Miguel Navasa

Hemodynamic Events in a Prospective Randomized Trial of Propranolol Versus Placebo in the Prevention of a First Variceal Hemorrhage

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 +/- 4.2 to 15.7 +/- 3.4 mm Hg; P less than 0.05) but not in patients receiving the placebo (19.6 +/- 6.8 to 17.5 +/- 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P less than 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P less than 0.01), all of whom had a hepatic venous pressure gradient greater than 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to less than or equal to 12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranolol-treated; P less than 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to less than 12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

Bacterial translocation of enteric organisms in patients with cirrhosis

BACKGROUND/AIMS The aim of the study was to investigate the prevalence and associated risk factors for bacterial translocation in patients with cirrhosis, a mechanism involved in the pathogenesis of bacterial infections in experimental cirrhosis. METHODS Mesenteric lymph nodes were obtained for microbiological culture from 101 patients with cirrhosis and from 35 non-cirrhotic patients. RESULTS Enteric organisms were grown from mesenteric lymph nodes in 8.6% of non-cirrhotic patients. In the 79 cirrhotic patients without selective intestinal decontamination, the prevalence of bacterial translocation significantly increased according to the Child-Pugh classification: 3.4% in Child A, 8.1% in Child B and 30.8% in Child C patients (chi2 = 6.106, P < 0.05). However, translocation by Enterobacteriaceae, the organisms commonly responsible for spontaneous bacteremia and peritonitis in cirrhosis, was only observed in 25% of the cases. The prevalence of bacterial translocation in the 22 cirrhotic patients undergoing selective intestinal decontamination, all Child-Pugh class B and C, was 4.5%. The Child-Pugh score was the only independent predictive factor for bacterial translocation (odds ratio 2.22, P = 0.02). CONCLUSIONS Translocation of enteric organisms to mesenteric lymph nodes is increased in patients with advanced cirrhosis and is reduced to the level found in non-cirrhotic patients by selective intestinal decontamination.

Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival

Relative adrenal insufficiency is frequent in patients with severe sepsis and is associated with hemodynamic instability, renal failure, and increased mortality. This study prospectively evaluated the effects of steroids on shock resolution and hospital survival in a series of 25 consecutive patients with cirrhosis and septic shock (group 1). Adrenal function was evaluated by the short corticotropin test within the first 24 hours of admission. Patients with adrenal insufficiency were treated with stress doses of intravenous hydrocortisone (50 mg/6 h). Data were compared to those obtained from the last 50 consecutive patients with cirrhosis and septic shock admitted to the same intensive care unit in whom adrenal function was not investigated and who did not receive treatment with steroids (group 2). Incidence of adrenal insufficiency in group 1 was 68% (17 patients). Adrenal dysfunction was frequent in patients with advanced cirrhosis (Child C: 76% vs. Child B: 25%, P = .08). Resolution of septic shock (96% vs. 58%, P = .001), survival in the intensive care unit (68% vs. 38%, P = .03), and hospital survival (64% vs. 32%, P = .003) were significantly higher in group 1. The main causes of death in group 1 were hepatorenal syndrome or liver failure (7 of 9 patients). In contrast, refractory shock caused most of the deaths in group 2 (20 of 34 patients). In conclusion, relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock. Hydrocortisone administration in these patients is associated with a high frequency of shock resolution and high survival rate. (HEPATOLOGY 2006;44:1288–1295.)

A Randomized Unblinded Pilot Study Comparing Albumin Versus Hydroxyethyl Starch in Spontaneous Bacterial Peritonitis

The administration of albumin improves circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis. This randomized unblinded pilot study compared the effect of albumin (10 patients) and the synthetic plasma expander hydroxyethyl starch 200/0.5 (10 patients) on the systemic hemodynamics of patients with spontaneous bacterial peritonitis. Baseline measurements were performed within 12 hours after diagnosis of infection. Patients then received 2 doses of the volume expander (1.5 g/kg body weight after baseline measurements and 1 g/kg body weight on day 3). Measurements were repeated after infection resolution. Treatment with albumin was associated with a significant increase in arterial pressure and a suppression of plasma renin activity, indicating an improvement in circulatory function. This occurred in the setting of a significant expansion of central blood volume (increase in cardiopulmonary pressures and atrial natriuretic factor) and an increase in systolic volume and systemic vascular resistance. In contrast, no significant changes were observed in these parameters in patients treated with hydroxyethyl starch. Von Willebrand–related antigen plasma levels significantly decreased in patients treated with albumin but not in those treated with hydroxyethyl starch. Serum nitrates and nitrites increased in patients treated with hydroxyethyl starch but not in those treated with albumin. These data suggest an effect of albumin on endothelial function. In conclusion, albumin but not hydroxyethyl starch improves systemic hemodynamics in patients with spontaneous bacterial peritonitis. This effect is due not only to volume expansion but also to an action on the peripheral arterial circulation. (HEPATOLOGY 2005.)

