Ascites in Cirrhosis With Severe Portal Hypertension
Ascites in Cirrhosis With Severe Portal Hypertension
All consecutive patients referred to our Hepatic Hemodynamic Laboratory for entering into a program of prevention of first variceal bleeding episode were considered for inclusion in this study. Patients were enrolled between January 2001 and January 2008, and were followed up until July 2009. Informed consent was obtained from all the patients and the hospital's ethics committee approved the protocol.
Cirrhotic patients with large esophageal varices and without any previous episode of gastrointestinal bleeding or previous history of ascites, jaundice, or encephalopathy were eligible. Cirrhosis was diagnosed by liver biopsy or by unequivocal clinical and echographic findings. Esophageal varices were diagnosed by endoscopy performed in the previous 6 months by any of the members of our bleeding unit and those with a diameter >5 mm were defined as large.
The NIEC (North Italian Endoscopie Club) index, a score which includes Child-Pugh class and endoscopic parameters (size of varices and red wale marks), was used to predict variceal bleeding risk.
Exclusion criteria included contraindications to β-blockers, hepatocellular carcinoma, Child-Pugh score >10, splanchnic venous thrombosis, age <18 or >80 years, treatment with diuretics or with vasoactive drugs, and comorbidity expected to decrease life expectancy to <1 year.
Hemodynamic studies were performed after an overnight fast. Under local anesthesia, a catheter introducer was placed in the right internal jugular vein using the Seldinger technique and was used to advance, under fluoroscopic guidance, a 7-F balloon-tipped catheter into the right main hepatic vein and a Swan-Ganz catheter into the pulmonary artery. Portal pressure was measured as the HVPG, which is the difference between wedged and free hepatic venous pressure. All intravascular pressure measurements were performed in triplicate using a previously calibrated, highly sensitive transducer, with external zero at the mild-axiliary line. Permanent recording of tracings was obtained. The occluded position was checked by the absence of reflux after injection of contrast medium. Cardiopulmonary pressures and cardiac output were also measured. Electrocardiography, arterial pressure, heart rate, and oxygen saturation were monitored noninvasively throughout the study with an automatic monitor. To assess the prognostic value of acute β-blockers test in a single hemodynamic study, after completing baseline hemodynamic measurements, a single intravenous bolus of 0.15 mg/kg of propranolol was administered and 20 min later hemodynamic measurements were repeated.
Continuous treatment with nadolol was started immediately after the baseline hemodynamic study. Nadolol was administered orally with a starting dose of 40 mg once daily. This was subsequently adjusted over 1–2 weeks, with a stepwise increase or decrease of 20 mg every 2–3 days up to the maximum tolerate dose without reducing resting heart <50 beats per minute or up to 240 mg per day. A second hemodynamic study was repeated 1–3 months later to evaluate chronic response. Hemodynamic response was not predefined.
Sodium restricted diet, without fluid restriction, was indicated in all cases. Nadolol was used for primary prophylaxis of variceal bleeding. Endoscopic variceal ligation was indicated in case of intolerance to β-blockers.
After inclusion, patients were followed at months 1 and 3, and every 6 months thereafter. Each visit included physical examination, blood tests, and abdominal ultrasound. Treatment adherence was assessed by extensive interrogation with the patient and relatives and by heart rate measurements. Follow-up data were gathered for at least 18 months or until liver transplantation or death. The end points evaluated were development of ascites or complications of ascites (refractory ascites, SBP, hepatorenal syndrome). Development of other decompensations (bleeding and encephalopathy) and death from any cause were also evaluated.
Ascites were defined by the presence of signs and symptoms suggestive of ascites on physical examination and was always confirmed on ultrasonography or paracentesis. The diagnostic criteria for refractory ascites, hepatorenal syndrome, and SBP were those proposed by the International Ascites Club. Gastrointestinal bleeding was defined as any episode of hematemesis or melena, or both, that occurred during the follow-up and was evaluated by emergency endoscopy. Variceal bleeding was defined according to the Baveno IV criteria. Any death occurring during follow-up was recorded. Patients lost to follow-up were censored as alive the day of the last visit.
Statistical analysis was performed according to an intention-to-treat strategy.
Categorical variables, which are reported as frequencies, were compared using the Fisher exact test. Continuous variables, which were reported as mean values±standard deviations, were compared using the unpaired Student's t-test or the nonparametric Mann–Witney rank-sum test. Actuarial probabilities were calculated according to the Kaplan–Meier method and compared using the Long-rank test. Follow-up was censored at the time of death, liver transplantation, or last visit. The possible role of confounding variables was investigated with the Cox proportional hazards regression analysis or with stepwise logistic regression (SLR) analysis, by introducing covariates that were related to the analyzed events in a univariate analysis (P ≤ 0.1). The maximum number of variables included in the multivariate analysis was 1 per 5–10 outcomes. The contribution of each significant variable to the risk of reaching the end point was estimated by the relative hazard with its 95% confidence interval (CI). Stratification according to different risk subsets groups, with respect to ascites development, was made by classification-and-regression-tree analysis. All P values were two-tailed and the level of values of less statistical significance was taken at P<0.05. The relationship between the sensitivity and specificity of the HVPG value at different cutoff points, as a predictor of ascites development during follow-up, was evaluated from a receiver operating characteristic (ROC) curve. Calculations were performed with SPSS18 statistical package (SPSS, Chicago, III).
