141
Vol. 35 No.4
Dec. 31 2019
中華民國一○八年十二月卅一日出版

Terlipressin-induced Reversible Cyanosis Side Effect


I-Cheng Sung, Chun-Liang Liu, Hsiu-O Hsu
Division of Pharmacy, Pingtung Hospital, Ministry of Health and Welfare

Abstract

The most recommended medication to reverse type I hepatorenal syndrome (HRS) is terlipressin concomitant with albumin. However, we presented a 65-year-old male suffering from the rare side effect of skin cyanosis in his fingers, scrotal region and umbilical hernia. This phenomenon had been observed for 48 hours after the dose of terlipressin, and began to recover after drug withdrawal. Terlipressin was the most suspected causative drug according to the Naranjo score, and the presentations were consistent with previous case reports. Various adverse effects of terlipressin have been reported in terms of cardiopulmonary, gastrointestinal, skin ischemia and sodium/potassium imbalance. Furthermore, the possible mechanisms of terlipressin-induced cyanosis are the abilities of enhancing vasoconstriction and escalating coagulation. In addition to discontinuing or reducing the dose, changing the manners of administrating and avoiding high risk patients, norepinephrine might be an alternative medication depending on the clinicians' consideration. This case report aims to demonstrate an uncommon adverse effect of terlipressin, to explain possible mechanisms and to suggest a substitutable medication.

Key words: terlipressin, cyanosis, hepatorenal syndrome

Introduction

Hepatorenal syndrome (HRS) is a fatal complication of advanced liver cirrhosis and portal hypertension, characterized by renal failure and circulatory dysfunction. It may occur in 40% of patients with liver cirrhosis and ascites over 5 years. According to the international club of ascites (ICA) guideline, HRS can be roughly categorized into two types: the acute form (type I HRS) and chronic form (type II HRS). Type I HRS manifests the rapidly progressive renal dysfunction that the serum creatinine is doubling the initial value and greater than 2.5 mg/dL or 220 μmol/L in less than 2 weeks. Type II HRS displays the moderate renal impairment that the serum creatinine is more than 1.5 mg/dL or 133 μmol/L1.

The most effective regimen is liver transplantation. Besides, transjugular intrahepatic portosystemic stent shunt (TIPS) is an alternative treatment for type 1 HRS, as it can decrease the sinusoidal portal hypertension and revive substantial splanchnic volume2. However, there are several medications, such as vasoconstrictors (terlipressin and midorine), albumin, dopamine and norepinephrine used as initial choice. Vasoconstrictors have been the effective medical therapy currently available, and terlipressin is the most commonly used drug for type I HRS treatments. Terlipressin has been reported for improving renal function, systemic hemodynamics and clinical outcome in patients with HRS3.

Terlipressin is a synthetic long-acting vasopressin analogue and its half-life is six hours. The chemical structure is designed by adding triglycyl-lysin to vasopressin, which acts the same receptor with vasopressin. The indications of terlipressin are esophageal variceal bleeding, HRS and septic shock. Yet, the commercial product of terlipressin is available in Taiwan, but not in the United States4. There are two ongoing phase 3 clinical trials in the United States, which recruit 300 and 196 participants respectively and adopt the methods of multi-center, randomized, placebo controlled, double-blind study to confirm efficacy and safety of terlipressin in treatment with type 1 HRS. The current primary outcome is increasing the percentage of HRS reversal, restoring the serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours.

In our case, the patient was diagnosed of HRS and started employing terlipressin 2 mg per 6 hours. Nevertheless, the patient manifested cyanotic side effect in his fingers, the skin surface of scrotum and umbilical hernia. Terliperssin was the suspected candidate for this adverse effect, since the occurrence rate was reported as 10% in the patients using terlipressin. Therefore, this case report aims to illustrate the potentially adverse drug reaction of terlipressin in a patient with HRS.

Case description

A 65-year-old male suffered from abdominal pain for several days and came to our emergency room on June 25th 2018. He had previous history of liver cirrhosis Child–Pugh B, alcoholism, esophageal varices, and hypertension.

