasoconstriction of mesenteric vessels resulting in increased tissue oxygen extraction along with vasodilation of the collateral vessels. Owing to this mechanism, intestine is able to compensate for around 75% reduction in blood flow.

Factors contributing in the pathogenesis of mesenteric ischemia:

• (a) Mesenteric blood supply (General circulation)
• (b) Collateral circulation
• (c) Response of mesenteric vasculature to ischemia
• (d) Vasoactive and humoral factors

(A) Mesenteric blood supply (General circulation)

• The mesenteric circulation recevies approximately 25% of the resting and 35% of the postprandial cardiac output.
• Mucosal and submucosal layers of the intestine receive 70% of the mesenteric blood flow, with the rest supplying the muscularis and serosal layers.

• The arterial supply of the intestine originates from three major arteries which include superior mesenteric artery, inferior mesenteric artery and celiac artery:

Arterial	Region supplied
Superior mesenteric artery (SMA)	Small intestine, proximal and mid colon upto the splenic flexure.
Inferior mesenteric artery (IMA)	Hind gut starting from the splenic flexure to the rectum.
Celiac artery (CA)	Foregut, hepatobiliary system and spleen.
Venous supply
The venous system parallels the arterial branches and drains into the portal venous system.

Commonly affected arteries:

• Embolus can typically lodge into points of normal anatomic narrowing.
• This makes superior mesenteric artery the most vulnerable site because of its relatively larger diameter (more blood flow) and low take off angle (more likely to from the aorta.
• The majority of emboli lodge 3-10cm distal to the origin of superior mesenteric artery, classically sparing the proximal jejunum and colon.

(B) Collateral circulation

The role of collateral circulation in the development of mesenteric ischemia is as follows:

• Intestines receive collateral blood supply at all levels from the superior and inferior pancreaticoduodenal arteries, branches of the celiac artery, which provide protection from ischemia.
• These arteries can compensate for 75% reduction in mesenteric blood flow for upto 12 hours, without substanial injury.
•  An extensive collateral circulation protects the intestines from transient periods of inadequate perfusion. However, prolonged reduction in splanchnic blood flow leads to vasoconstriction in the affected vascular bed, and eventually reduces collateral blood flow.  
• The SMA and IMA communicate via the marginal artery of Drummond and the meandering mesenteric artery.
• Collateralization between the IMA and systemic circulation occurs in the rectum as the superior rectal (hemorrhoidal) vessels merge with the middle rectal vessels from the internal iliac arteries.
• The areas lacking this collateralization are prone towards ischemia.

(C) Response of mesenteric vasculature to ischemia

• Mesenteric ischemia occurs when the blood supply to mesentery is reduced leading to disruption of cellular metabolism owing to oxygen and nutrient deficiency.
• In the first 4 hours following ischemia, necrosis of the mucosal villi occurs.
• Persistent ischemia for more than 6 hours results in transmural, mural or mucosal infarction, ultimately leading to bowel perforation.
• Prolonged ischemia leads to progressive vasoconstriction of the mesenetric vessels which raises the pressure in them resulting in lowering the collateral flow.
• This is followed by vasodilation, trying to restore blood flow to the area of ischemic insult.

The sequence of events that take place in the small intestine subsequent to decreased blood flow:

Ischemic insult

Decreased delivery of oxygen and nutrients

Disruption in cellular metabolism

Tissue injury due to hypoxia and reperfusion

Full thickness necrosis of the bowel

Perforation of the bowel wall

Post ischemic cellular changes:
Time duration since ischemia	Pathological changes in the small intestine
3-4 hours	Necrosis of the mucosal villi
6 hours	Transmural, mural or mucosal infarction
1-4 days	Bowel hemorrhage

Reperfusion injury:

• Restoration of blood flow to the area of ischemic insult results in reperfusion injury.
• This leads to release of oxygen free radicals, toxic byproducts of ischemic injury and neutrophil activation.
• Immune cells remove dead and damaged cells releasing cytokines such as TNF-alpha
• Blood vessels become more permeable leading to edema of the small intestine.
• As the ischemia progresses from mucosa to all the layers beneath (transmural), it leads to breaks in the epithelial lining.
• This allows bacteria in the intestinal lumen to enter into the peritoneal cavity causing peritonitis.
• If bacteria enter into the blood stream, it results in systemic inflammatory response syndrome, which ultimately results in sepsis and septic shock.

(D) Vasoactive and humoral factors regulating the mesenteric blood flow

• Vasoactive and humoral factors control the regulation of vascular tone of mesenteric circulation in response to periods of stress such as systemic hypotension or postprandial state.

• Physiologically mesenteric circulation is affected by:
  • Intrinsic regulatory system that includes metabolic and myogenic factors.
  • Extrinsic regulatory system that includes neural and humoral factors.

