Prognostic Significance of Bacterial Infection in Bleeding Cirrhotic Patients: A Prospective Study

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1 GASTROENTEROLOGY 1995;108: Prognostic Significance of Bacterial Infection in Bleeding Cirrhotic Patients: A Prospective Study BRIGITTE BERNARD,* JEAN-FRANCOIS CADRANEL,* DOMINIQUE VALLA,* SYLVIE ESCOLANO,* VINCENT JARLIER, and PIERRE OPOLON* *Service d'h6pato-gastroen%rologie, ~Groupe d' Epid~miologie et de Recherche Clinique, Service de Biostatistique et d'informatique M~dicale, and gservice de Bact6riologie, Groupe Hospitalier Piti~-Salpetri~re, Paris, France Background/Aims: In cirrhotic patients, bacterial infection is frequently associated with gastrointestinal bleeding and seems to increase mortality. The aims of this study were to determine the incidence of bacterial infections in bleeding cirrhotic patients and the influence of infections on the risk of rebleeding and death. Methods: Cirrhotic patients admitted for gastrointestinal bleeding who had not received antimicrobial chemotherapy in the previous 7 days were included. Blood, urine, and ascitic fluid cultures were systematically performed 1, 2, 4, and 7 days after admission. Results: Sixty-four patients were enrolled. Forty-two bacterial infections were documented in 23 patients (36%) within 7 days of admission. In patients with bacterial infection, mean Child-Pugh score and mean number of blood units transfused were significantly higher, early rebleeding was more frequent (43.5% vs. 9.8%; P < 0.01), and 4-week mortality was higher (47.8% vs. 14.6%; P < 0.01). Multivariate analysis only identified bacterial infections as predictive of early rebleeding (P < 0,02) and a high Child-Pugh score as predictive of death (P < 0.001). Conclusions: In bleeding cirrhotic patients, bacterial infections only increase the risk of early rebleeding, and mortality is related to the severity of cirrhosis. ~ '~irrhotic patients with liver failure have a well-docu- 1 4 ~.~mented susceptibility to bacterial infections. - The in-hospital incidence of such infections is about 40% 1'5 and appears to correlate with the severity of liver disease.5 Bacterial infections were the immediate cause of death in 7% of a series of cirrhotic patients. 4 Bacterial infections are documented in 35%-66% of cirrhotic patients hospitalized for upper gastrointestinal bleeding. 6-1 The risk of death appears to be higher when a bacterial infection is diagnosed within 48 hours of admission to hospital.ll However, although routine antimicrobial therapy after upper gastrointestinal bleeding reduces the frequency of bacterial infections, it does not significantly influence the mortality rate. 8-1 In fact, the respective influence of the degree of liver failure, the severity of bleeding, and the occurrence of bacterial infec- tions on the prognosis of upper gastrointestinal bleeding in cirrhotic patients is not known. The aims of this prospective study were to determine the incidence of bacterial infections in cirrhotic patients admitted for upper gastrointestinal bleeding and the prognostic influence of bacterial infections on the risk of rebleeding and death. Patients and Methods Inclusion Criteria We enrolled all cirrhotic patients aged between 18 and 80 years hospitalized between June 1, 1991, and December 31, 1992, in our intensive care unit who had upper gastrointestinal bleeding and who had not received antimicrobial chemotherapy in the previous 7 days. Patients who died within 24 hours after admission were excluded. Definitions The diagnosis of cirrhosis was based on needle liver biopsy findings or, if unavailable, the association of signs of liver failure and portal hypertension and a known cause of cirrhosis. Upper gastrointestinal bleeding was defined as gastrointestinal bleeding (melena, hematemesis, rectorrhagia, or emergence of red blood in gastric lavage fluid) together with a bleeding lesion or a lesion likely to have bled in the upper digestive tract (esophagus, stomach, or proximal duodenum) and either a decrease in the hemoglobin concentration of more than 2 g/dl or the need for at least two packed red cell units to obtain a hemoglobin concentration of at least 8 g/dl. The rebleeding rate in this study refers to early rebleeding, i.e., within 7 days after admission. Bleeding was attributed to rupture of esophageal varices if it was active, or if a white plug was found on a varix, in the absence of other lesions. An ulcer was incriminated if bleeding was active, if a vessel was visible in the ulcer crater, or a clot was found on the ulcer. In the case of more than one lesion with no signs of recent bleeding, the cause of bleeding was defined as undetermined. Shock was defined as a systolic pressure below 90 mm Hg during or after the bleeding episode by the American Gastroenterological Association /95/$3.00

