Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections-Results from the ICA "Global Study" (EABCIR-Global Study).

BACKGROUND: The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study." METHODS: Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. RESULTS: From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27). CONCLUSIONS: Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.

Geographic disparities in access to liver transplant for advanced cirrhosis: Time to ring the alarm!

Decompensated cirrhosis and hepatocellular cancer are major risk factors for mortality worldwide. Liver transplantation (LT), both live-donor LT or deceased-donor LT, are lifesaving, but there are several barriers toward equitable access. These barriers are exacerbated in the setting of critical illness or acute-on-chronic liver failure. Rates of LT vary widely worldwide but are lowest in lower-income countries owing to lack of resources, infrastructure, late disease presentation, and limited donor awareness. A recent experience by the Chronic Liver Disease Evolution and Registry for Events and Decompensation consortium defined these barriers toward LT as critical in determining overall survival in hospitalized cirrhosis patients. A major focus should be on appropriate, affordable, and early cirrhosis and hepatocellular cancer care to prevent the need for LT. Live-donor LT is predominant across Asian countries, whereas deceased-donor LT is more common in Western countries; both approaches have unique challenges that add to the access disparities. There are many challenges toward equitable access but uniform definitions of acute-on-chronic liver failure, improving transplant expertise, enhancing availability of resources and encouraging knowledge between centers, and preventing disease progression are critical to reduce LT disparities.

Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome.

BACKGROUND: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

Decreased need for RRT in liver transplant recipients after pretransplant treatment of hepatorenal syndrome-type 1 with terlipressin.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin ( p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo ( p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Terlipressin for hepatorenal syndrome.

PURPOSE OF REVIEW: The definition and diagnostic criteria of hepatorenal syndrome-acute kidney injury (HRS-AKI) has undergone recent changes. A major vasoconstrictor, terlipressin, has recently been approved as pharmacotherapy for HRS-AKI in the United States. The purpose of this review is to familiarize the readers with these new diagnostic criteria of HRS-AKI, and how best to use terlipressin. RECENT FINDINGS: Terlipressin is effective either as bolus dosing or continuous infusion and can achieve reversal of HRS-AKI in approximately 40% of patients. Continuous infusion allows lower daily dose with equal efficacy and less side effects but not an approved mode of administration in the United States. Response to terlipressin in the randomized controlled trials was defined as repeat reduction of serum creatinine to less than 1.5 mg/dl. Newer studies will likely require response to treatment to be defined as a repeat serum creatinine to be less than 0.3 mg/dl from baseline. Terlipressin use is associated with ischemic side effects and potential for respiratory failure development. SUMMARY: Careful patient selection and close monitoring are necessary for its use. Response to terlipressin with HRS-AKI reversal is associated with improved outcomes with better survival and less requirement for renal replacement therapy.

Development and external validation of a model to predict multidrug-resistant bacterial infections in patients with cirrhosis.

With the increasing rate of infections caused by multidrug-resistant organisms (MDRO), selecting appropriate empiric antibiotics has become challenging. We aimed to develop and externally validate a model for predicting the risk of MDRO infections in patients with cirrhosis. METHODS: We included patients with cirrhosis and bacterial infections from two prospective studies: a transcontinental study was used for model development and internal validation (n = 1302), and a study from Argentina and Uruguay was used for external validation (n = 472). All predictors were measured at the time of infection. Both culture-positive and culture-negative infections were included. The model was developed using logistic regression with backward stepwise predictor selection. We externally validated the optimism-adjusted model using calibration and discrimination statistics and evaluated its clinical utility. RESULTS: The prevalence of MDRO infections was 19% and 22% in the development and external validation datasets, respectively. The model's predictors were sex, prior antibiotic use, type and site of infection, MELD-Na, use of vasopressors, acute-on-chronic liver failure, and interaction terms. Upon external validation, the calibration slope was 77 (95% CI .48-1.05), and the area under the ROC curve was .68 (95% CI .61-.73). The application of the model significantly changed the post-test probability of having an MDRO infection, identifying patients with nosocomial infection at very low risk (8%) and patients with community-acquired infections at significant risk (36%). CONCLUSION: This model achieved adequate performance and could be used to improve the selection of empiric antibiotics, aligning with other antibiotic stewardship program strategies.

Pathophysiology of Hepatorenal Syndrome - Acute Kidney Injury.

