Sildenafil for Treating Peripheral Ischemia and Gangrene: A Case Report and Review

Peripheral gangrene is a clinical condition characterized with digital ischemia of extremities usually seen in patients with sepsis or shock that resulted in a hypoperfusion state. It is not common but often complicated with high mortality rate. Currently, there is no definite treatment for peripheral gangrene which often result in amputation. We reported a 74-year-old female case of shock-related peripheral gangrene of both feet who was partially and successfully treated by oral sildenafil with a dose of 50mg twice daily. We also reviewed present evidences regarding effectiveness of sildenafil in managing distal ischemia caused by different clinical conditions. The into darker of after random glucose 67 mg/dl, VBG-pH 7.3, VBG-PCO 2 35.9 mmHg, VBG-PO 2 49.2 mmHg, VBG-O 2 saturation 79.6%, VBG-Act cHCO 3 18.3 mmol/L, VBG-ctCO 2 19.4 mmol/L, VBG-Base Excess − 6.7 mmol/L, VBG-Std cHCO 3 18.7 mmol/L; BUN 59 mg/dL, Creatinine 138.9 mmol/L, 5.09 mmol/L, Albumin W.B.C. 1.8 10^3/uL, g/dL, Platelet count 24000/uL, Band lactate 5.0 mmole/L.


Introduction
Peripheral gangrene is characterized by ischemic and necrotic changes of digital extremities and is mostly associated with failure of microcirculation induced by disseminated intravascular coagulation (DIC) or other causes. (1,2) Peripheral gangrene is usually presented symmetrically in acral limb and is more likely to be known as symmetrical peripheral gangrene (SPG).(1) SPG is complicated with high amputation rate and mortality. Here, we presented a case of suspected shock-related peripheral gangrene treated by sildenafil. Our aim is to review potential mechanism of sildenafil in treating peripheral gangrene and to investigate the effectiveness of this medication. Clinical use of sildenafil in treating acral ischemia or peripheral gangrene and other conditions such as scleroderma and some autoimmune disorders are discussed as well.

Case presentation
A 74-year-old female with hypertension history suffered from back pain due to a fall on Oct 26, 2018. The pain persisted and she was sent to emergency department on Oct 28, 2018. T-L spine x-ray showed T12 compression fracture and the patient was admitted to our ward for further treatment. The patient had been noted for presenting with lower blood pressure (97/61 mmHg) and tachycardia (heart rate 100 beats per minute) on 10/29 with shortness of breath. Dyspnea and hypotension progressed on 10/30-31 and lab tests revealed: random glucose 67 mg/dl, VBG-pH 7.3, VBG-PCO 2 35.9 mmHg, VBG-PO 2 49.2 mmHg, VBG-O 2 saturation 79.6%, VBG-Act cHCO 3 18.3 mmol/L, VBG-ctCO 2 19.4 mmol/L, VBG-Base Excess − 6.7 mmol/L, VBG-Std cHCO 3 18.7 mmol/L; BUN 59 mg/dL, Creatinine 2.97 mg/dL, Na 138.9 mmol/L, K 5.09 mmol/L, Albumin 2.0 g/dL; W.B.C. 1.8 10^3/uL, Hb 11.0 g/dL, Platelet count 24000/uL, Band 24.8%; lactate 5.0 mmole/L. Septic shock was impressed. We performed endotracheal intubation for the patient and gave fluid resuscitation and applied norepinephrine for unstable hemodynamics. We initiated empirical antibiotic with piperacillin/tazobactam and provided respiratory support for the patient and transferred her to ICU for further care.
During ICU, patient's platelet count further decreased to 5000/uL, suggested an ongoing DIC. Acute kidney injury with metabolic acidosis and systemic edema was also noted; therefore we applied continuous venovenous hemofiltration since 11/01. We added ceftriaxone besides piperacillin/tazobactam due to Salmonella infection being identified.
Vasopressin had been added to norepinephrine for low systemic vascular resistance noted on 10/31. Norepinephrine was kept from 10/31 to 11/5 and had been gradually tapered from 10ug/min to 1ug/min. It was discontinued on 11/5 after recovery of blood pressure (134/72 mmHg). Under the use of vasopressors, distal toes of both feet presented with ischemic change and persistent coldness. On 11/06, obvious purple-blue discoloration was developed on right plantar foot ( Fig. 1-a, 1-b) while mild discoloration noted on left one ( Fig. 1-c, 1-d). Shock with hypoperfusion state and use of vasopressor were thought to be possible causes for digital ischemia of the feet.

Treatment and follow-up
We communicated with the family and decided to try oral sildenafil for treating the ischemia. Sildenafil 50 mg Q12H was administered from 11/07 to 11/15. Among all toes, the 4th toe on the right foot displayed more sever ischemic change which eventually developed into total gangrene despite the treatment ( Fig. 2-a, 2

Discussion
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 hypoperfusion 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)  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. The legal guardian of the patient (i.e., the son of the patient) gave us permission to review her medical records and publish this study.

Consent for publication
The legal guardian of the patient (i.e., the son of the patient) gave us permission to review her medical records and publish this study.

Availability of data and materials
Due to individual privacy, data sharing is not applicable to this study. The legal guardian of the patient gave consent to only the study authors to access the patient's medical records.

Competing interests
The authors declare that they have no competing interests.

Funding
The authors accept no funding in this study.

Authors' contributions
Ms. Miyuki Hsing-Chun Hsieh organized the patient's clinical information and wrote this manuscript. Doctor Chi-Lun Tsai is the attending who took care of this patient during her hospitalization. Dr. Hui-Chen Su and Edward Chia-Cheng Lai helped review and revise the manuscript.

Figure 1
On 11/06, obvious purple-blue discoloration was developed on right plantar foot ( Fig. 1-a, 1-b) while mild discoloration noted on left one ( Fig. 1-c, 1-d). Shock with hypoperfusion state and use of vasopressor were thought to be possible causes for digital ischemia of the feet.

Figure 2
Among all toes, the 4th toe on the right foot displayed more sever ischemic change which eventually developed into total gangrene despite the treatment ( Fig. 2-a, 2-b). There was a limited area (involved the 2nd and 5th toe) on right plantar foot presented with lighter ischemic discoloration and relatively clear margin of the involved region. Other areas of peripheral ischemia significantly improved after use of sildenafil ( Fig. 2-b, 2-c, 2-d).
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