Hemorragia digestiva alta / Upper Gastrointestinal Bleeding

Introducción: La hemorragia digestiva alta tiene una elevada morbimortalidad. La endoscopía digestiva alta es el estudio de elección para su diagnóstico y tratamiento. Objetivo: Describir la conducta ante la hemorragia digestiva alta. Métodos: Para la revisión bibliográfica se consultaron artículos científicos indexados en idioma español e inglés, relacionados con la hemorragia digestiva, publicados en las bases de datos PubMed, SciELO, Medline y Cochrane, pertenecientes a autores dedicados al estudio de este tema. Desarrollo: La hemorragia digestiva alta se clasifica, según la etiología de origen, en variceal y no variceal. La mayoría de los pacientes con hemorragia digestiva alta el sangrado se autolimita. La causa más habitual es la úlcera péptica, pero en caso de sangrado masivo la etiología más frecuente es la variceal. El empleo precoz de la terlipresina en los pacientes con hemorragia digestiva alta variceal mejora el control del sangrado y disminuye la mortalidad. Se debe hacer uso de escalas validadas de estratificación del riesgo: escala de riesgo de Rockall (tiene como propósito principal predecir la mortalidad y riesgo de resangrado del paciente) y la escala de Glasgow-Blatchford). Conclusiones: Sospechar la presencia de hemorragia digestiva alta, estratificar su riesgo e instaurar el manejo inicial y apropiado constituye una prioridad para el médico de urgencia(AU)

Introduction: Upper gastrointestinal bleeding presents high morbidity and mortality. Upper gastrointestinal endoscopy is the study of choice for its diagnosis and treatment. Objective: To describe the management of upper gastrointestinal bleeding. Methods: For the bibliographic review, the consultation was carried out of scientific articles indexed in Spanish and English, related to gastrointestinal bleeding, published in the databases PubMed, SciELO, Medline and Cochrane, belonging to authors dedicated to the study of this subject. Development: Upper gastrointestinal bleeding is classified, according to the etiology of origin, into variceal and nonvariceal. In most patients with upper gastrointestinal bleeding the bleeding as such is self-limiting. The most common cause is peptic ulcer; however, in the case of massive bleeding, the most frequent etiology is variceal. Early use of terlipressin in patients with variceal upper gastrointestinal bleeding improves bleeding control and decreases mortality. Validated risk stratification scales should be used: Rockall risk scale (its main purpose is to predict patient mortality and risk of bleeding recurrence) and the Glasgow-Blatchford scale. Conclusions: Suspecting the presence of upper gastrointestinal bleeding, stratifying its risk, as well as instituting initial and appropriate management, are a priority for the emergency physician(AU)

Custo efetividade do uso da terlipressina no tratamento da síndrome hepatorrenal / Cost effectiveness of using terlipressin to treat hepatorenal syndrome

ABSTRACT Background Hepatorenal syndrome (HRS) is the most severe form of acute kidney injury in patients with advanced cirrhosis, and it is associated with high mortality. It is usually diagnosed according to criteria defined by the International Ascites Club. Currently, the most frequently indicated pharmacological therapy for the treatment of HRS is a combination of splanchnic vasoconstrictors (terlipressin or norepinephrine) in combination with albumin. With the progressive increase in healthcare spending, it is important to conduct a cost-effectiveness analysis of pharmacological treatment in patients who are diagnosed with HRS. Objective: To perform a cost-effectiveness assessment for the use of terlipressin in combination with albumin to treat HRS in patients with cirrhosis. Methods: Economic evaluation of cost-effectiveness based on secondary data from studies showed the efficacy of terlipressin therapy compared with norepinephrine combined with albumin or albumin alone. The cost-effectiveness analysis was calculated using an incremental cost-effectiveness ratio (ICER), and a sensitivity analysis was developed by varying the values of therapies and probabilities. The Brazilian real was the currency used in the analysis, and the results were converted to US dollars. Results: After selection, eligibility, and evaluation of the quality of publications, the results demonstrated that administration of terlipressin or norepinephrine in combination with albumin in patients diagnosed with HRS type 1 was efficacious. The cost of treatment with terlipressin in combination with albumin was USD $1,644.06, administration of albumin alone was USD $912.02, and norepinephrine plus albumin was USD $2,310.78. Considering that the combination therapies demonstrated effectiveness, the incremental cost of terlipressin and norepinephrine in combination with albumin was USD $666.73, and an effectiveness of 0.570 was found for terlipressin in combination with albumin and 0.200 for norepinephrine in combination with albumin. The incremental effectiveness was 0.370, and the ICER was USD $1,801.97. Thus, the parameters of increasing cost per therapy and ICER indicated that the combined therapy of terlipressin plus albumin was cost effective compared to albumin alone or norepinephrine plus albumin in a public single-payer healthcare system. Conclusion: A cost-effectiveness analysis showed that terlipressin in combination with albumin when administered concomitantly to patients who were diagnosed with type 1 HRS is cost-effective compared to norepinephrine in combination with albumin administered in a controlled environment.

