BACKGROUND: Liver disease causes 2 million deaths annually, accounting for 4% of all deaths worldwide. Liver surgery is one of the effective therapeutic options. Bleeding is a major complication during liver surgery. Perioperative bleeding and allogeneic blood transfusion may deteriorate the prognosis. Terlipressin (TP), a synthetic analogue of the antidiuretic hormone, may reduceblood loss during abdominal surgery. Several clinical centres have attempted to use TP during liver surgery, but the evidence for its effectiveness in reducing blood loss and the need for allogeneic blood transfusion, as well as its safety during the perioperative period, remains unclear. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of TP in reducing blood loss and allogeneic blood transfusion needs during liver surgery.
METHODS: We will search PubMed, EMBASE, the Cochrane Library and Web of Science for studies on perioperative use of TP during liver surgery from inception to July 2023. We will limit the language to English, and two reviewers will independently screen and select articles. The primary study outcomes are estimated blood loss and the need for allogeneic blood transfusion. Secondary outcomes include operating time, intensive care unit stay, length of stay, intraoperative urine output, acute kidney injury rate, postoperative complications, hepatic and renal function during follow-up, and TP-related adverse effects. We will include studies that met the following criteria: (1) randomised controlled trials (RCTs), cohort studies or case-control studies; (2) the publication time was till July 2023; (3) adult patients (≥18 years old) undergoing elective liver surgery; (4) comparison of TP with other treatments and (5) the study includes at least one outcome. We will exclude animal studies, case reports, case series, non-original articles, reviews, paediatric articles, non-controlled trials, unpublished articles, non-English articles and other studies that are duplicates. We will use Review Manager V.5.3 software for meta-analysis and perform stratification analysis for the study quality of RCTs based on the Jadad score. For cohort or case-control studies, the study quality will be analysed based on Newcastle-Ottawa Scale scores. Grading of Recommendations, Assessment, Development and Evaluation will be used to assess confidence in the cumulative evidence. For primary outcomes, we will conduct subgroup analyses based on meta-regression. We will also perform leave-one-out sensitivity analyses to evaluate the effect of each individual study on the combined results by removing the individual studies one by one for outcomes with significant heterogeneity. The protocol follows the Cochrane Handbook for Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines.
BACKGROUND: This study is a secondary analysis of existing data; therefore, it does not require ethical approval. We will disseminate the results through peer-reviewed publications.
UNASSIGNED: CRD42023450333.

OBJECTIVE: 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.
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.

The treatment of choice for hepatorenal syndrome-acute kidney injury (HRS-AKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. In the absence of larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine, meta-analysis of smaller studies can provide insights needed to understand the comparative effects of these medications. Additionally, recent changes in the HRS diagnosis and treatment guidelines underscore the need for newer analyses comparing terlipressin and norepinephrine. In this systematic review, we aimed to assess reversal of hepatorenal syndrome (HRS) and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRS-AKI. We searched literature databases, including PubMed, Cochrane, Clinicaltrials.gov, International Clinical Trials Registry Platform, Embase, and ResearchGate, for randomized controlled trials (RCTs) published from January 2007 to June 2023 on June 26, 2023. Only trials comparing norepinephrine and albumin with terlipressin and albumin for the treatment of HRS-AKI in adults were included, and trials without HRS reversal as an endpoint or nonresponders were excluded. Pairwise meta-analyses with the random effects model were conducted to estimate odds ratios (ORs) for HRS reversal and 1-month mortality as primary outcomes. Additional outcomes assessed, included HRS recurrence, predictors of response, and incidence of adverse events (AEs). We used the Cochrane risk of bias assessment tool for quality assessment. We included 7 RCTs with a total of 376 subjects with HRS-AKI or HRS type 1. This meta-analysis showed numerically higher rates of HRS reversal (OR 1.33, 95% confidence interval [CI] [0.80-2.22]; P = 0.22) and short-term survival (OR 1.50, 95% CI [0.64-3.53]; P = 0.26) with terlipressin, though these results did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with a reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Limitations of this analysis included small sample size and study differences in HRS-AKI diagnostic criteria. As more studies using the new HRS-AKI criteria comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge.

