Chapter 50. Peripheral Vascular Disease

By late middle age 5% of men and women have developed peripheral arterial disease, and within 5 years one quarter of these will develop pain at rest, ulceration, and gangrene (critical limb ischemia).1 Physicians practicing in the specialty of pain medicine need to be familiar with the causes and management of pain due to peripheral vascular disease because it has a high prevalence and appropriate management can significantly improve the quality of life for these patients. The pain physician may also be able to significantly improve life expectancy because one half of the patients with symptomatic peripheral vascular disease also have coronary and/or carotid artery disease, and many will not be receiving recommended secondary and tertiary preventive therapy. This chapter outlines the disease conditions and treatments for pain associated with peripheral vascular disease.2

Pain similar to that experienced with peripheral vascular disease can be experimentally produced using a sustained tourniquet inflation on an extremity. In experimental studies, as time passes, tissue oxygenation levels fall, metabolic byproducts accumulate, reactive cellular agents are released, nociceptive signals entering the central nervous system increase, and patients report increasing pain intensity. The affective descriptors for this pain may differ and be more difficult to tolerate than pain produced by other experimental modalities. Patients with peripheral vascular disease experience this type of pain but without the ability to restore blood flow by releasing the tourniquet. Effective management of this pain can make a significant difference in quality of life for these patients.

Arterial insufficiency is most commonly the result of occlusive diseases with atheroma formation (arteriosclerosis obliterans), but less commonly it occurs in thromboangiitis obliterans (Buerger disease), Raynaud syndrome, diabetic arteritis, and arteritis associated with collagen disease. Other diseases with vascular-related causes such as migraine and cluster headache are discussed elsewhere (Chapter 20).

Atheroma and Its Consequences: Arteriosclerosis

The role of lipids was suggested with the early appearance of fatty streaks in young soldiers during emergency surgery and at autopsy in the 1970s. The role of lipids distinguishes arteriosclerosis from other arterial disease. Primary and secondary prevention strategies are available to reduce the incidence and/or aggressively treat the known risk factors of hypercholesterolemia, hypertension, cigarette smoking, and poor control of diabetes. As the disease progresses, plaque formation tends to occur at bifurcations in large- and medium-sized arteries, where turbulence, alteration of laminar flow, and shear stress may provoke an endothelial and/or vascular smooth muscle response. Arteriosclerosis is a dynamic process that involves vascular and inflammatory tissue responses with decreased release of nitric oxide and other protective secretions, increased release of cytokines by inflammatory cells responding to exposed matrix, and release of growth factors from the endothelium, as well as platelet activation. Arteries may initially respond to this process with an increase in size, but this arterial remodeling may not be sustained in the face of ongoing plaque accumulation. Although a full discussion of the process is beyond the scope of this chapter, further understanding of the causes at the gene and cellular level will suggest more effective treatment options.

Progression of Atheromatous Plaques

Although arteriosclerosis is most prominent at bifurcations, the straight femoropopliteal segment is involved in 60% of lower limb disease. Interestingly, the upper limbs are less often involved. Initially, as vessel diameter begins to decrease, flow can be maintained if velocity increases until luminal loss approaches 80 percent (Fig. 50-1). Vessel size also may increase, especially at the arteriolar level, forming a collateral supply. As vessel diameter continues to decrease beyond 70%, the patient may develop symptoms, especially if the process is affecting collateral vessels as well. The initial symptoms usually occur during exercise when the circulation is stressed. Even in patients with severe claudication, blood flow may be near normal at rest. With progression, critical limb ischemia develops with an incidence of 0.5 to 1 per 1000.3

Mechanism of Pain from Arterial Disease

Oxygen is the most flow-limited nutrient for muscle and skin. Striated muscle is capable of working anaerobically, with delayed repayment of the oxygen debt. Lactate and pyruvate levels rise as oxygen debt continues. It is assumed that the accumulation of these products of metabolism trigger firing of C-fiber nociceptors, thus triggering the pain cascade.