2 June 1995 INFECTION IN BLEEDING CIRRHOTIC PATIENTS 1829 Septicemia and bacteremia were defined as a combination of clinical signs of infection and two consecutive blood cultures yielding the same organism (septicemia) or a blood culture yielding the same organism in the two aerobic and anaerobic bottles (bacteremia). Spontaneous bacterial peritonitis was defined as (1) the presence in ascitic fluid of more than 250 polymorphonuclear neutrophils/mm 3, associated with isolation of a pathogen in the absence of signs of secondary peritonitis; or (2) the presence of more than 500 polymorphonuclear neutrophils/mm 3 in the absence of pancreatitis, peritoneal carcinosis, tuberculosis, and bloody ascites. Bacterial pneumonia was defined as the association of clinical and radiological signs of lung infection on chest radiographs. The diagnosis of urinary tract infection was based on the association of leukocyturia above 104/mL and bacteriuria above 105/mL. Early bacterial infections were those documented within 48 hours after admission. Monitoring and Management Management on admission comprised insertion of two peripheral infusions, nasal oxygen therapy, and gastric lavage with a Salem or Faucher catheter. Esophagogastroduodenal fibroscopy (Olympus Gastroscope GIF-1T-10 and GIF-1T-20; Rungis, France) was performed within 6 hours of admission unless the patient was too ill. In cases of active bleeding from esophageal varices, endoscopic obturation was performed with enbucrylate (n-butyl-2-cyanocrylate) preceded by, if necessary, esophageal tamponade with a Sengstaken-Blakemore tube. Gastroduodenal ulcers were treated with polidocanol injection if they were bleeding actively or if a clot or vessel was visible. In the case of grade II or II1 esophageal varices, administration of propranolol was started at mg/day by mouth or continued if the patient was undergoing propranolol therapy before admission as soon as vital signs were stable. Antimicrobial chemotherapy was started after the first bacteriologic samples had been taken if one or more of the following criteria were present: temperature of <36.5 C or >38 C; leukocytosis of > 12,000/mm3; urinary tract infection; spontaneous bacterial peritonitis; or clinically documented focal infection. It consisted of 1 g amoxicillin plus 200 mg clavulanate (Augmentin; Beecham, Nanterre, France) three times a day intravenously, unless otherwise indicated. The antimicrobial regimen was adapted to the results of susceptibility tests or withdrawn after 48 hours if bacteriologic test results were negative. Screening for Bacterial Infections A clinical examination was performed every day. The following bacteriologic tests and chest radiography were performed routinely on the day of admission (day 1) and days 2, 4, 5, and 7: three aerobic and anaerobic blood cultures, cytobacteriologic examination of urine, cytobacteriologic examination of ascitic fluid, and inoculation of blood culture bottles with ascitic fluid. 12 Other samples were taken as indicated (pleu- ral fluid, cerebrospinal fluid, bronchial secretions, etc.). If rebleeding occurred, the same 7-day series of tests was performed. Statistical Analysis To determine the prognostic significance of bacterial infections, the prevalence of rebleeding and death were compared in the groups of patients with and without bacterial infections during the first 7 days and then in the groups of patients with and without early bacterial infections. To identify factors influencing the risk of rebleeding and the risk of death, we performed two series of univariate and multivariate analyses including bacterial infections within 7 days in the first and early bacterial infections in the second, together with the Child-Pugh score on admission, hemoglobin concentration on admission, hematocrit on admission, number of packed red cell units transfused for the initial bleeding episode, and presence of hepatocellular carcinoma. The results of the descriptive analyses are expressed as the mean _+ SD. Quantitative variables were compared between groups by means of Student's t test. Interdependence between qualitative factors was assessed by the Z 2 test (exact method when the theoretical number of patients was below 5). Logistic regression models were fitted to determine the prognostic value of risk factors analyzed individually (univariate analysis) or simultaneously (multivariate analysis). Analyses were performed using the SAS software pack (SAS/STAT; SAS Institute Inc., Cary, NC, 1989). Results Characteristics of the Patients Of the 68 patients enrolled, 4 died