Cirrhosis is a major cause of morbidity and mortality in the United States and worldwide. It consists of compensated, decompensated, and further decompensated stages; median survival is more than 15 years, 2 years, and 9 months for each stage, respectively. With each stage, there is progressive worsening of portal hypertension and the vasodilatory-hyperdynamic circulatory state, resulting in a progressive decrease in effective arterial blood volume and renal perfusion. Vasoconstrictors reduce portal pressure via splanchnic vasoconstriction and are used in the management of variceal hemorrhage. Intravenous (IV) albumin increases effective arterial blood volume and is used in the prevention of acute kidney injury (AKI) and death after large-volume paracentesis and in patients with spontaneous bacterial peritonitis (SBP). The combination of vasoconstrictors and albumin is used in the reversal of hepatorenal syndrome (HRS-AKI), the most lethal complication of cirrhosis. Because a potent vasoconstrictor, terlipressin, was recently approved by the US Food and Drug Administration, and because recent trials have explored use of IV albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and IV albumin in the following 3 specific scenarios: variceal hemorrhage, ascites and SBP, and HRS.
This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. It underwent internal peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Some of the statements are unchanged from published guidelines because of lack of new evidence in the literature. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality and evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Vasoactive drugs should be initiated as soon as the diagnosis of variceal hemorrhage is suspected or confirmed, preferably before diagnostic and/or therapeutic endoscopy. BEST PRACTICE ADVICE 2: After initial endoscopic hemostasis, vasoactive drugs should be continued for 2-5 days to prevent early rebleeding. BEST PRACTICE ADVICE 3: Octreotide is the vasoactive drug of choice in the management of variceal hemorrhage based on its safety profile. BEST PRACTICE ADVICE 4: IV albumin should be administered at the time of large-volume (>5 L) paracentesis. BEST PRACTICE ADVICE 5: IV albumin may be considered in patients with SBP. BEST PRACTICE ADVICE 6: Albumin should not be used in patients (hospitalized or not) with cirrhosis and uncomplicated ascites. BEST PRACTICE ADVICE 7: Vasoconstrictors should not be used in the management of uncomplicated ascites, after large-volume paracentesis or in patients with SBP. BEST PRACTICE ADVICE 8: IV albumin is the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with AKI. BEST PRACTICE ADVICE 9: Vasoactive drugs (eg, terlipressin, norepinephrine, and combination of octreotide and midodrine) should be used in the treatment of HRS-AKI, but not in other forms of AKI in cirrhosis. BEST PRACTICE ADVICE 10: Terlipressin is the vasoactive drug of choice in the treatment of HRS-AKI and use of concurrent albumin can be considered when accounting for patient\'s volume status. BEST PRACTICE ADVICE 11: Terlipressin treatment does not require intensive care unit monitoring and can be administered intravenously through a peripheral line. BEST PRACTICE ADVICE 12: Terlipressin use is contraindicated in patients with hypoxemia and in patients with ongoing coronary, peripheral, or mesenteric ischemia, and should be used with caution in patients with acute-on-chronic liver failure grade 3. The benefits may not outweigh the risks in patients with serum creatinine >5 mg/dL and in patients listed for transplantation with a Model for End-stage Liver Disease ≥35.

UNASSIGNED: Portal hypertension, a major complication of chronic liver disease, often leads to life-threatening variceal bleeding, managed effectively with vasoactive drugs like terlipressin. However, the most optimal method of terlipressin administration, continuous versus intermittent infusion, remains a subject of debate, necessitating this systematic review and meta-analysis for evidence-based decision-making in managing this critical condition.
UNASSIGNED: This systematic review and meta-analysis adhered to the PRISMA standards and explored multiple databases until 6 April 2023, such as MEDLINE through PubMed, Scopus, Web of Science, and CENTRAL. Independent reviewers selected randomized controlled trials (RCTs) that met specific inclusion criteria. After assessing study quality and extracting necessary data, statistical analysis was performed using Review Manager (RevMan), with results presented as risk ratios (RR) or mean differences.
UNASSIGNED: Five RCTs (n=395 patients) were included. The continuous terlipressin group had a significantly lower risk of rebleeding (RR=0.43, P=0.0004) and treatment failure (RR=0.22, P=0.02) and fewer total adverse effects (RR=0.52, P<0.00001) compared to the intermittent group. However, there were no significant differences between the two groups in mean arterial pressure (P=0.26), length of hospital stays (P=0.78), and mortality rates (P=0.65).
UNASSIGNED: This study provides robust evidence suggesting that continuous terlipressin infusion may be superior to intermittent infusions in reducing the risk of rebleeding, treatment failure, and adverse effects in patients with portal hypertension. However, further large-scale, high-quality RCTs are required to confirm these findings and to investigate the potential benefits of continuous terlipressin infusion on mortality and hospital stays.

Hepatorenal syndrome (HRS), defined by the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduced renal blood flow and glomerular filtration rate. It is diagnosed with reduced kidney function confirming the absence of intrinsic kidney disease, such as hematuria or proteinuria. HRS is potentially reversible with liver transplantation or vasoconstrictor drugs. The condition carries a poor prognosis with high mortality rates, particularly in patients with advanced cirrhosis. The latest management for HRS involves a combination of pharmacological and non-pharmacological interventions, aiming to improve renal function and reduce the risk of mortality. Pharmacological treatments include vasoconstrictors, such as terlipressin and midodrine, and albumin infusion, which have been shown to improve renal function and reduce mortality in HRS patients. Non-pharmacological interventions, including invasive procedures such as transjugular intrahepatic portosystemic shunt (TIPS), plasma exchange, liver transplantation, and renal replacement therapy, may also be considered. Though TIPS has been shown to be effective in improving renal function in HRS patients, liver transplantation remains at the top of the consideration for the treatment of end-stage liver disease and HRS. Recent studies have placed importance on early recognition and prompt intervention in HRS patients, as delaying treatment can result in poorer outcomes. Although there are numerous reviews that summarize various aspects of HRS, the recent advancements in the management and pathophysiology of HRS are still insufficient. Therefore, in this review, we summarized a brief pathophysiology and highlighted recent advancements in the management of HRS with a quick review of the latest articles.