As oxygen tissue levels fall, hypoxia triggers altered Ca2+ signaling in vascular smooth muscle,4 gene transcription for expression of inflammatory cytokines such as tumor necrosis factor,5 interleukin-1 and 106, and cytokine factors promoting vessel growth, particularly growth of small vessel less than 200 microns in diameter.9 Endothelial dysfunction is associated with an altered release of mediators such as NO, eicosanoids, endothelium-derived hyperpolarizing factor, endothelin, and angiotensin II.10 Inflammatory cytokines also affect the coagulation system, for example hypoxia-triggered release of IL-1 can decrease tissue plasminogen activator and stimulate release of plasminogen activator inhibitor-1.11 Decreased release of NO leads to an increase of endothelial adhesiveness to circulating white blood cells.12 Inflammatory mediators may both directly and indirectly trigger C-fiber nociceptor barrage into the CNS.

Clinical Picture of Occlusive Arterial Disease

The patient may complain of claudication and/or rest pain. Claudication is defined as pain in a muscle group (commonly the calf, less often the thigh, instep, or buttock) that occurs while walking and forces the patient to stop. Pain is rapidly relieved by rest, after which walking can be resumed. Walking distance typically decreases as the disease progresses. The diagnosis can often be made with a careful history. Sometimes another disease such as arthritis produces infirmity so the patient cannot exercise. In these cases the diagnosis may be made by examination. In cases of severe coronary disease, the angina linked to very low effort walking may occur before claudication, masking this presentation of the disease. Often the reverse is true, and the presence of claudication may limit the patient’s exercise tolerance so that even significant coronary disease may remain quiescent. Because one half of the patients with symptomatic peripheral vascular disease also have coronary artery disease, patients with claudication have only a 50% chance for a 10-year survival rate, with most deaths due to myocardial infarction.13 For this reason, all patients with claudication should receive preventive treatment to reduce the risk of myocardial infarction and stroke. The differential diagnosis includes venous and neurogenic claudication. The latter is caused by stenosis of the central spinal canal. Spinal stenosis, constricting the cauda equina, can cause pain in the legs during walking. In this case, pain may be worse with trunk extension and better with flexion, so walking downhill (extending the spine) may be more painful than uphill and the peripheral pulses may be good. This diagnosis can be confirmed with computed tomography (CT) or magnetic resonance imaging (MRI) study. If the history is adequate, the site of claudication also may indicate the level of occlusion (Table 50-1). Intermittent claudication is more common in men than in women, in whom it is rare before menopause.

Rest pain (pedal ischemia) consists of pain in the toes or forefoot with or without ulceration or gangrene. The history of ischemic pain is invariably that of pain occurring at night (after a variable recumbent period). This causes the patient to arise and is relieved by dependency of the limb. Patients may volunteer that they prefer to sleep in a chair. As the condition progresses, rest pain becomes more continuous and the condition of the toes deteriorates. Ulceration or gangrene may occur. Spontaneous tissue necrosis may occur in the most peripheral distribution and is likely to affect the toes. It may also occur following trauma, overzealous chiropody, or orthopedic procedures such as operations for bunions and ingrown toenails. Rest pain usually is preceded by claudication, but sometimes it appears in patients who have little or no claudication pain.

Other Relevant History

Arteriosclerosis is a systemic disease, and the history may be positive for myocardial ischemia (infarcts or angina), stroke, hypertension, arrhythmias, and transient ischemic attacks (in the form of focal neurologic deficits resolving within 24 hours). A careful medication history may reveal the extent to which secondary prevention efforts have been successful. The extent of aspirin use and monitoring of cholesterol concentration in a follow-up of patients in the British regional heart study showed that the majority of patients with intermittent claudication who did not have a history of myocardial infarction (MI), angina, or cardiovascular artery disease were not receiving appropriate secondary prevention.14 Behavioral interventions may be helpful if a history of tobacco use is elicited and psychosocial stressors are present.15

The general examination includes blood pressure measurement, cardiac auscultation, and funduscopy. Local examination will reveal ischemic tissue loss and poor capillary circulation. Low input arterial pressure can be enhanced by elevating the legs above the heart for 2 minutes while the patient repeatedly dorsoplantar flexes the ankles; this will produce elevation pallor.