Cyclosporin a treatment in primary biliary cirrhosis: Results of a long-term placebo controlled trial

BACKGROUND Effective treatment for primary biliary cirrhosis (PBC) resulting in slower progression and improved survival remains elusive. Cyclosporin A (CyA), which has been so effective in preventing human allograft rejection, has shown promise in small numbers of patients in early studies. METHODS Three hundred forty-nine patients with PBC were randomized to receive CyA, 3 mg.kg-1.day-1, or placebo in a multicenter study with follow-up for 6 years. The end point was death or liver transplantation. RESULTS Cox multivariate analysis showed time from entry to death or transplantation was significantly prolonged (by up to 50%) in the CyA-treated group. Liver-related mortality was also significantly lower. However, a univariate analysis of survival showed no statistical differences between the two groups. Biochemical liver indices deteriorated more slowly in the CyA-treated group, but serum creatinine concentration was elevated > 150 mumol/L in 9%, necessitating permanent discontinuation in half of these. A reduction in the dose of CyA was required in 11% because of hypertension. CONCLUSIONS CyA has some therapeutic potential in primary biliary cirrhosis, providing blood pressure and renal function are closely monitored.

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial‐DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial‐DNA(−) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial‐DNA(+) as compared with bacterial‐DNA(−) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. Conclusion: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction. (HEPATOLOGY 2010;.)

Bacterial infections in cirrhosis

Abstract: Spontaneous bacterial peritonitis, urinary tract infections, respiratory infections and bacteremia are the most frequent infective complications in cirrhosis. These infections are due to the concomitant presence of different facilitating mechanisms including changes in the intestinal flora and in the intestinal barrier, depression of activity of the reticuloendothelial system, decreased opsonic activity of the ascitic fluid, neutrophil leukocyte dysfunction and iatrogenic factors among others. The fact, that the probability of having a microorganism responsible for the infection quinolone resistant is higher than 30% should be taken into account when treating any infection in a cirrhotic patient receiving selective intestinal decontamination with quinolones, and therefore, quinolones as empiric treatment are not indicated.

Restricted use of albumin for spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) may precipitate deterioration of circulatory function with severe hepatic insufficiency, hepatic encephalopathy, and type-1 hepatorenal syndrome (HRS) and has 30% hospital mortality despite infection resolution.1 Predictors of this acute-on-chronic liver failure include ascitic fluid concentrations of granulocytes and cytokines and renal and hepatic insufficiency at diagnosis.1–3 Endotoxemia and the inflammatory response precipitate renal failure (RF) by accentuating splanchnic vasodilatation and impairing cardiac function.3–5 Compensatory activation of the renin-angiotensin and sympathetic nervous systems further decrease renal perfusion. Volume expansion with albumin (1.5 g/kg day one, 1 g/kg day three) significantly reduces the incidence of HRS and hospital mortality.2 In the sole reported trial, only patients with serum bilirubin (bili) >68.4 μmol/l, blood urea nitrogen (BUN) >30 mg/dl or serum creatinine (Cr) >88.4 μmol/l appeared …

Ascites after liver transplantation

Massive ascites after liver transplantation, although uncommon, usually represents a serious adverse event. The pathogenesis of this complication has not been adequately investigated. To determine the incidence, characteristics, and pathogenic factors of massive ascites after liver transplantation (ascitic fluid > 500 mL/d for >10 days), the charts of 378 liver transplant recipients were reviewed. Massive ascites occurred in 25 patients (7%). Mean ascitic fluid production was 960 mL/d (range, 625 to 2,350 mL/d), and the duration of ascites was 77 days (range, 15 to 223 days). The ascitic fluid had a high protein content (36 ± 7 g/L; range, 25 to 50 g/L). When patients who did and did not develop massive ascites were compared, significant differences were found in receptor sex (men, 88% v 60%, respectively; P < .01) and surgical technique (inferior vena cava preservation with piggyback technique, 72% v 41%P < .01). Significantly increased wedged and free hepatic venous pressures and gradients between hepatic vein and right atrial pressures were found in patients who developed ascites, suggesting a difficulty in graft blood outflow. Massive ascites was associated with renal impairment, increased incidence of abdominal infection, prolonged hospitalization, and a tendency toward reduced survival. In conclusion, massive ascites after liver transplantation is relatively uncommon but associated with increased morbidity and mortality and is predominantly related to difficulties of hepatic venous drainage. Measurement of hepatic vein and atrial pressures to detect a significant gradient and correct possible alterations in hepatic vein outflow should be the first approach in the management of these patients.

A prospective randomized trial of heater probe thermocoagulation versus injection therapy in peptic ulcer hemorrhage

BACKGROUND A prospective, randomized study was performed to compare the hemostatic effect of injection therapy and heater probe thermocoagulation in the treatment of peptic ulcer bleeding. METHODS This study includes 104 patients with upper gastrointestinal bleeding in whom endoscopy revealed a gastric or duodenal ulcer with nonbleeding or bleeding vessel (n = 66), oozing hemorrhage (n = 21), or adherent red clot (n = 17). Patients with other stigmata or clean ulcers were excluded. Patients were randomly assigned during endoscopy to receive injection therapy (adrenaline and polidocanol) (n = 51) or heater probe thermocoagulation (10F probe, at setting of 30 J (n = 53). Therapy was considered successful if there was no further hemorrhage or only minor rebleeding that was controlled with a second endoscopic procedure. Patients with major rebleeding or failure of retreatment underwent emergency surgery. RESULTS There were no significant differences in effectiveness between injection therapy and thermocoagulation in any of the assessed parameters: the percentage of patients with major recurrent hemorrhage (4% vs 6%) or minor rebleeding (16% vs 17%), need for emergency surgery (two patients from each group), transfusion requirement (0.45 +/- 0.9 units vs 0.51 +/- 1.1 units), the mean number of hospitalization days (7.1 +/- 4.2 vs 6.9 +/- 4.9), and mortality (one patient from each group died). CONCLUSION Injection therapy and heater probe have similar efficacies in the treatment of bleeding peptic ulcers.