Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension, and a normal creatinine.

UNLABELLED: We investigated left ventricular diastolic dysfunction (LVDD) and its relationship with circulatory function and prognosis in cirrhosis with portal hypertension and normal creatinine. Conventional and tissue Doppler (TDI) echocardiography, systemic and hepatic hemodynamics, and the activity of endogenous vasoactive systems (AEVS) were measured prospectively in 80 patients. Plasma renin activity (PRA; >4 ng/mL/hour) was used as a surrogate of effective arterial blood volume. Patients were followed up for 12 months. Thirty-seven patients had LVDD (19 with grade 1 and 18 with grade 2). Left ventricular hypertrophy, left atrial volume, AEVS, and natriuretic peptide levels were significantly greater in patients with LVDD than without LVDD. Patients with grade 2 LVDD, compared to grade 1 LVDD and without LVDD, had significantly lower mean arterial pressure and higher Model for End-Stage Liver Disease (MELD) score, E-wave transmitral/early diastolic mitral annular velocity (E/e' ratio), cardiopulmonary pressures, PRA, and natriuretic peptide levels. Systolic and cardiac chronotropic function were significantly lower in patients with grade 2 LVDD than without LVDD. LVDD was more frequent in patients with ascites and increased PRA than patients without ascites or with ascites but normal PRA. Fourteen patients with LVDD developed hepatorenal syndrome (HRS) type 1 on follow-up. Survival was different according to degree of LVDD (without LVDD: 95%; grade 1 LVDD: 79%; grade 2 LVDD: 39%; P < 0.001). Independent predictive factors of mortality were MELD score and E/e' ratio. CONCLUSION: LVDD occurs simultaneously with other changes in cardiac structure and function and is associated with an impairment of effective arterial blood volume. LVDD is a sensitive marker of advanced cirrhosis, type 1 HRS development, and mortality.

Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration.

Hyponatraemia is common in patients with advanced cirrhosis and is associated with remarkable changes in brain cells, particularly a reduction in myoinositol and other intracellular organic osmolytes related to the hypo-osmolality of the extracellular fluid. It has been recently suggested that hyponatraemia may be an important factor associated with the development of overt hepatic encephalopathy (HE). To test this hypothesis, we retrospectively analysed the incidence and predictive factors of overt HE using a database of 70 patients with cirrhosis included in a prospective study comparing transjugular intrahepatic portosystemic shunts (TIPS) vs large-volume paracentesis in the management of refractory of ascites. Variables used in the analysis included age, sex, previous history of HE, treatment assignment (TIPS vs large volume paracentesis plus albumin), treatment with diuretics, serum bilirubin, serum creatinine and serum sodium concentration. Laboratory parameters were measured at entry, at 1 month and every 3 months during follow-up and at the time of development of HE in patients who developed this complication. During a mean follow-up of 10 months, 50 patients (71%) developed 117 episodes of HE. In the whole population of patients, the occurrence of HE was independently associated with serum hyponatraemia, serum bilirubin and serum creatinine. In conclusion, in patients with refractory ascites, the occurrence of HE is related to the impairment of liver and renal function and presence of hyponatraemia.

Cirrhotic cardiomyopathy.

During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to a failure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e' ratio may be used in the follow-up progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function.

Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage.

BACKGROUND & AIMS: Oral norfloxacin is the standard of therapy in the prophylaxis of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage. However, during the last years, the epidemiology of bacterial infections in cirrhosis has changed, with a higher incidence of infections caused by quinolone-resistant bacteria. This randomized controlled trial was aimed to compare oral norfloxacin vs intravenous ceftriaxone in the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding. METHODS: One hundred eleven patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin >3 mg/dL) and gastrointestinal hemorrhage were randomly treated with oral norfloxacin (400 mg twice daily; n = 57) or intravenous ceftriaxone (1 g/day; n = 54) for 7 days. The end point of the trial was the prevention of bacterial infections within 10 days after inclusion. RESULTS: Clinical data were comparable between groups. The probability of developing proved or possible infections, proved infections, and spontaneous bacteremia or spontaneous bacterial peritonitis was significantly higher in patients receiving norfloxacin (33% vs 11%, P = .003; 26% vs 11%, P = .03; and 12% vs 2%, P = .03, respectively). The type of antibiotic used (norfloxacin), transfusion requirements at inclusion, and failure to control bleeding were independent predictors of infection. Seven gram-negative bacilli were isolated in the norfloxacin group, and 6 were quinolone resistant. Non-enterococcal streptococci were only isolated in the norfloxacin group. No difference in hospital mortality was observed between groups. CONCLUSIONS: Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage.

Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites.

Nonselective inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs frequently induces renal failure in decompensated cirrhosis. Studies in experimental cirrhosis suggest that selective inhibitors of the inducible isoform COX-2 do not adversely affect renal function. However, very limited information is available on the effects of these compounds on renal function in human cirrhosis. This investigation consists of a double-blind, randomized, placebo-controlled trial aimed at comparing the effects of the selective COX-2 inhibitor celecoxib (200 mg every 12 hours for a total of 5 doses) on platelet and renal function and the renal response to furosemide (40 mg intravenously) with those of naproxen (500 mg every 12 hours for a total of 5 doses) and placebo in 28 patients with cirrhosis and ascites. A significant reduction (P < .05) in glomerular filtration rate (113 +/- 27 to 84 +/- 22 mL/min), renal plasma flow (592 +/- 158 to 429 +/- 106 mL/min) and urinary prostaglandin E(2) excretion (3430 +/- 430 to 2068 +/- 549 pg/min) and suppression of the diuretic (urine volume: 561 +/- 128 to 414 +/- 107 mL/h) and natriuretic (urine sodium: 53 +/- 13 to 34 +/- 10 mEq/h) responses to furosemide were observed in the group of patients treated with naproxen but not in the other two groups. Naproxen, but not celecoxib or placebo, significantly inhibited platelet aggregation (72% +/- 8% to 47% +/- 8%, P < .05) and thromboxane B(2) production (41 +/- 12 to 14 +/- 5 pg/mL, P < .05). In conclusion, our results indicate that short-term administration of celecoxib does not impair platelet and renal function and the response to diuretics in decompensated cirrhosis. Further studies are needed to evaluate the long-term safety of this drug in cirrhosis.

Circulatory function and hepatorenal syndrome in cirrhosis.

The pathogenic mechanism of hepatorenal syndrome is not well established. We investigated the circulatory function in cirrhosis before and after the development of hepatorenal syndrome. Systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems were measured in 66 patients who had cirrhosis with tense ascites and normal serum creatinine levels; measurements were repeated at follow-up in 27 cases in whom hepatorenal syndrome had developed. At baseline, mean arterial pressure and cardiac output were significantly higher, and hepatic venous pressure gradient, plasma renin activity, and norepinephrine concentration were significantly lower in patients who did not develop hepatorenal syndrome compared with those presenting with this complication. Peripheral vascular resistance was decreased to the same extent in the two groups. Plasma renin activity and cardiac output were the only independent predictors of hepatorenal syndrome. Hepatorenal syndrome occurred in the setting of a significant reduction in mean arterial pressure (83 +/- 9 to 75 +/- 7 mmHg; P < .001), cardiac output (6.0 +/- 1.2 to 5.4 +/- 1.5 L/min; P < .01), and wedged pulmonary pressure (9.2 +/- 2.6 to 7.5 +/- 2.6 mmHg; P < .001) and an increase in plasma renin activity (9.9 +/- 5.2 to 17.5 +/- 11.4 ng/mL . hr; P < .001), norepinephrine concentration (571 +/- 241 to 965 +/- 502 pg/mL; P < .001), and hepatic venous pressure gradient. No changes were observed in peripheral vascular resistance. In conclusion, these data indicate that hepatorenal syndrome is the result of a decrease in cardiac output in the setting of a severe arterial vasodilation.

Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is frequently associated with renal failure. This study assessed if systemic and hepatic hemodynamics are also affected by this condition. Standard laboratory tests, tumor necrosis factor alpha (TNF-alpha) in plasma and ascitic fluid, plasma renin activity (PRA) and norepinephrine (NE), and systemic and hepatic hemodynamics were determined in 23 patients with SBP at diagnosis and after resolution of infection. Eight patients developed renal failure during treatment. At diagnosis of infection, patients developing renal failure showed significantly higher values of TNF-alpha, blood urea nitrogen (BUN), PRA and NE, peripheral vascular resistance, and hepatic venous pressure gradient (HVPG) and lower cardiac output than patients not developing renal failure. During treatment, a significant reduction in cardiac output and arterial pressure and increase in PRA and NE, HVPG, and Child-Pugh score were observed in the first group but not in the second. Peripheral vascular resistance remained unmodified in both groups. Changes in PRA and NE correlated inversely with changes in arterial pressure and directly with changes in BUN, Child-Pugh score, and HVPG. Five patients in the renal failure group developed encephalopathy, and 6 died. In the group without renal failure, none of the patients developed encephalopathy or expired. In conclusion, patients with SBP frequently develop a rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure, aggravation of portal hypertension, encephalopathy, and death. This occurs despite rapid resolution of infection and is associated with an extremely poor prognosis.

Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis.

Endoscopic therapy, involving either injection sclerosis or band ligation, is considered the intervention of first choice for acute variceal bleeding (AVB). Pharmacologic agents have also been shown to be highly effective in the control of the bleeding episode. The purpose of this meta-analysis was to assess whether vasoactive drugs may improve the efficacy of endoscopic therapy (injection sclerosis or band ligation) in the control of AVB and thus increase survival rates. Computer databases and scientific meeting abstracts from 1994 to 2001 were used to search for randomized trials that compared the combined use of endoscopic and drug therapy with endoscopic therapy alone in the control of AVB. Eight trials involving 939 patients fulfilled the selection criteria and the following evaluated by standard meta-analysis methods: initial hemostasis, 5-day hemostasis, 5-day mortality, and adverse events. Combined treatment improved initial control of bleeding (relative risk [RR], 1.12; 95% confidence interval (CI), 1.02-1.23), and 5-day hemostasis (RR, 1.28; 95% CI, 1.18-1.39), with numbers of patients needed to treat (NNT) of 8 and 5, respectively. The difference in favor of combined treatment remained significant when trials that used drugs other than octreotide or that included a low proportion of alcoholic patients (<40%) or high-risk cirrhotic patients (<35%) were excluded. Mortality was not significantly decreased by combined therapy (RR, 0.73; 95% CI, 0.45-1.18). Severe adverse events were similar in both groups. In conclusion, in patients with AVB, pharmacologic agents improve the efficacy of endoscopic therapy to achieve initial control of bleeding and 5-day hemostasis, yet fail to affect mortality.

Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 +/- 0.7 versus 6.06 +/- 0.5 microg/mL, P <.01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P <.05) levels of sCD14, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), nitrites + nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P <.01) LBP (from 16.6 +/- 0.5 to 5.82 +/- 0.8 microg/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process.

Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding.

Increased portal pressure during variceal bleeding may have an influence on the treatment failure rate, as well as on short- and long-term survival. However, the usefulness of hepatic hemodynamic measurement during the acute episode has not been prospectively validated, and no information exists about the outcome of hemodynamically defined high-risk patients treated with early portal decompression. Hepatic venous pressure gradient (HVPG) measurement was made within the first 24 hours after admission of 116 consecutive patients with cirrhosis with acute variceal bleeding treated with a single session of sclerotherapy injection during urgent endoscopy. Sixty-four patients had an HVPG less than 20 mm Hg (low-risk [LR] group), and 52 patients had an HVPG greater than or equal to 20 mm Hg (high-risk [HR] group). HR patients were randomly allocated into those receiving transjugular intrahepatic portosystemic shunt (TIPS; HR-TIPS group, n = 26) within the first 24 hours after admission and those not receiving TIPS (HR-non-TIPS group). The HR-non-TIPS group had more treatment failures (50% vs. 12%, P =.0001), transfusional requirements (3.7 +/- 2.7 vs. 2.2 +/- 2.3, P =.002), need for intensive care (16% vs. 3%, P <.05), and worse actuarial probability of survival than the LR group. Early TIPS placement reduced treatment failure (12%, P =.003), in-hospital and 1-year mortality (11% and 31%, respectively; P <.05). In conclusion, increased portal pressure estimated by early HVPG measurement is a main determinant of treatment failure and survival in variceal bleeding, and early TIPS placement reduces treatment failure and mortality in high risk patients defined by hemodynamic criteria.