He presented with low blood pressure (77/58 mmHg) initially and the blood examinations revealed renal function impairment (creatinine: 2.41 mg/dL; reference range: 0.64-1.72 mg/dL), hyponatremia (blood sodium level: 129 mM/L; reference range: 136-144 mM/L), increased high sensitivity C-reactive protein (CRP: 17.6 mg/L; reference range: 0-10 mg/L), liver function impairment (AST/ALT: 114/44 IU/L; reference range: 5-41/5-40 IU/L), anemia (Hb: 10.2 g/dL; reference range: 13.5-17.5 g/dL), hyperammonemia (ammonia: 83 μg/dL; reference range: 5-70 μg/dL), elevated total bilirubin (3.5 mg/dL; reference range: 0.3-1.2 mg/dL). His chest X-ray showed bilateral pleural effusion. Later, he was transferred to the intensive care unit (ICU) due to septic shock, suspicious spontaneous bacterial peritonitis (SBP), alcoholic liver cirrhosis with massive ascites and chronic kidney disease with acute exacerbation.

During the first two days in ICU, the diagnosis of SBP was confirmed on the basis of ascites polymorphonuclearneutrophil (PMN) count: 344.19 cells/mm3 in ascites. Flomoxef was given as empirical antibiotics for SBP. He still had unstable blood pressure with oliguria and was treated with the intravenous infusion of norepinephrine, silymarin for alleviating liver damage and lactulose for covering hyperammonemia. After 4-day care, the blood level of ammonia and lactate were improved, but the level of creatinine and total bilirubin exacerbated to 4 mg/dL respectively. The blood and ascites cultures were all negative. Besides, the concentration of blood sodium level kept in 129 mM/L, and his urine output decreased from 300 mL to 60 mL. Based on the ICA criteria of HRS, the patient was diagnosed as type I HRS, due to serum creatinine > 1.5 mg/dL (patient's serum creatinine was 5.4 mg/dL), presence of ascites and liver cirrhosis, and exclusion of any possible drug correlated with nephrotoxicity5. The recommended therapy of HRS was terlipressin (2-12 mg per day) plus albumin (20-40 mg/day). Therefore, the patient was administered with terlipressin (1 mg/ vial) 2 vials per 6 hours concomitant with albumin (20%, 50 mL/bottle) 1 bottle per day.

With the intravenous infusion of terlipressin, the patient's blood pressure returned to 130/72 mmHg, urine output ameliorated to 600 mL and the creatinine level improved to 3.57 mg/dL. However, 48 hours after the initial terlipressin dose, he started to exhibit peripheral cyanosis reaction and purple-like discoloration in his extremities, especially in the fingers, scrotal region and umbilical hernia. On the 3rd day, the presentation of peripheral cyanosis in the fingers, scrotal region and umbilical hernia was evidently progressed (figure 1), although the dosage of terlipressin was reduced from 2 mg per 6 hours to 1 mg per 6 hours. On the 4th day, the cyanosis phenomena still unrecovered in the scrotal region and umbilical hernia, yet the cyanosis in fingers began to restore (figure 2). To prevent further gangrene formation, terlipressin was halted instantly, albeit the gradual improvement in HRS. On the 5th day, the appearances of cyanosis in fingers and umbilical hernia gradually attenuated, but the scrotal region was still involved. After the cessation of terlipressin for four days, the cyanosis phenomena were entirely retrieval in the fingers while that in the region of umbilical hernia and the scrotum were remarkably regressed, although those areas still needed to be cared by antibiotic ointments (figure 3). As a result, the most suspected medication was terlipressin, since the cyanosis happened after administration and began improvement as the drug suspended.

To evaluate the correlation of cyanosis and terlipressin, we utilized adverse drug reaction probability scale (Naranjo) to calculate the score6. Since the side effect was previously reported, appeared after the suspected drug was administered and got improvement when the drug was discontinued, we evaluate the Naranjo score of 4 (Table 1).

Figure 1: On the third day of treatment with terlipressin, patient's fingers (A), scrotum (B) and umbilical hernia (C) were inspected peripheral cyanosis reaction.

Figure 2: On the fourth day after treatment with terlipressin (discontinued terlipressin for 24 hours), patient's fingers (A) became better, but scrotum (B) and umbilical hernia (C) were still observed peripheral cyanosis reaction.

Figure 3: On the seventh day (discontinued terlipressin for fourth days), patient's fingers (A) were totally recovery. In addition, peripheral cyanosis around scrotum (B) and umbilical hernia (C) were obviously improved.

 

Table 1 The Naranjo algorithm of our case.

