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1.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451043

RESUMO

Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating CD14+highCD16-, CD14+highCD16+, and CD14+lowCD16+ monocytes, membrane TLR2, TLR4, and TLR9, phagocytic activity, ROS generation, and intracytoplasmic TNF-α, IL-1, IL-6, and IL-10 after lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. Serum TNF-α, IL-1, IL-6 and IL-10 levels were measured by Luminex and LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and zonulin by ELISA. SCI patients had normal monocyte counts and subset distribution. CD14+highCD16- and CD14+highCD16+ monocytes exhibited decreased TLR4, normal TLR2 and increased TLR9 expression. CD14+highCD16- monocytes had increased LPS-induced TNF-α but normal IL-1, IL-6, and IL-10 production. Monocytes exhibited defective phagocytosis but normal ROS production. Patients had enhanced serum TNF-α and IL-6 levels, normal IL-1 and IL-10 levels, and increased circulating LBP, I-FABP, and zonulin levels. Chronic SCI patients displayed impaired circulating monocyte function. These patients exhibited a systemic proinflammatory state characterized by enhanced serum TNF-α and IL-6 levels. These patients also had increased bacterial translocation and gut barrier damage.

2.
J Hepatol ; 74(2): 486-487, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33309115
3.
Rev Esp Enferm Dig ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33256421

RESUMO

BACKGROUND: Drug-induced pancreatitis is an unexplored entity. METHODS: Retrospective cohort study conducted at a referral center. Patients with drug-induced acute pancreatitis between 2008-2018 were included. Baseline patients´ characteristics, involved drugs, clinical course and recurrence were analyzed. RESULTS: Drug-induced pancreatitis represented 2.8% of acute pancreatitis (47/1665), and 18 different involved drugs were identified (thiopurines 61.8%). Latency period was less than one month in 87.2%. Pancreatitis was mild in 89.3%. Recurrence risk was 2.3%. CONCLUSION: Drugs are a rare cause of pancreatitis, which mostly occurs within the first month of treatment, is usually mild and associates a low risk of recurrence.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33279783

RESUMO

BACKGROUND & AIMS: Few prospective studies have assessed the safety of direct oral anticoagulants (DOACs) in elective endoscopy. Our primary aim was to compare the risks of endoscopy-related gastrointestinal bleeding and thromboembolic events in patients on DOACs or vitamin K antagonists (VKAs) in this setting. Secondarily, we examined the impact of the timing of anticoagulant resumption on the risk of delayed bleeding in high-risk therapeutic procedures. METHODS: We conducted a multicenter, prospective, observational study from January 2018 to March 2020 of 1602 patients on oral anticoagulants (1004 on VKAs and 598 on DOACs) undergoing 1874 elective endoscopic procedures. Our primary outcomes were 90-day thromboembolic events and 30-day endoscopy-related gastrointestinal bleeding. The inverse probability of treatment weighting propensity score method was used for baseline covariate adjustment. RESULTS: The 2 groups had similar risks of endoscopy-related gastrointestinal bleeding (VKAs vs DOACs, 6.2% vs 6.7%; adjusted odds ratio [OR], 1.05; 95% CI, 0.67-1.65) and thromboembolic events (VKAs vs DOACs, 1.3% vs 1.5%; adjusted OR, 0.90; 95% CI, 0.34-2.38). In high bleeding risk procedures (n = 747), delayed anticoagulant resumption (> 48 hours or 24-48 hours vs < 24 hours) did not reduce the risk of postprocedural bleeding (10.3%, 9%, and 5.8%, respectively; adjusted P = .43). Hot and cold snare polypectomy were the most frequent high-risk interventions (41.8% and 39.8%, respectively). CONCLUSION: In a prospective study of patients on DOACs or VKAs undergoing elective endoscopy, endoscopy-related bleeding and thromboembolic events showed similar risk. Our study suggests that early anticoagulant resumption is safe in most patients, but more data are needed for advanced high-risk therapeutic procedures.

