- Email: [email protected]
Systemic nitric oxide production: A mechanism supporting the glomerular filtration rate in non-azotemic human cirrhosis?
PRA and significantly higher A plasma levels (131.4 +- 92.7 vs. 70.8 -+ 32.9 pg/ml, P
1923 Isosorbide Mononilrata with Nadolol Cemparedta Nadolel Alone for Prevention of Recurrent Bleeding in Cirrhosis. A Double-Blind Placebo-Controlled Randomised Pasta Linda, Gennaro D'Amico, Divisione di Medicine, Hosp V Cervello, Palermo Italy; Rosalia Patti, Div Medicine, Palermo Italy; Flavia Politi, Giovanni Vi77ini, Div Medicine, Hosp V Cervello, Palermo Italy; Mario Traina, Service Endoscopia,Hosp V Cervello, Palermo Italy; Agostino Contino, Maria Caltagirone, Salvatore Madonia, Div Medicine, Hosp V Cervello, Palermo Italy; Luigi Pagliaro, Clin Medical, Univ Palermo, Palermo Italy Background.p-blockers are recommendedfor preventionof first or recurrent varicealbleeding in cirrhosis. Isosorhide mononitrate enhances the the portal pressure lowering effect of propranolol and causes a significant portal pressure reduction even in non responders to propranolol. Aim. To assess if isosorbide mononitrate and nadolol are more effective than nadolol alone in the prevention of recurrent portal hypertensivebleeding in cirrhotic patients. Methods. In a double-blind placebo-controlledtrial 104 cirrhotic patients surviving a portal hypertensive bleeding, were randomly assigned to isosorbide mononitrate (40 mg twice a day) and nadolol (to reduce resting heart rate by 25%) (n=53) or to placebo and nadolol (n=51). Samplesize calculation was based on the expectedtwo-year bleeding rate. Results. Child-Pugh classification of patients was A 12, B 30, C 9, in the placebo group and A 9, B 34, C 10 in the mononitrate group. Two-year bleeding rate was 20/51 (39%) in the placebo group and 27/53 (51%) in the mononitrete group (p=0.23) and mortality 7/51 (14%) and 17/53 (32%) respectively (p=O.02). Corresponding end of follow-up (median 28 months, range 4-55) figures were: bleeding 25/51 (49%) and 30/53 (57%) (p=0.44), mortality 10/ 51(20%) and 17/53 (32%) (p = 0.15). Causesof death in the placeboand mononitrate group were respectively:Liver failure 5 and 8, varicealbleeding5 and 7, sepsis0 and 1, hepatocellular carcinoma O and 1. Side effects were more frequent in the mononitrete group. New onset ascites developed in 9/28 patients in the mononitrate group and 5/20 in the placebo group (p=O.6). Conclusions. In this study the combination therapy with isosorbide monunitrate and nadolol was not superior to nadolol alone. The trend towards an increase in mortality with the combination therapy, significant at two years, suggests that this therapy should be further assessed before it is introduced in clinical practice.
1926 Systemic Nitric Oxide Production:A Mechanism SupportingThe Glomerular Filtration Hate In Non-Azotnmic Human Cirrhosis? Giovanni G. Sansoe', Gradenigo Hosp, Torino Italy; Alessandra M. Biava, Stefano Silvano, Stefania Battista, Molinette Hosp, Torino Italy; Floriano Rosina, Gradenigo Hosp, Toting Italy; Antonina Smedile, Molinette Hosp, Torino Italy; Lorenzo Bonardi, Gradenigo Hosp, Torino Italy; Mario Ri~etto, Molinette Hosp, Torino Italy Several studies in human cirrhosis have demonstratedincreasednitric oxide (NO) production and the role of NO as a mediator of the systemic hyperdynamic circulation in this disease. In experimental animals, direct infusion of nitric oxide synthase (NOS) inhibitors into the renal artery produced a fall in glomerolar filtration rate (GFR), due to the physiological role of NO in promoting mesangialcell relaxationand in reducing renal arterial vascular resistance. Aim of this study is to evaluatethe interaction betweenthe systemic venous plasma levels of NO and the main parameters of renal function in a mixed group of patients with liver cirrhosis. Twenty-one patients with liver cirrhosis (eleven with preascitic and ten with nonazotemicdiuretic-free ascitic disease)were submitted to the following measurements:a) basal plasma renin activity (PRA) and aldosteronelevels; b) renal clearancesof sodium, potassium, inulin, para-aminohippurete(PAl) and lithium (the latter being a measureof the fluid deliveryto the distal nephron); c) NO systemic plasma levels computed through paramagneticresonance spectroscopy as nitrosylhemoglohin complexes; d) endogenousdopaminergic activity, measured as incremental prolactin plasma levels during dopaminergic blockadewith i.v. metocloprumide. NO plasma levels did not show significant correlations with any parameterof liver function or the Child-Pughscore. In the whole group of patients, NO levelscorrelatedinversely with creetinine plasma concentrations (r:-O.60; P
