Peripheral gangrene is characterized by distal ischemia without arterial vessel occlusion or vasculitis. It is usually presents symmetrically and involved two or more extremities and is more often called symmetric peripheral gangrene (SPG).(8, 9) SPG is mostly associated with failure of microcirculation induced by DIC in patients with septicemia. Infected bacteria that had been reported include Streptococci, Staphylococci, Pneumococci, Pseudomonas and Escherichia coli, etc.(10) It is suggested that bacterial endotoxin might impair the coagulation system and platelet function in peripheral arterioles.(11) Other possible causes of SPG include shock-related hypo-perfusion state, use of certain vasoconstrictive agents, antiphospholipid syndrome, Raynaud’s syndrome and diabetes, etc.(11, 12) Though peripheral gangrene is not common, high mortality rate of 40% is noted and approximately half of the survived patients required amputation.(3, 11) Our case had experienced septic shock resulted from Salmonella bacteremia and use of vasopressors had possibly exacerbated the ischemia changes of distal limbs.
Before eventual gangrene develops, former stages of SPG include the initial hypo-perfusion state—which is usually presents as septic shock, and the following ischemia. For the first stage, restoration of peripheral circulatory system is the most important. Timely fluid resuscitation with empirical use of broad-spectrum antibiotics is of gold standard.(12) In addition, vasopressors such as norepinephrine and dopamine are recommended by the Sepsis Campaign guideline as drug of choices to treat shock. However, it had been reported to cause peripheral ischemia under therapeutic dosage range.(13) If not managed properly at the initial stage, erythematous, cold and pallor extremities followed by dusky discoloration of skin would be noted, implying profound ischemia.(12) Once ischemic change is noted, aggravating factors should be identified and rigorous intervention is prompted. Due to shock, our patient was prescribed norepinephrine and vasopressin since the first 2 days after admission, and both agents were discontinued no later than 11/05 due to relatively stable blood pressure. However, dusky discoloration of toes and plantar foot was identified. Shock-related hypo-perfusion and DIC was believed to be the cause of the distal ischemia with vasopressors being an exacerbating factor.
Even though several medications had been proposed in managing peripheral gangrene, no specific effective treatment exists to date.(3, 12) Except for correcting underlying conditions that may cause DIC, different medications which include vasodilators or antithrombotic drugs might be tried according to literature. These include sympathetic blockers such as intravenous chlorpromazine hydrochloride and topical infiltration of phentolamine hydrochloride. Numerous classes of vasodilators such as IV prostaglandins (e.g., epoprostenol)(14), phosphodiesterase inhibitors (e.g., pentoxifylline, sildenafil)(6, 11), endothelin receptor antagonist (e.g., bosentan)(15), IV nitroprusside, IV trimethaphan(16) and topical use of nitroglycerin(17) were all reported with various extent of effectiveness for digital ulceration or peripheral gangrene. Clinical use of anticoagulants, antiplatelets, thrombolytic agents and application of hyperbaric oxygen therapy were also documented.(18) Final and definite management is to perform amputation once demarcation of the necrotic gangrene develops.(1)
Among available treatment options, sildenafil appears to be a relatively effective therapy in the management of peripheral gangrene or digital necrosis.(5–7, 19, 20) Sildenafil selectively inhibits phosphodiesterase 5 (PDE5) and prevents cyclic guanosine monophosphate (cGMP) from breaking down. This results in smooth muscle relaxation in blood vessels.(21) The vasodilating effect of sildenafil promotes microcirculation of blood flow in the digital limbs. Thus, ameliorating acral ischemia under circumstances in which vasospasm is believed to be the etiology. The potential benefits of sildenafil were found from both in vitro and in vivo studies. In animal studies, sildenafil demonstrates angiogenesis in ischemic limbs of mice through protein kinase G-dependent (PKG) pathway.(22, 23) It was found to increase vascular density, promotes proliferation of endothelial cells and enhances vascular perfusion and tissue blood flow. Furthermore, sildenafil-mediated blood vessel growth was proven dose-dependent in which in vivo incubation of chicken chorioallantoic membranes with larger dose of sildenafil was observed with increasing vascular length.(24) Preliminary human study also revealed sustained protection of endothelial function from ischemia and reperfusion injury under sildenafil dose of 50 mg per day.(25) In addition to vasodilation and improvement in endothelial dysfunction, inhibition of platelet activation was noted following administration of sildenafil and it overall contributed to increased cutaneous capillary circulation in patients with coronary artery disease.(26, 27)
