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*

No abstract available.
Adult ; Hepatitis C/diagnosis ; Hepatorenal Syndrome/*diagnosis/drug therapy/surgery ; Humans ; Liver Cirrhosis/*diagnosis ; Lypressin/analogs & derivatives/therapeutic use ; Male ; Portasystemic Shunt, Transjugular Intrahepatic ; Stomach Neoplasms/*surgery ; Tomography, X-Ray Computed ; Vasoconstrictor Agents/therapeutic use

BACKGROUND/AIMS: This prospective study aimed to determine if Doppler ultrasonography can be representative of hepatic venous pressure gradient (HVPG) in assessing the severity of portal hypertension and response to drug reducing portal pressure. METHODS: The HVPG and the parameters of Doppler ultrasonography including portal venous velocity (PVV) and splenic venous velocity, the pulsatility and resistive index of hepatic, splenic and renal arteries were measured in 105 patients with liver cirrhosis. In 31 patients the changes of hepatic venous pressure gradient and portal venous velocity after administration of terlipressin were evaluated. The patients who showed a reduction in HVPG of more than 20% of the baseline were defined as responders to terlipressin. RESULTS: Any Doppler ultrasonographc parameters did not correlate with HVPG. Both HVPG and PVV showed a highly significant reduction after the administration of terlipressin(-28.3 +/- 3.9%, -31.2 +/- 2.2% respectively). However, PVV decreased significantly not only in responders(31.7 +/- 2.4%) but also in nonresponders(29.5 +/- 6.1%). CONCLUSION: Doppler ultrasonography can not be representative of HVPG in assessing the severity of portal hypertension and response to drug reducing portal pressure in liver cirrhosis.
Antihypertensive Agents/therapeutic use ; Blood Flow Velocity ; Comparative Study ; English Abstract ; Female ; *Hepatic Veins ; Human ; Hypertension, Portal/drug therapy/etiology/physiopathology/*ultrasonography ; Liver Cirrhosis/*complications ; Lypressin/*analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Prospective Studies ; *Ultrasonography, Doppler ; *Venous Pressure

OBJECTIVETo perform an analysis and comparative study of the clinical data for patients with cirrhosis and type 1 hepatorenal syndrome (HRS) who received treatment with terlipressin using high-or low-dose regimens.

METHODSA total of 56 patients with cirrhosis and type 1 HRS who presented for treatment to the Wuhan Medical Treatment Center and Taizhou Central Hospital between March 2010 and October 2012 were enrolled in the study. The patients were randomly assigned to the terlipressin treatment groups for receipt of the high-dose regimen (1 mg/6-8 h;n =27) or low-dose regimen (1 mg/12 h;n =29). All patients were assessed for 24-hour urine volume, serum blood urea nitrogen (BUN) and creatinine (Cr) levels, therapeutic effect and prognosis, and adverse reactions. Measurements were made before and after the treatment, and on post-treatment days 3, 7 and 14. Inter-group differences were assessed by statistical analyses.

RESULTSThe high-dose group showed an increase in 24-hour urine volumes from post-treatment day 3 (1112 ± 262 ml) to day 7 (1938 ± 312 ml), and the volumes on both days were significantly better than those of the low-dose group (day 3:986 ± 162 ml and day 7:1760 ± 300 ml, t =1.500, 1.830, P=0.038, 0.041). The high-dose group also showed a significantly better decreases in serum BUN levels (35.1 ± 8.6 to 30.2 ± 6.3 mmol/L vs.low-dose group: 43.2 ± 10.9 to 35.1 ± 7.6 mmol/L, t =3.200, 5.901, P =0.043, 0.047) and in serum Cr values (219.0 ± 35.1 to 128.2 ± 41.6 vs.low-dose group: 230.3 ± 82.1 to 151.5 ± 38.7, t =2.997, 5.765, P =0.036, 0.046).On post-treatment day 14 the 24-hour urine volume of patients in the high-dose group decreased (to 720+/-136 ml), but the difference from that of the low-dose group was not significant (vs. 620 ± 164 ml, t =1.855, P =0.069). The serum BUN level increased in the high-dose group (to 54.4 ± 15.0 mmol/L), which was statistically different from that in the low-dose group (vs .57.7 ± 17.3 mmol/L, t=5.166, P =0.022); the same trend was seen for the serum Cr value (397.8 ± 127.4 mumol/L vs. 480.3 ± 179.8 mumol/L, t =5.638, P =0.047). No statistically significant differences were observed for the groups in regard to significant efficiency, efficiency or 2-week survival rate (x2 =2.314, 1.767, 0.678, P =0.128, 0.128, 0.410 respectively), but the total efficiency was significantly different between the two groups (x² =5.793, P =0.016). In addition, no serious adverse reactions (including precordial pain, myocardial infarction or intestinal necrosis) were observed in either group.