1924 Primary Prevention of Variceal Hemorrhage in High-Risk Patients: A CostEffectiveness Analysis Incorporating Patient Compliance Benjamin J. Park, Thomas M. Shehab, Univ of Michigan Medical Ctr, Ann Arbor, MI; John M. Inadomi, VA HSR&D Ctr of Excellenceand Univ of Michigan, Ann Arbor, MI Background: Esophagealvadceal bleeding in cirrhotics is associatedwith high morbidity and mortality, as well as high managementcosts. Several treatment modalities have illustrated efficacy in preventing the first variceal bleed. Objective:To examine the influence of patient compliance on costs and outcomes of strategiesto prevent the first variceal bleed in patients with known esophagealvarices. Methods: A decision analysis simulating the natural history of variceal bleeding without intervention in patients with known high-risk varices was constructed using DATA(TreeAge,Boston MA). Strategiesusing medicaltherapy (MED) (proprsnolol dose varied to decrease heart rate by 25%) or endoscopic band ligation (EBL) (4 initial sessions followed by every 6 month surveillance endoscopy with EBL if necessary) were compared to no therapy. The outcomes of the analysis were the incremental cost to prevent the first hemorrhageand the number of first variceal bleeds over a 3-year period. The model used transition rates derived from published data, HCFAestimatesfor costs, and varied levels of compliance with therapy. Perspective was from a third-party payer. Results: Baseline assumptions (compliance100%; costs of: EBL= $583, variceal bleed= $3,894, medicaltherapy=$25/month; rate of bleed without therapy=O.O1/month; odds ratio of variceal bleed with: medicaltherapy= .54, EBL= .18; mortality = O.O2/month)yieldedthe fewest b~eedswith EBL (17% absolute risk reduction versus no therapy, 8% versus medical therapy) over a 3year period. The incremental cost per bleed preventedwas $1,754 (MED vs. no therapy) and $36,123 (EBL vs. MED). Compliancerates with therapy of 70% reduced the incremental cost of EBL compared with MED to $28,752 per bleed prevented,while rates of bleeding without therapy of _O.02/month allowed MED to dominate no therapy (lower costs with fewer bleeds). The model was sensitive to the baseline rate of variceal bleeding, odds of bleeding with medical therapy or EBL,the cost of varicealhemorrhageand the compliancerate with therapy. Conclusions: Primary prevention of variceal hemorrhage using medical therapy is likely a cost-effective strategy. Endoscopic band ligation may be a preferred alternative in poorly compliant patients.
1927 Causative Organisms and Changes of Their Antibiotic Resistance During the Recent 5 Years in 641 Cases of SpontaneousBacterial Peritonitis (SBP) in Korea Yung Sang Lee, Yeon-Ho Jog, Han Chu Lee, Young-Hwa Chung, Oong Jin Suh, Asan Medical Ctr, Seoul South Korea Increasing antibiotic resistance in infectious diseases is a world wide problem. To document the changes of antibiotic resistance and resultant clinical profiles in SBP, we analyzedthe microbilogical and clinical data of 270 cases in 1999, 222 cases in 1998, and 149 cases in 1995. The mean age was 52.8 and male to female ratio was 3:1. The most common cause of liver cirrhosis was hepatitis B virus (81%) followed by alcohol (7%) and hepatitis C virus(6%). The positive microbiological culture rate from the ascites or blood was 41%. Frequently isolated organisms were E. coil (47%), K. pneumoniae (14%), Aeromonas (7%) and viridans streptococci (7%) followed by group B streptococci, Staphylococcus,Enterococcus, etc. The resistance rate of Enterobactedaceaefamily to cefotaxime(9%, 12%, 29% from 1995 to 1999) and ciprofloxacin (11%, 21%, 35%) was significantly increased. Extended spectrum beta-lactamase(ESBL) producing organisms were significantly increasedfrom 13% in 1995 to 30% in 1999. Carbapenemwas used to treat these ESBL cases. The in-hospital mortality of SBP was 22%, 21% and 23% according to the study years. However, the proportion of in-hospital mortality due to SBP per se showed significant increase (56%, 80%, 77%). In conclusion, SBP with antibiotic resistant organisms and the proportion of in-hospital mortality due to SBP were significantly increased in recent 5 years. The survival of SBP patient is expectedto be lowered if the carbapenemresistanceemergesin the future. Therefore, it is urgently neededto establish the plans to reducethe appearanceand spread of antibiotic resistant strains among the cirrhotic patients with SBP.