Intrinsic regulation:

(a) Metabolic factors:

• Reduction in blood supply to the mesentery causes adaptive changes in the splanchnic circulation.
• A discrepancy between tissue oxyegn demand and supply raises the concentration of local metabolites such as hydrogen, potassium, carbon dioxide, and adenosine, resulting in vasodilation and hyperemia.

(b) Myogenic factors:

• Myogenic theory suggests that arteriolar tension receptors act to regulate vascular resistance in accordance with the transmural pressure.
• An acute decrease in perfusion pressure is compensated for by a reduction in arteriolar wall tension, thereby maintaining splanchnic blood flow.

Extrinsic regulation:

(a) Neural component:

• The extrinsic neural component of splanchnic circulatory regulation comprises the alpha-activated vasoconstrictor fibers.
• Intense activation of vasoconstrictor fibers through alpha-adrenergic stimulation results in vasoconstriction of small vessels and a decrease in mesenteric blood flow.
• After periods of prolonged alpha-adrenergic vasoconstriction, blood flow increases, presumably through β-adrenergic stimulation, which acts as a protective response.
• Although numerous types of neural stimulation (e.g. vagal, cholinergic, histaminergic, and sympathetic) can affect the blood supply of the gut, the adrenergic limb of the autonomic nervous system is the predominant neural influence on splanchnic circulation.

(b) Humoral component:

• Numerous endogenous and exogenous humoral factors affect the splanchnic circulation.
• Norepinephrine and high doses of epinephrine produce intense vasoconstriction by stimulating the adrenergic receptors.
• Other pharmacologic compounds that decrease splanchnic blood flow include:
  • Vasopressin
  • Phenylephrine
  • Digoxin
• Low-dose dopamine causes splanchnic vasodilation, whereas higher doses lead to vasoconstriction by stimulating alpha adrenergic receptors.
• Exogenous agents that increase mesenteric blood flow include:
  • Papaverine
  • Adenosine
  • Dobutamine
  • Fenoldopam
  • Sodium nitroprusside
• In addition, numerous natural neurotransmitters can serve as splanchnic vasodilators, such as:
  • Acetylcholine
  • Histamine
  • Nitric oxide
  • Leukotrienes
  • Thromboxane analogues
  • Glucagon

Factors regulating mesenteric blood flow
Extrinsic reguatory system
Humoral (endogenous and exogenous)		Neural component
Decrease blood flow	Increase blood flow	Decrease blood flow	Increase blood flow
Epinephrine (high dose) Norepinephrine (moderate to high dose) Dopamine (high dose) Phenylephrine Vasopressin Angiotensin Digoxin	Epinephrine (low dose) Norepinephrine (low dose) Dopamine (low dose) Dobutamine Sodium nitroprusside Papaverine Nitric oxide Acetylcholine Histamine	Alpha-adrenergic receptors Dopamenergic receptors	Beta adrenergic receptors
Intrinsic regulatory component
Decrease blood flow (Myogenic factors)		Increase blood flow (Metabolic factors)
Arteriolar tension receptors		Hydrogen Potassium Carbon dioxide Adenosine

Areas prone to ischemia:

Areas prone to ischemia	Blood supply
Splenic flexure	End arteries of superior mesenteric artery
Rectosigmoid junction	End arteries of inferior mesenteric artery

Watershed areas lacking collateralization:

• Splenic flexure
  • Supplied by the end arteries of SMA with no collateral circulation.
• Rectosigmoid junction
  • Supplied by the end arteries of IMA with no collateral circulation.

• Middle segment of jejunum
  • This area is the farthest from collateral circulation and hence prone to ischemia as compared to other segments of jejunum.

Pathogenesis of occlusive mesenteric ischemia:

Vascular occlusion

Blood flow<metabolic demand

Mucosal barrier disruption and bacterial translocation into the circulation

Anaerobic glycolysis in mucosa and lactate production

Activation of vascular and humoral factors leading to vasoconstriction

Systemic activation of inflammatory response

Lactic acidosis

Intestinal necrosis

Multiorgan failure

Pathogenesis of non-occlusive mesenteric ischemia:

Hypovolemia

Cardiac failure

Endogenous vasoconstriction

Splanchnic vasoconstriction

Gut mucosal hypoperfusion

Restoration of blood by vasodialtion of collaterals

Gut mucosal barrier disruption

Ischemia-reperfusion injury

Increased mucosal perfusion to bacterial toxins

Activation of inflammatory response

Gross Pathology

Gross pathology shows following changes:

• Early stage of ischemia: Intestinal wall in congested.
• Late stage of ischemia: Edematous, friable and hemorrhagic bowel wall.