Hepatorenal syndrome is a complication of liver cirrhosis with ascites that results from the complex interplay of many pathogenetic mechanisms. Advanced cirrhosis is characterized by the development of hemodynamic changes of splanchnic and systemic arterial vasodilatation, with paradoxical renal vasoconstriction and renal hypoperfusion. Cirrhosis is also an inflammatory state. The inflammatory cascade is initiated by a portal hypertension-induced increased translocation of bacteria, bacterial products, and endotoxins from the gut to the splanchnic and then to the systemic circulation. The inflammation, whether sterile or related to infection, is responsible for renal microcirculatory dysfunction, microthrombi formation, renal tubular oxidative stress, and tubular damage. Of course, many of the bacterial products also have vasodilatory properties, potentially exaggerating the state of vasodilatation and worsening the hemodynamic instability in these patients. The presence of cardiac dysfunction, related to cirrhotic cardiomyopathy, with its associated systolic incompetence, can aggravate the mismatch between the circulatory capacitance and the circulation volume, worsening the extent of the effective arterial underfilling, with lower renal perfusion pressure, contributing to renal hypoperfusion and increasing the risk for development of acute kidney injury. The presence of tense ascites can exert an intra-abdominal compartmental syndrome effect on the renal circulation, causing renal congestion and hampering glomerular filtration. Other contributing factors to renal dysfunction include the tubular damaging effects of cholestasis and adrenal dysfunction. Future developments include the use of metabolomics to identify metabolic pathways that can lead to the development of renal dysfunction, with the potential of identifying biomarkers for early diagnosis of renal dysfunction and the development of treatment strategies.

Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort.

BACKGROUND & AIMS: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation. METHODS: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited. RESULTS: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity. CONCLUSIONS: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.

Role of Oral Health, Frailty, and Minimal Hepatic Encephalopathy in the Risk of Hospitalization: A Prospective Multi-Center Cohort of Outpatients With Cirrhosis.

BACKGROUND & AIMS: Hospitalizations are a sentinel event in cirrhosis; however, the changing demographics in patients with cirrhosis require updated hospitalization prediction models. Periodontitis is a risk factor for liver disease and potentially progression. The aim of this study was to determine factors, including poor oral health, associated with 3-month hospitalizations in a multi-center cohort of outpatients with cirrhosis. METHODS: North American Consortium for Study of End-stage Liver Disease (NACSELD-3), a new study cohort, recruits outpatients with cirrhosis. Cirrhosis details, demographics, minimal hepatic encephalopathy (MHE), frailty, and comorbid conditions including oral health were collected. All patients were followed for 3 months for nonelective hospitalizations. Multi-variable models were created for this outcome using demographics, cirrhosis details, oral health, MHE, frailty, and comorbid conditions with K-fold internal validation using 25%/75% split. RESULTS: A total of 442 outpatients (70% men; 37% compensated; Model for End-stage Liver Disease-Sodium, 12; 42% ascites; and 33% prior HE) were included. MHE was found in 70%, frailty in 10%; and both in 8%. In terms of oral health, 15% were edentulous and 10% had prior periodontitis. Regarding 3-month hospitalizations, 14% were admitted for mostly liver-related reasons. These patients were more likely to be decompensated with higher cirrhosis complications, MHE, frailty and periodontitis history. Multi-variable analysis showed prior periodontitis (P = .026), composite MHE + frailty score (P = .0016), ascites (P = .004), prior HE (P = .008), and hydrothorax (P = .004) were associated with admissions using the training and validation subsets. CONCLUSIONS: In a contemporaneous, prospective, multi-center cohort study in outpatients with cirrhosis, poor oral health is significantly associated with 3-month hospitalizations independent of portal hypertensive complications, MHE, and frailty. Potential strategies to reduce hospitalizations should consider oral evaluation in addition to MHE and frailty assessment in practice pathways.

Organ dysfunction and failure in liver disease.

Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

Needs and experiences of cancer care in patients' perspectives among the lesbian, gay, bisexual, transgender and queer community: a systematic review.

Individuals within the Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ) community who are diagnosed with cancer experience inequitable treatment in healthcare systems worldwide, resulting in dissatisfaction, communication challenges with healthcare providers, and a deep sense of disappointment. Stigma, discrimination, and perceived homophobia further heighten the risk of psychological and attitudinal disorders, including depression and suicidal tendencies, among LGBTQ cancer patients. To comprehensively assess the discrimination faced by LGBTQ cancer patients and gain deeper insights into their needs and experiences, we conducted a systematic review following PRISMA guidelines. We searched for relevant articles using specific keywords in reputable databases such as PubMed, Google Scholar, and PsycINFO. We rigorously evaluated article quality using the CASP (Critical Appraisal Skills Programme) checklist. From a total of 75 eligible studies, we carefully selected 14 studies, specifically examining LGBTQ cancer patients who were currently undergoing or had previously undergone cancer treatment. The studies revealed various factors, including unmet needs related to anxiety and depression, instances of discrimination, disparities in care, and inadequate support systems. A majority of patients expressed dissatisfaction with their cancer care and continued to encounter discrimination and disparities throughout their treatment journeys. Consequently, this led to heightened levels of anxiety, stress, depression, and negative perceptions of healthcare providers. Based on these findings, we recommend providing specialized training to social workers and healthcare providers. This training will equip them with the necessary skills and knowledge to deliver culturally sensitive care tailored to the unique needs of LGBTQ cancer patients. By addressing discrimination, reducing disparities, and fostering an inclusive environment, healthcare professionals can strive to ensure that LGBTQ cancer patients receive the care they deserve.

AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with suspected acute kidney injury in patients with cirrhosis. METHODS: This article provides practical advice for the management of patients with cirrhosis and acute kidney injury based on the best available published evidence. This best practice document is not based on a formal systematic review. This expert review was commissioned and approved by the 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 and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Clinical Gastroenterology & Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Acute kidney injury (AKI) should be diagnosed when the serum creatinine increases by ≥0.3 mg/dL within 48 hours or is ≥50% from baseline or when the urine output is reduced below 0.5 mL/kg/h for >6 hours. BEST PRACTICE ADVICE 2: Preventive measures against the development of AKI in cirrhosis include (1) avoidance of potentially nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs), (2) avoidance of excessive or unmonitored diuretics or nonselective beta-blockade, (3) avoidance of large-volume paracentesis without albumin replacement, and (4) counseling patients to avoid alcohol use. BEST PRACTICE ADVICE 3: (A) Investigation is directed to determining the cause of AKI, which can be due to hypovolemic causes (volume responsive, and the most common cause of AKI in patients with cirrhosis); acute tubular necrosis; hepatorenal syndrome with AKI (HRS-AKI) (a functional renal failure that persists despite volume repletion); HRS with acute kidney disease, a type of functional renal failure of <3 months- duration in which criteria for HRS-AKI are not met; or postrenal, which occurs only rarely. (B) The specific type of AKI should be identified through a careful history, physical examination, blood biochemistry, urine microscopic examination, urine chemistry (Na+ and urea) and selected urinary biomarkers, and renal ultrasound. BEST PRACTICE ADVICE 4: A rigorous search for infection is required in all patients with AKI. A diagnostic paracentesis should be carried out to evaluate for spontaneous bacterial peritonitis; blood and urine cultures and chest radiograph are also required. There is no role for routine prophylactic antibiotics in patients with AKI, but broad-spectrum antibiotics should be started whenever infection is strongly suspected. BEST PRACTICE ADVICE 5: When AKI is diagnosed, diuretics and nonselective beta-blockers should be held, NSAIDs discontinued, the precipitating cause of AKI treated, and fluid losses replaced, administering albumin 1 g/kg/d for 2 days if the serum creatinine shows doubling from baseline. Urine output, vital signs, and when indicated, echocardiography or CVP (if there is a pre-existing central line) should be used to monitor fluid status. BEST PRACTICE ADVICE 6: When the serum creatinine remains higher than twice the baseline value despite these measures, treatment of HRS-AKI should be initiated with albumin at a dose of 1 g/kg intravenously on day 1 followed by 20-40 g daily along with vasoactive agents (terlipressin; if terlipressin is not available, either a combination of octreotide and midodrine; or norepinephrine, depending on institutional preferences) and continued either until 24 hours following the return of the serum creatinine level to within ≤0.3 mg/dL of baseline for 2 consecutive days or for a total of 14 days of therapy. BEST PRACTICE ADVICE 7: Terlipressin should be initiated as a bolus dose of 1 mg every 4-6 hours (total 4-6 mg/d). The dose should be increased to a maximum of 2 mg every 4-6 hours (total 8-12 mg/d) if there is no reduction in serum creatinine at day 3 of therapy by at least 25% compared to the baseline value. Alternatively, clinicians can administer terlipressin by continuous intravenous infusion at a lower starting dose of 2 mg/d, which may reduce ischemic side effects and increase the dose gradually every 24-48 hours up to a maximum dose of 12 mg/d, or reversal of HRS. As per Food and Drug Administration restrictions, terlipressin should not be used in patients with a serum creatinine ≥5 mg/dL, or oxygen saturation of <90%. BEST PRACTICE ADVICE 8: Oral midodrine when used should be initiated at doses of 7.5 mg and titrated upward to 12.5 mg 3 times daily with octreotide (starting with 100 µg and titrating upward to 200 µg subcutaneously 3 times daily). BEST PRACTICE ADVICE 9: Norepinephrine should be used as a continuous intravenous infusion at a starting dose of 0.5 mg/h and the dose increased every 4 hours by 0.5 mg/h to a maximum of 3 mg/h with the goal of increasing the mean arterial pressure by ≥10 mm Hg and/or the urine output to >50 mL/h for at least 4 hours. BEST PRACTICE ADVICE 10: The risks of ischemic side effects of terlipressin and norepinephrine include angina and ischemia of fingers, skin, and intestine. These side effects may be lowered by starting at the lowest dose and gradually titrating upward. BEST PRACTICE ADVICE 11: Fluid status should be closely monitored because of the risk of pulmonary edema with excessive use of albumin. BEST PRACTICE ADVICE 12: Renal replacement therapy (RRT) may be used in the management of (A) AKI secondary to acute tubular necrosis; (B) HRS-AKI in potential candidates for liver transplantation (that is, RRT should not be used in patients with HRS-AKI who are not candidates for liver transplantation); and (C) AKI of uncertain etiology in which the need for RRT may be considered on an individual basis. BEST PRACTICE ADVICE 13: Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI. BEST PRACTICE ADVICE 14: Liver transplantation is the most effective treatment for HRS-AKI. Pharmacotherapy for HRS-AKI before proceeding with liver transplantation may be associated with better post-liver transplantation outcomes. Selected patients with HRS-AKI may require simultaneous liver kidney transplantation based on updated Organ Procurement and Transplantation Network listing criteria.