RESUMO Contexto: A Síndrome Hepatorrenal (SHR) é a forma mais grave de lesão renal aguda em pacientes com cirrose avançada, estando diretamente associada a alta taxa de mortalidade. Normalmente é diagnosticada seguindo critérios definidos pela International Ascites Club (IAC). Atualmente, as terapias farmacológicas mais indicadas no tratamento da SHR são a combinação de vasoconstritores esplâncnicos (terlipressina ou norepinefrina) associados à albumina. Com o aumento progressivo dos gastos em saúde, torna-se relevante realizar uma análise de custo-efetividade do tratamento farmacológico em pacientes com diagnóstico de SHR. Objetivo: Realizar avaliação de custo-efetividade do uso da terlipressina associada à albumina no tratamento da SHR em pacientes com cirrose. Métodos: Avaliação econômica de custo-efetividade, com base em dados secundários de estudos publicados com resultado da eficácia da terapia com terlipressina, em comparação com norepinefrina combinada com albumina ou apenas albumina. A análise de custo-efetividade foi calculada usando a razão de custo-efetividade incremental (RCEI) e uma análise de sensibilidade foi desenvolvida variando os valores das terapias e probabilidades. O real foi a moeda utilizada na análise. Resultados: Após a seleção, elegibilidade e avaliação da qualidade das publicações, os resultados demonstraram que a administração da associação de terlipressina ou norepinefrina com albumina em pacientes diagnosticados com SHR tipo 1 possui eficácia comprovada. Os custos do tratamento com a terapia combinada de terlipressina com albumina foram de USD $1,644.06, administração de somente albumina USD $912.02 e norepinefrina mais albumina USD $2,310.78. Considerando as terapias combinadas com efetividade terapêutica comprovada, isto é, terlipressina e norepinefrina associada a albumina, o custo incremental foi de USD $666.73 e efetividade de 0,570 para o grupo da terlipressina associada a albumina e de 0,200 para o grupo da norepinefrina associada a albumina. A efetividade incremental foi de 0,370 e o valor da RCEI foi de USD $1,801.97. Assim, os fatores de incremento do custo por terapia e razão de custo-efetividade incremental definem que a terapia combinada de terlipressina mais albumina é custo efetiva quando comparada a administração de somente albumina ou norepinefrina no cenário do sistema único de saúde. Conclusão: O estudo demonstrou por meio de uma análise de custo-efetividade que a terlipressina associada à albumina quando administrada concomitantemente a pacientes com diagnóstico de SHR tipo 1 é custo-efetiva quando comparada à albumina sozinha e com norepinefrina associada à albumina administrada em um ambiente controlado.

O uso contínuo da terlipressina após a ligadura endoscópica em hemorragia varicosa aguda necessita de mais evidências: um estudo piloto / Rational for continuing terlipressin after endoscopic variceal ligation in acute variceal haemorrhage needs further evidence: a pilot study

ABSTRACT Background Variceal hemorrhage (VH) is a medical emergency. Prompt endoscopic variceal ligation (EVL) is therapeutic. Terlipressin is used in VH and continued for 2—5 days even after EVL. As hemostasis is primarily achieved by EVL, the benefit of continuing trelipressin after EVL is unknown. Objective To evaluate the efficacy of continuing terlipressin after EVL to prevent re-bleed and mortality. Methods In this pilot study, after EVL 74 patients of VH were randomized into two treatment groups TG2 & TG5, received terlipressin (1 mg IV bolus q 4 hourly) for 2 days and 5 days respectively and one control group (TG0), received 0.9% normal saline (10 mL IV bolus q 4 hourly) and followed up for 8 weeks. Results A total of 9 (12.6%) patients had re-bleed with maximum 4 (5.6%) patients in TG5 group followed by 3 (4.2%) in TG2 and 2 (2.8%) in TG0 groups (P=0.670). The overall mortality was 15 (21.1%) patients, 6 (8.5%) patients in TG0 group, followed by 5 (7.0%) in TG5 and 4 (5.6%) in TG2 group (P=0.691). Adverse drug reactions were significantly higher in treatment groups with maximum 18 (24.32%) patients in TG5, followed by 8 (10.8%) in TG2 and 2 (2.7%) in TG0 groups (P=0.00). Duration of hospital stay was also significantly higher in treatment group, 6.63 (±0.65) days in TG5 followed by 3.64 (±0.57) in TG2 and 2.40 (±0.50) days in TG0 groups (P=0.00). Conclusion The rational for continuing terlipressin after EVL is doubtful as it didn't have any benefit for the prevention of re-bleed or mortality; rather it increased the risk of adverse drug reactions and duration of hospital stay. Further randomized clinical trials are encouraged to generate more evidence in support or against continuing terlipressin after EVL.

