Terlipressin: An Asset for Hepatologists!

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1 DIAGNOSTIC AND THERAPEUTIC ADVANCES IN HEPATOLOGY Terlipressin: An Asset for Hepatologists! S.K. Sarin and Praveen Sharma One Case Scenario A 48-year-old male with alcoholic cirrhosis who was abstinent from alcohol for 6 months was admitted for management of esophageal variceal bleeding. He had ascites and paracentesis ruled out spontaneous bacterial peritonitis (SBP). On admission, his hemoglobin was 8.6 g/dl, white blood cell (WBC) count 9,200, and platelets 66,000/lL. The serum bilirubin was 3.2 mg/dl, direct 2.8 mg/dl, creatinine 2.9 mg/dl in spite of volume resuscitation, and international normalized ratio (INR) 1.8. The primary questions were: What would be the role of terlipressin in the control of variceal bleeding; what is the role of terlipressin in the treatment of hepatorenal syndrome? Are there any factors that may be used a priori to determine which patient will benefit from terlipressin therapy? The Problems Management of Patients with Acute Variceal Bleeding General Measures. Patients with acute variceal hemorrhage (AVB) should be admitted to an intensive care unit for resuscitation and management. Initial management includes protecting the airway and obtaining peripheral venous access. Red cell transfusions should be undertaken with the goal of maintaining hemoglobin of approximately 7-8 g/dl. 1,2 However, the transfusion policy should consider other Abbreviations: AVB, acute variceal hemorrhage; HRS, hepatorenal syndrome; SBP, spontaneous bacterial peritonitis. From the Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India. Address reprint requests to: S.K. Sarin, Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, , India. shivsarin@gmail.com. Copyright VC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report. factors such as comorbidities, age, hemodynamic status, and ongoing bleeding. The INR is not a reliable indicator of the coagulation status in patients with cirrhosis; however, fresh-frozen plasma and platelets can be considered in patients with significant coagulopathy and/or thrombocytopenia. 1-3 Oral quinolones (norfloxacin orally at a dose of 400 mg twice a day for 7 days) are recommended to decrease the rate of bacterial infections and improve survival. Intravenous ceftriaxone 1 gm/day is considered in patients with advanced cirrhosis, in hospital settings with a high prevalence of quinolone-resistant bacterial infections, and in patients on previous quinolone prophylaxis. 3,4 More data are required before recommending prophylactic lactulose routinely in patients with AVB to prevent development of hepatic encephalopathy. 5 Specific Measures. In suspected variceal bleeding, vasoactive drugs should be started as soon as possible, and at least 30 minutes before endoscopy and continued for up to 2-5 days. A recent meta-analysis of 15 trials comparing emergency sclerotherapy versus pharmacological treatment (vasopressin with nitroglycerin, terlipressin, somatostatin, or octreotide) showed a similar efficacy but fewer side effects with pharmacological therapy. 6 Combination of pharmacological therapy and endoscopic therapy is the most rational approach in the treatment of AVB. Terlipressin, a synthetic analog of vasopressin that has longer biological activity and significantly fewer side effects than vasopressin, is effective in controlling AVB and is associated with decreased mortality. Terlipressin is not yet available in many countries, including the United States. 4 Terlipressin is administered at an initial dose of 2 mg intravenously every 4 hours and can be titrated down to 1 mg intravenously every 4 hours once hemorrhage is controlled. Upper endoscopy should be performed as soon as possible after admission, preferably within 12 hours of admission. Variceal ligation is the preferred endoscopic therapy if a variceal source of hemorrhage is confirmed. 1,4 Terlipressin infusion is continued for up to 5 days. 724