within 24 hours of admission and were excluded. The analysis thus involved 64 patients (45 men and 19 women; mean age, years). Cirrhosis was histologically proven in 42 cases. The cause of cirrhosis was alcohol abuse in 35 cases (55%); viral hepatitis in 13 cases (20%) (hepatitis B virus in 5, hepatitis C virus in 6, and hepatitis D and hepatitis C virus in 2 cases); viral hepatitis C with alcohol abuse in 7 cases (11%); primary biliary cirrhosis in 2 cases (3%); hemochromatosis in 2 cases (3%); and undetermined in 5 cases (8%). According to the Child-Pugh classification, 13 the cirrhosis was class A in 9 cases (14%), B in 22 cases (34%), and C in 33 cases (52%); the mean score on admission was Hepatocellular carcinoma was diagnosed in 5 patients and was histologically proven in all cases (biopsy of an hepatic mass in 3 and autopsy in 2). Gastrointestinal Bleeding and Death Shock occurred in 24 patients (37.5%). The mean hemoglobin level on admission was g/dl, and the mean hematocrit was 21.8% _ 5.4%. The cause of the initial gastrointestinal bleeding was rupture of

3 1830 BERNARD ET AL. GASTROENTEROLOGY Vo1.108, No. 6 Table 1, Bacterial Isolates Gram-negative Gram-positive Obligate bacilli cocci anaerobes Polymicrobial ND Total Septicemia Bacteremia Pneumonia Spontaneous bacterial peritonitis Urinary tract infection Total ND, not determined. esophageal or cardial varices in 45 cases (70.3%); portal hypertensive gastropathy in 5 cases (7.8%); rupture of fundic varices in 1 case (1.6%); gastric or duodenal ulcer in 8 cases (12.5%, including 1 patient whose gastric ulcer was found to be an adenocarcinoma at autopsy); esophageal ulcer in 2 cases (3.1%); and undetermined (because of lesions, duodenal ulcer, esophageal ulcer or esophagitis, associated with esophageal varices) in 3 cases (4.7%). Fibroscopy showed active bleeding in 26.6% of cases. The mean number of packed red cell units transfused was _ 3.03 for the initial episode and a total of per patient. Early rebleeding occurred in 14 patients (21.9%). Seventeen patients (26.6%) died within 28 days of admission. The main cause of death was massive gastrointestinal bleeding in 3 cases, septic shock in 4, liver failure in 6, multiorgan failure in 3, and adult respiratory distress syndrome in 1. Bacterial Infections Overall, 42 bacterial infections were documented in 23 patients (36%) within 7 days of admission (Table 1). The number of infections per patient was as follows: 1 in 11 patients, 2 in 6, 3 in 5, and 4 in 1. Twentyfour infections (57%) were documented within 48 hours of admission (referred as early infections), and 18 infections (43%) were documented between day 3 and day 7. In 14 patients (22%), 24 early infections were documented (5 cases of septicemia, 6 bacteremia, 4 pneumonia, 5 spontaneous bacterial peritonitis, and 4 urinary tract infections). In 9 patients (14%), 18 bacterial infections were documented between day 3 and day 7 (3 cases of septicemia, 4 bacteremia, 4 pneumonia, 4 spontaneous bacterial peritonitis, and 3 urinary tract infections). No bacterial infections were documented within 7 days of admission in 41 patients. The chronology of the initial infections is shown in Figure 1. The analysis of the 23 initial infections showed a bimodal distribution. The first peak of incidence was on day 1, corresponding to infections documented on admission, and the second peak was on day 5, corresponding to hospital-acquired infections. Comparison of Patients With and Without Bacterial Infections Within 7 Days of Admission The main characteristics of the two groups on admission are given in Table 2. There was no significant difference in age, sex, or the cause of cirrhosis. In contrast, the patients with bacterial infections had significantly higher bilirubinemia and Child-Pugh score and significantly lower albuminemia and factor V levels. The hemoglobin and hematocrit values on admission were lower in the patients with bacterial infections, but the difference was not significant. The causes of bleeding were similar in the two groups, as was the proportion of patients with active bleeding on fibroscopy (Table 3). The mean number of packed red cell units transfused for the initial bleeding episode was significantly higher in the patients with bacterial infections (P < 0.001) (Table 3). The frequency of early rebleeding was also significantly higher in the patients with bacterial infections (P < 0.01) (Table 3). The lesions responsible for the initial bleeding and rebleeding were not different in 10 of the Number patients I } Early bacterial infection (n = 14) II 7 Hospitalization day Figure 1. Distribution of the date of first bacterial infection occurrence (day 1 is the day of admission).