5.
J Hepatol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33227350

RESUMO

INTRODUCTION: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes. PATIENTS AND METHODS: The PREDICT study included 1273 non-electively hospitalized patients with AD (No-ACLF=1071; ACLF=202). Medical history, clinical and laboratory data were collected at enrolment and during 90-day follow up, with particular attention to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, four distinct events were precipitants consistently related to AD, including proven bacterial infections, severe alcoholic hepatitis, gastrointestinal (GI) bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. In both AD phenotypes, patients with proven bacterial infections or severe alcoholic hepatitis had a similar survival. The number of precipitants was associated with significantly increased 90-day mortality, and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD and specific preventive and therapeutic strategies targeting these events may improve outcome in decompensated cirrhosis.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33184937

RESUMO

BACKGROUND AND AIM: Significant human and material resources have been diverted to COVID-19. Healthcare workers are at high risk of SARS-CoV-2 infection. We assess the impact of the COVID-19 pandemic on Gastroenterology and Hepatology departments and specialists in Spain. METHODS: Nationwide survey addressing the impact of COVID-19 on resources, procedures and physicians of Gastroenterology and Hepatology departments in 81 hospitals representative of the Spanish National Health Service. RESULTS: Overall, 41.8% of hospital beds and 40.7% of Gastroenterology and Hepatology beds were allocated to COVID-19 patient care, as well as 24.8% of gastroenterologists and 58.3% of residents. Outpatient visits, abdominal ultrasounds and endoscopies were reduced by 81.8-91.9%. Nine large university hospitals had 75% and 89% reductions in therapeutic endoscopies and hepatocellular carcinoma surgery, respectively, with cancellation of elective liver transplant and TIPS. Prevalence of infected physicians was 10.6% and was dependent on regional population incidence (r = 0.74, P = 0.001), with 11% hospitalized and one physician dying. Up to 63.4% of physicians may have been infected before or shortly after Spain entered lockdown, 57% of them having recently performed endoscopies. Adequate protection was acknowledged in >80% hospitals but only 2.9% performed regular SARS-CoV-2 testing. CONCLUSIONS: The impact of the COVID-19 pandemic on healthcare delivery has been massive. A wave of Gastroenterology-related complications is expected due to resource diversion. Gastroenterologists have a high prevalence of infection although they may have been infected during a first phase of lower awareness and protection. Regular SARS-CoV-2 screening, adequate protection and quick reorganization of healthcare resources are still needed.

7.
Hepatol Res ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037858

RESUMO

AIM: Fontan surgery is often the procedure of choice for patients with congenital single effective ventricle. In the long term, elevated systemic venous pressure and chronic ischaemia following this procedure may lead to advanced chronic liver disease and there is also a risk of hepatocellular carcinoma (HCC). This review systematically summarizes the characteristics and outcomes of this rare condition. METHODS: Pubmed and Embase were searched from inception to January 2020 for studies reporting on HCC after Fontan surgery. The factors analyzed were clinical presentation, histology, imaging findings, treatments and survival. Our primary analysis was based on biopsy-proven HCC. RESULTS: The records selected were 26 observational studies (19 case reports/case series, 7 cohort studies) including 65 biopsy-proven HCC. Age at the time of HCC diagnosis ranged from 12 to 52 years, and 62% were female. Only one case occurred earlier than ten years after Fontan surgery. Twenty patients had no imaging or histological evidence of liver cirrhosis and 78.3% had elevated alpha-fetoprotein levels. Advanced stage was the most common at diagnosis. The most frequent treatments were transarterial chemoembolization (n=18) and surgery (n=12). One-year survival was 50% and only four patients (6.2%) were under liver imaging surveillance. We also analyzed 17 patients with non-biopsy-proven HCC. CONCLUSIONS: After Fontan surgery, HCC usually occurs at least ten years later and can develop in the absence of cirrhosis. Biopsy is mandatory to confirm the diagnosis. Patients were diagnosed at a late stage and survival outcomes were poor, highlighting a need for liver surveillance.