1925 Renal Tubular Electrolyte Handling And Systemic Aldosterone Plasma Levels In Patients With Liver Cirrhosis Without Functional Renal Failure. Giovanni G. Sansoe', Gradenigo Hosp, Torino Italy; Alessandra M. Biava, Stetano Silvano, Antonio Touscoz, Molinette Hosp, Torino Italy; Floriano Rosina, Gradenigu Hosp, Torino Italy; Antonina Smedile, Molinette Hosp, Torino Italy; Lorenzo Bonardi, Gradenigo Hosp, Todno Italy; Mario Rizzetto, Molinette Hosp, Torino Italy In patients with preascitic cirrhosis, the amount of sodium reabsorhedby the distal nephron is independent of basal aldosterone (,k) plasma levels and the aldosterone-renal sodium excretion relationship is completely deranged.On the other hand, in ascitic cirrhosis previous studies have shown increased values of plasma A and found an inverse correlation between A levels and renal sodium excretion. Aim of this study is to evaluatethe interaction between basal A systemic plasma levels and the main parameters of renal tubular sodium handling in a mixed group of patients with liver cirrhosis. Twenty-one patients with liver cirrhosis (elevenwith preasciticand ten with non-azotemicdiuretic-free ascitic disease)were submitted to the following measurements: a) basal plasma renin activity (PRA) and A levels; b) renal clearances of sodium, potassium, inulin, para-aminohippurate(PAl) and lithium (the latter being a measureof the fluid deliveryto the distal nephron);c) determinationof the endogenous dopaminergicactivity, measuredas incrementalA responsesto i.v. metoclopramideadministration. Compared with preascitic cirrhotics, patients with ascites showed similar values of
A-375
1923 Isosorbide Mononilrata with Nadolol Cemparedta Nadolel Alone for Prevention of Recurrent Bleeding in Cirrhosis. A Double-Blind Placebo-Controlled Randomised Pasta Linda, Gennaro D'Amico, Divisione di Medicine, Hosp V Cervello, Palermo Italy; Rosalia Patti, Div Medicine, Palermo Italy; Flavia Politi, Giovanni Vi77ini, Div Medicine, Hosp V Cervello, Palermo Italy; Mario Traina, Service Endoscopia,Hosp V Cervello, Palermo Italy; Agostino Contino, Maria Caltagirone, Salvatore Madonia, Div Medicine, Hosp V Cervello, Palermo Italy; Luigi Pagliaro, Clin Medical, Univ Palermo, Palermo Italy Background.p-blockers are recommendedfor preventionof first or recurrent varicealbleeding in cirrhosis. Isosorhide mononitrate enhances the the portal pressure lowering effect of propranolol and causes a significant portal pressure reduction even in non responders to propranolol. Aim. To assess if isosorbide mononitrate and nadolol are more effective than nadolol alone in the prevention of recurrent portal hypertensivebleeding in cirrhotic patients. Methods. In a double-blind placebo-controlledtrial 104 cirrhotic patients surviving a portal hypertensive bleeding, were randomly assigned to isosorbide mononitrate (40 mg twice a day) and nadolol (to reduce resting heart rate by 25%) (n=53) or to placebo and nadolol (n=51). Samplesize calculation was based on the expectedtwo-year bleeding rate. Results. Child-Pugh classification of patients was A 12, B 30, C 9, in the placebo group and A 9, B 34, C 10 in the mononitrate group. Two-year bleeding rate was 20/51 (39%) in the placebo group and 27/53 (51%) in the mononitrete group (p=0.23) and mortality 7/51 (14%) and 17/53 (32%) respectively (p=O.02). Corresponding end of follow-up (median 28 months, range 4-55) figures were: bleeding 25/51 (49%) and 30/53 (57%) (p=0.44), mortality 10/ 51(20%) and 17/53 (32%) (p = 0.15). Causesof death in the placeboand mononitrate group were respectively:Liver failure 5 and 8, varicealbleeding5 and 7, sepsis0 and 1, hepatocellular carcinoma O and 1. Side effects were more frequent in the mononitrete group. New onset ascites developed in 9/28 patients in the mononitrate group and 5/20 in the placebo group (p=O.6). Conclusions. In this study the combination therapy with isosorbide monunitrate and nadolol was not superior to nadolol alone. The trend towards an increase in mortality with the combination therapy, significant at two years, suggests that this therapy should be further assessed before it is introduced in clinical practice.