4 June 1995 INFECTION IN BLEEDING CIRRHOTIC PATIENTS 1831 Table 2, Demographic, Clinical, and Biological Characteristics at Admission in Patients With and Without Bacterial Infections During the First 7 Days in Hospital Patients with bacterial infection Patients without bacterial infection (n = 23) (n = 41) P Age (yr) NS Sex ratio (M/F) 16/7 29/12 NS Etiology of cirrhosis (n) NS Alcoholic Posthepatic 8 12 Other 1 8 Child-Pugh score _ <0.01 Hepatocellular carcinoma 1 4 NS Ascites (%) 12 (52) 18 (44) NS Encephalopathy (%) 12 (52) 12 (29) NS Shock (%) 12 (52) 12 (29) NS Heart rate (beats/min) _ _ NS Hematocrit (%) NS Hemoglobin (g/dl) _ NS White blood cell count (xiog/l) 13, ,282 10,815 ± 6914 NS Serum creatinin (#tool/l) _ NS Serum bilirubin (#mol/l) 72.8 _ <0.01 Serum albumin (g/l) _+ 6.4 <0.05 Factor V (%) 36.1 _ _ <0.001 NS, not significant at the 0.05 level. 14 patients who rebled (esophageal varices in 7 patients with infection and 2 patients without infection and gastric varices in 1 patient without infection). In the remaining 4 patients, bleeding lesions occurred as follows: multiple, then esophageal varices in 2 patients with infection; esophageal varices, then gastric erosions in 1 Table 3. Main Characteristics of Bleeding, Endoscopic Treatment, Early Rebleeding Rate, and 4-Week Mortality Rate in Patients With and Without Bacterial Infections During the First 7 Days in Hospital Patients Patients with without bacterial bacterial infection infection (n = 23) (n = 41) P Active bleeding (%) 7 (30.4) 10 (24.4) NS Etiology (%) NS Esophageal varices 19 (82.6) 26 (63.4) Peptic ulcer 2 (8.7) 5 (12.2) Portal hypertensive gastropathy 0 5 (12.2) Other or multiple 2 (8.7) 5 (12.2) Blood units transfused for initial bleeding 6.0 _ _+ 2.5 <0.001 Variceal sclerotherapy Peptic ulcer sclerotherapy 2 1 Recurrent bleeding (%) 10 (43.5) 4 (9.8) < Week mortality rate (%) 11 (47.8) 6 (14.6) <0.01 NS, not significant at the 0.05 level. patient with infection; and gastroduodenal ulcer, then unknown in 1 patient without infection. The mortality rate at 28 days was significantly higher in the patients with bacterial infections (P < 0.01) (Table 3). The main cause of death was gastrointestinal bleeding in 1 patient with bacterial infection and 2 patients without bacterial infections; liver failure in 4 and 2 patients, respectively; multiorgan failure in 2 and 1 patients, respectively; septic shock in 4 patients with bacterial infections; and adult respiratory distress syndrome in 1 patient without bacterial infection. In the 46 patients who bled from esophageal or gastric varices, recurrent bleeding was more frequent in patients with bacterial infection (8 of 19 vs. 3 of 27; P < 0.04) and 4-week mortality was higher (8 of 19 vs. 2 of 27; P < 0.01) than in patients without bacterial infection. The same analyses have been performed to compare the outcome of patients with and without early bacterial infections. In the patients with early bacterial infections, the frequency of early rebleeding was significantly higher (50% vs. 14%; P < 0.01), and the mortality rate at 28 days was significantly higher (50% vs. 20%; P < 0.04) than in those without early bacterial infections. Identification of Factors Associated With Rebleeding and Death Bleeding from any source. The severity of liver disease (Child-Pugh score) and the degree of gastrointes-

5 1832 BERNARD ET AL. GASTROENTEROLOGY Vol. 108, No. 6 Table 4. Univariate Analysis of Potential Risk Factors for Rebleeding and Death and Associated Probability Rebleeding Death Variables ratio P ratio P Bacterial infection 7.1 < <0,005 Early bacterial infection 6.1 < <0.04 Child-Pugh score 1,3 <0.03 2,7 < Hemoglobin 1.0 NS 1.1 NS Hematocrit 1.0 NS 1.0 NS Blood units transfused 1.1 NS 1.1 NS Hepatocellular carcinoma a NS NS, not significant at the 0.05 level. aanalysis not practicable for rebleeding because no patients with carcinoma rebled. tinal bleeding (hemoglobin and hematocrit values on admission and the number of packed red cell units transfused) were greater in the patients with bacterial infections. Univariate analysis showed that the