Methods
All consecutive patients referred to our Hepatic Hemodynamic Laboratory for entering into a program of prevention of first variceal bleeding episode were considered for inclusion in this study. Patients were enrolled between January 2001 and January 2008, and were followed up until July 2009. Informed consent was obtained from all the patients and the hospital's ethics committee approved the protocol.
Selection of Patients
Cirrhotic patients with large esophageal varices and without any previous episode of gastrointestinal bleeding or previous history of ascites, jaundice, or encephalopathy were eligible. Cirrhosis was diagnosed by liver biopsy or by unequivocal clinical and echographic findings. Esophageal varices were diagnosed by endoscopy performed in the previous 6 months by any of the members of our bleeding unit and those with a diameter >5 mm were defined as large.
The NIEC (North Italian Endoscopie Club) index, a score which includes Child-Pugh class and endoscopic parameters (size of varices and red wale marks), was used to predict variceal bleeding risk.
Exclusion criteria included contraindications to β-blockers, hepatocellular carcinoma, Child-Pugh score >10, splanchnic venous thrombosis, age <18 or >80 years, treatment with diuretics or with vasoactive drugs, and comorbidity expected to decrease life expectancy to <1 year.
Hemodynamic Measurements and Study Design
Hemodynamic studies were performed after an overnight fast. Under local anesthesia, a catheter introducer was placed in the right internal jugular vein using the Seldinger technique and was used to advance, under fluoroscopic guidance, a 7-F balloon-tipped catheter into the right main hepatic vein and a Swan-Ganz catheter into the pulmonary artery. Portal pressure was measured as the HVPG, which is the difference between wedged and free hepatic venous pressure. All intravascular pressure measurements were performed in triplicate using a previously calibrated, highly sensitive transducer, with external zero at the mild-axiliary line. Permanent recording of tracings was obtained. The occluded position was checked by the absence of reflux after injection of contrast medium. Cardiopulmonary pressures and cardiac output were also measured. Electrocardiography, arterial pressure, heart rate, and oxygen saturation were monitored noninvasively throughout the study with an automatic monitor. To assess the prognostic value of acute β-blockers test in a single hemodynamic study, after completing baseline hemodynamic measurements, a single intravenous bolus of 0.15 mg/kg of propranolol was administered and 20 min later hemodynamic measurements were repeated.
Continuous treatment with nadolol was started immediately after the baseline hemodynamic study. Nadolol was administered orally with a starting dose of 40 mg once daily. This was subsequently adjusted over 1–2 weeks, with a stepwise increase or decrease of 20 mg every 2–3 days up to the maximum tolerate dose without reducing resting heart <50 beats per minute or up to 240 mg per day. A second hemodynamic study was repeated 1–3 months later to evaluate chronic response. Hemodynamic response was not predefined.
Sodium restricted diet, without fluid restriction, was indicated in all cases. Nadolol was used for primary prophylaxis of variceal bleeding. Endoscopic variceal ligation was indicated in case of intolerance to β-blockers.
Follow-up
After inclusion, patients were followed at months 1 and 3, and every 6 months thereafter. Each visit included physical examination, blood tests, and abdominal ultrasound. Treatment adherence was assessed by extensive interrogation with the patient and relatives and by heart rate measurements. Follow-up data were gathered for at least 18 months or until liver transplantation or death. The end points evaluated were development of ascites or complications of ascites (refractory ascites, SBP, hepatorenal syndrome). Development of other decompensations (bleeding and encephalopathy) and death from any cause were also evaluated.
Ascites were defined by the presence of signs and symptoms suggestive of ascites on physical examination and was always confirmed on ultrasonography or paracentesis. The diagnostic criteria for refractory ascites, hepatorenal syndrome, and SBP were those proposed by the International Ascites Club. Gastrointestinal bleeding was defined as any episode of hematemesis or melena, or both, that occurred during the follow-up and was evaluated by emergency endoscopy. Variceal bleeding was defined according to the Baveno IV criteria. Any death occurring during follow-up was recorded. Patients lost to follow-up were censored as alive the day of the last visit.
Statistical Analysis
Statistical analysis was performed according to an intention-to-treat strategy.
Categorical variables, which are reported as frequencies, were compared using the Fisher exact test. Continuous variables, which were reported as mean values±standard deviations, were compared using the unpaired Student's t-test or the nonparametric Mann–Witney rank-sum test. Actuarial probabilities were calculated according to the Kaplan–Meier method and compared using the Long-rank test. Follow-up was censored at the time of death, liver transplantation, or last visit. The possible role of confounding variables was investigated with the Cox proportional hazards regression analysis or with stepwise logistic regression (SLR) analysis, by introducing covariates that were related to the analyzed events in a univariate analysis (P ≤ 0.1). The maximum number of variables included in the multivariate analysis was 1 per 5–10 outcomes. The contribution of each significant variable to the risk of reaching the end point was estimated by the relative hazard with its 95% confidence interval (CI). Stratification according to different risk subsets groups, with respect to ascites development, was made by classification-and-regression-tree analysis. All P values were two-tailed and the level of values of less statistical significance was taken at P<0.05. The relationship between the sensitivity and specificity of the HVPG value at different cutoff points, as a predictor of ascites development during follow-up, was evaluated from a receiver operating characteristic (ROC) curve. Calculations were performed with SPSS18 statistical package (SPSS, Chicago, III).