The Cardiorenal Connection: Is Cardiac Output the Sole Determinant of Renal Dysfunction in Cirrhosis?

ABSTRACT: Hemodynamic abnormalities are the hallmarks of advanced cirrhosis. An increased cardiac output maintains hemodynamic stability until the very late stage of cirrhosis, when the cardiac output starts to fall, which has been attributed to the development of renal dysfunction in these patients. The study by Daniesen showed that cardiac output was increased rather than decreased in patients with hepatorenal syndrome-acute kidney injury, potentially conflicting with previous understanding. It is possible that the authors were only assessing 1 aspect of cardiac dysfunction in a group of patients who were not at the very end stage of cirrhosis. Their unexpected findings will certainly stimulate further research into the role of cardiac dysfunction in the pathogenesis of acute kidney injury in cirrhosis.

Acute-on-Chronic Liver Failure Clinical Guidelines.

In patients with cirrhosis and chronic liver disease, acute-on-chronic liver failure is emerging as a major cause of mortality. These guidelines indicate the preferred approach to the management of patients with acute-on-chronic liver failure and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.

Association of serum metabolites and gut microbiota at hospital admission with nosocomial infection development in patients with cirrhosis.

Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography-mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End-Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1-linolenoyl-glycerolphosphocholine (GPC) and 1-stearoyl-GPC and higher N-acetyltryptophan and N-acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial-metabolite correlation networks were complex and dense in patients with NIs, especially sub-networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial-metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Admission Urinary and Serum Metabolites Predict Renal Outcomes in Hospitalized Patients With Cirrhosis.

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Prognosis of hospitalized patients with cirrhosis and acute kidney disease.

BACKGROUND: The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known. AIM: To study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD. METHODS: The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes. RESULTS: 1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in-hospital and 30-day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53). CONCLUSIONS: Patients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.

Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort.

OBJECTIVE: Comorbid conditions are associated with poor prognosis in COVID-19. Registry data show that patients with cirrhosis may be at high risk. However, outcome comparisons among patients with cirrhosis+COVID-19 versus patients with COVID-19 alone and cirrhosis alone are lacking. The aim of this study was to perform these comparisons. DESIGN: A multicentre study of inpatients with cirrhosis+COVID-19 compared with age/gender-matched patients with COVID-19 alone and cirrhosis alone was performed. COVID-19 and cirrhosis characteristics, development of organ failures and acute-on-chronic liver failure (ACLF) and mortality (inpatient death+hospice) were compared. RESULTS: 37 patients with cirrhosis+COVID-19 were matched with 108 patients with COVID-19 and 127 patients with cirrhosis from seven sites. Race/ethnicity were similar. Patients with cirrhosis+COVID-19 had higher mortality compared with patients with COVID-19 (30% vs 13%, p=0.03) but not between patients with cirrhosis+COVID-19 and patients with cirrhosis (30% vs 20%, p=0.16). Patients with cirrhosis+COVID-19 versus patients with COVID-19 alone had equivalent respiratory symptoms, chest findings and rates of intensive care unit transfer and ventilation. However, patients with cirrhosis+COVID-19 had worse Charlson Comorbidity Index (CCI 6.5±3.1 vs 3.3±2.5, p<0.001), lower presenting GI symptoms and higher lactate. Patients with cirrhosis alone had higher cirrhosis-related complications, maximum model for end-stage liver disease (MELD) score and lower BiPAP/ventilation requirement compared with patients with cirrhosis+COVID-19, but CCI and ACLF rates were similar. In the entire group, CCI (OR 1.23, 95% CI 1.11 to 1.37, p<0.0001) was the only variable predictive of mortality on multivariable regression. CONCLUSIONS: In this multicentre North American contemporaneously enrolled study, age/gender-matched patients with cirrhosis+COVID-19 had similar mortality compared with patients with cirrhosis alone but higher than patients with COVID-19 alone. CCI was the only independent mortality predictor in the entire matched cohort.