RESUMO Contexto A hemorragia varicosa (HV) é emergência médica. A ligadura endoscópica imediata das varizes (LEV) é terapêutica. A terlipressina é usada em HV e contínua por 2—5 dias mesmo após a LEV. Como a hemostasia é alcançada principalmente pela LEV, o benefício do uso contínuo da terlipressina após o evento é desconhecido. Objetivo Avaliar a eficácia da terlipressina contínua após a LEV para evitar o ressangramento e a mortalidade. Métodos Neste estudo piloto, após a LEV, 74 pacientes com HV foram randomizados em dois grupos de tratamento TG2 & TG5, que receberam terlipressina (1 mg EV em bolus a cada 4 horas) durante 2—5 dias, respectivamente, e um grupo controle (TG0), que receberam soro fisiológico normal de 0,9% (10 mL EV em bolus a cada 4 horas) e foram seguidos por 8 semanas. Resultados Um total de 9 (12,6%) pacientes tiveram ressangramento, 4 (5,6%) no grupo TG5, seguidos por 3 (4,2%) no TG2 e 2 (2,8%) no grupo TG0 (P=0,670). A mortalidade geral de pacientes foi de 15 (21,1%), 6 (8,5%) no grupo TG0, seguidos por 5 (7,0%) no TG5 e 4 (5,6%) no TG2 (P=0,691). As reações adversas de medicamentos foram significativamente maiores em grupos de tratamento em 18 (24,32%) pacientes no TG5, seguidos por 8 (10,8%) no TG2 e 2 (2,7%) em grupo TG0 (P=0,00). A duração da internação hospitalar também foi significativamente maior no grupo de tratamento, 6,63 (±0,65) dias no TG5, seguido por 3,64 (±0,57) em TG2 e 2,40 (±0,50) dias em grupos TG0 (P=0,00). Conclusão O uso racional para a continuação da terlipressina após a LEV é duvidoso, pois não teve qualquer benefício para a prevenção de ressangramento ou mortalidade; pelo contrário, aumentou o risco de efeitos adversos e duração da internação hospitalar. Outros ensaios clínicos randomizados são necessários para gerar mais evidências em apoio ou contra a terlipressina contínua após a LEV.

Effects of terlipressin combined with norepinephrine on liver function and prognosis of patients with septic shock / 国际生物医学工程杂志

Objective:To investigate the effects of terlipressin (TP) combined with norepinephrine (NE) on liver function and prognosis of patients with septic shock.Methods:From June 2018 to December 2019, 96 patients with septic shock and liver function impairment admitted to the ICU of Tianjin First Central Hospital were selected for prospective study. The patients were divided into control group( n=48) and experiment group( n=48) by randomize number table derived by computer. Based on conventional treatment, NE was used in control group, and the low dose continuous infusion of TP combined with NE was used in experiment group. Serial measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum total bilirubin (TBIL), heart rate and mean arterial pressure (MAP), and blood lactic acid levels were made before the treatment and after the treatment at 24 and 48 hours. The mechanical ventilation time, intensive care unit (ICU) stay, and total length of hospital stay of the two groups were compared, and the 28-day mortality and serious adverse reactions of the two groups was also calculated. Results:The levels of ALT, AST, TBIL, heart rate and blood Lac of the two groups were significantly decreased after the treatment (all P<0.01), and the level of MAP was significantly increased (all P<0.01). Compared with the control group, the levels of 24-hour and 48-hour ALT, AST, TBIL, blood Lac of the experiment group were significantly decreased (all P<0.05), and the 48-hour level of MAP was significantly increased (all P<0.05), but there was no statistically significant difference between the two groups in the levels of 24-hour heart rate and 24-hour MAP (all P>0.05). Besides, there was no statistically significant difference between the two groups in the mechanical ventilation time, ICU stay, total length of hospital stay and the 28-day mortality (all P>0.05). And there were no serious adverse reactions such as avascular necrosis of the fingers and myocardial infraction in the two groups. Conclusions:In the treatment of septic shock, on the basic of adequate fluid resuscitation, continuous intravenous pumping of low-dose TP combined with NE can play a certain protective effect on the live, and the mechanisms of action may be mediated by stabilizing hemodynamics, reducing heart rate, reducing the level of blood Lac and improving liver perfusion, thereby protecting liver function in patients with septic shock.

Content Determination of Related Substances in Terlipressin for Injection by UPLC / 中国药房

OBJECTIVE：To establish UPLC method for the content determination of related substances in Terlipressin for injection. METHODS ：UPLC method was used to determine the contents of related substances in 5 batches of Terlipressin for injection. The separation was performed on Xtimate UPLC C 18 column with mobile phase A consisted of ammonium sulfate buffer （pH 2.3）-methanol（90 ∶ 10，V/V）and mobile phase B consisted of ammonium sulfate buffer （pH 2.3）-methanol（60 ∶ 40，V/V） （gradient elution ）at the flow rate of 0.2 mL/min. The detection wavelength was set at 210 nm，and sample size was 5 μL. RESULTS：The linear range of impurity A ，B，C，D，F，H，I，K，L and N were 0.43-3.86，0.44-3.95，0.44-3.97，0.45-4.08， 0.45-4.05，0.50-4.50，0.47-4.26，0.47-4.23，0.46-4.13，0.44-3.96 μg/mL（r≥0.999 7），respectively. The detection limits were 0.04， 0.04，0.05，0.04，0.05，0.05，0.05，0.05，0.04 μg/mL. The quantitation limits were 0.13，0.13，0.14，0.13，0.15，0.14，0.14， 0.14，0.13 μg/mL，respectively. RSDs of precision ，reproducibility and stability tests were all lower than 8％. The average recoveries were 94.95％，97.81％，101.88％，95.26％，93.40％，102.48％，104.26％，102.31％，96.42％，90.42％，with RSD s of 1.89％，1.86％，0.68％，1.30％，1.98％，3.36％，1.26％，1.30％，1.19％，1.40％（n＝9），respectively. Total contents of impurities in 5 batches of Terlipressin for injection were all lower than 4％. CONCLUSIONS ：Established method is rapid ，simple， accurate and specific ，which can be used for the quantitative analysis for related substances in Terlipressin for injection.