1926 Systemic Nitric Oxide Production:A Mechanism SupportingThe Glomerular Filtration Hate In Non-Azotnmic Human Cirrhosis? Giovanni G. Sansoe', Gradenigo Hosp, Torino Italy; Alessandra M. Biava, Stefano Silvano, Stefania Battista, Molinette Hosp, Torino Italy; Floriano Rosina, Gradenigo Hosp, Toting Italy; Antonina Smedile, Molinette Hosp, Torino Italy; Lorenzo Bonardi, Gradenigo Hosp, Torino Italy; Mario Ri~etto, Molinette Hosp, Torino Italy Several studies in human cirrhosis have demonstratedincreasednitric oxide (NO) production and the role of NO as a mediator of the systemic hyperdynamic circulation in this disease. In experimental animals, direct infusion of nitric oxide synthase (NOS) inhibitors into the renal artery produced a fall in glomerolar filtration rate (GFR), due to the physiological role of NO in promoting mesangialcell relaxationand in reducing renal arterial vascular resistance. Aim of this study is to evaluatethe interaction betweenthe systemic venous plasma levels of NO and the main parameters of renal function in a mixed group of patients with liver cirrhosis. Twenty-one patients with liver cirrhosis (eleven with preascitic and ten with nonazotemicdiuretic-free ascitic disease)were submitted to the following measurements:a) basal plasma renin activity (PRA) and aldosteronelevels; b) renal clearancesof sodium, potassium, inulin, para-aminohippurete(PAl) and lithium (the latter being a measureof the fluid deliveryto the distal nephron); c) NO systemic plasma levels computed through paramagneticresonance spectroscopy as nitrosylhemoglohin complexes; d) endogenousdopaminergic activity, measured as incremental prolactin plasma levels during dopaminergic blockadewith i.v. metocloprumide. NO plasma levels did not show significant correlations with any parameterof liver function or the Child-Pughscore. In the whole group of patients, NO levelscorrelatedinversely with creetinine plasma concentrations (r:-O.60; P
1924 Primary Prevention of Variceal Hemorrhage in High-Risk Patients: A CostEffectiveness Analysis Incorporating Patient Compliance Benjamin J. Park, Thomas M. Shehab, Univ of Michigan Medical Ctr, Ann Arbor, MI; John M. Inadomi, VA HSR&D Ctr of Excellenceand Univ of Michigan, Ann Arbor, MI Background: Esophagealvadceal bleeding in cirrhotics is associatedwith high morbidity and mortality, as well as high managementcosts. Several treatment modalities have illustrated efficacy in preventing the first variceal bleed. Objective:To examine the influence of patient compliance on costs and outcomes of strategiesto prevent the first variceal bleed in patients with known esophagealvarices. Methods: A decision analysis simulating the natural history of variceal bleeding without intervention in patients with known high-risk varices was constructed using DATA(TreeAge,Boston MA). Strategiesusing medicaltherapy (MED) (proprsnolol dose varied to decrease heart rate by 25%) or endoscopic band ligation (EBL) (4 initial sessions followed by every 6 month surveillance endoscopy with EBL if necessary) were compared to no therapy. The outcomes of the analysis were the incremental cost to prevent the first hemorrhageand the number of first variceal bleeds over a 3-year period. The model used transition rates derived from published data, HCFAestimatesfor costs, and varied levels of compliance with therapy. Perspective was from a third-party payer. Results: Baseline assumptions (compliance100%; costs of: EBL= $583, variceal bleed= $3,894, medicaltherapy=$25/month; rate of bleed without therapy=O.O1/month; odds ratio of variceal bleed with: medicaltherapy= .54, EBL= .18; mortality = O.O2/month)yieldedthe fewest b~eedswith EBL (17% absolute risk reduction versus no therapy, 8% versus medical therapy) over a 3year period. The incremental cost per bleed preventedwas $1,754 (MED vs. no therapy) and $36,123 (EBL vs. MED). Compliancerates with therapy of 70% reduced the incremental cost of EBL compared with MED to $28,752 per bleed prevented,while rates of bleeding without therapy of _O.02/month allowed MED to dominate no therapy (lower costs with fewer bleeds). The model was sensitive to the baseline rate of variceal bleeding, odds of bleeding with medical therapy or EBL,the cost of varicealhemorrhageand the compliancerate with therapy. Conclusions: Primary prevention of variceal hemorrhage using medical therapy is likely a cost-effective strategy. Endoscopic band ligation may be a preferred alternative in poorly compliant patients.
