Comparison of continuous versus intermittent infusions of terlipressin for the control of acute variceal bleeding in patients with portal hypertension: An open-label randomized controlled trial.

BACKGROUND: Continuous infusion of terlipressin causes more stable reduction in portal venous pressure than intermittent infusion. The aim of the study was to compare the efficacy of continuous infusion vs. intermittent boluses of terlipressin to control acute variceal bleeding (AVB) in patients with portal hypertension. METHODS: Eighty-six consecutive patients with portal hypertension and AVB were randomized to receive either continuous intravenous infusion (Group A, n = 43) or intravenous boluses of terlipressin (Group B, n = 43). Group A received 1 mg intravenous bolus of terlipressin followed by a continuous infusion of 4 mg in 24 h. Group B received 2 mg intravenous bolus of terlipressin followed by 1 mg intravenous injection every 6 h. Upper gastrointestinal (UGI) endoscopy was done within 12 h of admission. Endoscopic variceal ligation (EVL) was done using a multi-band ligator. In both groups, treatment was continued up to 5 days. The primary endpoint was rebleeding or death within 5 days of admission. RESULTS: Patients in group A had lower rate of treatment failure (4.7%) as compared to patients in group B (20.7%) (p = 0.02). Within 6 weeks, four and eight patients died in group A and B, respectively (p = 0.21). Model for end-stage liver disease sodium (MELD-Na) score and continuous infusion of terlipressin showed significant relationship with treatment failure on multivariate analysis. CONCLUSIONS: Continuous infusion of terlipressin may be more effective than intermittent infusion to prevent treatment failure in patients with variceal bleeding. There is significant relationship between MELD-Na score [Odd ratio = 1.37 (95% CI-1.16 - 1.62), p-value < 0.001] and continuous infusion of terlipressin [Odd ratio = 0.18 (95% CI-0.037 - 0.91), p-value - 0.04] with treatment failure.

Systemic hemodynamic response to terlipressin predicts development of hepatorenal syndrome and survival in advanced cirrhosis.

BACKGROUND: The aim of this study was to predict the occurrence of hepatorenal syndrome (HRS) and death in patients with advanced cirrhosis and ascites. PATIENTS AND METHODS: We retrospectively evaluated 2-year data of 78 patients with cirrhosis and ascites (Child-Pugh B/C: 45/43). The mean arterial pressure (MAP) and cardiac output (CO) were measured in all patients just before administration of 2 mg of terlipressin and 30 min later. Systemic vascular resistance (SVR) was calculated as MAP/CO. ΔMAP, and ΔCO, and ΔSVR were defined as the percentage change of MAP, CO, and SVR, respectively, after terlipressin injection. Plasma renin activity (PRA) and plasma aldosterone were evaluated at baseline. Two multivariate models were used: one excluding (model 1) and one including (model 2) the Model of End-stage Liver Disease score. RESULTS: Higher ΔSVR, Model of End-stage Liver Disease score, and PRA were related independently to the severity of cirrhosis. Independent predictors of HRS at 12 and 24 months were ΔSVR (models 1/2: P=0.008/0.01 and 0.01/0.02, respectively), ΔCO (models 1/2: P=0.01/0.03 and 0.03/0.04, respectively), and PRA (models 1/2: P=0.04 and model 1: P=0.04, respectively). ΔSVR at 12 and 24 months (models 1/2: P=0.005/0.01 and 0.01/0.03, respectively) and ΔCO at 24 months (models 1/2: P=0.02/0.01, respectively) were related independently to survival. Patient groups with significantly higher probability of HRS and mortality were identified by certain cutoffs of ΔSVR (20.6 and 22.8%, respectively) and ΔCO (-10.6 and -11.8%, respectively). ΔSVR and ΔCO independently predicted survival in patients with the most advanced cirrhosis and infection-related survival. CONCLUSION: An increase in SVR by at least 20% and a decrease in CO at least 10% in response to terlipressin could predict HRS and mortality in patients with advanced cirrhosis.

Management of ascites and hepatorenal syndrome.