Terlipressin versus norepinephrine to prevent milrinone-induced systemic vascular hypotension in cardiac surgery patient with pulmonary hypertension

Introduction: Milrinone at inotropic doses requires the addition of a vasoconstrictive drug. We hypothesized that terlipressin use could selectively recover the systemic vascular hypotension induced by milrinone without increasing the pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) as norepinephrine in cardiac surgery patients. Patients and Methods: Patients with pulmonary hypertension were enrolled in this study. At the start of rewarming a milrinone 25 μg/kg bolus over 10 min followed by infusion at the rate of 0.25 μg/kg/min. Just after the loading dose of milrinone, the patients were randomized to receive norepinephrine infusion at a dose of 0.1 μg/kg/min (norepinephrine group) or terlipressin infusion at a dose of 2 μg/kg/h (terlipressin group). Heart rate, mean arterial blood pressure (MAP), central venous pressure, MPAP, systemic vascular resistance (SVR), PVR, cardiac output were measured after induction of anesthesia, after loading dose of milrinone, during skin closure, and in the intensive care unit till 24 h. Results: Milrinone decreased MAP (from 79.56 ± 4.5 to 55.21 ± 2.1 and from 78.46 ± 3.3 to 54.11 ± 1.1) and decreased the MPAP (from 59.5 ± 3.5 to 25.4 ± 2.6 and from 61.3 ± 5.2 to 25.1 ± 2.3) in both groups. After norepinephrine, there was an increase in the MAP which is comparable to terlipressin group (P > 0.05). Terlipressin group shows a significant lower MPAP than norepinephrine group (24.5 ± 1.4 at skin closure vs. 43.3 ± 2.1, than 20.3 ± 2.1 at 24 h vs. 39.8 ± 3.8 postoperatively). There is a comparable increase in the SVR in both group, PVR showed a significant increase in the norepinephrine group compared to the terlipressin group (240.5 ± 23 vs. 140.6 ± 13 at skin closure than 190.3 ± 32 vs. 120.3 ± 10 at 24 h postoperatively). Conclusion: The use of terlipressin after milrinone will reverse systemic hypotension with lesser effect on the pulmonary artery pressure.

Observation of the therapeutic and characteristic effects of terlipressin on refractory cirrhotic ascites / 中华肝脏病杂志

Objective@#To observe the therapeutic effect of terlipressin on refractory ascites (RA) in cirrhosis, and its role and impact on acute kidney injury (AKI).@*Methods@#A non-randomized controlled clinical trial data of 111 hospitalized cases of liver cirrhosis accompanied with RA was collected from Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Zhongshan Hospital of Hubei Province, The First Affiliated Hospital of Zhengzhou University, The First Affiliated Hospital of Medical School of Zhejiang University, and People's Hospital of Pudong New Area of Shanghai between March 2015 and March 2017. 26 cases of conventional treatment group (control group) were divided into two subgroups: RA without AKI (RA-NAKI) and RA with AKI (RA-AKI), and each subgroup consisted 13 cases. Patients with bacterial infection were treated with diuretics, albumin supplementation and antibiotics. 85 cases were presented in terlipressin combined treatment group, of which 27 cases were of RA-NAKI and 58 cases were of RA-AKI. Control group was injected terlipressin 1mg of intravenous drip or static push (once q6 h ~ 12 h) for more than 5 days. The treatment duration lasted for 2 weeks with 4 weeks of follow-up. Body weight, 24-hour urine volume, abdominal circumference, mean arterial pressure (MAP), liver and kidney function, anterior hepatic ascites, deepest point of ascites, and ultrasonographic detection of ascites in supine position before treatment, one and two weeks after treatment and 4 weeks after follow-up were compared. Count data were tested by χ 2. Samples of four groups at baseline were compared. One-way analysis of variance was used for normal distribution data and Kruskal-Wallis H test for non-normal distribution data. Repeated measures analysis of variance was used to compare the difference in efficacy between different time points before and after treatment in the group. The LSD method of one-way ANOVA was used to compare the two groups. A t-test of independent samples was used to compare the efficacy of different time series between the two groups. Mann-Whitney rank- sum test was used to compare the data of non-normal distribution between the two groups.@*Results@#(1) Baseline data were compared among 4 subgroups of terlipressin RA-NAKI and control RA-AKI. Control group age was higher than that of terlipressin group, and the serum creatinine (SCr) of the RA-AKI group was higher than RA-NAKI group, and there was no significant difference in the rest of the baseline data and the combined medication (P > 0.05). (2) An intra-group comparison between control and trelipressin before and after treatment showed that all patients had lower body mass, abdominal circumference and deepest ascites, and higher serum albumin (P < 0.05). 24-hour urine volume and MAP was significantly increased in the terlipressin group, while the pre-ascites, SCr and child Turcotte Pugh (CTP) scores were decreased. Body weight, abdominal circumference, pre-ascites, and deepest ascites of the terlipressin group were decreased, while MAP was increased during the treatment and follow-up periods. The differences were statistically significant when compared with the control group at the same time (P < 0.05). There was a statistically significant difference in the increase of 24-h urine volume in the terlipressin group compared with the control group (P < 0.05). The decrease in SCr and CTP in the terlipressin group after 2 weeks of treatment and 4 weeks of follow-up was statistically significant compared with the control group (P < 0.05). (3) Among the two subgroups of RA-AKI and RA-NAKI in the terlipressin group, the baseline SCr value of the former was higher than that of the latter. After treatment, the body weight, abdominal circumference, pre-ascites, deepest ascites and CTP scores were decreased. In the RA-AKI group, 24-hour urine volume, MAP, SCr and serum albumin concentration were significantly increased. The difference between the two subgroups before and after treatment was compared, and the body weight of RA-AKI group at 1, 2 weeks of treatment and 4 weeks of follow-up was significantly lower than RA-NAKI group, which were (- 2.3 ± 0.2 vs. - 1.5 ± 0.2) kg, (- 4.1 ± 0.2 vs. - 2.6 ± 0.2) kg, (- 4.2 ± 0.3 vs. - 2.4 ± 0.3) kg, respectively. RA-NAKI group urine volume was significantly increased at 2 weeks of treatment and 4 weeks of follow-up, which was (468 ± 42 vs. 110 ± 131) ml, (272 ± 34 ml vs. 11 ± 112) ml, respectively. SCr reduction (18.3 ± 4.7 vs. 0.9 ± 2.4) µmol/l at 4 weeks of follow-up was apparent in RA-NAKI group, and the difference was statistically significant (P < 0.05).@*Conclusion@#Addition of terlipressin to conventional treatment may significantly increase MAP, 24-h urine volume, improve renal function and promote ascites resolution in patients with refractory cirrhotic ascites. Moreover, its combination effect is more obvious in AKI patients, and adverse reactions are mild.

