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.

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.

Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality.

BACKGROUND: Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients. METHODS: An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis. RESULTS: The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality. CONCLUSION: The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.

An Integrated Review of the Hepatorenal Syndrome.

Among the complications of cirrhosis, hepatorenal syndrome (HRS) is characterized by having the worst survival rate. HRS is a disorder that involves the deterioration of kidney function caused primarily by a systemic circulatory dysfunction, but in recent years, systemic inflammation and cirrhotic cardiomyopathy have been discovered to also play an important role. The diagnosis of HRS requires to meet the new International Club of Ascites-Acute Kidney Injury (ICA-AKI) and Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) criteria after ruling out other causes of kidney injury. At the time of diagnosis, it is important to start the medical treatment as soon as possible where three types of vasoconstrictors have been recognized: vasopressin analogs (ornipressin and terlipressin), alpha-adrenergic agonists (norepinephrine and midodrine) and somatostatin analogues (octreotide); all should be combined with albumin infusion. Among them, terlipressin and albumin are the first lines of treatment in most cases, although terlipressin should be monitor closely due to its adverse events. The best treatment of choice is a liver transplant, because it is the only definitive treatment for this disease.

Vasoconstrictors in hepatorenal syndrome - A critical review.

Hepatorenal syndrome has the worst prognosis among causes of acute kidney injury in cirrhotic patients. Its definitive treatment is liver transplantation. Nevertheless, considering its high short-term mortality rate and the shortage of liver grafts, a pharmacological treatment is of utmost importance, serving as a bridge to liver transplant. The clinical management of hepatorenal syndrome is currently based on the use of a vasoconstrictor in association with albumin. Terlipressin, noradrenaline and the combination of midodrine and octreotide could be used to treat hepatorenal syndrome. Among these options, terlipressin seems to gather the strongest body of evidence regarding efficacy and should be considered the first line of treatment whenever available and in the absence of contraindications. Treatment with a vasoconstrictor and albumin should be promptly initiated after the diagnosis of hepatorenal syndrome in order for patients to have higher chances of recovery.

Involvement of the microvasculature in the pathogenesis of terlipressin-related myocardial infarction.

We report an autopsy case of a 24-year-old man with diagnoses of advanced alcoholic liver cirrhosis, portal hypertension, and esophageal variceal bleeding that presented extensive myocardial infarction after treatment with terlipressin. On postmortem examination the cut surface of the heart presented myocardial infarction implicating the left ventricle free wall, apex of the heart and ventricular septum. Light microscopic examination revealed that the extensive area of cardiac infarction was the result of the sum of diffuse foci of microinfarction of various ages interspersed with small clusters of preserved myocytes. Moreover, the epicardial vessels were patent while the small intramyocardial vessels presented thickened wall, apparent reduction in lumen diameter and disruption of endothelial cells indicative of spasm. The observations in this case allow clear insight into the involvement of the microcirculation in the pathogenesis of myocardial infarction with the use of terlipressin.

Terlipressina como novo recurso terapêutico no choque séptico: [revisão] / Terlipressin as a new therapeutic agent in septic shock: [review]

JUSTIFICATIVA E OBJETIVOS: A terlipressina tem sido inserida em protocolos de suporte hemodinâmico da sepse, como recurso em casos de choque refratário, o que motiva análise crítica a respeito do assunto. CONTEÚDO: Foram revistas para a análise terapias hemodinâmicas com objetivos finais bem delineados e novas recomendações para reanimação volêmica, uso de vasopressores e agentes inotrópicos em adultos e crianças sépticos. CONCLUSÕES: A terlipressina tem sido considerada nova alternativa nos cuidados intensivos da sepse, embora ainda controversa.

BACKGROUND AND OBJECTIVES: The hemodynamic support of sepsis is now formulated trying to insert terlipressin as salvage drug in catecholamine resistant shock, justifying a broad critical analysis. CONTENTS: The analysis included hemodynamic therapies with defined specific goals and new recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic in adult and pediatric patients. CONCLUSIONS: Terlipressin appears as a new but controversial alternative for vasopressor therapy in sepsis.