In clinical setting, sildenafil is formally approved with the indication of erectile dysfunction and pulmonary arterial hypertension, taking advantages of its vasodilating effect. In addition, sildenafil is used off-label to improve digital ischemia and ulcerations associated with Raynaud’s disease. A meta-analysis with 6 randomized controlled trials have shown that PDE5 inhibitors (sildenafil, tadalafil and vardenafil) present with moderate yet significant improvement in symptoms of secondary Raynaud's phenomenon (RP), included decreased frequency and duration of RP attacks.(28) Other studies disclosed similar therapeutic benefits brought by PDE5 inhibitors.(29) A recent randomized, placebo-controlled trial was designed to investigate the efficacy of sildenafil on ischemic digital ulcer healing in systemic sclerosis.(30) Sildenafil was administered 20 mg three times a day for 12 weeks. The study outcome revealed a favorable healing rate of sildenafil when compared to placebo at week 8 and week 12. However, shortening of healing time was not observed. Side effects resulted in drug discontinuation included drowsiness, syncope, headache, facial, edema and rash. The study results have confirmed clinical benefits of sildenafil.
Taken its potential efficacy, sildenafil was first reported to be applied in sepsis-induced symmetrical peripheral gangrene in 2012.(19) Sepsis-induced vasoconstriction and vasospasm aggravated by vasopressors use shares common presentation of RP in which vasoconstriction is too excessive it becomes vasospasm and is leading to reduction of blood flow and decreased digital perfusion. The authors believed management of RP might help alleviating signs and symptoms of SPG. As a result, sildenafil was provided and it turned out working very well. Apart from this case, more case reports applying sildenafil in managing peripheral ischemia due to different causes have been published. We summarized characteristics of these cases in Table 1. These patients with various ages were mostly female. The causes or exacerbating factors of peripheral ischemia include sepsis-induced low-perfusion status, RP caused by autoimmune diseases such as systemic sclerosis or antiphospholipid antibody syndrome, and few of them were heavy smokers. Nearly all cases manifested with cyanotic change from the digital extremities, i.e., fingers or toes. The peripheral ischemia was accompanied with pain, pallor, cold or swelling. Before sildenafil administration, many patients had tried anticoagulants, antiplatelets, calcium channel blockers, NTG paste or IV prostaglandins but failed. Until sildenafil with a daily dose of 75 to 150 mg usually given in three times per day was provided, the symptoms of digital ischemia became significantly improved in most cases. Most of the patients experienced marked reduction in pain and ischemic symptoms and some of them even avoided amputation. The treatment duration of sildenafil ranged from months to years and all the cases remained with sustained medication effectiveness with mild or no side effects during the follow-up visits.
Table 1
Reported cases applying sildenafil in treatment of peripheral ischemia
NO. | Age | Sex | Clinical condition | Aggravating factors | Peripheral ischemia sign | Treatment | Dose of sildenafil* | Outcome (time after treatment) | Ref. |
1 | 8 | F | Cutaneous polyarteritis nodosa | Immune-mediated systemic vasculitis | Raynaud’s phenomenon + fingertip ulceration and necrosis | IV steroids, nifedipine, sildenafil, pentoxifylline, nitroglycerin paste, aspirin, LMWH, IVIG | 20 mg three times a day | Improve in swelling, discoloration; regained color, perfusion, sensation with residual necrotic distal fingertips (at 2-mon.) | (31) |