12.
J Hepatol ; 73(4): 842-854, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32673741

RESUMO

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32478437

RESUMO

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a sinister prognosis, and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores. METHODS: We reevaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort. RESULTS: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The newly developed CLIF-C AD + sMR score in patients without ACLF improved 90-day mortality prediction compared with the original CLIF-C AD score (C-index 0.82 [0.78-0.86] vs 0.74 [0.70-0.78, P = 0.004]). Further, the new CLIF-C ACLF + sCD163 + UNGAL improved the original CLIF-C ACLF score for 28-day mortality (0.85 [0.79-0.91] vs 0.75 [0.70-0.80], P = 0.039). CONCLUSIONS: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF.

14.
J Hepatol ; 73(6): 1415-1424, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32535060

RESUMO

BACKGROUND & AIMS: Clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg, persists 24 weeks after sustained virological response (SVR) in up to 78% of patients with HCV-related cirrhosis treated with direct-acting antivirals. These patients remain at risk of decompensation. However, long-term paired clinical and hemodynamic data are not available for this population. METHODS: We conducted a prospective multicenter study in 226 patients with HCV-related cirrhosis and CSPH who achieved SVR after antiviral therapy. Patients with CSPH 24 weeks after end of treatment (SVR24) were offered another hemodynamic assessment 96 weeks after end of treatment (SVR96). RESULTS: All patients were clinically evaluated. Out of 176 patients with CSPH at SVR24, 117 (66%) underwent an HVPG measurement at SVR96. At SVR96, 55/117 (47%) patients had HVPG <10 mmHg and 53% had CSPH (65% if we assume persistence of CSPH in all 59 non-evaluated patients). The proportion of high-risk patients (HVPG ≥16 mmHg) diminished from 41% to 15%. Liver stiffness decreased markedly after SVR (median decrease 10.5 ± 13 kPa) but did not correlate with HVPG changes (30% of patients with liver stiffness measurement <13.6 kPa still had CSPH). Seventeen (7%) patients presented with de novo/additional clinical decompensation, which was independently associated with baseline HVPG ≥16 mmHg and history of ascites. CONCLUSIONS: Patients achieving SVR experienced a progressive reduction in portal pressure during follow-up. However, CSPH may persist in up to 53-65% of patients at SVR96, indicating persistent risk of decompensation. History of ascites and high-risk HVPG values identified patients at higher risk of de novo or further clinical decompensation. LAY SUMMARY: As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly.

15.
N Engl J Med ; 383(16): 1522-1534, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32558485

RESUMO

BACKGROUND: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODS: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTS: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10-8) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10-10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10-8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10-4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10-5). CONCLUSIONS: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Betacoronavirus , Cromossomos Humanos Par 3/genética , Infecções por Coronavirus/genética , Predisposição Genética para Doença , Pneumonia Viral/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Respiratória/genética , Idoso , Estudos de Casos e Controles , Cromossomos Humanos Par 9/genética , Infecções por Coronavirus/complicações , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Família Multigênica , Pandemias , Pneumonia Viral/complicações , Insuficiência Respiratória/etiologia , Espanha
16.
J Infect Dis ; 222(5): 726-733, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32563190

RESUMO

BACKGROUND: COVID-19 is a potentially severe disease caused by the recently described SARS-CoV-2. Whether liver fibrosis might be a relevant player in the natural history of COVID-19 is currently unknown. We aimed to evaluate the association between FIB-4 and the risk of progression to critical illness in middle-aged patients with COVID-19. METHODS: In this multicenter, retrospective study with prospective follow-up of 160 patients aged 35-65 years with COVID-19, FIB-4, clinical, and biochemical variables were collected at baseline. FIB-4 ≥2.67 defined patients with risk for advanced liver fibrosis. RESULTS: Risk for advanced fibrosis was estimated in 28.1% of patients. Patients with FIB-4 ≥2.67 more frequently required mechanical ventilation (37.8% vs 18.3%; P = .009). In multivariate analysis, FIB-4 ≥2.67 (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.30-8.92), cardiovascular risk factors (OR, 5.05; 95% CI, 1.90-13.39), previous respiratory diseases (OR, 4.54; 95% CI, 1.36-15.10), and C-reactive protein (OR, 1.01; 95% CI, 1.01-1.02) increased significantly the risk of ICU admission. Bootstrap confirmed FIB-4 as an independent risk factor. CONCLUSIONS: In middle-aged patients with COVID-19, FIB-4 may have a prognostic role. The link between liver fibrosis and the natural history of COVID-19 should be evaluated in future studies.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Cirrose Hepática/virologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
17.
Rev. esp. enferm. dig ; 112(6): 483-490, jun. 2020. ilus, tab
Artigo em Inglês | IBECS-Express | IBECS | ID: ibc-FGT-5281

RESUMO

Pancreatic fluid collections frequently occur in the context of moderate and severe acute pancreatitis, and may also appear as a complication of chronic pancreatitis, pancreatic surgery or trauma. It is essential to adhere to the Atlanta classification nomenclature that subclassifies them into four categories (acute peripancreatic fluid collections, acute necrotic collections, pseudocysts, and walled-off necrosis) since it has an impact on prognosis and management. Pseudocysts and walled-off pancreatic necrosis are encapsulated pancreatic fluid collections characterized by a surrounding inflammatory wall, which typically develops three to four weeks after the onset of acute pancreatitis. Most pancreatic fluid collections resolve spontaneously and do not require intervention. However, when they become symptomatic or complicated drainage is indicated, and endoscopic ultrasound-guided drainage has become first-line treatment of encapsulated collections. Drainage of pseudocysts is relatively straightforward due to their liquid content. However, in walled-off necrosis the presence of solid necrotic debris can make treatment more challenging and therefore multidisciplinary management in experienced centers is recommended, being a step-up approach the current standard of care. In this review, we aim to address the management of pancreatic fluid collections with an especial focus on endoscopic drainage


No disponible

18.
Clin Infect Dis ; 2020 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-32386053

RESUMO

This prospective study of 34 patients with HCV-cirrhosis (17 HIV+) with baseline clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) and SVR after DAAs therapy, showed that disappearance of CSPH (primary endpoint) is a rare event (6/18 patients; 18 %), indicating a persistent risk of clinical progression or death.

19.
Rev Esp Enferm Dig ; 112(6): 483-490, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32450706

RESUMO

Pancreatic fluid collections frequently occur in the context of moderate and severe acute pancreatitis, and may also appear as a complication of chronic pancreatitis, pancreatic surgery or trauma. It is essential to adhere to the Atlanta classification nomenclature that subclassifies them into four categories (acute peripancreatic fluid collections, acute necrotic collections, pseudocysts, and walled-off necrosis) since it has an impact on prognosis and management. Pseudocysts and walled-off pancreatic necrosis are encapsulated pancreatic fluid collections characterized by a surrounding inflammatory wall, which typically develops three to four weeks after the onset of acute pancreatitis. Most pancreatic fluid collections resolve spontaneously and do not require intervention. However, when they become symptomatic or complicated drainage is indicated, and endoscopic ultrasound-guided drainage has become first-line treatment of encapsulated collections. Drainage of pseudocysts is relatively straightforward due to their liquid content. However, in walled-off necrosis the presence of solid necrotic debris can make treatment more challenging and therefore multidisciplinary management in experienced centers is recommended, being a step-up approach the current standard of care. In this review, we aim to address the management of pancreatic fluid collections with an especial focus on endoscopic drainage.

20.
J Hepatol ; 73(6): 1404-1414, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32446716

RESUMO

BACKGROUND & AIMS: The safety of non-selective ß-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. ß-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, ß-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

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