Ischemic Pain

This article discusses the pathophysiology, presentation, cause, and treatment of ischemic pain in the surgical patient. Causes of ischemic pain vary but all fundamentally cause local acidosis in the peripheral tissues, which causes signals to be passed through ascending pain pathways to the thalamus and eventual cerebral cortex where it is interpreted as ischemic pain. Ischemic pain is classically associated with an insidious onset but can present in the acute or chronic setting. Treatments are aimed at improving perfusion to the affected tissue. Surgical options include repairing damaged vessels, bypassing diseased vessels, performing thrombectomy, or embolectomy. Numerous conservative therapies exist.

Key points

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The sensation of ischemic pain is of neuropathic etiology, caused by the detection of acidosis in peripheral tissues.
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Ischemic pain signals ascend through spinothalamic and spinobrachial tracts to the cerebral cortex where they are interpreted.
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Upper extremity ischemic pain can present in the acute or chronic setting.
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Treatment revolves around restoring perfusion to the affected tissue, from surgical measures to conservative pharmacotherapy.

Pathophysiology

Ischemic insults in the upper and lower extremities have many manifestations, the most significant being skin necrosis and pain. Ischemia results in a lack of oxygen and nutrients to tissues in cellular damage. Ischemic pain was once thought to be a result of direct nerve injury or stimulation, but is now thought to be a symptom of the breakdown of damaged tissue and subsequent local peripheral nerve receptor activation. When musculoskeletal tissue is deprived of oxygen, aerobic cellular metabolism is compromised resulting in the depletion of intracellular ATP. As a cons.equence, failure of the ATP-dependent sodium-potassium pump causes osmotic cellular swelling as sodium and water are retained within the cell. As the cell swells and becomes depolarized, the influx of calcium ions causes an overexcitation of the cell membrane, which results in the formation of reactive oxidative species. Reactive oxidative species cause damage to the cell, resulting in an overall extracellular acidosis. Although lactic acid also contributes to acidification of the extracellular space, it is not the primary source. During prolonged periods of ischemia, anaerobic pathways of metabolism predominate resulting in the additional build-up of lactic acid.

The sensation of ischemic pain is of neuropathic etiology, caused by the detection of acidosis in peripheral tissues. This results in increased hydrogen ions, growth factors, and cytokines, which are detected by acid-sensing ion channels and sensory pathways. Acid-sensing ion channels are a voltage-insensitive, amiloride-sensitive sodium channel family of excitatory cation channels. Once activated, these channels stimulate group III and IV muscle nerve afferent fibers, which are the muscular analogue of cutaneous Aδ and C nerve fibers. This information passes to the spinal cord dorsal horn where signals are directed through the spinothalamic and spinobrachial tracts en route to the thalamus. They are then relayed to the cerebral cortex where they are interpreted as ischemic pain.

Presentation

Ischemic pain presents differently than other types of acute pain and is dependent on how quickly the perfusion is interrupted. Ischemic pain is classically associated with an insidious onset compared with acute pain associated with limb trauma. Lower extremity claudication is an example of the ischemic pain presenting with burning, muscle cramping, calf pain with exertion, or even calf pain at rest in the later stages. Paresthesia and numbness, and motor weakness in the affected limb, have been observed. Other signs of ischemia include blanching or purple discoloration of digits, ulceration, and eventual tissue necrosis (gangrene).

Etiology

Upper extremity ischemic pain can present in the acute or chronic setting. Acute causes are diagnostically straightforward, and are often the result of traumatic penetrating injuries to arteries or vascular beds. Quantitative evidence of perfusion is available in the form of finger pressure readings in special circumstances where further evidence is desired. Digital brachial index values greater than 0.7 are widely held as evidence of adequate distal perfusion.

Chronic ischemic pain is caused by two broad categories of occlusive arterial disease: atherosclerotic and nonatherosclerotic. Atherosclerotic etiologies comprise most ischemic disease and are associated with inflammatory and fibroproliferative changes within the vessel lumen incited by comorbidities including hypercholesterolemia, diabetes, smoking, and hypertension. The pathophysiology follows a sequence of increased plasma cholesterol levels leading to increased arterial wall permeability and then to the eventual accumulation of lipids within the subendothelial space. Circulating monocytes follow into the arterial wall and eventually behave as foamy macrophages, expressing scavenger receptors leading to the mass import of cholesterol into the vessel wall. This leads to vascular changes including the development of intimal thickening, fatty streaks, fibroatheromas, and plaques, which serve to reduce overall flow through the vessel.

Less common nonatheroma causes of ischemic pain in the upper extremity include vasospasm (Raynaud disease), vasoocclusive disorders, and vasculitis ( Table 1 ). Vasospastic disease is a temporary restriction in distal perfusion compromise tissue perfusion. Raynaud disease is one such example, which like other vasospastic conditions is further divided into primary and secondary disorders. Primary vasospastic conditions can cause ischemic pain and associated dysesthesias but rarely cause ulcerations. Secondary vasospastic conditions do cause ulcerations in the distal extremities and are coexistent with ischemic pain. These are caused by and related to a variety of other conditions (see Table 1 ). Maurice Reynaud’s description of arterial insufficiency to the fingers in 1862 led to his name being the eponym of this condition. Raynaud described the process as a “local asphyxia of the extremities” as a result of “increased irritability of the central parts of the cord presiding over vascular innervation.” The asphyxia was vasospasm that resulted in anoxia to the distal digits. The anoxia manifest as paraesthesias, ischemic pain, discoloration, and eventually ulceration in many patients. Raynaud disease is often associated with an autoimmune connective tissue disorder.

Table 1

Raynaud phenomenon associated conditions

Category	Connective Tissue Disorders	Vasooclusive Disorders	Vasospastic Disorders	Pharmacologic	Occupational Exposures	Other
Examples	Scleroderma Lupus Rheumatoid arthritis Ehlers-Danlos syndrome Polymyositis Blood disorders CREST syndrome Sjögren syndrome Dermatomyositis	Atherosclerosis Thoracic outlet syndrome Buerger disease Takayasu arteritis Thromboangiitis obliterans Angiocentric lymphoma	Pheochromocytoma Carcinoid syndrome Thyroid disease	Beta-blockers Cyclosporine Bromocriptine Nicotine Ergotamine Cisplatin Vinblastine Dextroamphetamine Methylphenidate Bleomycin Clonidine Cocaine Gemcitabine Arsenic Interferon alpha Doxorubicin Cyclophosphamide	Vibration Mercury Vinyl chloride Traumatic injury	Lyme disease Multiple sclerosis Pulmonary hypertension Frostbite Anorexia