All accessible pulses should be palpated and large vessels (such as the femoral) should be auscultated for presence of a bruit as an indication of proximal stenosis. These data should be charted; an example is shown in Table 50-2.

Investigations

The general assessment of the patient is aided by chest radiography, cardiography, complete blood count, and blood chemistries that include a lipid profile. Echocardiography,16 testing of coagulation activity including PT, PTT, and INR for patients being treated with coumarin, and, in the future, testing fibrinogen and plasminogen activator inhibitor-1 levels may offer further management options.17 Noninvasive localization of disease by technology such as combined echocardiography and Doppler (duplex) is preferred for both diagnosis and choosing between surgery and percutaneous transluminal angioplasty (PTA).18 MRI technology is also capable of providing high-quality noninvasive studies with sensitivity and specificity, comparing favorably with digital subtraction angiography.19 The standard test remains the ankle-to-arm ratio (ankle-brachial-index [ABI]). Systolic pressure at the ankle is compared with systemic arterial pressure measured in the arm. This measure is far more sensitive then pulse oximetry.20 Observed values are related to clinical state (Table 50-3). When distal vessels are calcified and poorly compressible, the ABI may be unhelpful and values >1.50 may be obtained. Angiography is generally performed prior to reconstructive surgery.

Management of Major Arterial Occlusion

Management of a patient with an ischemic lower limb is summarized in the flow chart seen below:

Treatment of Claudication

Conservative treatment includes observation and treatment of associated conditions such as diabetes, anemia, or polycythemia. Efforts to assist patients with smoking cessation and to engage in regular exercise have been shown to improve outcome and quality of life.21 The severity of claudication, response (or lack of response) to medical management, and impact on lifestyle and quality of life must be weighed against the risks of proceeding with a surgical or percutaneous treatment. PTA has high success rates for large vessels with short lesions such as the common iliac, and may be performed as a same-day procedure. Stenting may improve success rates when lesions are more complex or repeat therapy is required. PTA is less effective in smaller vessels, so that, for example, prominent pedal ischemia mandates consideration of vascular surgery if it is technically feasible. Arterial reconstruction may utilize endarterectomy, in situ or reverse venous or synthetic grafting material. The many variations and details are beyond the scope of this chapter; however the efficacy of bypass surgery for treatment of lower limb ischemia is supported by evidence-based medicine review.22

Sympathectomy

Interruption of the lumbar sympathetic chain has a time-honored place in the treatment of peripheral ischemia. Before the advent of arterial reconstruction, it was the only surgical measure that produced pain relief. The indications for sympathectomy have diminished considerably over the last 40 years. Currently, this is a treatment with a limited role.23,24 Successful reports for the procedure performed by laparoscopy and with chemical sympathectomy continue to appear in the literature.25,26 Sympathectomy may improve blood flow to the foot and may improve rest pain, heal ulceration, and prevent skin necrosis.

If the affected foot is warmer than the unaffected foot, this suggests that autosympathectomy has occurred (especially in diabetic patients), and that the procedure will not be beneficial. However, there are patients who do not respond despite favorable characteristics. If the popliteal inflow index (Doppler inflow pressure in a popliteal artery versus arm pressure) is ≥0.7, a good response can be predicted. It is unlikely that a favorable response will be obtained if the ankle-to-arm ratio is <0.35.27

Lumbar sympathectomy can be achieved by injection or surgery. The technique of lumbar sympathetic block is well described in the references.28 An accurate block of the sympathetic chain at L3 may be adequate and it may not be necessary to use multiple needles (See Appendix A, II). However, the use of radiographic control will make the procedure easier and safer. If repeated blocks with dilute local anesthetic solution produce appreciable circulatory improvement, a neurolytic block with 5 mL aqueous phenol 5% solution can be considered as an alternative to surgical sympathectomy.29

Operative sympathectomy may be completed by a relatively atraumatic extraperitoneal approach under general anesthesia in which lumbar ganglia 2, 3, and 4 are excised together with the chain connecting them. Post-sympathectomy neuralgia, an aching pain in the femoral nerve distribution, is a complication that may resolve in 6 to 8 weeks. This is also a complication of chemical sympathectomy if the agent spreads through the prevertebral fascia to the level of the L1 nerve root or through the psoas fascia to reach its major peripheral nerve.