Discussion

Terlipressin is the analogue of vasopressin, having a substitutive lysine for arginine at the position 8 of the molecule and an N-triglycyl residue that can be cleaved by endothelial peptidases to the active form, lysine-vasopressin. By slow release of the active form, this modification prolongs the effective duration on portal vein. The pharmacological mechanism is similar to vasopressin, while other experimental hypotheses showed that the vasoconstriction effect of terlipressin is to inhibit K+-ATP channels on smooth muscle cells and reduce the blood flow in the splanchnic vessels. This effect can approximately reduce the pressure by 5-35% and foster the correction of hyperdynamic circulation with portal hypertension in cirrhotic patient. The higher the variceal pressure displays, the better the potency of terlipressin functions4.

Vasopressin, secreting from pituitary, is one of the human hormones, which acts in respective V1 (also known as V1a), V2 and V3 (V1b) receptors, respectively. V1 and V2 receptors, having seven transmembrane spanning domains, are G-protein coupled receptors.While activated, V1 receptors trigger phospholipase C that release calcium ion to elicit vasoconstriction, V2 receptors are identified as Gs protein linked receptors that activate adenylyl cyclase to increase cyclic adenosine monophosphate (cAMP), which boosts aquaporin 2 water channel and increases renal water, optional sodium and urea reabsorption. However, V1 receptors prevail abundant in vascular smooth muscle cells in kidney, myometrium, bladder, hepatocytes, platelets, adipocytes and spleen, whilst V2 receptors are mostly found in distal nephron7. V3 receptors are response for the activation on central nerve system and associated with modulation of memory, blood pressure, body temperature and release of pituitary hormones. Clinically, the stimulation of V1 receptors by vasopressin leads to vasoconstriction of the splanchnic vessels, and the effect is important in both reviving the vascular tone in the patients with septic shock and HRS8.

The characteristic of HRS manifests the splanchnic and systemic arterial vasodilatation at first. Since the patient has been suffered from liver cirrhosis, the configuration of liver is distorted and develops resistance to portal blood flow, which gives rise to augmenting the pressure and increasing the production of vasodilators, such as nitric oxide, carbon monoxide and endogenous cannabinoids in the portal circulation. The entrance of vasodilators into circulation induces systemic vasodilation and reduces the effective arterial blood volume, despite no decrement of the actual total blood volume. Hence, the reduction spurs the activation of renin-angiotensin-aldosterone system (RAAS), increasing the cardiac output for compensation and maintenance of hemodynamic stability, which indirectly damages renal function and decreases sodium retention2. Therefore, this cascade of process eventually precipitates renal failure.

The mostly exerted treatment of HRS is terlipressin, which can augment mean arterial pressure and ameliorate the systematic vascular resistance from the compensating mechanisms of circulatory dysfunction. Additionally, after the treatment with terlipressin, the cardiac output and ejection fraction reduce 16 and 17% respectively in the advanced cirrhosis patients9, since terlipressin activates at both V1 and V2 receptors and specifically influences splanchnic and extra-renal vasoconstriction by spurring V1 receptors. Also, terlipressin can decrease water clearance and boost sodium reabsorption, leading to refining type I HRS prognosis. Most recent studies have proved terlipressin has superiority in improving type I HRS reversal rate and renal function with or without albumin compared to placebo. The rate of the HRS reversal was 39.8% in the terlipressin group and 15.4% in the placebo group. The renal function had been refined nearly 50% in terlipressin treatment group comparing to 23.6% in the placebo group. Additionally, treatment with terlipressin could lower the mortality for 10% in the comparison with the placebo group. However, there was no significant difference between the terlipressin and placebo group in the incidence of HRS recurrence11. In a recent systematic review, it showed that terlipressin plus albumin regimen crucially reduced the mortality and benefited renal function in type I HRS, but the side effects containing from severe ones, such as cardiovascular adverse effects (e.g. arrhythmia), to common side effects, for instance, gastrointestinal irritation (e.g. diarrhea), and rare side effects, like skin ischemia (e.g. cyanosis of extremities). Therefore, although terlipressin has been proven valid medication for type I HRS, there are some limitations and disadvantages for particular patients due to side effects.