BACKGROUND:  Hepatorenal syndrome (HRS), a consequence of liver cirrhosis, is the development of renal failure, which carries a grave prognosis. Reversing acute renal failure with various vasoconstrictor therapies at an appropriate time favors a good prognosis, especially when a liver transplant is not feasible.
OBJECTIVE:  This study aims to compare various treatment modalities to deduce an effective way to manage HRS.
METHODS:  The authors conducted a literature search in PubMed, Google Scholar, the Cochrane Library, and Science Direct in October 2022, using regular and MeSH keywords. A total of 1072 articles were identified. The PRISMA guidelines were used, the PICO framework was addressed, and the inclusion criteria were set based on studies from the past 10 years. After quality assessment, 14 studies were included for in-depth analysis in this review.  Results: A total of 14 studies were included after quality assessment, including randomized controlled trials, systematic reviews, meta-analyses, and observational cohort studies. Nine hundred and forty-one patients represented this review\'s experimental and observational studies, apart from the other systematic reviews analyzed. Nine studies discovered that Terlipressin, especially when administered with albumin, was more effective than other conventional treatment modalities, including norepinephrine and midodrine, in terms of improving mortality and reversing the HRS. Four studies suggested that terlipressin exhibited similar effectiveness but found no significant difference. In contrast, one study found that norepinephrine was superior to terlipressin when particularly considering the adverse effects.
CONCLUSIONS:  Terlipressin, one of the most widely used vasoconstrictor agents across the world, seems to be effective in reversing renal failure in HRS. Although adverse effects are seen with this agent, it is still beneficial when compared to other medications. Further studies with larger sample sizes may be warranted.

Objective: The objective of this study was to provide an in-depth analysis of the advantages and potential research directions concerning the utilization of terlipressin (TP) in combination with norepinephrine (NE) for the management of septic shock. Methods: A systematic search was conducted across five major electronic databases, namely, PubMed, Cochrane, Embase, ScienceDirect, and MEDLINE, using the Boolean method. The search encompassed articles published until May 22, 2023. Randomized controlled trials investigating the efficacy of TP combined with NE in the treatment of patients with septic shock were considered for inclusion. Results: A total of seven trials met the inclusion criteria. The combination therapy of TP and NE exhibited potential benefits in the treatment of adult patients suffering from septic shock. Furthermore, the concurrent administration of TP with NE demonstrated improvements in cardiac output and central venous pressure. However, it is important to acknowledge the presence of certain risks and potential adverse events, including an elevated risk of peripheral ischemia. Conclusions: The available evidence supports the notion that early combination therapy involving NE and TP holds promise in terms of reducing the required dosage of NE, enhancing renal perfusion, and improving microcirculation in patients diagnosed with septic shock.

Background: Septic shock is a distributive shock with decreased systemic vascular resistance and MAP. Septic shock contributes to the most common causes of death in the intensive care unit (ICU). Current guidelines recommend the use of norepinephrine as the first-line vasopressor, whereas adrenergic agonists and vasopressin analogs are also commonly used by physicians. To date, very few studies have synthetically compared the effects of multiple types of vasoactive medications. The aim of this study was to systemically evaluate the efficacy of vasoactive agents both individually and in combination to treat septic shock. Methods: The PubMed, MEDLINE, Embase, Web of Science, and Cochrane Central Register for Controlled Trials (CENTRAL) were searched up to May 12, 2022, to identify relevant randomized controlled trials. A network meta-analysis was performed to evaluate the effect of different types of vasopressors. The primary outcome was 28-day all-cause mortality. The secondary outcome was the ICU length of stay. Adverse events are defined as any undesirable outcomes, including myocardial infarction, cardiac arrhythmia, peripheral ischemia, or stroke and cerebrovascular events. Findings: Thirty-three randomized controlled trials comprising 4,966 patients and assessing 8 types of vasoactive treatments were included in the network meta-analysis. The surface under the cumulative ranking curve provided a ranking of vasoactive medications in terms of 28-day all-cause mortality from most effective to least effective: norepinephrine plus dobutamine, epinephrine, vasopressin, terlipressin, norepinephrine, norepinephrine plus vasopressin, dopamine, and dobutamine. Dopamine was associated with a significantly shorter ICU stay than norepinephrine, terlipressin, and vasopressin, whereas other vasoactive medications showed no definite difference in ICU length of stay. Regarding adverse events, norepinephrine was associated with the highest incidences of myocardial infarction and peripheral ischemia. Dopamine was associated with the highest incidence of cardiac arrhythmia. Epinephrine and terlipressin were associated with the highest incidences of myocardial infarction and peripheral ischemia. Interpretation: The results of this network meta-analysis suggest that norepinephrine plus dobutamine is associated with a lower risk of 28-day mortality in septic shock patients than other vasoactive medications, and the use of dopamine is associated with a higher risk of 28-day mortality due to septic shock than norepinephrine, terlipressin, and vasopressin.

Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people.
The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.
Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.