Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis.

BACKGROUND: Terlipressin has been widely used for various cirrhosis-related complications, but its safety profile remains controversial. Herein, this issue was systematically evaluated. METHODS: All studies reporting adverse events (AEs) of terlipressin in cirrhosis were screened. Incidences were pooled using a random-effects model. Subgroup analyses were performed according to the patient's characteristics and treatment regimens. Interaction among subgroups was evaluated. RESULTS: Seventy-eight studies with 7257 patients with cirrhosis were included. The pooled incidences of any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs were 31%, 22%, 5%, 5%, 4%, and 4% in patients with cirrhosis receiving terlipressin, respectively. Patients with hepatorenal syndrome had higher incidences of any SAEs (29% vs. 0% vs. 0%, pinteraction = 0.01) and treatment-related SAEs (8% vs. 1% vs. 7%, pinteraction = 0.02) than those with variceal bleeding or ascites. Patients who received terlipressin with human albumin had higher incidences of any SAEs (18% vs. 1%, pinteraction = 0.04) and treatment-related SAEs (7% vs. 0%, pinteraction = 0.09) than those without albumin. Patients with total bilirubin level >4.3 mg/dL had higher incidences of any AEs (69% vs. 24%, pinteraction = 0.02), any SAEs (64% vs. 0%, pinteraction < 0.01), and treatment-related SAEs (8% vs. 1%, pinteraction = 0.04) than those ≤4.3 mg/dL. CONCLUSIONS: AEs are common in patients with cirrhosis receiving terlipressin and influenced by clinical scenarios, combination with albumin, and bilirubin levels.

Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Hepatorenal Syndrome Type 1: Diagnosis and Treatment.

Hepatorenal syndrome (HRS) is a feared complication in patients with advanced cirrhosis and is associated with significant morbidity and mortality. While recognized as a distinct physiologic condition for well over one hundred years, a lack of objective diagnostic tests has made the diagnosis one of exclusion. Since 1979, multiple sets of diagnostic criteria have been proposed. Though varying in detail, the principal intent of these criteria is to identify patients with severe, functional acute kidney injury that is unresponsive to volume resuscitation and exclude those with structural injury. However, accurate differential diagnosis remains challenging. Recently, multiple urinary biomarkers of kidney injury, including neutrophil gelatinase-associated lipocalin, have been studied as a means of objectively phenotyping etiologies of acute kidney injury in patients with cirrhosis. Along with markers reflecting tubular functional integrity, including the fractional excretion of sodium, injury markers will likely be incorporated into future diagnostic criteria. Making an accurate diagnosis is critical, as therapeutic options exist for HRS but must be given in a timely manner and only to those patients likely to benefit. Terlipressin, an analog of vasopressin, is the first line of therapy for HRS in much of the world and has recently been approved for use in the United States. Significant questions remain regarding the optimal dosing strategy, metrics for titration, and the potential role of point-of-care ultrasound to help guide concurrent albumin administration.

Efficacy and safety of terlipressin and albumin vs. noradrenaline and albumin in adult patients with hepatorenal syndrome: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and safety compared to albumin and noradrenaline in adult hepatorenal disease patients. MATERIALS AND METHODS: Clinical trials from four databases were included. Cochrane's approach for calculating bias risk was utilized. We rated the quality evaluation by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included the following outcomes: serum creatinine (mg/dl), urine output (ml/24 h), mean arterial pressure (mmHg), reversal rate of HRS, mortality rate, blood plasma renin activity (ng/ml/h), plasma aldosterone concentration (pg/ml), urine sodium (mEq/l), and creatinine clearance (ml/min). RESULTS: Our analysis of nine clinical studies revealed that the noradrenaline group was associated with higher creatinine clearance (MD = 4.22 [0.40, 8.05]), (P = 0.03). There were no significant differences in serum creatinine levels (MD = 0.03 [-0.07, 0.13]), urinary sodium (MD = -1.02 [-5.15, 3.11]), urine output (MD = 32.75 [-93.94, 159.44]), mean arterial pressure (MD = 1.40 [-1.17, 3.96]), plasma renin activity (MD = 1.35 [-0.17, 2.87]), plasma aldosterone concentration (MD = 55.35 [-24.59, 135.29]), reversal rate of HRS (RR = 1.15 [0.96, 1.37]), or mortality rate (RR = 0.87 [0.74, 1.01]) between the two groups (p-values > 0.05). CONCLUSIONS: Noradrenaline is a safe alternative medical therapy for HRS.

Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis.

BACKGROUND & AIMS: The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice. METHODS: We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy. RESULTS: A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema. CONCLUSIONS: The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy. IMPACT AND IMPLICATIONS: The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice.

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.

[Effects of terlipressin on blood pressure and survival in septic mice following trauma and its mechanism].

OBJECTIVE: To investigate the effects of terlipressin (TP) on blood pressure and survival in septic mice following trauma and its mechanism. METHODS: (1) Survival experiment: 120 male C57BL/6 mice aged 6-8 weeks were enrolled, the posttraumatic sepsis mice model was reproduced by traumatic hemorrhage (bilateral femoral fracture + 45% of total blood loss) followed by cecal ligation and puncture (CLP) after 8 hours. Intraperitoneal injection of TP was used for intervention. Sixty model mice were used to observe the effect of 0.05 µg/g TP at different intervention times (the drug was given immediately after traumatic hemorrhage + the administration was repeated after 6 hours, the drug was given immediately after traumatic hemorrhage + the administration was repeated every 6 hours until the end of the experiment, the drug was given at 4 hours after CLP + the administration was repeated every 6 hours until the end of the experiment) on 48-hour cumulative survival rate of mice with posttraumatic sepsis for finding the best intervention time of TP. The other 60 model mice were used to observe the effect of different TP intervention doses (0.01, 0.05, 0.25 µg/g) at the best intervention time on the 48-hour cumulative survival rate of mice with posttraumatic sepsis for finding the best intervention dose of TP. (2) Intervention experiment: the other 45 mice were enrolled, and they were randomly divided into traumatic hemorrhage + sham group (TH+sham group, only laparotomy without CLP), TH+CLP group, and TH+CLP+TP group (the best intervention time and dose of TP shown by survival experiment were used), with 15 mice in each group. Mean arterial pressure (MAP) of mice was monitored continuously. The orbital whole blood was collected at 2 hours after successful reproduction of the model, and the lung tissues were harvested at 12 hours and 24 hours, respectively. The pathological changes in lung tissue were observed with light microscope. The contents of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum and lung tissue were determined by enzyme linked immunosorbent assay (ELISA). The expressions of IL-1ß and TNF-α mRNA in lung tissue were determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The expressions of nuclear factor-κB p65 (NF-κB p65) in the nucleus and cytoplasm of lung tissue were determined by Western Blot. RESULTS: (1) Survival experiment results showed that the 48-hour cumulative survival rate of mice was highest with TP intervention by 0.05 µg/g administration immediately after traumatic hemorrhage and repeated every 6 hours, which was the best intervention method of TP. (2) Intervention experiment results showed that the pulmonary alveolar wall fracture accompanied by inflammatory cell infiltration was found at 12 hours after the successful reproduction of traumatic sepsis model, and the pathological damage was gradually increased with time prolongation. MAP was decreased sharply after traumatic hemorrhage, and it was continued to decrease after two-hit of CLP. The contents of IL-1ß and TNF-α in serum and lung tissue, the expressions of IL-1ß and TNF-α mRNA in lung tissue, and expressions of NF-κB p65 protein in cytoplasm and nucleus of TH+CLP group were significantly higher than those in TH+sham group. Compared with TH+CLP group, the pathological changes in lung tissue were improved significantly, and the MAP was decreased gently after TP intervention, the levels of inflammatory mediators in serum were significantly decreased [IL-1ß (pg/L): 164.32±25.25 vs. 233.11±23.02, TNF-α (pg/L): 155.56±31.47 vs. 596.38±91.50, both P < 0.05], and their expressions in lung tissue [IL-1ß content (ng/mg): 262.68±16.56 vs. 408.15±17.85, IL-1ß mRNA (2-Δ ΔCt): 2.63±0.68 vs. 6.22±0.74; TNF-α content (ng/mg): 311.07±17.35 vs. 405.04±24.83, TNF-α mRNA (2-Δ ΔCt): 2.04±0.62 vs. 5.32±0.55, all P < 0.01], and NF-κB p65 protein expressions were significantly down-regulated (gray value: 0.47±0.01 vs. 1.28±0.05 in cytoplasm, 0.45±0.02 vs. 1.95±0.06 in nucleus, both P < 0.01]. CONCLUSIONS: The continuous intervention with TP 0.05 µg/g administration immediately after traumatic hemorrhage and repeated every 6 hours could improve the MAP of mice with traumatic sepsis, and improve the prognosis. The mechanism may be related to alleviating the inflammatory response and inhibiting the activation of the NF-κB signaling pathway in the lung tissue.