2 HEPATOLOGY, Vol. 54, No. 2, 2011 SARIN AND SHARMA 725 Management of Patients with Hepatorenal Syndrome Hepatorenal syndrome (HRS) represents one of the most serious complications of endstage liver disease, occurring in patients with ascites and profound circulatory dysfunction. The current diagnostic criteria for HRS includes presence of cirrhosis, ascites, serum creatinine >1.5 mg/dl or 133 lmol/l after at least 48 hours of diuretic withdrawal and volume expansion with albumin in the absence of shock, treatment with nephrotoxic drugs, and parenchymal renal disease. The use of minor criteria and exclusion of patients with infections is abandoned. Type 1 HRS is defined by renal dysfunction with serum creatinine increasing to >2.5 mg/dl (226 lmol/l) within 2 weeks. Type 2 HRS is defined by a moderate to slowly progressive renal failure with serum creatinine between 1.5 and 2.5 mg/dl ( lmol/ L). 8,9 Without treatment, HRS type 1 has a median survival of about 2 weeks, whereas HRS type 2 has a median survival of about 6 months. 7-9 HRS is best characterized as an extreme expression of the profound circulatory dysfunction in cirrhosis. There is marked splanchnic and systemic arterial vasodilatation and reduction in the effective blood volume, activation of vasoactive systems, with intense renal vasoconstriction, ultimately resulting in a critical decrease in renal blood flow. 9 HRS is also associated with significant reductions in both cardiopulmonary pressures (i.e., right atrial and pulmonary capillary wedge pressures) and stroke volume. 10 Patients who develop type 1 HRS have a reduction in stroke volume, which is not compensated for by a rise in heart rate. As a result, cardiac output eventually decreases. These findings suggest that type 1 HRS is the result of a decrease in cardiac output during marked systemic vasodilation. 10 Whereas HRS type 2 is a more chronic functional renal failure occurring in the setting of refractory ascites, HRS type 1 represents an acute functional renal failure often triggered by an insult, leading to profound renal, cardiac, and cerebrovascular dysfunction and multiorgan failure. Vasoconstrictors have the potential to reverse HRS because of their unique properties of counteracting the effects of intense splanchnic vasodilatation and augmenting effective arterial blood volume, thereby suppressing endogenous renal vasoconstrictors and improving renal function. Several classes of vasoconstrictors have been employed in the treatment of HRS, including vasopressin analogs (terlipressin and ornipressin), somatostatin analogs (octreotide), and alpha-1 adrenergic receptor agonists (midodrine and norepinephrine) Terlipressin. Terlipressin is the drug used most in the treatment of HRS. Terlipressin is a prohormone of lysine-vasopressin (triglycyl lysine vasopressin). Following intravenous administration, the glycyl residues are cleaved from the prohormone by endothelial peptidases, allowing prolonged release of lysine-vasopressin. This mechanism prolongs the half-life of terlipressin, enabling administration in divided doses without the need for an infusion as with vasopressin and minimizes systemic toxicity (Fig. 1). Terlipressin has affinity for both V1 and V2 receptors. Terlipressin selectively causes splanchnic and extrarenal vasoconstriction by stimulation of V1 receptors, which are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region and thereby reduces splanchnic blood flow and portal pressure. 14 Following terlipressin administration for 30 minutes there is an increase in mean arterial pressure and systemic vascular resistance while the heart rate, cardiac output, hepatic venous pressure gradient, and portal venous blood flow decrease. 15 Reduction in portal pressure results in amelioration in the hyperdynamic circulation, thereby improving the effective circulatory volume and renal perfusion pressure. V2 receptor stimulation by terlipressin increases water reabsorption in the renal collecting ducts by increasing the number of aquaporin-2 water channels in the apical plasma membrane. 14,16 Hyponatremia may result in some patients. In an initial randomized controlled trial in HRS patients, terlipressin was shown to significantly improve the renal dysfunction and survival compared to placebo. 17 Several subsequent studies provided further evidence of the benefit of terlipressin and albumin in HRS patients Terlipressin is administered in initial doses of mg every 4-6 hours, increasing to 2 mg every 4 hours. The dose is titrated to achieve an increase in mean arterial pressure of 10 mmhg. HRS reversal occurs in 25%-80% of patients over 7-15 days with improvement in short-term survival In some studies, terlipressin was given at fixed doses (1 mg every 8 or 12 hours). However, the effect of a dose of terlipressin may differ from one patient to another, especially according to the degree of liver failure. The higher the Child-Pugh score, the greater the dose of terlipressin required. Interestingly, other studies used goal-directed terlipressin therapy. Terlipressin was initially given at a dose of 0.5 mg/4 h and, if a significant reduction in serum creatinine (of at least 88 lmol/l [1 mg/dl]) was not observed, the dose was increased in a stepwise fashion every 3 days to 1 mg/4 h and 2 mg/4 h. 19,20 The impact of more

3 726 SARIN AND SHARMA HEPATOLOGY, August 2011 Fig. 1. The pathogenesis of hepatorenal syndrome and mechanisms of action of terlipressin. rapid increases in doses of terlipressin according to therapeutic goals rather than a 3-day decrease in serum creatinine levels has not yet been studied. All patients with HRS should receive intravenous albumin at a dose of 1 g/kg body weight during the initial 24 hours, followed by g daily titrated to a central venous pressure of 8-12 mmhg. 19,20 Monitoring for Drug-Related Adverse Events. Most clinical trials excluded patients with important comorbidities. Still, terlipressin was associated with several adverse events, including abdominal cramps and diarrhea occurring in about 20%. The assessment ofthisadverseeventmaybedifficult,becausemany patients received lactulose after developing hepatic encephalopathy. Cardiovascular adverse events occur in about 6%-40% of these selected groups of patients and the frequency is likely to be higher in unselected patient populations treated in everyday clinical practice Accordingly, all patients should be monitored in the intensive care unit with continuous monitoring of arterial pressure and electrocardiograms to detect cardiac of central venous pressure, ischemia or arrhythmia, especially in patients with hepatic encephalopathy or diabetes (Table 1). Likewise, frequent inspection of the patient to detect peripheral ischemia with cyanosis, livedo reticularis, or skin necrosis of the fingers or extremities is necessary. Hyponatremia and its associated problems of seizures and altered sensorium is an important side effect of terlipressin in patients with acute variceal bleed. However, most studies in HRS have not noted significant hyponatremia when terlipressin is used with albumin; rather, hyponatremia has been shown to improve with such treatment Terlipressin should be discontinued promptly or dose reduced in the event of any complication. Finally, because of the administration of albumin, patients should also be evaluated closely during treatment for early recognition of signs of circulatory overload. Patients should be informed of the Table 1. Situations Where Terlipressin Should Be Avoided History of coronary artery disease, cardiac arrhythmias, cardiomyopathies Obliterative arterial disease of the lower limbs Asthma, chronic obstructive pulmonary disease Cerebrovascular disease Age >70 years