Research progress of terlipressin in the treatment of cirrhotic ascites-related complications / 中华肝脏病杂志

Ascites is the most common clinical symptom in the decompensated stage of patients with liver cirrhosis, and its co-existence in complex conditions, such as refractory ascites, hyponatremia, hepatorenal syndrome and other complications may harm seriously. Splanchnic vasodilation is the key pathological link of cirrhotic ascites-related complications and the treatment of this link can help to eliminate the symptoms of ascites and prevent the further deterioration of decompensated cirrhosis. This paper summaries the pharmacological basis, clinical evidence and application characteristics of a vasocative drugs-terlipressin in the treatment of cirrhotic ascites-related complications, and further analyzes the problems existing in the current research, then proposes a prospect.

Application of terlipressin in the treatment of esophagogastric variceal bleeding in liver cirrhosis / 临床肝胆病杂志

Esophagogastric variceal bleeding (EVB) is a common fatal complication secondary to cirrhotic portal hypertension. Terlipressin can shrink visceral blood vessels, reduce portal pressure, and increase renal perfusion and is mainly used in the treatment of EVB. This article summarizes the mechanism of action and clinical effect of terlipressin in the treatment of EVB in liver cirrhosis and points out that if conditions permit, terlipressin combined with endoscopic variceal ligation should be the preferred treatment method for EVB.

Efficacy and safety of norepinephrine combined with albumin versus terlipressin combined with albumin in treatment of type 1 hepatorenal syndrome: A Meta-analysis / 临床肝胆病杂志

ObjectiveTo systematically review the efficacy and safety of norepinephrine combined with albumin versus terlipressin combined with albumin in the treatment of type 1 hepatorenal syndrome (HRS1). MethodsPubMed, EMBASE, Medline, Cochrane Library, CNKI, Wanfang Data, and VIP were searched for comparative studies on norepinephrine combined with albumin versus terlipressin combined with albumin in the treatment of HRS1. Quality assessment was performed for articles. Related indicators were extracted, including hepatorenal syndrome (HRS) reversal rate, mortality rate, incidence of adverse events, mean arterial pressure, and renal function, and Review Manager 5.3 was used for data analysis. The chi-square test was used to determine the heterogeneity between studies. Odds ratio (OR) was used for the analysis of dichotomous variables, weighted mean difference (WMD) was used for the analysis of continuous variables, and 95% confidence interval (CI) was calculated for these two types of variables. ResultsA total of 6 randomized controlled trials which met the inclusion criteria were included, with a total sample size of 298 patients (149 patients in the norepinephrine+albumin group and 149 in the terlipressin+albumin group). The meta-analysis showed that there were no significant differences between the two groups in HRS reversal rate (OR=0.95, 95%CI: 0.6-1.49, P=0.81), mortality rate (OR=0.84, 95%CI: 0.51-1.41, P=0.51), incidence rate of adverse events (OR=042, 95%CI: 0.16-1.07, P=0.07), mean arterial pressure (standardized mean difference=0.05, 95%CI: -0.92 to 1.03, P=092), and renal function. ConclusionNorepinephrine combined with albumin has similar efficacy and safety as terlipressin combined with albumin in the treatment of HRS1, and terlipressin can be replaced by norepinephrine in clinical practice when necessary.