Plenty of case reports and trials had shown that the different adverse effects of terlipressin were exploited in the treatment with HRS, septic shock or hemorrhagic esophageal varices, including cardiac and pulmonary adverse effects, peripheral ischemia, gastrointestinal adverse events and serum cation imbalance. However, among those side effects that the conditions of peripheral ischemia, containing livedo reticularis, cyanosis, peripheral ischemic gangreneand necrosis, are reported approximately 5% prevalence in the patients treated with terlipressin. Moreover, the common places of peripheral ischemia had been observed in extremities and scrotal region. The possible mechanisms of vasopressin-induced peripheral ischemia are due to V1 receptors-related vasoconstriction and V2 receptors-mediated von Willebrand factor (vWF) secretion from endothelium cells. In endothelium cells, the way of vWF synthesis, storage and release from Weibel-Palade (WP) bodies, specialized secretory organelles, which are responsible for acute vWF release. WP bodies will liberate vWF in acute situation and increase intracellular cAMP concentrations, when WP bodies are stimulated by agonists. Thus, vasopressin activates V2 receptors in endothelium cells, leading to augmenting cAMP concentrations for signal transmission and impelling vWF release in an effort to enhance factor VIII levels for blood coagulation10.

On the other hand, myocardial ischemia or infarction has been reported in rare cases as the cardiac adverse effect. Terlipressin may interfere with vascular hemodynamics, oxygen transported by reducing oxygen consumption but increasing oxygen extraction and microvascular blood flow in the ways of activating V1 receptors for vasoconstriction and stimulating V2 receptors for platelet coagulation by enhancing vWF release. As a consequence, the region of extremities, scrotum and peripheral blood vessel indicate cyanosis phenomena probably due to terlipressin-induced hypoxia circumstance.

One systemic review of terlipressin-induced adverse effects indicated that among thirty-three cases for ischemic complications, twenty-three cases displayed in the limbs, abdominal wall, and other miscellaneous body parts, including scrotum, five cases exhibited cardiac complications and other five cases showed ischemia in gastrointestinal tract. In the group of peripheral gangrene (23 cases), ten cases accounting for 43.3% was diagnosed with HRS used terlipressin as remedy, and the latency of period for manifestation of peripheral ischemia ranged from 2 to 11 days. On the other hand, there were two cases from Taiwan, and reporting the side effect about cardiac muscle infarction. Compared to heart complications, the risk factors for peripheral ischemia were more common and hard to deduce, yet the patients diagnosed with HRS might be one of risk populations due to the data showed in the systemic review. In Taiwan, the studies of terlipressin-induced adverse effects were rare, and lacked systemic review or other epidemiological information to calculate the incidence12.

Although there is no specific antidote to reverse terlipressin-induced peripheral cyanosis, the effective managements are to diminish the dosage of terlipressin, shift the administrating method from intravenous bolus to intravenous infusion, monitor daily dose plus patients' conditions closely, prevent occurrence of potential adverse effects or, at last, withdraw it if necessary. Observation with oxygen supply and reducing terlipressin dosage may be applied if cyanosis in skin and extremities is mild without necrosis. But it should be halted if more severe side effects happen, like skin necrosis or gangrene change, myocardial infarctions and arrhythmias, etc. In addition, there are some alternatives choices, such as midodrine, octreotide, norepinephrine and dopamine for HRS patients. Midodrine and octreotide can both enhance the splanchnic vasoconstriction via directly stimulating adrenergic-alpha 1 receptors and inhibiting glucagon-regulated splanchnic vasodilatation respectively1. In the United States, midodrine combination with octreotide plus albumin had been reported reversal of HRS reached 40% and improved renal function compared to placebo2. Nevertheless, the recent studies showed that terlipressin plus albumin displayed more effective in terms of three-month survival rate, reversal of HRS and improvement of renal function than the group of the combination of midodrine with octreotide plus albumin11, despite the greater vasoconstriction effect and cardiovascular side effects observed in the group of terlipressin plus albumin13. As for norepinephrine, no differences in survival rate, renal function and efficacy on type I HRS were observed if comparing with terlipressin group11. Nevertheless, norepinephrine may have fewer side effects and less financial cost in the comparison with terlipressin2,14. Consequently, in addition to reducing the dose, altering injection manner to low dose for infusion, averting patients having moderate to severe cardiovascular disease from terlipressin regimen15, norepinephrine might be an advisable and practical substitution for type I HRS.

In summary, we presented the whole drug profile for our patient from June 26th to July 16th 2018 (Table 2 and 3). Our case underwent terlipressin-induced cyanosis adverse effect after 48 hours of treatment. After discontinued medication for four days, patient's cyanosis in fingers, scrotal region and umbilical hernia embarked to recover. We identified this terlipressin-induced cyanosis as 4 of Naranjo scale, which supported that terlipressin was the probable drug to cause this adverse effect.