4 HEPATOLOGY, Vol. 54, No. 2, 2011 SARIN AND SHARMA 727 potential adverse events before starting terlipressin and informed consent should be sought. 25 Predictors of Response. Various studies have reported a number of baseline parameters as predictors of response to therapy like baseline serum creatinine, serum bilirubin, mean arterial pressure, plasma renin activity, urine volume, Child-Pugh score, and treatment with terlipressin >3mg/d. The most consistent predictor of the response to terlipressin and of survival is baseline serum creatinine. Patients most likely to benefit from terlipressin have early onset renal failure (i.e., serum creatinine <5.0 mg/dl). A sustained rise in mean arterial pressure during therapy is required for HRS reversal. The risk of unnecessary exposure to terlipressin in patients unlikely to respond may also be mitigated by stopping treatment at day 4 in those in whom the serum creatinine has not started to decrease. 26,27 Areas of Uncertainty. The recurrence of type 1 HRS has been described in up to 20% of responders to terlipressin and albumin after the discontinuation of treatment. 10,13,28 There are limited data on the use of long-term treatment with terlipressin and albumin in patients with HRS as a bridge to liver transplantation. Similarly, the optimal dose and timing of terlipressin remains unclear, although studies suggest that goaldirected regimens adjusted to achieve an increase in mean arterial pressure by 10 mmhg and improvement in renal function is superior to a fixed-dose regimen. Continuous infusion as an alternative to bolus doses in the treatment of HRS needs validation. 29 There is no established treatment role for terlipressin in patients with type 2 HRS. These patients generally receive standard medical therapy of refractory ascites, i.e. repeated large-volume paracentesis with intravenous albumin, or transjugular intrahepatic portosystemic shunt in selected cases. Nonrandomized studies that enrolled a small number of patients with type 2 HRS show that 1 to 2 weeks of terlipressin administration (with or without albumin) improves renal function in these patients. However, no information exists on the long-term efficacy and safety of terlipressin therapy in type 2 HRS. 13 The influence of terlipressin on cerebral blood flow, especially in patients with cirrhosis with hepatic encephalopathy needs further study. Recommendations. The patient under discussion had acute variceal bleeding and probably type 1 HRS. Such patients should be admitted to the intensive care unit for continuous monitoring of heart rate, mean arterial pressure, and central venous pressure. Because the hemoglobin was 8.6 g/dl, this patient did not require any red cell transfusion; however, measurement of the hemoglobin after volume resuscitation will give a more accurate assessment of the need for red cell transfusions. Prophylactic parenteral ceftriaxone 1 g intravenously daily for 5 days should be given in view of advanced liver disease. Combination of endoscopic band ligation and vasoactive drug is the treatment of choice for treatment of AVB. Terlipressin should be started after excluding any obvious contraindication and at least 30 minutes before endoscopy at a dose of 2 mg every 4 hours. Endoscopic band ligation should be carried out when the patient is hemodynamically stable, and within 12 hours of admission. As this patient also had Type 1 HRS, terlipressin should be supplemented with albumin at a dose of 1 g/kg body weight to maintain the central venous pressure at 8-12 mmhg. The patient should be monitored regularly for any side effects of terlipressin. The hematocrit, serum creatinine, and serum sodium should be monitored daily to determine control of bleed and hyponatremia. This patient s baseline serum creatinine, bilirubin, and absence of alcoholic hepatitis favor response to terlipressin. Based on day 3 serum creatinine levels, the dose of terlipressin could be decreased to 1 mg every 4 hours if the level is <1.5 mg/dl or 30% lower than baseline. If the decrease in serum creatinine is not greater than 30% compared to baseline, terlipressin at a dose of 2 mg every 4 hours is continued until the serum creatinine is <1.5 mg/dl, or for a maximum of 15 days of therapy. The patient requires 5 days of therapy with terlipressin in view of the variceal bleed. If the serum creatinine increases on treatment, terlipressin should be continued after 5 days. Finally, this patient should be listed for liver transplantation as definitive therapy. References 1. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. HEPATOLOGY 2007;46: Sarin SK, Kumar A, Angus PW, Baijal SS, Baik SK, Bayraktar Y, et al. Asian Pacific Association for the Study of the Liver (APASL) Working Party on Portal Hypertension. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int 2011;5: de Franchis R, Baveno V. Faculty revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53: Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding unresolved issues. Summary of an American Association for the study of liver diseases and European Association for the study of the liver single-topic conference. HEPATOLOGY 2008;47: Sharma P, Agrawal A, Sharma BC, Sarin SK. Prophylaxis of Hepatic Encephalopathy in Acute Variceal Bleed: A Randomized Controlled Trial of Lactulose Versus no Lactulose. J Gastroenterol Hepatol 2011;26:

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