Effects of terlipressin on blood pressure and survival in septic mice following trauma and its mechanism / 中华危重病急救医学

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-ΔΔCt): 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-ΔΔCt): 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.

The role of terlipressin in treatment of septic shock: a single center randomized controlled double-blind clinical trial / 中华急诊医学杂志

Objective To evaluate the efficacy and safety of terlipressin for septic shock.Methods A randomized double-blind placebo-controlled pilot study was carried out in the general ICU of the First Affiliated Hospital of Zhengzhou University from June 1st 2015 to May 31st 2016.The septic shock patients with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation were enrolled.Patients were randomized (random number) to give continuous infusions of either terlipressin[0.6-2.6 μg/(kg·h)] or norepinephrine(7-30 μg/min).Open label norepinephrine or other catecholamines were additionally infused if the mean arterial pressure failed to reach 65 mmHg.Treatment was continued until shock corrected,death or withdrawn from this study.Correcting rate of shock was the primary end point,the secondary end points included open labeled norepinephrine requirements,the 28 d survival rate and adverse events.The quantitative data of the two groups were compared by t test or Wilcoxon rank sum test.The enumeration data were compared by chi square test or Fisher exact probability method,and the survival data were analyzed by Kaplan-Meier method.Results A total of 28 patients were enrolled.The full analysis set was 28,the per-protocol set was 25,and the safety set was 28.The key demographics and baseline characteristics were similar between the two groups(P＞0.05).The results for the per-protocol set were followed up.The correcting rate of shock between the two groups were similar at the end of treatment[81.82％(9/11)vs.57.14％(8/14),P=0.190].The open label norepinephrine requirements of the trial group and control group for the 0,6,12,24,48 h time point were 0.661,0.921,1.583,1.241,2.143,1.371,1.071,1.261,0.370,1.001 μg/(kg·min),respectively with no significant difference(P＞0.05).The 28 d survival rate of the trial group and control group were 63.64％(7/11)and 50.00％(7/14) respectively with no statistical significance(P＞0.05).There was no significant difference in 28 d survival analyzed using Kaplan-Meier plot between two groups(P=0.470).There were two patients with ischemia of fingers,one patient with hyponatraemia and one patient with ischemia of intestine accompanied by hyponatraemia occurred after treatment with terlipressin,and one patient with isehemia of fingers occurred after treatment with norepinephrine.The incidence of adverse event for the trial group and control group were 30.77％(4/13) and 6.67％(1/15) with no significant difference(P=0.122).Conclusions Terlipressin is an effective agent for treating septic shock.The total adverse event rate of terlipressin was similar to that ofnorepinephrine.

Effects of splanchnic vasoconstrictors on liver regeneration and survival after 90% rat hepatectomy

PURPOSE: Posthepatectomy liver failure is a serious complication and considered to be caused by increased portal pressure and flow. Splanchnic vasoactive agents and propranolol are known to decrease portal pressure. The aim of this study was to identify optimal candidates with potential for clinical use among somatostatin, terlipressin, and propranolol using rats with 90% hepatectomy. METHODS: Rats were divided into 5 groups: sham operation (n = 6), control (n = 20), propranolol (n = 20), somatostatin (n = 20), and terlipressin group (n = 20). Seven-day survival rates and portal pressure change were measured, and biochemical, histologic, and molecular analyses were performed. RESULTS: Portal pressure was significantly decreased in all 3 treatment groups compared to control. All treatment groups showed a tendency of decreased liver injury markers, and somatostatin showed the most prominent effect at 24 hours postoperatively. Histologic liver injury at 24 hours was significantly decreased in propranolol and terlipressin groups (P = 0.016, respectively) and somatostatin group showed borderline significance (P = 0.056). Hepatocyte proliferation was significantly increased after 24 hours in all treatment groups. Median survival was significantly increased in terlipressin group compared to control group (P < 0.01). CONCLUSION: Terlipressin is considered as the best candidate, while somatostatin has good potential for clinical use, considering their effects on portal pressure and subsequent decrease in liver injury and increase in liver regeneration.

Comparison of effect of norepinephrine and terlipressin on patients with ARDS combined with septic shock: a prospective single-blind randomized controlled trial / 中华危重病急救医学

