Primary Prophylaxis of Spontaneous Bacterial Peritonitis Delays Hepatorenal Syndrome and Improves Survival in Cirrhosis
2007; Elsevier BV; Volume: 133; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2007.06.065
ISSN1528-0012
AutoresJavier Fernández, Miquel Navasa, Ramón Planas, Silvia Montoliu, David Monfort, Germán Soriano, Carmen Vila, A. Pardo, Enrique Quintero, Vı́ctor Vargas, José M. Such, Pere Ginès, Vicente Arroyo,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoBackground & Aims: Norfloxacin is highly effective in preventing spontaneous bacterial peritonitis recurrence in cirrhosis, but its role in the primary prevention of this complication is uncertain. Methods: Patients with cirrhosis and low protein ascitic levels (<15 g/L) with advanced liver failure (Child–Pugh score ≥ 9 points with serum bilirubin level ≥ 3 mg/dL) or impaired renal function (serum creatinine level ≥ 1.2 mg/dL, blood urea nitrogen level ≥ 25 mg/dL, or serum sodium level ≤ 130 mEq/L) were included in a randomized controlled trial aimed at comparing norfloxacin (35 patients) vs placebo (33 patients) in the primary prophylaxis of spontaneous bacterial peritonitis. The main end points of the trial were 3-month and 1-year probability of survival. Secondary end points were 1-year probability of development of spontaneous bacterial peritonitis and hepatorenal syndrome. Results: Norfloxacin administration reduced the 1-year probability of developing spontaneous bacterial peritonitis (7% vs 61%, P < .001) and hepatorenal syndrome (28% vs 41%, P = .02), and improved the 3-month (94% vs 62%, P = .003) and the 1-year (60% vs 48%, P = .05) probability of survival compared with placebo. Conclusions: Primary prophylaxis with norfloxacin has a great impact in the clinical course of patients with advanced cirrhosis. It reduces the incidence of spontaneous bacterial peritonitis, delays the development of hepatorenal syndrome, and improves survival. Background & Aims: Norfloxacin is highly effective in preventing spontaneous bacterial peritonitis recurrence in cirrhosis, but its role in the primary prevention of this complication is uncertain. Methods: Patients with cirrhosis and low protein ascitic levels (<15 g/L) with advanced liver failure (Child–Pugh score ≥ 9 points with serum bilirubin level ≥ 3 mg/dL) or impaired renal function (serum creatinine level ≥ 1.2 mg/dL, blood urea nitrogen level ≥ 25 mg/dL, or serum sodium level ≤ 130 mEq/L) were included in a randomized controlled trial aimed at comparing norfloxacin (35 patients) vs placebo (33 patients) in the primary prophylaxis of spontaneous bacterial peritonitis. The main end points of the trial were 3-month and 1-year probability of survival. Secondary end points were 1-year probability of development of spontaneous bacterial peritonitis and hepatorenal syndrome. Results: Norfloxacin administration reduced the 1-year probability of developing spontaneous bacterial peritonitis (7% vs 61%, P < .001) and hepatorenal syndrome (28% vs 41%, P = .02), and improved the 3-month (94% vs 62%, P = .003) and the 1-year (60% vs 48%, P = .05) probability of survival compared with placebo. Conclusions: Primary prophylaxis with norfloxacin has a great impact in the clinical course of patients with advanced cirrhosis. It reduces the incidence of spontaneous bacterial peritonitis, delays the development of hepatorenal syndrome, and improves survival. See editorial on page 1029. See editorial on page 1029. Spontaneous bacterial peritonitis (SBP), an infection of ascites caused by translocation of bacteria from the intestinal lumen into the systemic circulation, is a frequent event and a common cause of death in patients with cirrhosis.1Navasa M. Rimola A. Rodes J. Bacterial infections in liver disease.Semin Liver Dis. 1997; 17: 323-333Crossref PubMed Scopus (128) Google Scholar, 2Wong F. Bernardi M. Balk R. Christman B. Moreau R. Garcia-Tsao G. Patch D. Soriano G. Hoefs J. Navasa M. International Ascites ClubSepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.Gut. 2005; 54: 718-725Crossref PubMed Scopus (304) Google Scholar In some patients the mechanism of death is an uncontrolled infection and septic shock. More commonly, however, the infection is cured with antibiotics but patients develop hepatorenal syndrome (HRS) and die with severe hepatic and renal insufficiency.3Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. Rimola A. Gassull M.A. Arroyo V. Rodés J. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20 (1495–1401)Crossref PubMed Scopus (467) Google Scholar, 4Navasa M. Follo A. Filella X. Jimenez W. Francitorra A. Planas R. Rimola A. Arroyo V. Rodés J. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.Hepatology. 1998; 27: 1227-1232Crossref PubMed Scopus (354) Google Scholar, 5Ruiz-del-Arbol L. Urman J. Fernandez J. Gonzalez M. Navasa M. Monescillo A. Albillos A. Jimenéz W. Arroyo V. Systemic, renal and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.Hepatology. 2003; 38: 1210-1218Crossref PubMed Scopus (395) Google Scholar, 6Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. Castells L. Vargas V. Soriano G. Guevara M. Gines P. Rodes J. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1277) Google Scholar Prophylaxis of SBP should, therefore, be associated with an increase in survival. Most data on prophylaxis of SBP derive from studies assessing long-term intestinal decontamination with oral norfloxacin (or other antibiotics) in patients recovering from an episode of this infection (secondary prophylaxis).7Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Forné M. Miranda M.L. Llach J. Salmerón J.M. Esteve M. Marqués J.M. Jiménez de Anta M.T. Arroyo V. Rodés J. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (526) Google Scholar, 8Rolanchon A. Cordier L. Bacq Y. Nousbaum J.B. Franza A. Paris J.C. Fratte S. Bohn B. Kitmacher P. Stahl J.P. Zarski J.P. Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial.Hepatology. 1995; 22: 1171-1174PubMed Google Scholar, 9Singh N. Gayowski T. Yu V.L. Wagener M.M. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial.Ann Intern Med. 1995; 122: 595-598Crossref PubMed Scopus (176) Google Scholar, 10Bauer T.M. Follo A. Navasa M. Vila J. Planas R. Clemente G. Vargas V. Bory F. Vaquer P. Rodés J. Daily norfloxacin is more effective than weekly rufloxacin in prevention of spontaneous bacterial peritonitis recurrence.Dig Dis Sci. 2002; 47: 1356-1361Crossref PubMed Scopus (53) Google Scholar, 11Sandhu B.S. Gupta R. Sharma J. Singh J. Murthy N.S. Sarin S.K. Norfloxacin and cisapride combination decreases the incidence of spontaneous bacterial peritonitis in cirrhotic ascites.J Gastroenterol Hepatol. 2005; 20: 599-605Crossref PubMed Scopus (30) Google Scholar The probability of SBP recurrence was reduced drastically in all studies. However, no significant effect on survival was observed. The role of norfloxacin in the primary prophylaxis of SBP is unclear. In the only randomized, placebo-controlled study published to date, no significant effect in the probability of developing SBP or survival was found.12Grange J.D. Roulot D. Pelletier G. Pariente E.A. Denis J. Ink O. Blanc P. Richardet J.P. Vinel J.P. Delisle F. Fischer D. Flahault A. Amiot X. Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial.J Hepatol. 1998; 29: 430-436Abstract Full Text PDF PubMed Scopus (147) Google Scholar An important limitation of these studies, however, was that their design and the patient’s selection were inadequate to detect differences in survival. The ideal population to assess the impact of prophylaxis with norfloxacin in the natural history of cirrhosis is one that includes patients at high risk of developing SBP and HRS. Advanced liver failure and low ascitic fluid protein concentration are important predictors of SBP.13Runyon B.A. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.Gastroenterology. 1986; 91: 1343-1346Abstract PubMed Google Scholar, 14Llach J. Rimola A. Navasa M. Ginès P. Salmerón J.M. Ginès A. Arroyo V. Rodés J. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (180) Google Scholar, 15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar, 16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Impairment of circulatory and renal function is the best predictor of HRS.3Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. Rimola A. Gassull M.A. Arroyo V. Rodés J. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20 (1495–1401)Crossref PubMed Scopus (467) Google Scholar, 4Navasa M. Follo A. Filella X. Jimenez W. Francitorra A. Planas R. Rimola A. Arroyo V. Rodés J. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.Hepatology. 1998; 27: 1227-1232Crossref PubMed Scopus (354) Google Scholar, 5Ruiz-del-Arbol L. Urman J. Fernandez J. Gonzalez M. Navasa M. Monescillo A. Albillos A. Jimenéz W. Arroyo V. Systemic, renal and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.Hepatology. 2003; 38: 1210-1218Crossref PubMed Scopus (395) Google Scholar, 6Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. Castells L. Vargas V. Soriano G. Guevara M. Gines P. Rodes J. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1277) Google Scholar, 17Ruiz-del-Arbol L. Monescillo A. Arocena C. Valer P. Ginès P. Moreira V. Milicua J.M. Jiménez W. Arroyo V. Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (466) Google Scholar, 18Ginès A. Escorsell A. Ginès P. Salo J. Jimenez W. Inglada L. Navasa M. Claria J. Rimola A. Arroyo V. Rodes J. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar This article reports the results of a double-blind, randomized, placebo-controlled trial showing that primary prophylaxis with norfloxacin in patients at high risk of developing SBP and HRS is associated with a significant improvement in the clinical course of the disease and an increase in survival. We studied patients with cirrhosis and ascites admitted between September 2000 and June 2004. Diagnosis was based on clinical, laboratory, and ultrasonographic data or on histology. Criteria for inclusion were as follows: (1) age 18–80 years, (2) protein levels in ascitic fluid of less than 15 g/L, (3) impaired renal function (serum creatinine level ≥ 1.2 mg/dL, BUN ≥ 25 mg/dL, or serum sodium level ≤ 130 mEq/L) or severe liver failure (Child–Pugh score ≥ 9 points with serum bilirubin level ≥ 3 mg/dL). The protein concentration in ascitic fluid was selected because it is an important predictor of SBP.13Runyon B.A. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.Gastroenterology. 1986; 91: 1343-1346Abstract PubMed Google Scholar, 14Llach J. Rimola A. Navasa M. Ginès P. Salmerón J.M. Ginès A. Arroyo V. Rodés J. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (180) Google Scholar, 15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar, 16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Serum bilirubin,14Llach J. Rimola A. Navasa M. Ginès P. Salmerón J.M. Ginès A. Arroyo V. Rodés J. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Scopus (180) Google Scholar, 15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar, 16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar serum albumin,15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar and prothrombin time15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar also have been identified as independent predictors of SBP, and for this reason the Child–Pugh score also was chosen. However, because serum bilirubin has been reported as a very powerful predictor of SBP in several studies,15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar, 16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar the Child–Pugh score was combined with serum bilirubin. A cut-off level of 3 mg/dL of serum bilirubin was selected on the basis of 2 studies that showed that levels greater than 2.5 or 3.2 mg/dL were associated with a high incidence of SBP.15Andreu M. Solá R. Sitges-Serra A. Alia C. Gallen M. Vila M.C. Coll S. Oliver M.I. Risk factors for spontaneous bacterial peritonitis.Gastroenterology. 1993; 104: 1133-1138Abstract PubMed Google Scholar, 16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Hyponatremia and increased serum creatinine or blood urea nitrogen concentrations were chosen because they are powerful predictors of type-1 HRS.3Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. Rimola A. Gassull M.A. Arroyo V. Rodés J. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20 (1495–1401)Crossref PubMed Scopus (467) Google Scholar, 4Navasa M. Follo A. Filella X. Jimenez W. Francitorra A. Planas R. Rimola A. Arroyo V. Rodés J. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.Hepatology. 1998; 27: 1227-1232Crossref PubMed Scopus (354) Google Scholar, 18Ginès A. Escorsell A. Ginès P. Salo J. Jimenez W. Inglada L. Navasa M. Claria J. Rimola A. Arroyo V. Rodes J. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar, 19Bataller R. Gines P. Guevara M. Arroyo V. Hepatorenal syndrome.Semin Liver Dis. 1997; 17: 233-247Crossref PubMed Scopus (108) Google Scholar, 20Angeli P. Wong F. Watson H. Gines P. CAPPS investigatorsHyponatremia in cirrhosis: results of a patient population survey.Hepatology. 2006; 44: 1535-1542Crossref PubMed Scopus (308) Google Scholar Exclusion criteria were as follows: (1) previous SBP or norfloxacin prophylaxis, (2) allergy to quinolones, (3) hepatocellular carcinoma, (4) data of organic renal failure (ultrasonographic evidence of obstructive uropathy or parenchymal renal disease or hematuria and/or proteinuria), and (5) human immunodeficiency virus infection. The protocol was approved by the ethics committee of each hospital. Written informed consent was obtained from the patients. Baseline evaluation included history and physical examination, liver and renal tests, ascitic fluid analysis and culture, fresh urine sediment, and abdominal ultrasonography. Patients who fulfilled the inclusion criteria were allocated into 2 groups: patients in the study group received norfloxacin 400 mg/day (1 tablet); patients in the control group received placebo (1 tablet per day). Identical norfloxacin and placebo tablets were prepared by Madaus S.A. (Barcelona, Spain). Randomization was performed using consecutively numbered, computer-generated envelopes containing treatment assignment. Treatment was started immediately after randomization, which was independent at each hospital. Follow-up visits were performed every 2 months. Treatment compliance was assessed by interviewing the patient and by tablet count at each visit. A new box with the study medication then was given. A patient was considered noncompliant when the study medication was not taken for 7 days or more every 2 months. Norfloxacin or placebo were interrupted when patients developed an episode of SBP, received a liver transplant, or completed a follow-up period of 1 year. They were considered censored at that time. The selection of a maximal period of follow-up evaluation of 1 year was based on 3 points. First, a previous study showed that the greatest difference in the incidence of SBP recurrence between patients treated with norfloxacin or placebo occurred at the 11th month of follow-up evaluation.7Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Forné M. Miranda M.L. Llach J. Salmerón J.M. Esteve M. Marqués J.M. Jiménez de Anta M.T. Arroyo V. Rodés J. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (526) Google Scholar Although patients included in the current study did not have a previous history of SBP, we expected a similar difference in the probability of SBP development between groups because of the extremely high risk of infection estimated in patients receiving placebo. Second, we hypothesized that mortality during the study period would be related closely to complications triggered by SBP. Therefore, we decided to assess survival at the time of the greatest difference in the probability of SBP development. Finally, considering that our patients had severely impaired liver and/or renal function, a high mortality rate was expected to occur within the first year after inclusion. Diagnostic paracentesis was performed only when clinically indicated. Diagnosis of spontaneous bacteremia, SBP, urinary infection, and other infections was made as described previously.21Fernandez J. Navasa M. Gómez J. Colmenero J. Vila J. Arroyo V. Rodes J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (764) Google Scholar Type-1 and type-2 HRS were diagnosed according to the criteria of the International Ascites Club.22Arroyo V. Ginès P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. Reynolds T.B. RingLarsen H. Scholmerich J. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis International Ascites Club.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar Transient renal failure was defined as a nonsustained increase in serum creatinine (by >50%) to levels higher than 1.5 mg/dL. Spontaneous bacteremia and SBP were treated with ceftriaxone. Treatment was modified, if required, according to clinical course and microbiologic results. Patients with SBP received intravenous albumin to prevent HRS (1.5 g/kg/bw at infection diagnosis and 1 g/kg/bw on day 3).6Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. Castells L. Vargas V. Soriano G. Guevara M. Gines P. Rodes J. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1277) Google Scholar Norfloxacin, 400 mg/12 h for 7 days, was given to patients from both groups who developed upper gastrointestinal hemorrhage to prevent bacterial infections.23Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J. Planas R. Bernard B. Inadomi J.M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document International Ascites Club.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar HRS was not treated with vasoconstrictors because at the time of protocol approval (1999) there were very few data on the efficacy of this treatment. The main end points of the trial were 3-month and 1-year probability of survival. Although previous investigations assessing SBP prophylaxis did not show significant differences in survival between patients receiving norfloxacin and those receiving placebo,7Gines P. Rimola A. Planas R. Vargas V. Marco F. Almela M. Forné M. Miranda M.L. Llach J. Salmerón J.M. Esteve M. Marqués J.M. Jiménez de Anta M.T. Arroyo V. Rodés J. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (526) Google Scholar, 12Grange J.D. Roulot D. Pelletier G. Pariente E.A. Denis J. Ink O. Blanc P. Richardet J.P. Vinel J.P. Delisle F. Fischer D. Flahault A. Amiot X. Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial.J Hepatol. 1998; 29: 430-436Abstract Full Text PDF PubMed Scopus (147) Google Scholar the current trial but not these studies included mainly patients at high risk of developing type-1 HRS associated with SBP and, therefore, with a high probability of dying within a short period of time. We estimated a 1-year probability of survival of 25% in the placebo group based on previous studies showing a 1-year probability of survival of 20%, 26%, and 38% in patients with type-2 HRS,24Arroyo V. Terra C. Gines P. New treatments of hepatorenal syndrome.Semin Liver Dis. 2006; 26: 254-264Crossref PubMed Scopus (34) Google Scholar dilutional hyponatremia (P. Gines, unpublished observation25Arroyo V. Rodes J. Gutierrez-Lizarraga M.A. Revert L. Prognostic value of spontaneous hyponatremia in cirrhosis with ascites.Am J Dig Dis. 1976; 21: 249-256Crossref PubMed Scopus (166) Google Scholar, 26Planas R. Montoliu S. Balleste B. Rivera M. Miquel M. Masnou H. Galeras J.A. Gimenez M.D. Santos J. Cirera I. Morillas R.M. Coll S. Sola R. Natural history of patients hospitalized for management of cirrhotic ascites.Clin Gastroenterol Hepatol. 2006; 4: 1385-1394Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar), and low protein ascites with high bilirubin level and/or low platelet count,16Guarner C. Solà R. Soriano G. Andreu M. Novella M.T. Vila C. Sàbat M. Coll S. Ortiz J. Gómez C. Balanzó J. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar respectively. The 1-year probability of survival of patients in the norfloxacin group was estimated as 55% considering that selective intestinal decontamination would drastically reduce the incidence of SBP, which is the most frequent precipitating event of type-1 HRS19Bataller R. Gines P. Guevara M. Arroyo V. Hepatorenal syndrome.Semin Liver Dis. 1997; 17: 233-247Crossref PubMed Scopus (108) Google Scholar and a common cause of death in patients with advanced cirrhosis. Moreover, recent studies have shown that the administration of norfloxacin to patients with cirrhosis and ascites is associated with a significant improvement in systemic hemodynamics, with an increase in mean arterial pressure and a suppression of plasma renin activity.27Albillos A. de la Hera A. Gonzalez M. Moya J.L. Calleja J.L. Monserrat J. Ruiz-del Arbol L. Alvarez-Mon M. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.Hepatology. 2003; 37: 208-217Crossref PubMed Scopus (366) Google Scholar, 28Rasaratnam B. Kaye D. Jennings G. Dudley F. Chin-Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis A randomized trial.Ann Intern Med. 2003; 139: 186-193Crossref PubMed Scopus (192) Google Scholar These 2 parameters are the most sensitive predictors of survival in patients with cirrhosis and ascites.19Bataller R. Gines P. Guevara M. Arroyo V. Hepatorenal syndrome.Semin Liver Dis. 1997; 17: 233-247Crossref PubMed Scopus (108) Google Scholar, 29Llach J. Gines P. Arroyo V. Rimola A. Tito L. Badalamenti S. Jimenez W. Gaya J. Rivera F. Rodes J. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.Gastroenterology. 1988; 94: 482-487Abstract PubMed Google Scholar Based on these assumptions, 34 patients had to be included in each group to obtain a P value of less than .05 with an α error of 5% and a β error of 20% in a 1-tailed test. Secondary end points were 1-year probability of developing SBP and HRS. The trial was evaluated on an intention-to-treat basis. Variables were compared by the Student t test or the χ2 test with the Yates correction when indicated. Probability curves were constructed with the Kaplan–Meier method and compared by the log-rank test. Results are given as relative hazard plus 95% confident interval or as mean ± SD. Calculations were performed with the SPSS Statistical Package (version 11.0, 2000; SPSS Inc., Chicago, IL). Differences were considered significant at the P value of .05. A total of 157 patients with low protein ascites and advanced liver failure or impaired renal function were screened. Of these, 83 were not studied because of the presence of exclusion criteria (61 patients), death between evaluation and randomization (14 patients), and refusal to participate (8 patients). Of the 74 patients randomized, 6 were excluded from the analysis of the results. Five (3 in the norfloxacin group and 2 in the placebo group) were lost to follow-up evaluation immediately after randomization. The sixth patient (from the placebo group) was excluded because of violation of the protocol (unknown primary prophylaxis with norfloxacin). Thus, the final analysis of the trial included 68 patients: 35 in the norfloxacin group and 33 in the placebo group. Reasons for inclusion in the study were impaired renal function in 20 patients (29%), severe liver failure in 14 (21%), and both criterion in 34 (50%). There were no differences between groups in the inclusion criteria. Sixty-five percent of the patients were included in the study during a hospitalization, 23 of 35 patients in the norfloxacin group (66%) and 21 of 33 in the placebo group (64%). The main cause of admission was ascites, followed by encephalopathy and infections other than SBP. No significant differences between patients receiving norfloxacin or placebo were observed at baseline (Table 1). Baseline characteristics also were similar between patients included in the study during a hospitalization and those who were not, except for refractory ascites, which was more frequent in patients included during hospitalization (43% vs 12%, P = .02).Table 1Baseline Clinical and Analytic DataNorfloxacin (n = 35)Placebo (n = 33)Age, y62 ± 1161 ± 12Sex, M/F22/1323/10Alcoholic cirrhosis, n (%)20 (57)16 (49)Active alcoholism, n (%)aArbitrarily defined as a daily alcohol intake greater than 20 g in patients with alcoholic cirrhosis.10 (29)7 (21)Mean arterial pressure, mm Hg83 ± 884 ± 9Hematocrit level, %31 ± 531 ± 5White cell count, per mm36880 ± 32276020 ± 2843Platelet count, per mm3120,314 ± 74,95294,061 ± 53,571Serum bilirubin level, mg/dL3.5 ± 2.34.4 ± 4.6Serum albumin level, g/L28 ± 626 ± 5International normalized ratio1.49 ± .301.56 ± .36Child–Pugh scorebThe Child–Pugh score (range, 5–15, where 5 indicates good liver function and 15 indicates poor liver function) was cal
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