Other Methods of Improving the Peripheral Circulation

Regional Sympathetic Block (See Appendix A)

An effective alternative means of producing sympathetic block in a limb is to administer intravenous agents affecting postganglionic neurons to produce noradrenergic block using an intravenous regional anesthesia (IVRA) technique. Before its manufacture was discontinued, guanethidine was used in the last decade with some success in complex regional pain syndrome and peripheral vascular disease.30,31 By acting on postganglionic neurons, guanethidine first released norepinephrine and then caused noradrenergic block by preventing the reuptake of norepinephrine by the neurons. Other drugs, such as clonidine,32 phentolamine,33 bretylium,34 ketorolac, and corticosteroid, reported effective in management of pain due to complex regional pain syndrome and administered by IVRA technique may also find application in management of pain due to peripheral vascular disease. In the IVRA technique, a tourniquet is placed around the proximal part of the limb and inflated. The limb may be elevated for several minutes to enhance venous drainage prior to inflating the tourniquet. The drug diluted in 50 mL of normal saline may be injected into an indwelling intravenous catheter in the affected leg or arm after tourniquet inflation. Lidocaine can be added to help the patient tolerate the tourniquet. The tourniquet is kept inflated for 15 minutes. This method may be valuable in patients who are receiving anticoagulant therapy in whom paravertebral lumbar sympathetic block could potentially cause significant hemorrhage. IVRA can also be considered in cases in which the effects of operative lumbar sympathectomy are receding.

Spinal Cord Stimulation

Initial reports of the value of large fiber nerve stimulation suggested that patients with pain from peripheral arteriosclerotic disease that had not responded to arterial bypass surgery and/or sympathectomy might respond to stimulation of posterior spinal roots using implanted electrodes. Plethysmographic blood flow and skin temperature were also noted to increase. More recently, it has been suggested that the primary effect may be occurring within the lamina of the dorsal horn of the spinal cord. Pain transmission in this layer is controlled by wide dynamic range neurons. Substance P was one of the first neuropeptides identified as modulating pain transmission, and may be particularly affected by descending traffic modulating pain transmission. It is likely that there are multiple mechanisms involved. The stimulating electrodes may be introduced into the epidural space under direct surgical visualization or by means of a 15-gauge Tuohy needle with the electrodes placed between T 9 and T11.35 This area of the spinal cord corresponds to lumbar segmental level output. Spinal cord stimulation at this level is associated with increased skin temperature, blood flow, decreased edema, and prolonged pain relief. The stimulating electrodes may be adjusted until stimulation of large fiber afferents produce a tingling paresthesia that overlies the painful region.36 According to Augustinsson and coworkers,37 these vasodilating effects of spinal stimulation could be explained by (1) segmental inhibition of vasoconstrictor fibers, (2) antidromic activation of posterior root fibers, and (3) activation of ascending pathways to supraspinal autonomic centers. Interestingly, stimulation over lumbar spines or peripheral nerves was ineffective in these patients.37,38 The long-term efficacy is reported to be excellent at 70% to 90% when compared with results of 50% to 70% for neuropathic pain.39,40

Drug Therapy

The search for a noninvasive treatment of peripheral ischemia has highlighted many drugs that, after a brief popularity, have vanished from our treatment armamentarium. The following discussion of drug therapy approaches includes vasodilators, antithrombotic measures, fibrinolysis, antiplatelet drugs, attempts to modify tissue response to anoxia, prostacyclin, and gene therapy.

Vasodilators

Because the regulation of blood flow in the normal foot is affected simply by decreasing or increasing sympathetic tone, alpha-adrenergic blocking agents have been used, including thymoxamine, phentolamine, phenoxybenzamine, and clonidine. Other drugs have a local effect on vascular smooth muscle. These include papaverine and derivatives of nicotinic acid. Priscoline is an alpha-receptor blocker that also has a direct effect.