Objective To approach the effect of different vasopressor on hemodynamics, volume responsiveness, fluid volume balance, renal function and prognosis in patients with acute respiratory distress syndrome (ARDS) complicated with septic shock.Methods A prospective single-blind randomized controlled trial was conducted. ARDS patients with septic shock admitted to the Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from January 1st, 2015 to May 1st, 2016 were enrolled. The patients satisfied ARDS Berlin diagnostic criteria, over 15 years old, needing vasopressor after fluid resuscitation were enrolled. The patients were divided into norepinephrine group (NE group) and terlipressin group (TP group) by randomise number table derived by computer. Patients in TP group were given terlipressin (0.01-0.04 U/min) with an intravenous pump, while those of NE group were given norepinephrine (> 1μg/min) with an intravenous pump, and the target mean arterial pressure (MAP) was maintained at 65-75 mmHg (1 mmHg = 0.133 kPa). Hemodynamics and extravascular lung water index (EVLWI) were monitored by pulse indicator continuous cardiac output (PiCCO). The volume responsiveness of patient was evaluated by passive leg raising (PLR) test, and cardiac index (CI) change (ΔCI ≥ 10%) served as positive volume responsiveness. The differences in hemodynamics, EVLWI, oxygenation index (OI), lactate clearance rate (LCR), rate of positive volume responsiveness, urinary output, fluid volume balance, renal function, and prognostic indicators were compared between the two groups.Results Fifty-seven patients with ARDS complicated with septic shock were enrolled, with 26 patients in NE group, and 31 patients in TP group, thebaseline data in both groups was balanced with comparability. Compare with NE group, 48-hour and 72-hour heart rate (HR) in TP group was significantly slowed (bpm: 82.1±6.8 vs. 87.6±7.4, 81.3±6.1 vs. 85.6±8.3, bothP 0.05).Conclusions Compared with norepinephrine, terlipressin for ARDS patients with septic shock is more conducive to restrict fluid load, improve the renal perfusion and increase urine output. However, in both groups therewas no significant difference in the efficiency of stabilizing hemodynamics, shortening the duration of mechanical ventilation, reducing ICU or hospital days and decreasing 28-day mortality.

Role of vasopressin in current anesthetic practice / 대한마취과학회지

Arginine vasopressin (AVP), also known as antidiuretic hormone, is a peptide endogenously secreted by the posterior pituitary in response to hyperosmolar plasma or systemic hypoperfusion states. When administered intravenously, it causes an intense peripheral vasoconstriction through stimulation of V₁ receptors on the vascular smooth muscle. Patients in refractory shock associated with severe sepsis, cardiogenic or vasodilatory shock, or cardiopulmonary bypass have inappropriately low plasma levels of AVP (‘relative vasopressin deficiency’) and supersensitivity to exogenously-administered AVP. Low doses of AVP and its synthetic analog terlipressin can restore vasomotor tone in conditions that are resistant to catecholamines, with preservation of renal blood flow and urine output. They are also useful in the treatment of refractory arterial hypotension in patients chronically treated with renin-angiotensin system inhibitors, cardiac arrest, or bleeding esophageal varices. In the perioperative setting, they represent attractive adjunct vasopressors in advanced shock states that are unresponsive to conventional therapeutic strategies.

Effect of terlipressin on hepatic and renal function in cirrhotic patients undergoing hepatectomy / 国际外科学杂志

Objective To investigate the effect of terlipressin on hepatic and renal function in cirrhotic patients undergoing hepatectomy.Methods Aanlyze the clinical data of 57 patients following irregular hepatectomy for hepatocellular carcinoma with cirrhosis,according to whether use terlipressin or not after operation,which were divided into terlipressin group (A group,n =27) and control group (B group,n =30).Liver function parameters (ALT,AST,TB),ascites,urine volume and renal function parameters (Cr,BUN) preoperatively and on postoperative day(POD) 1,3,5 and 7 were compared between the two gruops.Results Compared with those of POD 1,the levels of ALT,AST and ascites on POD 3,5,7 were significantly lower in two groups (P ＜ 0.05),urine volume was significantly increased (P ＜ 0.05),Cr of POD 7 was significantly lower (P ＜0.05),but it is more remarkable in group A than group B.The levels of ALT in terlipressin group on POD 5,7 were (144.9 ±76.3) U/L,(100.5 ±61.5) U/L,which were lower than those of (267.2±91.2) U/L,(199.3 ±70.5) U/L in control group.On POD 3,5,7,the levels of AST,BUN,Cr and peritoneal fluid in terlipressin group,which were respectively(211.1 ±99.8) U/L,(80.4 ±54.6) U/L,(50.6 ±46.5) U/L,(6.6 ± 1.9) mmol/L,(6.5 ± 1.7) mmol/L,(6.3 ± 2.1) mmol/L,(74.3 ± 10.9) μmol/L,(71.5 ± 8.9) μmol/L,(58.7 ±4.1) μmol/L,(247.6±60.3) ml,(58.8±54.3) ml,(40.2±31.8) ml,were significantly lower than those in control group which were (298.7 ±131.2) U/L,(201.1 ±93.4) U/L,(114.7 ±70.3) U/L,(7.3 ± 1.9) mmol/L,(7.2±1.8) mmol/L,(7.1±1.7) mmol/L,(79.5±15.1) μmol/L,(76.9±16.2) μmol/L,(69.4±11.4) μmol/L,(275.2±88.1) ml,(191.7±71.6) ml,(93.2±50.2) ml.while urine volume of (2232.3±409.8) ml,(2270.5 ±395.8) ml,(2179.0±301.4) ml was much more than that of (1921 ± 510.4) ml,(2019.1 ±411.2) ml,(1978.7±323.7) ml in the control group,the differences in the two groups were statistically significant (P ＜ 0.05).There were 11 (36.7％) patients with hepatic and renal dysfunction and hepatorenal syndrome after operation in group B,while only 2 (7.4％) patients in group A.Conclusions The use of terlipressin after partial liver resection has a protective effect on hepatic and renal function in patients with cirrhosis,and can reduce postoperative ascites and prevent hepatorenal syndrome.