Ascites represents the most common decompensating event in patients with liver cirrhosis. The appearance of ascites is strongly related to portal hypertension, which leads to splanchnic arterial vasodilation, reduction of the effective circulating volume, activation of endogenous vasoconstrictor systems, and avid sodium and water retention in the kidneys. Bacterial translocation further worsens hemodynamic alterations of patients with cirrhosis and ascites. The first-line treatment of uncomplicated ascites is a moderate sodium-restricted diet combined with diuretic treatment. In patients who develop refractory ascites, paracentesis plus albumin represents the most feasible option. Transjugular intrahepatic portosystemic shunt placement is a good alternative for selected patients. Other treatments such as vasoconstrictors and automated low-flow pumps are two potential options still under investigations. Ascites is associated with a high risk of developing further complications of cirrhosis such as dilutional hyponatremia, spontaneous bacterial peritonitis and/or other bacterial infections and acute kidney injury (AKI). Hepatorenal syndrome (HRS) is the most life-threatening type of AKI in patients with cirrhosis. The most appropriate medical treatment in patients with AKI-HRS is the administration of vasoconstrictors plus albumin. Finally, ascites impairs both the quality of life and survival in patients with cirrhosis. Thus, all patients with ascites should be evaluated for the eligibility for liver transplantation. The aim of this article is to review the management of patients with cirrhosis, ascites and HRS.

Acute variceal bleeding: risk stratification and management (including TIPS).

Acute variceal bleeding should be suspected in all patients with cirrhosis presenting with upper gastrointestinal bleeding. Vasoactive drugs and prophylactic antibiotics must be started as soon as possible, even before performing the diagnostic endoscopy. Once the patient is hemodynamically stable, upper gastrointestinal endoscopy should be performed in order to confirm the diagnosis and provide endoscopic therapy (preferably banding ligation). After this initial approach, the most appropriate therapy to prevent both early and late rebleeding must be instituted following a risk stratification strategy. The present chapter will focus on the initial management of patients with acute variceal bleeding, including general management and hemostatic therapies, as well as the available treatments in case of failure to control bleeding or development of rebleeding.

Terlipressin: Current and emerging indications in chronic liver disease.

Terlipressin is an analogue of vasopressin that has potent vasoactive properties and has been available for use in most countries for nearly two decades. It has both established roles and emerging indications in the management of complications of decompensated chronic liver disease. We explore historic and emerging literature regarding the use of terlipressin for a range of indications including hepatorenal syndrome, portal hypertensive bleeding, and disruptions in sodium homeostasis. Novel methods of infusion-based terlipressin administration including the beneficial effect in reduction of adverse events are explored, in addition to new indications for the use of terlipressin in decompensated cirrhosis in an outpatient setting.

A randomized trial comparing terlipressin and noradrenaline in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: The choice of vasopressor for treating cirrhosis with septic shock is unclear. While noradrenaline in general is the preferred vasopressor, terlipressin improves microcirculation in addition to vasopressor action in non-cirrhotics. We compared the efficacy and safety of noradrenaline and terlipressin in cirrhotics with septic shock. PATIENTS AND METHODS: Cirrhotics with septic shock underwent open label randomization to receive either terlipressin (n=42) or noradrenaline (n=42) infusion at a titrated dose. The primary outcome was mean arterial pressure (MAP) >65 mm Hg at 48 h. RESULTS: Baseline characteristics were comparable between the terlipressin and noradrenaline groups.SBP and pneumonia were major sources of sepsis. A higher proportion of patients on terlipressin were able to achieve MAP >65 mm of Hg (92.9% vs 69.1% P=.005) at 48 h. Subsequent discontinuation of vasopressor after hemodynamic stability was better with terlipressin (33.3% vs 11.9%, P<.05). Terlipressin compared to noradrenaline prevented variceal bleed (0% vs 9.5%, P=.01) and improved survival at 48 h (95.2% vs 71.4%, P=.003). Percentage lactate clearance (LC) is an independent predictor of survival [P=.0001, HR=3.9 (95% CI: 1.85-8.22)] after achieving the target MAP.Therapy related adverse effect were comparable in both the arms (40.5% vs 21.4%, P=.06), mostly minor (GradeII-88%) and reversible. CONCLUSIONS: Terlipressin is as effective as noradrenaline as a vasopressor in cirrhotics with septic shock and can serve as a useful drug. Terlipressin additionally provides early survival benefit and reduces the risk of variceal bleed. Lactate clearance is a better predictor of outcome even after achieving target MAP, suggesting the role of microcirculation in septic shock.

Terlipressin Induced Severe Hyponatremia.

Terlipressin is a vasopressin analogue used for its vasoconstrictor effect in the treatment of variceal bleeding. Despite its good safety profile compared to vasopressin, some adverse reactions may occur during its use - e.g. hyponatremia. We describe a case of a cirrhotic patient with active variceal bleeding treated during two separate hospitalizations with terlipressin. In both drug treatment periods, severe laboratory hyponatremia developed. After terlipressin discontinuation, mineral disbalance corrected rapidly. Positive dechallenge and rechallenge corresponding to the drug administration schedule confirms the causality between terlipressin administration and hyponatremia. Hyponatremia was preceded with substantial fluid retention in both episodes. In this case report we want to highlight the need for fluid balance monitoring immediately after first terlipressin dose, which may individually predict the patient risk for the development of hyponatremia as other risk factors have rather limited predictive value in real clinical settings.

Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.

BACKGROUND & AIMS: Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. METHODS: Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. RESULTS: Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P < .001). Decreases in SCr and survival were correlated (r(2) = .882; P < .001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P < .001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. CONCLUSIONS: Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.

Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study.

UNLABELLED: In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy-eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI-INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI-BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20-40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 µmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value >133 µmol/L. The rate of adverse events was lower in the TERLI-INF group (35.29%) than in the TERLI-BOL group (62.16%, P < 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI-INF group than in the TERLI-BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P < 0.05). CONCLUSION: Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration.

Evaluation of acute kidney injury and its response to terlipressin in patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) have high mortality. Cirrhotics with acute kidney injury (AKI) have poor outcome but relevance of AKI and response to terlipressin in ACLF is not known. METHODS: Consecutive ACLF patients with AKI at admission were compared with those without AKI (controls) for mortality at day 7, month 1 and 3, presence of hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP) and acute variceal bleed (AVB). Patients were also compared based on severity of AKI (mild; S.cr 1.5-3 mg/dl and marked; S.cr >3 mg/dl). Response to terlipressin was also evaluated. RESULTS: Of 241 ACLF patients, 55 (22.8%) had AKI at admission. Patients with AKI had higher mortality at day 7, 1 and 3 month and more often developed HE [54.1% vs. 30.6%; P = 0.001] and SBP [9.1% vs. 5.9%; P = 0.02]. Patients with marked AKI neither had higher mortality or complications in comparison to mild AKI. Presence of AKI [Odds ratio; OR, 2.4], S.bilirubin >20 mg/dl [OR, 3.1] and INR [OR, 2.9] were independent baseline predictors of mortality. Terlipressin was used in 28 of 55 patients with AKI who were volume non-responsive (hepatorenal syndrome, AKI-HRS). Ten (35.7%) of these showed response (S.Cr < 1.5 mg/dl) [median 4 days] and had lower mortality compared to terlipressin non-responders (10% vs. 50%, P = 0.05). There was no difference in terlipressin response in mild vs. marked AKI. CONCLUSIONS: Almost one-fourth of the ACLF patients have AKI at admission and presence of AKI, but not its severity predicts complications and high mortality. Terlipressin effectively reverses AKI-HRS within a week in ~35% of ACLF patients resulting in improved survival.

Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on kidney function and transplantation outcomes.

There is little information on the effects of treatment with vasoconstrictors plus albumin in patients with type 2 hepatorenal syndrome (HRS), particularly those awaiting liver transplantation (LT). This study reports the effects of treatment of type 2 HRS in patients on the waiting list for LT. We included 56 patients with type 2 HRS who were awaiting LT. Out of these 56 patients, 31 were treated with terlipressin and albumin. Nineteen (61%) of these 31 patients had response to therapy, and 11 of them relapsed after treatment withdrawal. There were no differences in mortality on the waiting list between responders and nonresponders. Among the 46 (82%) patients who underwent transplantation, 15 underwent transplantation with reversal of type 2 HRS, whereas the remaining 31 underwent transplantation with type 2 HRS. There were no significant differences in serum creatinine or estimated glomerular filtration rate between the 2 cohorts of patients at 3, 6, and 12 months after transplantation. There were no significant differences regarding development of acute kidney injury, need for renal replacement therapy, frequency of chronic kidney disease 1 year after transplant, length of hospitalization, and survival. In conclusion, treatment of patients with type 2 HRS with terlipressin and albumin does not appear to have beneficial effects either in pretransplantation or in posttransplantation outcomes.

The Treatment of Hepatorenal Syndrome.

Hepatorenal syndrome (HRS) is a severe complication that often occurs in patients with cirrhosis and ascites. HRS is a functional renal failure that develops mainly as a consequence of a severe cardiovascular dysfunction which is characterized by an extreme splanchnic arterial vasodilation and a reduction of cardiac output. HRS may develop in two clinical types: as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS). Several small studies and some randomized control studies have been published on the use of terlipressin plus albumin in the treatment of HRS, mainly on AKI-HRS. Terlipressin plus albumin was shown to improve renal function in almost 35-45% of patients with AKI-HRS, as well as to improve short-term survival in these patients. Terlipressin was most commonly used by intravenous boluses moving from an initial dose of 0.5-1 mg every 4 h to 3 mg every 4 h in the case of a nonresponse. In other studies, terlipressin was also given by continuous intravenous infusion. Thus, the best way to administer terlipressin in the treatment of HRS has not yet been defined. α-Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been used in the treatment of AKI-HRS, with promising results. However, we need further studies in order to define whether they can represent a real therapeutic alternative. In conclusion, available data are sufficient to state that the use of terlipressin plus albumin has really changed the management of HRS. Nevertheless, some crucial unsolved issues still exist, in particular: (a) how to predict nonresponse to treatment, (b) how to manage nonresponse to treatment and (c) how to consider the response in those patients who are candidates for liver transplant in the priority allocation process.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.

