INTRODUCTION: Hepatorenal syndrome (HRS) is a functional renal impairment associated with advanced cirrhosis. The best treatment is liver transplantation; however, many patients die before this can be done. Terlipressin improves renal function in HRS, but recent studies have shown similar effects with the cheaper and more readily available norepinephrine. This review included randomized trials comparing noradrenaline to terlipressin for patients with type 1 HRS, as defined by the International Ascites Club.

OBJECTIVE: To determine the safety and effectiveness of noradrenaline in the management of HRS in terms of 1) reducing mortality, 2) reversal and 3) occurrence of adverse events

METHODOLOGY: For this meta-analysis paper, the researchers utilized an electronic search of databases and manual scanning of reference lists were performed. Standardized eligibility assessment was performed independently by three reviewers. Review Manager 5.0.23 was used to calculate odds ratios (OR) with 95% confidence intervals (CIs) as well as I2 values for inter-trial heterogeneity. Standardized eligibility assessment was performed independently by three reviewers.

RESULTS: Thirty-six articles were found after electronic and manual searching. Three were assessed for validity and included in the final analysis. The total number of patients across all trials was 95. Noradrenaline was found not to differ from terlipressin in terms of 15-day survival rate (OR 01.17; 95% CI: 0.51-2.66), reversal of HRS (OR1.07; 95% CI: 0.47-2.44), and a post-hoc analysis on disease-free survival (OR 0.78; 95% CI: 0.34-1.79). Results of sensitivity analysis were consistent with the previous findings (15-day survival: OR=1.21 95% CI = 0.52-2.83; HRS reversal: OR= 1.33, 95% CI = 0.56-3.13; disease-free survival: 1.35, CI =0.56-3.25). Only transient adverse effects were noted with either drugs.

CONCLUSION: There is inconclusive evidence that noradrenaline and terlipressin are significantly different in the reversal of HRS and reduction of mortality. Larger trials on noradrenaline or a non-inferiority trial may be needed to establish the equivalence of noradrenaline with terlipressin.

Hepatorenal Syndrome ; Terlipressin ; Norepinephrine ; Survival Rate ; Liver Transplantation ; Ascites ; Disease-free Survival ; Lypressin ; Liver Cirrhosis ; Renal Insufficiency

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-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and lung tissue were determined by enzyme linked immunosorbent assay (ELISA). The expressions of IL-1β 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-1β and TNF-α in serum and lung tissue, the expressions of IL-1β 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-1β (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-1β content (ng/mg): 262.68±16.56 vs. 408.15±17.85, IL-1β 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.
Animals ; Blood Pressure ; Interleukin-1beta ; Lypressin/analogs & derivatives* ; Male ; Mice ; Mice, Inbred C57BL ; Sepsis ; Terlipressin ; Tumor Necrosis Factor-alpha

Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis related complications has been recognized during recent years. This paper aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis related complications. Hepatobiliary Study Group of Chinese Society of Gastroenterology of Chinese Medical Association and Hepatology Committee of Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts' clinical experiences. Overall, 10 major statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis related complications.
Electrolytes ; Esophageal and Gastric Varices/drug therapy* ; Gastrointestinal Hemorrhage/etiology* ; Hepatorenal Syndrome/etiology* ; Humans ; Liver Cirrhosis/drug therapy* ; Lypressin/adverse effects* ; Terlipressin/adverse effects* ; Vasoconstrictor Agents/adverse effects*