Systemic use of vasodilators actually may reduce blood flow in the worst affected limb by shunting blood to healthier areas (the vasodilator paradox).41 A local effect may be obtained by direct intraarterial injection or by retrograde intravenous infusion (Bier technique). Ketanserin, a serotonin2-receptor antagonist, and nifedipine may play a role in therapy,42 although lowered systemic blood pressure and hence perfusion pressure to the ischemic tissue, and the presence of maximal dilation of local vessels in the ischemic region, suggest vasodilator treatment might not be effective.

Antithrombotic Measures

Anticoagulant treatment has not been shown to be helpful in peripheral vascular disease because thrombosis, when it occurs, is only the final episode in the generation of the ischemic limb.

Fibrinolysis

Fibrinogen is the substrate for thrombin that converts it to fibrin. Dissolution of fibrin can be achieved using streptokinase, urokinase, and tissue-plasminogen activator. Although it would not affect the atheroma, and restenosis may follow cessation of therapy, it may delay progression and be useful therapy in acute occlusion. Its use should be followed by arteriography to assess the need for reconstruction.

Phosphodiesterase Inhibitors

Currently, the only two drugs approved by the FDA for use in intermittent claudication are Cilostazol and pentoxifylline. Both drugs show phosphodiesterase inhibition that can increase the concentration of cyclic AMP, leading to inhibition of platelet aggregation, thromboxane release, and increase in prostacyclin release. Unlike milrinone, which has similar effects on vessels and platelets, Cilostazol does not display significant inotropic effect.43 Pentoxifylline also affects blood rheology and specifically increases flexibility of red blood cells.

Antiplatelet Therapy

Drugs such as aspirin, dipyridamole, ticlopidine, and prostacyclin inhibit release of thromboxane A and prevent platelet aggregation. Because the latter occurs in turbulent flow proximal or distal to atheromatous stenosis or occlusion, such treatment is only of secondary importance in peripheral arterial disease. However, along with lipid-lowering drugs, antiplatelet therapy is the mainstay of secondary prevention to prevent MI and stroke in all patients with peripheral artery disease, even those who do not have signs or symptoms of coronary or carotid disease. Low-dose aspirin, between 81 and 325 mg per day, is the mainstay of preventive treatment for these patients.

Metabolic Agents

Naftidrofuryl was marketed first as a vasodilator, but it is purported to influence muscle metabolism beneficially through the Krebs cycle. Although a meta-analysis of seven randomized controlled trials involving 229 patients showed reduction in pain and analgesic consumption, these results were not statistically significant and the drug was withdrawn in the United States for treatment of peripheral arterial disease in 1995.44 Levocarnitine and propionyl levocarnitine are two drugs that may provide benefit by lessening the acylcarnitine metabolite buildup resulting from an impaired mitochondrial electron transport in ischemic muscle, though propionyl levocarnitine is not yet FDA approved.45

Arachidonic Acid Derivatives

The term prostaglandin was coined by Von Euler,46 who discovered some of the pharmacologic effects of semen. Endoperoxides derived from cell membrane arachidonic acid are converted to thromboxane A2 in platelets (vasoconstrictor and platelet aggregator) or to prostacyclin in blood vessel endothelium (vasodilator and inhibitor of platelet aggregation). The balance between these two classes of compounds maintains intravascular hemostasis.

The earliest report of the use of prostacyclin for treating ischemic feet used prostaglandin E1 by intraarterial infusion; the same team later administered the drug by the intravenous route. In both instances, they reported dramatic relief of rest pain in small patient groups and healing of some ulcers.47,48 More recently, prostaglandin I2, also a platelet inhibitor and vasodilator, was administered daily as an intravenous infusion (iloprost), or given orally (beraprost) with encouraging results.49