UNLABELLED: Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 µg thrice daily and up to 200 µg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. CONCLUSION: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

Intraoperative terlipressin therapy reduces the incidence of postoperative acute kidney injury after living donor liver transplantation.

OBJECTIVE: To evaluate the effect of intraoperative infusion with terlipressin on the incidence of acute kidney injury (AKI) after living donor liver transplantation (LDLT). DESIGN: Retrospective case-controlled study. SETTING: Government hospital. PARTICIPANTS: The medical records of 303 patients who underwent LDLT were reviewed retrospectively. INTERVENTIONS: Patients were divided into 2 groups on the basis of intraoperative administration of terlipressin. The primary outcome was AKI, as defined by the Acute Kidney Injury Network criteria. Secondary outcomes included the requirement for postoperative dialysis and in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: The incidence of AKI was 38% (n = 115); AKI occurred in 24 (24.2%) patients who received terlipressin versus 91 (44.6%) in the control group (p = 0.001). The incidence of postoperative dialysis was 9.2% (n = 28). Postoperative dialysis was needed by 8 patients (8.1%) in the terlipressin group versus 20 patients (9.8%) in the control group (p = 0.62). Multivariate logistic regression analysis indicated that terlipressin protected against AKI (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.2-0.8; p = 0.013) but not the need for dialysis (OR, 0.7; 95% CI, 0.2-2.2; p = 0.53) or the in-hospital mortality (OR, 1.1; 95% CI, 0.5-2.3; p = 0.7). Adjustment, using the propensity score, did not alter the association between the use of terlipressin and AKI reduction (OR, 0.46; 95% CI, 0.22-0.89; p = 0.03). CONCLUSION: These results suggested that intraoperative terlipressin therapy is associated with significant reductions in the risk of AKI in LDLT patients.

[Response to Terlipressin and albumin is associated with improved outcome in patients with cirrhosis and hepatorenal syndrome]. / Leberzirrhose und hepatorenales Syndrom: Das Ansprechen auf Terlipressin und Albumin ist mit besserem Überleben assoziiert.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) is a severe but potentially reversible complication in patients with cirrhosis. Untreated it is associated with a poor prognosis. Several randomized controlled trials (RCT) demonstrated that treatment with terlipressin and albumin improves renal function. However the effect on overall survival is unclear. Aim of the study was to gain further insight into the effect of terlipressin treatment in patients with HRS on renal function, overall survival and survival without liver transplantation or renal replacement. METHODS: All patients presenting with HRS and treated with terlipressin in our tertiary referral liver and transplantation center between April 2013 and April 2014 were included. Clinically relevant parameters such as response to therapy, overall survival and transplant- and renal-replacement-free-survival were prospectively investigated. RESULTS: Overall 57 patients were prospectively followed over a median of 65 days. In the majority of patients cirrhosis was in an advanced stage (Child-Pugh C: 46; 81%). Median cumulative terlipressin dosage and treatment duration were 20 mg and 5 days, respectively. Complete or partial response to terlipressin with recovery from HRS was observed in 20 and 3 out of 57 patients (51%; 5%). Median overall survival was significantly better in patients with response to terlipressin than in patients with non-response (167 vs. 27 days; p > 0.0001), as well as median survival free of liver transplantation and renal-replacement-therapy (81 vs. 4 days; p > 0.0001). In uni- and multivariate analysis, non-response was associated with a high baseline serum-bilirubin-concentration. CONCLUSION: Terlipressin in combination with albumin is effective in the majority of patients with HRS. Response to therapy is associated with improved survival.

Acute kidney injury and hepatorenal syndrome in cirrhosis.

Cirrhosis is the eighth leading cause of "years of lost life" in the United States and accounts for approximately 1% to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of hepatorenal syndrome (HRS) are similar to prerenal uremia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis, and bleeding. The monitoring, prevention, early detection, and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin combined with albumin. In HRS type 2, transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation.