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JAMA May 2023Cirrhosis 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... (Review)
Review
IMPORTANCE
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.
OBSERVATIONS
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.
CONCLUSIONS AND RELEVANCE
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.
Topics: Adult; Humans; Male; Ascites; Carvedilol; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Hepatorenal Syndrome; Lactulose; Liver Cirrhosis; Liver Neoplasms; Muscle Cramp; Propranolol; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors; Terlipressin; United States
PubMed: 37159031
DOI: 10.1001/jama.2023.5997 -
Clinical Journal of the American... May 2019Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central... (Review)
Review
Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even in responders, early mortality rates are very high in the absence of liver transplantation. Liver transplantation is the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) is often a challenging yet important step because vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the decision for simultaneous liver-kidney transplantation.
Topics: Acute Kidney Injury; Biomarkers; Hepatorenal Syndrome; Humans; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation
PubMed: 30996046
DOI: 10.2215/CJN.12451018 -
Annals of Hepatology 2021Among the complications of cirrhosis, hepatorenal syndrome (HRS) is characterized by having the worst survival rate. HRS is a disorder that involves the deterioration of... (Review)
Review
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.
Topics: Hepatorenal Syndrome; Humans
PubMed: 32846202
DOI: 10.1016/j.aohep.2020.07.008 -
Medicine Apr 2018Hepatorenal syndrome is a fatal complication of advanced cirrhosis. Terlipressin is the most widely used treatment method, however, the therapy effects remain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hepatorenal syndrome is a fatal complication of advanced cirrhosis. Terlipressin is the most widely used treatment method, however, the therapy effects remain inconsonant. We aim to systematically assess the safety and efficacy of terlipressin for hepatorenal syndrome.
METHODS
We conducted a systematic review and meta-analysis. Randomized controlled trials involving terlipressin for hepatorenal syndrome were included in a systematic literature search. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of terlipressin for hepatorenal syndrome.
RESULTS
A total of 18 randomized controlled trials including 1011 patients were included. Hepatorenal syndrome reverse rate was 42.0% in the terlipressin group and 26.2% in the non-terlipressin group. Terlipressin had greater hepatorenal syndrome reverse rate and renal function improvement rate than placebo and octreotide in the management of HRS. Comparing to norepinephrine, terlipressin had similar efficacy, but with more adverse events. No significant difference of the efficacy was found between terlipressin and dopamine treatment. The subgroup analysis for type 1 HRS had the above same results, except that the adverse events were not significant different between norepinephrine group and terlipressin group.
CONCLUSIONS
Terlipressin was superior to placebo and octreotide for reversal of hepatorenal syndrome and improving renal function, but it had no superiority comparing to norepinephrine.
Topics: Hepatorenal Syndrome; Humans; Kidney; Lypressin; Recurrence; Terlipressin; Treatment Outcome; Vasoconstrictor Agents
PubMed: 29668606
DOI: 10.1097/MD.0000000000010431 -
PloS One 2015International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock.
METHODS
Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled.
RESULTS
Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels.
CONCLUSIONS
Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.
Topics: Epinephrine; Hemodynamics; Humans; Lypressin; Norepinephrine; Phenylephrine; Shock, Septic; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins
PubMed: 26237037
DOI: 10.1371/journal.pone.0129305 -
Minerva Anestesiologica May 2020Norepinephrine is the first line vasopressor used in patients with septic shock. However, norepinephrine doses above 1 µg/kg/min are associated with mortality rates of... (Review)
Review
Norepinephrine is the first line vasopressor used in patients with septic shock. However, norepinephrine doses above 1 µg/kg/min are associated with mortality rates of over 80%, suggesting a need to implement adjunctive strategies prior to reaching this dosage. The present study therefore sought to review the existing and emergent vasopressor agents for patients with refractory septic shock. This paper summarizes the use of vasoactive drugs that may be considered in the context of refractory shock. The clinical application of present and future therapies and the related outcome are discussed. A review of the available literature indicated that vasopressin may be a good first option in patients with refractory septic shock, but evidence remains somewhat sparse. Although the use of vasopressin in these circumstances is likely preferable to the use of terlipressin, a pro-drug with an extended half-life, the use of selepressin, a pure V1 agonist, should be further assessed in future studies. Angiotensin II is another emerging option that uses a different signaling pathway. However, nitric oxide synthase inhibitors and methylene blue do not appear to be appropriate in the management of patients with refractory septic shock. In conclusion, the use of different adjunctive agents in combination with the use of norepinephrine may be useful in patients with refractory septic shock, but care must be taken to avoid excessive vasoconstriction.
Topics: Humans; Norepinephrine; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins
PubMed: 31994366
DOI: 10.23736/S0375-9393.20.13826-4 -
Endoscopy Nov 20221: ESGE recommends that patients with compensated advanced chronic liver disease (ACLD; due to viruses, alcohol, and/or nonobese [BMI < 30 kg/m] nonalcoholic...
1: ESGE recommends that patients with compensated advanced chronic liver disease (ACLD; due to viruses, alcohol, and/or nonobese [BMI < 30 kg/m] nonalcoholic steatohepatitis) and clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] > 10 mmHg and/or liver stiffness by transient elastography > 25 kPa) should receive, if no contraindications, nonselective beta blocker (NSBB) therapy (preferably carvedilol) to prevent the development of variceal bleeding.Strong recommendation, moderate quality evidence. 2: ESGE recommends that in those patients unable to receive NSBB therapy with a screening upper gastrointestinal (GI) endoscopy that demonstrates high risk esophageal varices, endoscopic band ligation (EBL) is the endoscopic prophylactic treatment of choice. EBL should be repeated every 2-4 weeks until variceal eradication is achieved. Thereafter, surveillance EGD should be performed every 3-6 months in the first year following eradication.Strong recommendation, moderate quality evidence. 3: ESGE recommends, in hemodynamically stable patients with acute upper GI hemorrhage (UGIH) and no history of cardiovascular disease, a restrictive red blood cell (RBC) transfusion strategy, with a hemoglobin threshold of ≤ 70 g/L prompting RBC transfusion. A post-transfusion target hemoglobin of 70-90 g/L is desired.Strong recommendation, moderate quality evidence. 4 : ESGE recommends that patients with ACLD presenting with suspected acute variceal bleeding be risk stratified according to the Child-Pugh score and MELD score, and by documentation of active/inactive bleeding at the time of upper GI endoscopy.Strong recommendation, high quality of evidence. 5 : ESGE recommends the vasoactive agents terlipressin, octreotide, or somatostatin be initiated at the time of presentation in patients with suspected acute variceal bleeding and be continued for a duration of up to 5 days.Strong recommendation, high quality evidence. 6 : ESGE recommends antibiotic prophylaxis using ceftriaxone 1 g/day for up to 7 days for all patients with ACLD presenting with acute variceal hemorrhage, or in accordance with local antibiotic resistance and patient allergies.Strong recommendation, high quality evidence. 7 : ESGE recommends, in the absence of contraindications, intravenous erythromycin 250 mg be given 30-120 minutes prior to upper GI endoscopy in patients with suspected acute variceal hemorrhage.Strong recommendation, high quality evidence. 8 : ESGE recommends that, in patients with suspected variceal hemorrhage, endoscopic evaluation should take place within 12 hours from the time of patient presentation provided the patient has been hemodynamically resuscitated.Strong recommendation, moderate quality evidence. 9 : ESGE recommends EBL for the treatment of acute esophageal variceal hemorrhage (EVH).Strong recommendation, high quality evidence. 10 : ESGE recommends that, in patients at high risk for recurrent esophageal variceal bleeding following successful endoscopic hemostasis (Child-Pugh C ≤ 13 or Child-Pugh B > 7 with active EVH at the time of endoscopy despite vasoactive agents, or HVPG > 20 mmHg), pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) within 72 hours (preferably within 24 hours) must be considered.Strong recommendation, high quality evidence. 11 : ESGE recommends that, for persistent esophageal variceal bleeding despite vasoactive pharmacological and endoscopic hemostasis therapy, urgent rescue TIPS should be considered (where available).Strong recommendation, moderate quality evidence. 12 : ESGE recommends endoscopic cyanoacrylate injection for acute gastric (cardiofundal) variceal (GOV2, IGV1) hemorrhage.Strong recommendation, high quality evidence. 13: ESGE recommends endoscopic cyanoacrylate injection or EBL in patients with GOV1-specific bleeding.Strong recommendations, moderate quality evidence. 14: ESGE suggests urgent rescue TIPS or balloon-occluded retrograde transvenous obliteration (BRTO) for gastric variceal bleeding when there is a failure of endoscopic hemostasis or early recurrent bleeding.Weak recommendation, low quality evidence. 15: ESGE recommends that patients who have undergone EBL for acute EVH should be scheduled for follow-up EBLs at 1- to 4-weekly intervals to eradicate esophageal varices (secondary prophylaxis).Strong recommendation, moderate quality evidence. 16: ESGE recommends the use of NSBBs (propranolol or carvedilol) in combination with endoscopic therapy for secondary prophylaxis in EVH in patients with ACLD.Strong recommendation, high quality evidence.
Topics: Humans; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Carvedilol; Endoscopy, Gastrointestinal; Cyanoacrylates; Portasystemic Shunt, Transjugular Intrahepatic
PubMed: 36174643
DOI: 10.1055/a-1939-4887 -
Hepatology (Baltimore, Md.) Aug 2015Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the... (Comparative Study)
Comparative Study Randomized Controlled Trial
UNLABELLED
Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival.
CONCLUSION
Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.
Topics: Aged; Albumins; Analysis of Variance; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatorenal Syndrome; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Kidney Function Tests; Liver Function Tests; Lypressin; Male; Middle Aged; Midodrine; Octreotide; Predictive Value of Tests; Survival Analysis; Terlipressin; Treatment Outcome
PubMed: 25644760
DOI: 10.1002/hep.27709 -
Alimentary Pharmacology & Therapeutics Oct 2022Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute-on-chronic liver failure (ACLF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute-on-chronic liver failure (ACLF).
AIM
To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin.
METHODS
In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90-day mortality.
RESULTS
The incidence of RF with terlipressin (n = 200) was 9.4% in patients with grades 1-2 ACLF, and 30% with grade 3 ACLF (p = 0.0002); no such difference was observed in placebo-treated patients (n = 99) (6.2% grades 1-2 vs. 0% grade 3 ACLF, p > 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant (p = 0.01). Baseline predictors of RF with terlipressin were INR (p = 0.011), mean arterial pressure (p = 0.037), and SpO (p = 0.014). Prior albumin as a continuous variable was not a predictor of RF. 90-day survival between terlipressin and placebo arms was similar for grades 1-2 ACLF (55.5% and 56.6%, respectively), but lower for grade 3 ACLF (27.55% vs. 50.0%) (p = 0.122), mainly related to RF.
CONCLUSION
Terlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.
Topics: Acute-On-Chronic Liver Failure; Albumins; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Lypressin; Respiratory Insufficiency; Terlipressin; Vasoconstrictor Agents
PubMed: 35995728
DOI: 10.1111/apt.17195 -
Journal of Intensive Medicine Oct 2022Vasopressors are the cornerstone of hemodynamic management in patients with septic shock. Norepinephrine is currently recommended as the first-line vasopressor in these... (Review)
Review
Vasopressors are the cornerstone of hemodynamic management in patients with septic shock. Norepinephrine is currently recommended as the first-line vasopressor in these patients. In addition to norepinephrine, there are many other potent vasopressors with specific properties and/or advantages that act on vessels through different pathways after activation of specific receptors; these could be of interest in patients with septic shock. Dopamine is no longer recommended in patients with septic shock because its use is associated with a higher rate of cardiac arrhythmias without any benefit in terms of mortality or organ dysfunction. Epinephrine is currently considered as a second-line vasopressor therapy, because of the higher rate of associated metabolic and cardiac adverse effects compared with norepinephrine; however, it may be considered in settings where norepinephrine is unavailable or in patients with refractory septic shock and myocardial dysfunction. Owing to its potential effects on mortality and renal function and its norepinephrine-sparing effect, vasopressin is recommended as second-line vasopressor therapy instead of norepinephrine dose escalation in patients with septic shock and persistent arterial hypotension. However, two synthetic analogs of vasopressin, namely, terlipressin and selepressin, have not yet been employed in the management of patients with septic shock, as their use is associated with a higher rate of digital ischemia. Finally, angiotensin Ⅱ also appears to be a promising vasopressor in patients with septic shock, especially in the most severe cases and/or in patients with acute kidney injury requiring renal replacement therapy. Nevertheless, due to limited evidence and concerns regarding safety (which remains unclear because of potential adverse effects related to its marked vasopressor activity), angiotensin Ⅱ is currently not recommended in patients with septic shock. Further studies are needed to better define the role of these vasopressors in the management of these patients.
PubMed: 36788938
DOI: 10.1016/j.jointm.2022.05.001