Gene Therapy

Gene therapy may be helpful in restoring blood flow to ischemic extremities. A Boston group reported results in a small phase I study. Human DNA coded to make vascular endothelial growth factor (VEGF) was introduced into Escherichia coli plasmid, which was grown in culture, purified, and administered by intramuscular injection into ischemic muscles of patients with critical limb ischemia defined as rest pain with nonhealing ischemic ulcers in human volunteers felt to be poor candidates for revascularization surgery. VEGF, secreted by endothelial cells, is the same protein as vascular permeability factor. It has binding sites limited to endothelial cells and so is site-specific. Injection of plasmid VEGF DNA manufactured by E. coli produced significant transient edema in the limbs where it was injected. ELISA measured VEGF concentration also increased transiently and was associated in time with increased small blood vessel formation that persisted after VEGF levels returned to baseline, increased ankle-brachial index, healing of ulcers, increased exercise tolerance, and resolved the problem of rest pain. The authors cautiously interpreted their data as supportive for the strategy of intramuscular gene therapy for therapeutic angiogenesis in patients with critical limb ischemia.50

Raynaud Phenomenon

This condition differs from all other peripheral arteriopathies because it affects mainly the hands. It was described first by Maurice Raynaud51 in 1862. Allen and Brown52 advanced our understanding by separating affected patients into those with and without a known underlying cause.

Raynaud disease (also known as primary Raynaud phenomenon) includes the classic clinical picture of pallor in the distal two-thirds of the fingers (a result of arterial shutdown), cyanosis (from partial relaxation of arterial spasm and deoxygenation of blood), and rubor (reactive hyperemia), all occur in response to cold or emotion. As the condition progresses, the pain becomes more severe and continuous. The condition is more common in women than in men; usually it becomes apparent by the age of 40 years. It occurs much less often in the lower limbs. Raynaud disease describes patients in whom no underlying condition can be found.

Raynaud syndrome (also known as secondary Raynaud phenomenon) comprises those patients with Raynaud phenomenon secondary to underlying pathologic disorders (Table 50-4). Interestingly, 10% of patients with primary pulmonary hypertension may exhibit symptoms.53

Raynaud syndrome is particularly important because the associated condition may be treatable. In addition, the prognosis is worse, and these patients may develop pathologic changes of ulceration, subungual infection, and pulp loss after digital arterial occlusion (Fig. 50-2). Porter and Rivers54 reported 383 patients observed in a 10-year period. Of these, 162 had no associated disease and 137 had proven or suspected connective tissue disorder (57 of the latter had systemic sclerosis).

Raynaud Management

General Measures

Simple avoidance of cold, either of the body or of the hands, may be all that is required in mild cases. A change of occupation may be necessary if vibrating tools are used. Cessation of smoking has been advocated.

Sympathectomy

Because nervous control of digital blood flow occurs simply as a result of increasing or decreasing sympathetic tone, pharmacologic or surgical sympathectomy has been used extensively. Drugs, such as methyldopa, thymoxamine, reserpine, debrisoquine, and phentolamine have been administered orally and intraarterially. Most of the studies are anecdotal, uncontrolled, or rely on subjective assessment. If no effect can be proved when a drug is given intraarterially, it is unlikely that it will work systemically. The pain of Raynaud phenomenon has been controlled by intravenous regional anesthesia (IVRA) sympathetic block with guanethidine (no longer manufactured). Agents used in IVRA to treat other pain syndromes may find application in Raynaud treatment as guanethidine alternatives are investigated (See section, Other Methods of Improving the Peripheral Circulation).

Surgical sympathectomy can be done using an open procedure, but temporary and permanent Horner syndrome may occur. Transaxillary endoscopic coagulation to destroy thoracic ganglia 2 to 5 is another approach.55 A thoracoscopic approach that is minimally invasive has also been described.56,57 The immediate effect usually is good, although recurrence is common within 6 to 24 months and this treatment may be less helpful than others.58 Digital sympathectomy using microvascular techniques has also been reported.59

Sympathetic Blockade

Where the condition is not severe and particularly if it is seasonal, a stellate ganglion block can be helpful. A paratracheal approach at the C6 level reduces the risk of pneumothorax and intravertebral artery injection. The accuracy may be increased by use of radiographic control and a radiopaque dye that can identify the occurrence of dural cuff injection. A sympathetic block with local anesthetic does not tend to produce a sustained response.

