The “dark” side of terlipressin: a case report of ischemic skin necrosis and review of literature

Abstract

Background

Terlipressin is a commonly used drug in cirrhotic patients with acute variceal bleed (AVB) due to its vasoconstrictor effects. Ischemic complications are uncommon adverse events associated with worse outcomes.

Case presentation

We present a case of alcohol-related cirrhosis, who was started on terlipressin for AVB. However, he developed bilateral lower limb gangrene with ischemic skin necrosis and ultimately succumbed to death.

Conclusion

Although ischemic adverse events are uncommon with terlipressin, it is important to be aware of these complications as they may be severe and potentially life threatening.

Background

Terlipressin is widely used in the treatment of bleeding esophageal varices in patients with cirrhosis. It is found to decrease the mortality by reducing splanchnic blood flow and portal pressures and the need for emergency procedures required to stop rebleeding [1]. Ischemic adverse events are uncommonly observed with terlipressin of which cutaneous complications are among the rarest [2]. It is important to be aware of such uncommon events to facilitate early recognition and prompt withdrawal of terlipressin. Herein, we report a case of bilateral lower limb gangrene with ischemic skin necrosis in a patient of acute on chronic liver failure who was started on terlipressin for acute variceal hemorrhage.

Case report

A 45-year-old gentleman previously diagnosed with liver cirrhosis presented to the emergency with hematemesis, melena, and altered sensorium for 1 day. He had a history of significant alcohol consumption (60–80 g/day for last 20 years) but no tobacco or other substance abuse. There was no history of ischemic heart disease, peripheral vascular disease, or metabolic comorbidities including diabetes mellitus, hypertension, or obesity in the patient or his family members. On examination, he was disoriented, pale, and icteric with free fluid per abdomen as evidenced by shifting dullness. Patient was shifted to the intensive care unit and was intubated in view of poor sensorium. Intravenous ceftriaxone (1 g intravenously twice a day), terlipressin (intravenous boluses of 2-mg stat followed by 1 mg every 4 h), and other supportive management were started. Investigations revealed anemia (hemoglobin: 4.8 g/dL) with thrombocytopenia (92 × 10³/µL) and leukocytosis (2 × 10³/µL) with deranged liver (bilirubin: 3.8 mg/dL, AST: 384 IU/L, ALT: 141 IU/L), coagulation (INR: 1.7), and renal function parameters (blood urea nitrogen: 59.7 mg/dL, creatinine: 1.5 mg/dL). After stabilization, upper gastrointestinal endoscopy was performed which revealed large, high-risk esophageal varices with white nipple sign, and endoscopic variceal ligation was done. During the first 36 h of admission, he was also transfused with 3 units of packed red blood cells, and the hemoglobin was built up to 8.1 g/dL. On the 3rd day of admission, he developed cyanosis of bilateral lower limbs with absent peripheral pulses which progressed rapidly to bluish-black discoloration up to the knees and skin necrosis over left medial ankle (Fig. 1). Arterial Doppler corroborated the absence of flow in popliteal artery and its branches. Vasculitis work-up including ANA, ANCA, and complement levels was non-contributory. Terlipressin was stopped immediately. However, the patient continued to deteriorate with worsening sepsis, rise in total leukocyte counts, and development of new-onset shock. Despite upgradation of antibiotics and optimization of management, he had a rapidly downhill course and expired on day 5.

Fig. 1

Photograph depicting bilateral lower limb gangrenous changes with involvement up to the knee and skin necrosis over left ankle

Discussion

Acute variceal bleed (AVB) is a potentially life-threatening complication of cirrhosis. Mortality has decreased substantially over the last three decades due to advancements in medical and endoscopic therapies. Current guidelines advocate combined endoscopic and pharmacological therapy in patients with AVB due to improved outcomes as compared to either modality alone [3]. Pharmacotherapy in AVB includes vasoconstrictors like terlipressin, somatostatin, and octreotide. Where available, terlipressin is usually the preferred vasoconstrictor as it has been shown to have a survival benefit [3]. It acts on V1 receptors in vascular smooth muscle cells leading to splanchnic vasoconstriction and reduction of portal venous pressures. Apart from AVB, terlipressin is also used in the management of hepatorenal syndrome (HRS) in cirrhosis and has been recently approved by the US FDA based on the phase 3 CONFIRM trial [4].

Adverse events with terlipressin are infrequent. The most concerning adverse effects are related to respiratory failure, myocardial ischemia, arrhythmias, bradycardia, and fluid overload. Other commonly reported adverse events include abdominal pain, nausea, and dyspnea [4]. Ischemic complications with terlipressin are uncommon and were seen in 4.5% of patients in the phase 3 CONFIRM trial. These complications may range from intestinal ischemia and myocardial ischemia to peripheral gangrene. Cutaneous complications are rare and may include bulla, cyanosis, necrosis, and purpura. The exact incidence of ischemic skin necrosis and gangrene following terlipressin is difficult to estimate because of the rarity of the event. In a recently published prospective cohort study on the safety and efficacy of terlipressin, ischemic skin necrosis was documented in only one patient (0.9%) [5]. As such, fewer than 40 cases have been reported in the literature (Table 1), and it commonly involves legs followed by abdomen, scrotum, upper extremities, and hands. It is more common in patients with high MELD scores and those with underlying comorbidities like diabetes, hypertension, obesity, or cardiovascular disease [2, 6]. Our patient had a MELD score of 35 but did not have other comorbidities or risk factors for peripheral vascular disease.

Table 1 Case reports until date of terlipressin-induced ischemic events

It should be noted that our patient received bolus doses of terlipressin (2-mg stat followed by 1 mg 4 hourly) as is the usual practice in AVB [3]. In HRS, use of terlipressin as a continuous infusion instead of boluses has been shown to be equally effective with significantly less adverse effects and a lower cumulative dose [32]. However, data on the use of terlipressin as infusion for management of patients with AVB is virtually non-existent. Furthermore, ischemic complications including skin necrosis have also been reported with the use of continuous infusion of terlipressin in HRS [2, 6].

Development of ischemic complications with terlipressin is associated with increased morbidity and mortality, and there is no specific treatment to revert it. Terlipressin should be stopped immediately, and some cases may resolve with supportive care. Sildenafil has also been tried anecdotally with mixed results [2]. Therefore, patients receiving terlipressin should be closely watched out for terlipressin-induced ischemic events.

Conclusion

Terlipressin is the most enthusiastically used drug in clinical practice in patients with AVB or HRS. However, it is uncommonly associated with ischemic complications that can prove detrimental. Hence, it is necessary to be in knowledge of such adverse events to facilitate early recognition and prompt withdrawal of terlipressin.