Acute kidney injury in acute-on-chronic liver failure is different from in decompensated cirrhosis.

AIM: To evaluate the differences in acute kidney injury (AKI) between acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) patients. METHODS: During the period from December 2015 to July 2017, 280 patients with hepatitis B virus (HBV)-related ACLF (HBV-ACLF) and 132 patients with HBV-related DC (HBV-DC) who were admitted to our center were recruited consecutively into an observational study. Urine specimens were collected from all subjects and the levels of five urinary tubular injury biomarkers were detected,including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), liver-type fatty acid binding protein (L-FABP), cystatin C (CysC), and kidney injury molecule-1 (KIM-1). Simultaneously, the patient demographics, occurrence and progression of AKI, and response to terlipressin therapy were recorded. All patients were followed up for 3 mo or until death after enrollment. RESULTS: AKI occurred in 71 and 28 of HBV-ACLF and HBV-DC patients, respectively (25.4% vs 21.2%, P = 0.358). Among all patients, the levels of four urinary biomarkers (NGAL, CysC, L-FABP, IL-18) were significantly elevated in patients with HBV-ACLF and AKI (ACLF-AKI), compared with that in patients with HBV-DC and AKI (DC-AKI) or those without AKI. There was a higher proportion of patients with AKI progression in ACLF-AKI patients than in DC-AKI patients (49.3% vs 17.9%, P = 0.013). Forty-three patients with ACLF-AKI and 19 patients with DC-AKI were treated with terlipressin. The response rate of ACLF-AKI patients was significantly lower than that of patients with DC-AKI (32.6% vs 57.9%, P = 0.018). Furthermore, patients with ACLF-AKI had the lowest 90 d survival rates among all groups (P < 0.001). CONCLUSION: AKI in ACLF patients is more likely associated with structural kidney injury, and is more progressive, with a poorer response to terlipressin treatment and a worse prognosis than that in DC patients.

Terlipressin in the treatment of hepatorenal syndrome: A systematic review and meta-analysis.

BACKGROUND: Hepatorenal syndrome is a fatal complication of advanced cirrhosis. Terlipressin is the most widely used treatment method, however, the therapy effects remain inconsonant. We aim to systematically assess the safety and efficacy of terlipressin for hepatorenal syndrome. METHODS: We conducted a systematic review and meta-analysis. Randomized controlled trials involving terlipressin for hepatorenal syndrome were included in a systematic literature search. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of terlipressin for hepatorenal syndrome. RESULTS: A total of 18 randomized controlled trials including 1011 patients were included. Hepatorenal syndrome reverse rate was 42.0% in the terlipressin group and 26.2% in the non-terlipressin group. Terlipressin had greater hepatorenal syndrome reverse rate and renal function improvement rate than placebo and octreotide in the management of HRS. Comparing to norepinephrine, terlipressin had similar efficacy, but with more adverse events. No significant difference of the efficacy was found between terlipressin and dopamine treatment. The subgroup analysis for type 1 HRS had the above same results, except that the adverse events were not significant different between norepinephrine group and terlipressin group. CONCLUSIONS: Terlipressin was superior to placebo and octreotide for reversal of hepatorenal syndrome and improving renal function, but it had no superiority comparing to norepinephrine.

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.