2 | 16 | F | Thrombotic vasculopathy | Antiphospholipid antibody syndrome | Retiform purpura and digital gangrene of toes | Enoxaparin + IV methylprednisolone + topical NTG paste + nifedipine ◊ sildenafil | 20 mg three times a day | Rapid relief of pain; increase in dorsalis pedis pulses and fading of the reticular erythema; gangrene stabilized (day 2) | (32) |
3 | 17 | F | Symmetrical peripheral gangrene due to Pseudomonas septicemia | Sepsis, DIC | Dusky cyanosis of both feet with painful symmetrical swelling | Antibiotics + IV fluids + LMWH + PO sildenafil | 25 mg twice a day | Marked reduction in area of dusky erythema (day 7) | (19) |
4 | 28 | F | Scleroderma/lupus progressed to fibrosing alveolitis | Autoimmune dz, active TB + sepsis | Severe digital arthralgia, vasculitis, and progressive ischemia & gangrene | Iloprost IVF 2 weeks ◊ PO sildenafil | 50 mg three times a day | Becoming warm, less painful, and less discolored (day 1) | (5) |
5 | 35 | F | SLE with recurrence of Raynaud’s phenomenon | SLE with high titer apLs | Painful acrocyanosis of bilateral hands and feet | IV hydrocortisone + enoxaparin + amlodipine + IV iloprost ◊ increased dose of amlodipine and iloprost + sildenafil | 120 mg/day | Gradual resolution of critical ischemia (day 7) | (33) |
6 | 37 | F | Cervical rib | Raynaud phenomenon, heavy smoker, oral contraception use | Critical upper limb ischemia with increasing pain | Heparin + IV NTG + morphine ◊ iloprost + vascular bypass ◊ sildenafil | 25 mg three times a day | Decrease in pain and granulation tissue (1-week); re-epithelized ischemic fingers (at 1-mon.); improved vasculature permeability (at 2-mon.) | (20) |
7 | 42 | F | Dermatomyositis and thyrotoxicosis | Autoimmune dz, active TB + sepsis | Raynaud’s phenomenon + ischemic digital ulceration | Diltiazem + iloprost IVF ◊ PO sildenafil | 50 mg three times a day | Digital circulation & pain improved markedly (day 1) | (5) |
8 | 51 | F | Bilateral hand burns as a result of seizure attack | Scleroderma with significant Raynaud’s phenomenon | Deep dermal contact burns to the volar aspect of digits in both hands | Antimicrobial barrier silver dressings ◊ sildenafil + debridement and split skin graft | 20 mg three times a day | Healed wound with minimal functional issues (at 4-mon.); area of gangrene not fully recovered | (34) |
9 | 51 | F | Renal failure secondary to GI bleeding | Sepsis, IV terlipressin | Ischemia and necrosis of toes in the lower extremities | DC terlipressin + PO sildenafil | 50 mg twice a day | Rapid reversal (day 3) to final recovery (day 30) | (7) |
10 | 57 | M | Primary Raynaud’s disease | None | Painful, swollen, left index finger associated with purple discoloration | Nifedipine + aspirin + hydromorphone + digital microscopic sympathectomy ◊ sildenafil | 50 mg once daily | Relief of pain and ischemic symptoms (within hours); remained symptom free (at 3-mon.) | (6) |
11 | 62 | M | Buttock claudication | Heavy smoker | Severe bilateral buttock ischemia with walking limitation | Statin + antiplatelet + ACE inhibitor + rehabilitation + cilostazol ◊ sildenafil | 100 mg once daily | Increased walking distance (2 hour and at 1-mon.) and improved quality of life (at 1-mon.) | (35) |
12 | 76 | F | Dermatomyositis + disseminated malignancy | Autoimmune dz | Digital ischemia | Diltiazem + iloprost IVF ◊ PO sildenafil | Not mentioned | Immediate improvement in peripheral pain & ischemia & toe ulcers | (5) |
*The arrow indicates treatment in the order of time. |
Abbreviations: ACE, angiotensin converting enzyme; aPL, antiphospholipid; dz, disease; IV, intravenous; mon., month; NTG, nitroglycerine; SLE, systemic lupus erythematosus; PO, orally; wk, week |
By comparison, our case of a 75-year-old female with septic shock who suffered from peripheral ischemia of both her foot had been treated with oral sildenafil 50 mg twice a day. The area of digital gangrene was smaller, and symptoms of ischemia improved after 10-day use of sildenafil. The patient’s left foot manifested with greater improvement with acral ischemic discoloration being diminished after treatment. However, although the right foot also showed significant amelioration of the affected plantar area, its 2nd, 4th and 5th toes stayed ischemia with a relatively clear line of demarcation developed especially in the 4th toe displaying total gangrene at last. It might imply better effectiveness if sildenafil therapy is applied at the earlier stage of peripheral ischemia.