Table 2 The whole drug profile for the patient during June 26th to July 5th 2018. AC: before meals; BI and BH: twice a day; IN: intranasal; IV: intravenous; PC and PO: orally or by mouth after meals; ST: immediately; VD: intravenous infusion

Table 3 The whole drug profile for the patient during July 6th to July 15th 2018. AC: before meals; BI and BH: twice a day; IN: intranasal; IV: intravenous; PC and PO: orally or by mouth after meals; ST: immediately; TI: three times a day; VD: intravenous infusion

Reference:

1. Gines P, Guevara M, Arroyo V,et al: Hepatorenal syndrome. Lancet 2003;362:1819-27.

2. Wong F: Recent advances in our understanding of hepatorenal syndrome. Nat Rev Gastroenterol & hepatol 2012;9:382-91.

3. Solanki P, Chawla A, Garg R, et al: Beneficial effects of Terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003;18:152-6.

4. Saner FH, Canbay A, Gerken G, et al: Pharmacology, clinical efficacy and safety of Terlipressin in esophageal varices bleeding, septic shock and hepatorenal syndrome. Expert Rev Gastroenterol Hepatol 2007;1:207-17.

5. Salerno F, Gerbes A, Gines P, et al: Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-8.

6. Naranjo CA, Busto U, Sellers EM, et al: A method for estimating the probability of adverse drug reactions. Clinical pharmacology and therapeutics 1981;30:239-45.

7. Stockand JD: Vasopressin regulation of renal sodium excretion. Kidney international 2010;78:849-56.

8. Kam PC, Williams S, Yoong FF: Vasopressin and Terlipressin: pharmacology and its clinical relevance. Anaesthesia 2004;59:993-1001.

9. Krag A, Bendtsen F, Mortensen C, et al: Effects of a single Terlipressin administration on cardiac function and perfusion in cirrhosis. Eur J Gastroenterol Hepatol 2010;22:1085-92.

10. Kaufmann JE, Oksche A, Wollheim CB, et al: Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000;106:107-16.

11. Papaluca T, Gow P: Terlipressin: Current and emerging indications in chronic liver disease. J Gastroenterol Hepatol 2018;33:591-8.

12. Sarma P, Muktesh G, Singh RS, Mishra A, et al: Terlipressin-Induced ischemic complications:A systematic review of published case reports. J Pharmacol Pharmacother2018;9:76-85.

13. Cavallin M, Kamath PS, Merli M, et al:Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology 2015;62:567-74.

14. Nassar Junior AP, Farias AQ, LA DA, et al:Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PloS one 2014;9:e107466.

15. Krag A, Møller S:Ascites, Hyponatremia and Hepatorenal Syndrome: Progress in Treatment. In:Gerbes AL, eds. Frontiers in Gastrointestinal Research, vol 28. "Safety of Terlipressin for Hepatorenal Syndrome" Hvidovre, Basel Karger, 2011: 178-88

 

疑似Terlipressin引起可逆性發紺之不良反應

摘要

Terlipressin 併用白蛋白為目前對於逆轉第一型肝腎症候群之首選處方。本案例為一位65歲男性入院後,因第一型肝腎症候群給予 terlipressin 治療,在施打藥物後48小時出現四肢、肚臍疝氣以及陰囊部位有發紺的現象,且經由停止 terlipressin 之後明顯恢復。根據藥物不良反應相關性評估 (Naranjo score),強烈懷疑此不良反應為 terlipressin 所造成。此外,terlipressin 已被報導過許多不良反應,例如:心肺功能、腸胃道方面、皮膚缺血以及鈉鉀離子不平衡等。Terlipressin引起之發紺現象可能源自於藥物本身具有的血管收縮以及增強血小板凝集之能力有關。預防此藥物不良反應的方法為減少藥物之劑量、改變藥品給藥方式從靜脈推注改成靜脈點滴輸注以及防止給予高風險之病人。除了上述方法外,norepinephrine 亦可以當作替代藥物治療肝腎症候群。此篇案例報告旨在提供少見的 terlipressin 引起之發紺現象的探討。

作者

衛生福利部屏東醫院藥劑科藥師 宋懿宸、劉俊良、徐秀娥

通訊作者:宋懿宸/通訊地址:屏東縣屏東市自由路270號

服務單位:屏東醫院藥劑科藥師/聯絡電話:(O) 08-7363011 ext 2029