Other Treatments

While Ketanserin was initially60 thought a helpful therapy, recent reviews suggest no significant clinical effect.61 Temperature biofeedback was recently shown inferior to treatment with calcium antagonist.62 Nifedipine, or other calcium channel blockers, are highly effective for patients who do not suffer adverse effects. Interestingly, the dihydropyridine calcium channels are closely associated with the endothelin-1 receptor, suggesting endothelin-1, found in higher concentration in Raynaud patient serum, may be a neuron-independent vasoconstrictor.63 Prostacyclin infusion and administration of a stable oral preparation may be helpful and were previously described. Also as noted above, spinal cord stimulation could be of value.

Buerger Disease

Thromboangiitis obliterans was the name Leo Buerger64 gave to a specific arterial disease he believed was confined largely to Eastern Europeans. This disease subsequently was shown to be prevalent in Sri Lanka, Korea, and Japan, where it was the most common form of arterial pathology. By the 1970s it was reported that 75% of 1641 cases of femoropopliteal occlusion were caused by this condition.65 A gradual decrease in the incidence has been reported over the last decade.66

Clinical Picture

More than 90% of sufferers are men younger than 40 years of age who are smokers. They have instep claudication or painful ischemic changes in the feet. Just less than one half have manifestations in their upper limbs, usually thrombophlebitis or minor ischemic changes. Upper extremity circulation may be assessed with an Allen’s test. Have the patient make a fist while occluding radial and ulnar arteries at the wrist. The hand is relaxed and ulnar arterial pressure is released. Failure of the hand to regain color constitutes a positive test. The test is repeated for patency of radial artery. In these patients, foot pulses and, later, popliteal pulses are absent.

Buerger disease is an inflammatory process; the affected artery is surrounded by fibrosis while the normal structure of the vessel wall may be preserved, in contrast to the typical disruption of internal elastic lamina and media in arteriosclerosis and other systemic vasculitides.67 The pathology is specific with thrombosis in crural arteries and veins. Giant cells are a histologic feature, even in early cases.

Management

Universally, it is accepted that for smokers, treatment must begin with smoking cessation. If patients stop smoking, this alone may be sufficient to provide relief.

Local treatment is directed toward debridement and draining infections. Prostaglandin in the form of iloprost may provide benefit, particularly during the period when patients first discontinue smoking.68 Sympathectomy and spinal cord stimulators also have a place in management of difficult cases. As in arteriosclerosis, gene therapy also may offer some promise.69

This may be acute (deep venous thrombosis [DVT] or thrombophlebitis) or chronic (DVT with recanalization or gravitational disease). DVT occurs when normal venous flow is disturbed in accordance with the Virchow triad: (1) diminished flow velocity after illness, operation or childbirth; (2) alteration in the characteristics of the contained blood producing increased viscosity, such as polycythemia, abnormal plasma protein fractions, leukemia, or thrombocythemia; and (3) local intimal damage. In most cases more than one factor is responsible. Many cases apparently arise spontaneously in healthy people; however, a search for an underlying condition (such as malignancy or collagen-vascular disease) should be undertaken. Often without initial symptomatology, the disease may present with death due to pulmonary embolism. The focus should be on prevention rather than treatment, particularly for patients at increased risk due to immobility, including patients admitted to the hospital for surgery. For further information, the reader is referred to an excellent discussion of this topic by Geerts and colleagues.70

Acute Venous Disease

The clinical diagnosis of DVT is made by the triad of local tenderness, swelling, and color change. Clinical diagnosis alone does not detect the subtler changes, and may overdiagnose the condition. In the presence of atheroma, false-positive and false-negative results comprise 50% of all cases.

When edema is present, it implies that the deep veins are occluded; embolization is less likely, but local sequelae are more likely. The clinical picture is either the white leg (milk leg), which is pale and shows infra-genicular pitting edema, or the blue leg, which involves the entire leg as far proximally as the root of the limb. The former is a result of femoropopliteal obstruction; the latter indicates iliac-caval obstruction. The blue leg causes much discomfort, and if tissue pressure continues to rise, peripheral gangrene may supervene.

Acute thrombophlebitis is easily recognizable because there is visible swelling and tenderness along the course of a superficial vein. Apart from the underlying conditions already mentioned, the condition may be the harbinger of carcinoma of the pancreas or lung.