CONCLUSIONTerlipressin therapy at both high and low dosages can lead to significant beneficial effects within as little as 3 days after the treatment; however, the high-dose appears to produce a better lasting efficacy (at day 14 after the treatment). The difference in doses does not appear to markedly affect significant efficiency, efficiency, nor the 2-week survival rate.

Adolescent ; Adult ; Aged ; Dose-Response Relationship, Drug ; Female ; Hepatorenal Syndrome ; drug therapy ; etiology ; Humans ; Liver Cirrhosis ; complications ; drug therapy ; Lypressin ; administration & dosage ; analogs & derivatives ; therapeutic use ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult

Terlipressin is a vasopressin analogue that is widely used in the treatment of hepatorenal syndrome or variceal bleeding. Because it acts mainly on splanchnic vessels, terlipressin has a lower incidence of severe ischemic complications than does vasopressin. However, it can still lead to serious complications such as myocardial infarction, skin necrosis, or bowel ischemia. Herein we report a case of severe ischemic bowel necrosis in a 46-year-old cirrhotic patient treated with terlipressin. Although the patient received bowel resection, death occurred due to ongoing hypotension and metabolic acidosis. Attention should be paid to patients complaining of abdominal pain during treatment with terlipressin.
Bilirubin/blood ; Creatinine/blood ; Electrocardiography ; Fatal Outcome ; Hepatorenal Syndrome/*drug therapy ; Humans ; Intestinal Mucosa/pathology ; Intestines/surgery ; Liver Cirrhosis/diagnosis/therapy ; Lypressin/adverse effects/*analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Necrosis/*chemically induced/surgery ; Tomography, X-Ray Computed ; Vasoconstrictor Agents/*adverse effects/*therapeutic use

Variceal bleeding and hepatorenal syndrome (HRS) are serious and life-threatening complications of advanced liver disease. Terlipressin is widely used to manage both acute variceal bleeding and HRS due to its potency and long duration of action. The most severe (though rare) adverse event is ischemia. The present report describes the case of a patient with gangrene and osteomyelitis secondary to terlipressin therapy. A 71-year-old male with alcoholic liver cirrhosis (Child-Pugh B) and chronic hepatitis C was admitted due to a drowsy mental status. The patient had several experiences of orthopedic surgery. His creatinine level had gradually elevated to 4.02 mg/dL, and his urine output decreased to 500 mL/24 hr. The patient was diagnosed as having grade III hepatic encephalopathy (HE) and type II HRS. Terlipressin and albumin were administered intravenously to treat the HRS over 11 days. Although he recovered from the HE and HRS, the patient developed peripheral gangrene and osteomyelitis in both feet. His right toes were cured with the aid of rescue therapy, but his left three toes had to be amputated. Peripheral gangrene and osteomyelitis secondary to terlipressin therapy occur only rarely, and there is no specific rescue therapy for these conditions. Thus, attention should be paid to the possibility of ischemia of the skin and bone during or after terlipressin therapy.
Aged ; Creatinine/blood ; Foot/pathology ; Gangrene/*etiology ; Hepatitis C, Chronic/complications ; Humans ; Liver Cirrhosis/complications/diagnosis ; Liver Diseases/*diagnosis/drug therapy ; Lypressin/adverse effects/*analogs & derivatives/therapeutic use ; Male ; Osteomyelitis/*etiology ; Severity of Illness Index ; Toe Phalanges/radiography ; Vasoconstrictor Agents/*adverse effects/therapeutic use