1927 Causative Organisms and Changes of Their Antibiotic Resistance During the Recent 5 Years in 641 Cases of SpontaneousBacterial Peritonitis (SBP) in Korea Yung Sang Lee, Yeon-Ho Jog, Han Chu Lee, Young-Hwa Chung, Oong Jin Suh, Asan Medical Ctr, Seoul South Korea Increasing antibiotic resistance in infectious diseases is a world wide problem. To document the changes of antibiotic resistance and resultant clinical profiles in SBP, we analyzedthe microbilogical and clinical data of 270 cases in 1999, 222 cases in 1998, and 149 cases in 1995. The mean age was 52.8 and male to female ratio was 3:1. The most common cause of liver cirrhosis was hepatitis B virus (81%) followed by alcohol (7%) and hepatitis C virus(6%). The positive microbiological culture rate from the ascites or blood was 41%. Frequently isolated organisms were E. coil (47%), K. pneumoniae (14%), Aeromonas (7%) and viridans streptococci (7%) followed by group B streptococci, Staphylococcus,Enterococcus, etc. The resistance rate of Enterobactedaceaefamily to cefotaxime(9%, 12%, 29% from 1995 to 1999) and ciprofloxacin (11%, 21%, 35%) was significantly increased. Extended spectrum beta-lactamase(ESBL) producing organisms were significantly increasedfrom 13% in 1995 to 30% in 1999. Carbapenemwas used to treat these ESBL cases. The in-hospital mortality of SBP was 22%, 21% and 23% according to the study years. However, the proportion of in-hospital mortality due to SBP per se showed significant increase (56%, 80%, 77%). In conclusion, SBP with antibiotic resistant organisms and the proportion of in-hospital mortality due to SBP were significantly increased in recent 5 years. The survival of SBP patient is expectedto be lowered if the carbapenemresistanceemergesin the future. Therefore, it is urgently neededto establish the plans to reducethe appearanceand spread of antibiotic resistant strains among the cirrhotic patients with SBP.
1925 Renal Tubular Electrolyte Handling And Systemic Aldosterone Plasma Levels In Patients With Liver Cirrhosis Without Functional Renal Failure. Giovanni G. Sansoe', Gradenigo Hosp, Torino Italy; Alessandra M. Biava, Stetano Silvano, Antonio Touscoz, Molinette Hosp, Torino Italy; Floriano Rosina, Gradenigu Hosp, Torino Italy; Antonina Smedile, Molinette Hosp, Torino Italy; Lorenzo Bonardi, Gradenigo Hosp, Todno Italy; Mario Rizzetto, Molinette Hosp, Torino Italy In patients with preascitic cirrhosis, the amount of sodium reabsorhedby the distal nephron is independent of basal aldosterone (,k) plasma levels and the aldosterone-renal sodium excretion relationship is completely deranged.On the other hand, in ascitic cirrhosis previous studies have shown increased values of plasma A and found an inverse correlation between A levels and renal sodium excretion. Aim of this study is to evaluatethe interaction between basal A systemic plasma levels and the main parameters of renal tubular sodium handling in a mixed group of patients with liver cirrhosis. Twenty-one patients with liver cirrhosis (elevenwith preasciticand ten with non-azotemicdiuretic-free ascitic disease)were submitted to the following measurements: a) basal plasma renin activity (PRA) and A levels; b) renal clearances of sodium, potassium, inulin, para-aminohippurate(PAl) and lithium (the latter being a measureof the fluid deliveryto the distal nephron);c) determinationof the endogenous dopaminergicactivity, measuredas incrementalA responsesto i.v. metoclopramideadministration. Compared with preascitic cirrhotics, patients with ascites showed similar values of
A-375