Chronic Venous Disease

Occlusion of the major veins is followed by recanalization with valve destruction. This allows transmission of the full force of the column of blood from the right atrium to the heel (+80 to 90 mm Hg). The patient may complain of a resting pain in the calf, which, when associated with walking, is called venous claudication.

Gravitational changes are more serious because of their reputation for intractability. These changes include pigmentation, distended intracutaneous veins (in the inframalleolar position, so-called venous flare), edema, liposclerosis, and ulceration (See Fig. 50-3). The pain of a venous ulcer may be excruciating; it usually is worse at night and is unrelated to ulcer size. Investigation of venous disease is directed toward the following:

• 1. Proving the diagnosis. Isotope studies may be helpful in acute DVT. Duplex ultrasonography and impedance plethysmography are useful in establishing the diagnosis. The “gold standard” investigation is venography, which should be universally available. Testing for the D-dimer fibrin degradation product combined with clinical criteria has a high sensitivity and low false-negative results.71,72
• 2. Demonstrating an underlying cause. A complete blood count, erythrocyte sedimentation rate, chest x-ray, liver diagnostic tests, urinalysis, renal function tests, serum proteins and immunoglobin level tests, and tests for lupus erythematosus, rheumatoid, and other collagenoses may be required.

Management of Venous Disease

Acute Deep Venous Thrombosis

The classic mainstay of treatment used to be a 5000-unit bolus of heparin followed by a continuous intravenous infusion in a dose of 40,000 units in 24 hours. This treatment was designed to prevent the spread of the thrombus and embolization until the clot became adherent and stabilized. In the absence of bleeding complications, therapy was maintained for 5 days, the last 3 days of which overlap with the commencement of oral anticoagulation therapy with coumarin, which was maintained for 3 months. Vitamin K antagonist treatment to maintain an INR of 2.5 is the most frequent secondary treatment for patients with venous thromboembolism. In four studies with 1500 patients, a meta-analysis revealed reduction for risk of recurrent events as long as treatment was maintained. As the risk of recurrent event may decrease over time, this benefit may eventually become outweighed by the risk of hemorrhagic complication that does not decrease over time.73

The availability of a low-cost outpatient management option has resulted in shortened hospital stays, with many cases in this country being treated with subcutaneus injections of low-molecular-weight heparin. A meta-analysis of 4754 patients in 14 randomized, prospective, controlled studies showed low-molecular-weight heparin was as effective as unfractionated intravenous heparin in preventing recurrent DVT. The risk of hemorrhage was lower during treatment and mortality at follow-up was also lower for the outpatient treatment protocol.74

Acute Thrombophlebitis

This usually is a self-limited condition that can be treated by local warm compresses and an anti-inflammatory drug (such as ibuprofen.) If the process involves the saphenous vein in the thigh, it may be necessary to ligate it at the groin to prevent the thrombosis from spreading into the femoral vein.

Chronic Venous Insufficiency

The venous hypertension that follows extensive valvular obstruction after DVT includes various stigmata in the gaiter area of the leg, the most disabling of which is ulceration. There are many causes of leg ulceration, and it is important to exclude concomitant arterial disease, diabetes, and rheumatoid disease because these will render standard treatment ineffective. The linchpin of treatment of venous ulcers is effective, graded, dynamic-elastic compression to oppose the harmful effects of venous hypertension. Many topical therapies have been used, including antibiotics, corticosteroids, and enzymes. However, they are all largely ineffective. They also may be expensive and can produce sensitization reactions that may be worse than the original condition.

Pain control with analgesic drugs during the healing phase is important; a decreasing need for analgesia is a good indication of progress toward healing.

Interestingly, services for patients with pain due to peripheral vascular disease are delivered by a multitude of specialists including vascular surgeons, radiologists, anesthesiologists, rheumatologists, cardiologists, internists, dermatologists, primary care physicians, and podiatrists. The explosion of basic science and clinical research promises improved understanding and additional management options for these severely disabling diseases. Meanwhile, the author encourages the reader, whatever his or her specialty, to take every opportunity to encourage smoking cessation, regular daily exercise, and other preventive measures that produce so much benefit to so many.