Sandbox:Feham

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

Overview

Mesenteric ischemia is a type of intestinal ischemia primarily affecting the small intestine. It is one of the life-threatening gastrointestinal vascular emergencies which requires prompt surgical/medical intervention depending upon the underlying cause.

It can be divided into occlusive/non-occlusive, arterial or venous, localized/generalized and superficial or transmural.

Overview

The anatomy and physiology of the small intestine plays a vital role in the develpoment of mesenteric ischemia. Intestinal muscosa has a high metabolic rate 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. This can lead to disrutpion 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

Three major factors contributing towards the develpoment of mesenteric ischemia are:

(a) Mesenteric vascular anatomy and physiology

(b) Collateral circulation

(c) Factors regulating the mesenteric blood flow

(a) Mesenteric vascular anatomy and physiology:

The arterial supply of the intestine originates from three major arteries:

• Superior mesenteric artery (SMA)
  • Supplies the small intestine, proximal and mid colon upto the splenic flexure.
• Inferior mesenteric artery (IMA)
  • Supplies hind gut starting from the splenic flexure to the rectum.
• Celiac artery (CA)
  • Supplies the foregut, hepatobiliary system and spleen.

• The venous system parallels the arterial branches and drains into the portal venous system.
• 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.

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 provides 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) Factors regulating the mesenteric blood flow:

Mechansims that 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:

• 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.

• 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:

• 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.

• 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, including acetylcholine, histamine, nitric oxide, leukotrienes, thromboxane analogues, glucagon, and a couple of gastrointestinal hormones.

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		Increase blood flow
Arteriolar tension receptors		Hydrogen Potasssium 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

• The watershed areas that lack collateralization are as follows:

• 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.

Mechanism of ischemia:

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

• 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 which causes reperfusion injury.
• Reperfusion injury causes release of oxygen free radicals, toxic byproducts of ischemic injury and neutrophil activation.

 The pathophysiology of mesenteric ischemia can be explained on the basis of etiology:

• Acute mesenteric arterial embolism: Attributes to 50% cases of mesenteric ischemia.
• Mesenteric embolus can oringinate from the left atrium, associated with cardiac arrythmias such as atrial fibrillation.
• Recent myocardial infarction resulting in segmental wall motion abnormality leading to poor ejaction fraction and embolus formation.
• Infective endocarditis: vegetations on the cardiac valves resulting in turbulence in blood flow predisposing to formation of emboli into the blood stream.
• Acute mesenteric arterial thrombosis:
• 25% cases of mesenteric ischemia result from mesenteric arterial thrombosis.
• Most likely due to underlying atherosclerosis(plaque formation) leading to stenosis.
• An underlying plaque(fatty streak) in the superior mesenteric artery leads to critical stenosis over the years forming collaterals.
• It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

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.

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Risk Factors

Common Risk Factors

The following conditions pose a signifiacnt risk towards the development of mesenteric ischemia either by interrupting the blood flow through the artery or vein supplying the small intestine (e.g.thromboemboli) or by reducing the blood supply (e.g. vasoconstriction). Also, there are certain life-style related risk factors which predominantly cause mesenteric ischemia in the older age group.

Risk factors
Occlusive	Embolic	Atrial fibrillation
		Cardiac arrhythmia
		Valvular heart disease
		Infective endocarditis
		Recent myocardial infarction
		Ventricular aneurysm
		Aortic atherosclerosis
	Thrombotic	Advanced age
		Low cardiac output states
		Peripheral arterial disease
		Traumatic injury
		Inherited thrombophilia- Factor V Leidin mutation Prothrombin G20210A mutation Protein S deficiency Antithrombin III deficiency Activated protein C resistance Anti-phospholipid syndrome Myeloproliferative disorders(JAK2 V617F) mutation.
		Acquired thrombophilia- malignancy, oral contraceptives intake.
Non-occlusive		Heart failure
		Aortic insufficiency
		Septic shock
		Vasoconstrictive drugs: Digoxin Alpha-adrenergic agonists
		Cocaine abuse or ergot poisoning
		Hemodialysis
Other causes		Lifestyle related risk factors: High cholesterol levels History of smoking Immobility Recent surgery Less common risk factors: Fibromuscular dysplasia Beta receptor blocking agents Hepatitis

• Common risk factors in the development of mesenteric ischemia include:
  • Occlusive causes
    • Embolic causes:
    • Atrial fibrillation
    • Cardiac arrhythmias
    • Valvular heart diseases
    • Infective endocarditis
    • Recent myocardial infarction
    • Ventricular aneurysm
    • Aortic atherosclerosis
    • Aortic aneurysm
  • Thrombotic causes:
    • Advanced age
    • Low cardiac output states
    • Traumatic injury
    • Peripheral artery disease
• Non-occlusive causes:
  • Heart failure
  • Aortic insufficiency
  • Septic shock
  • Vasoconstrictive drugs(e.g. Digoxin, alpha-adrenergic agonists)

• • Cocaine abuse or ergot poisoning

• • Hemodialysis

Less Common Risk Factors

• Less common risk factors in the development of mesenteric ischemia include:
  • Fibromuscular dysplasia
  • Hepatitis
  • Beta recpetor blocking agents
  • Polyarteritis nodosa

Causes

Narrowing of the arteries that supply blood to the intestine causes mesenteric ischemia. The arteries that supply blood to the intestines run directly from the aorta. Mesenteric ischemia is often seen in people who have hardening of the arteries in other parts of the body (for example, those with coronary artery disease or peripheral vascular disease). The condition is more common in smokers and in patients with high blood pressure or blood cholesterol. Mesenteric ischemia may also be caused by an embolus that suddenly blocks one of the mesenteric arteries. The emboli usually come from the heart or aorta. These clots are more commonly seen in patients with arrhythmias, such as atrial fibrillation. They can be broadly classified into four categories:

• Arterial thrombosis
• Arterial embolism
• Venous thrombosis
• Non-occlusive ischemia

Classification based on etiology
Etiology	Cause	Incidence	Examples
Occlusive causes	Aterial embolism	50-70%	Superior mesenteric artery obstruction (most common cause) Arrhythmia Myocardial infarction Infective endocarditis Valvular heart diseases Ventricular aneurysms History of embolic events Recent angiography
	Arterial thrombosis	15-25%	Atherosclerosis Advanced age Prolonged hypotension Hypercoagulabilty states Peripheral arterial disease Traumatic injury
	Venous thrombosis	5%	Right-sided heart failure Previous deep venous thrombosis (20-40% risk) Primary clotting disorder Pancreatitis Polycythemia Sickle cell anemia Recent abdominal surgery or infection
Non-Occlusive causes	Non-occlusive ischemia	20-30%	Low cardiac output states(most commom cause) Hypovolemia Vasoconstrictive drugs (Digoxin, alpha-adrernergic agonists) Septic schock Aortic insufficiency Cocaine abuse or ergot poisoning