Hepatorenal Syndrome / 대한내과학회지

Hepatorenal syndrome is a functional renal failure occurred in end-stage liver disease. It is regarded as one of the most serious complications of liver disease; commonly occur in patients with cirrhosis or acute liver failure. Pathophysiologically, portal hypertension induced vasoconstriction in the renal cortex reduces glomerular filtration rate. There are no intrinsic renal diseases or histological abnormalities. In most patients, the natural course of the renal failure leads to fatal consequences, even though various treatment options have been provided. Liver transplantation and combination therapy of albumin and vasopressin analogs can restore the damage of the blood vessel.

Ischemic Colitis Caused by Terlipressin during Treatment of Hepatorenal Syndrome / 대한내과학회지

Terlipressin, a vasopressin agonist, is widely used to treat variceal bleeding and hepatorenal syndrome in patients with liver cirrhosis. Terlipressin increases systemic vascular resistance, particularly in the splanchnic area, thus decreasing portal pressure. Although terlipressin is associated with a lower incidence of severe cardiovascular complications than is vasopressin, terlipressin can induce serious ischemic complications including myocardial infarction, skin necrosis, and bowel ischemia in < 1% of patients. We report the case of a 79-year-old female with liver cirrhosis treated with terlipressin to control hepatorenal syndrome that developed into ischemic colitis. The patient improved upon cessation of terlipressin and provision of supportive care.

Efficacy of terlipressin therapy for refractory ascites in cirrhosis and type-2 hepatorenal syndrome / 临床肝胆病杂志

ObjectiveTo explore the efficacy of terlipressin therapy for refractory ascites in cirrhosis and type-2 hepatorenal syndrome (HRS-2). MethodsForty patients with refractory ascites in cirrhosis and HRS-2 who were admitted to our hospital from June 2009 to June 2014 were randomly divided into treatment group (n=23) and control group (n=17). The control group was given comprehensive medical treatment including liver protection therapy, anti-infection therapy, and nutritional support, and the treatment group was treated with terlipressin in addition to the treatment for the control group. The body weight, abdomen circumference, urine volume and urinary sodium output within 24 hours, liver and kidney function, and adverse reactions in both groups were evaluated before and after treatment. Between-group comparison of continuous data was performed by t test, and between-group comparison of categorical data was performed by χ2 test. ResultsIn the treatment group, the urine volume and urinary sodium output within 24 hours were significantly increased after treatment (270.0±120.0 vs 1200.0±490.0 ml, P＜0.05; 20.6±10.5 vs 62.5±16.5 mmol, P＜0.05), while the body weight and abdomen circumference were significantly reduced after treatment (58.5±5.3 vs 53.6±4.8 kg, P＜0.05; 97.6±7.5 vs 90.5±6.8 cm, P＜0.05). The serum levels of alanine aminotransferase, total bilirubin, blood urea nitrogen, and creatinine in the treatment group were significantly lower after treatment (P＜0.05), while the serum level of Alb in the treatment group was significantly higher after treatment (P＜005). All the above indices were significantly superior in the treatment group than in the control group (P＜0.05). The overall response rate in the treatment group was significantly higher than that in the control group (82.6% vs 52.9%, P＜0.05). There were no severe adverse reactions in both groups. ConclusionOn the basis of comprehensive medical treatment, terlipressin achieves good efficacy in the treatment of refractory ascites in cirrhosis and HRS-2 with few adverse reactions.

Clinical efficacy of terlipressin in treatment of type II hepatorenal syndrome / 临床肝胆病杂志

Objective To investigate the clinical efficacy of domestic terlipressin in the treatment of type II hepatorenal syndrome (HRS -II).Methods A total of 25 HRS -II patients admitted to our hospital from November 2011 to June 2014 were recruited into the treatment group,and 28 HRS -II patients treated with dopamine before 2011 were recruited into the control group.Patients in the treatment group were randomly divided into two subgroups:one subgroup (n =12)was given terlipressin once every 8 h,and the other subgroup (n =13) was given terlipressin once every 12 h.Both groups received albumin (Alb)infusion to expand the blood volume before treatment with terlip-ressin or dopamine,and the course of treatment was 7 days.The improvement in clinical symptoms,levels of blood urea nitrogen (BUN), serum creatinine and electrolytes,urine volume,changes in liver function,and ascites disappearance in the two groups before and after treat-ment were compared.Comparison of categorical data between the two groups was made by χ2 test,and comparison of continuous data was made by t test.Results Patients in the control group showed no obvious symptom relief,but those in the treatment group had varying de-grees of improvement in clinical symptoms.Neither group had significant changes in liver function and serum sodium level after treatment. The treatment group had significantly more patients whose ascites volume had decreased from large to medium than the control group (χ2 =5.705,P 0.05),whereas the urine volume showed significant difference after the treatment (t =15.534,P 0.05).Patients treated with terlipressin had mild and tolerable adverse reactions.Conclusion The domestic terlipressin combined with albumin infusion has good clinical efficacy and mild adverse effects in treating HRS -II.Its clinical application is highly recommended.