Pharmacologic Intervention Often Needed in Scleroderma-Associated Severe Digital Ischemia

By Soumya Chatterjee, MD, MS, FRCP

Raynaud phenomenon (RP) results from intense vasospasm of digital arteries on exposure to cold or with emotional stress. It leads to well-defined triphasic color changes of fingers and toes (white, blue, dusky red) in association with paresthesia and ischemic pain (Figure 1). RP may be primary (Raynaud disease) or secondary to autoimmune rheumatic diseases such as scleroderma.

Figure 1. Raynaud phenomenon (pallor phase) in a patient with limited systemic sclerosis.

Although Raynaud disease is thought to be a result of exaggerated vasospastic response of digital arterioles to cold temperatures, RP in scleroderma often results from an underlying vaso-occlusive process. As a result, ischemic symptoms are more severe and persistent, often necessitating pharmacologic intervention.

Treatment: Start Conservative When Possible

A conservative approach to RP is often attempted first.

Nondrug measures. Even in RP in scleroderma, certain general measures may be adopted to reduce the frequency, severity and duration of RP attacks, such as avoiding cold temperatures and temperature fluctuations, alleviating stress and adopting measures to keep the core body temperature and fingers warm. Tobacco exposure, sympathomimetic drugs and vibrating tools should be avoided.

Pharmacologic measures. We use dihydropyridine calcium channel blockers (CCBs) (e.g., nifedipine, amlodipine) first, as they are by far the most commonly studied and prescribed class of agents for treatment of RP. For patients who do not respond adequately or cannot tolerate a CCB, we try other classes of drugs that have been effective, such as topical nitrates (transdermal nitroglycerin patch), alpha-receptor antagonists, angiotensin receptor blockers, selective serotonin reuptake inhibitors or pentoxifylline.

In refractory cases of secondary RP with intractable digital ischemia often leading to digital ulceration or gangrene (Figure 2), we consider one of the more expensive second-line agents, such as a phosphodiesterase-5 inhibitor (e.g., sildenafil, tadalafil), an endothelin receptor antagonist (e.g., bosentan) or an IV prostacyclin analog (e.g., epoprostenol, alprostadil). These agents are either used alone or added to the first-line agents. We also ensure adequate pain control. Superadded infection, which is sometimes deep-seated, is identified and often requires prolonged courses of IV antibiotics.

Figure 2. Ischemic ulceration leading to digital gangrene at the tips of the left second and third fingers and the right third and fourth fingers in a patient with diffuse systemic sclerosis. There is a small ischemic ulcer at the tip of the left fourth finger.

Critical Digital Ischemia Requires Meticulous Management

Severe digital ischemia can threaten the viability of a digit and is considered an emergency. Early intervention is paramount to prevent irreversible tissue loss.

Our approach is to hospitalize the patient, ideally in a private room, with the room temperature kept warm. A thorough evaluation is carried out to identify and, if possible, correct any secondary reversible cause that may be contributing to the crisis. This includes careful evaluation for correctable macrovascular disease, superadded infection (skin and deeper structures), severe anemia, any cause of systemic hypoxia or a hypercoagulable state.

We ensure adequate analgesia with appropriate means and often need to use oral or parenteral narcotic analgesics. If the patient is not already on a long-acting dihydropyridine CCB and an antiplatelet agent (e.g., aspirin), these are started as initial therapies. Often a second vasodilator is necessary. The choice is between a transdermal nitroglycerin patch and a phosphodiesterase-5 inhibitor.

If these measures still do not reverse the ischemia, we consider a trial of continuous IV infusion of alprostadil (prostaglandin E1) for five days. In this situation, the patient is transferred (or directly admitted) to a telemetry bed in one of our cardiac step-down units (due to the increased level of hemodynamic monitoring required). Alprostadil induces vasodilation and also inhibits platelet aggregation. Close monitoring is needed to watch for alprostadil’s hemodynamic side effects, such as hypotension (which can be dose-limiting) and flushing. Other dose-limiting effects include nausea, headache and diarrhea. Due to the potential for hypotension, blood pressure and heart rate are monitored frequently.

We typically use peripheral IV access to administer alprostadil. Infusion is avoided if systolic blood pressure is less than 90 mm Hg. The starting dose of alprostadil is 0.5 to 1 ng/kg/min, which is titrated up by 1 ng/kg/min every two to four hours if the patient tolerates it (i.e., has no hypotension, headache or nausea). We titrate the dose based on improved perfusion, decreased pain and patient tolerance, with the goal of using the maximum tolerated dose. We do not exceed a maximum infusion rate of 6 ng/kg/min. The infusion is maintained for five days and then titrated down by 1 ng/kg/min every two to four hours while we closely monitor the affected digit for pain and other signs of worsening ischemia.

When the Digit Is Nonsalvageable

If the digital ischemia is advanced and irreversible, then a portion of the digit becomes necrotic and is nonsalvageable, regardless of all medical measures. In this situation, autoamputation is preferred to recover maximum perinecrotic tissue, provided the gangrenous area is dry and well-demarcated and pain and infection are controlled adequately. To reduce the ischemic penumbra, alprostadil is continued.

If all medical measures fail, surgical amputation of the affected part of the digit becomes the only therapeutic option, as advanced and irreversible digital ischemia leading to gangrene is unavoidable.

Dr. Chatterjee directs the scleroderma program in the Department of Rheumatic and Immunologic Diseases. He can be reached at chattes@ccf.org or 216.444.9945.