risk of rebleeding was significantly linked to bacterial infections regardless of the time of onset (P < 0.002), early bacterial infections (P < 0.007), and the Child-Pugh score (P < 0.03) (Table 4). In contrast, multivariate analysis of the factors selected only identified all bacterial infections regardless of the time of onset (P < 0.02) and early bacterial infections (P < 0.04) and as predictive of rebleeding (Table 5). Patients with bacterial infections had a risk of rebleeding 6-7 times higher than the remaining patients, after correction for other factors. Logistic regression model including hepatocellular carcinoma as a covariate could not be fitted because no patients with carcinoma had recurrent bleeding. We performed a stepwise selection of the covariates including carcinoma, which only identified bacterial infection as predictive of recurrent bleeding (P < 0.02 in the analysis including all bacterial infections and P < 0.01 in the analysis including only early infections). In the univariate analysis, the risk of death was linked to all bacterial infections regardless of the time of onset (P < 0.005), early bacterial infections (P < 0.04), and the Child-Pugh score (P < ) (Table 4). However, in the multivariate analysis, only the Child-Pugh score was predictive of death (P < in the analysis including all bacterial infections within 7 days of admission and P < in the analysis including early bacterial infections) (Table 5). The risk of death increased by a factor of 4 as the Child-Pugh score increased by one point, after correction for other factors. Variceal bleeding. We performed a stepwise selection of the covariates including hepatocellular carcinoma for the 46 patients who bled from esophageal or gastric varices, which only identified bacterial infection as predictive of recurrent bleeding (P < 0.03) and a high Child-Pugh score as predictive of death (P < 0.002). Discussion The incidence of bacterial infections was high in this study (36%). The incidence of early bacterial infections after gastrointestinal bleeding in patients with cirrhosis has only been assessed in retrospective studies; in the report by Pauwels et al., 7 13% of patients had bacterial infections within 24 hours of admission compared with 22% within 48 hours in the study by Bleichner et al. 11 In our prospective study, we found similar rates (18.8% within 24 hours and 21.9% within 48 hours). The results show that the majority of infections are documented within 48 hours of hospitalization, as suggested by a recent study involving unselected hospitalized cirrhotic patients) In other words, most such patients in whom bacterial infections are documented in hospital are infected on admission or very shortly afterwards. Univariate analysis showed that early bacterial infections, the onset of bacterial infections within 7 days of admission, and the severity of cirrhosis were risk factors for early rebleeding, in keeping with previous, retrospective studies. In one such study, the incidence of bacterial infections, ascites, jaundice, and hepatic encephalopathy was markedly higher in patients with early rebleeding than in other patients. 14 In a more recent retrospective Table 5. Multivariate Analysis of Potential Risk Factors for Rebleeding and Death and Associated Probability Recurrent bleeding Mortality Variables ratio P ratio P Bacterial infection 7.1 <0, NS Child-Pugh score 1.2 NS 4.3 <0.001 Hemoglobin 2.2 NS 0.2 NS Hematocrit 0.8 NS 2.3 NS Blood units transfused 0.9 NS 1.3 NS Hepatocellular carcinoma a NS Early bacterial infection 6.1 < NS Child-Pugh score 1.2 NS 4.5 <0,001 Hemoglobin 1.8 NS 0.2 NS Hematocrit 0.9 NS 2.3 NS Blood units transfused 1.0 NS 1.4 NS Hepatocellular carcinoma a NS NS, not significant at the 0,05 level, ~Not included as a covariate for rebleeding.

6 June 1995 INFECTION IN BLEEDING CIRRHOTIC PATIENTS 1833 study, univariate analysis of 13 variables (including the Child-Pugh score and the number of packed red cell units transfused) only identified hypoalbuminemia and gastric varices as prognostic of in-hospital rebleeding~5; bacterial infections were not analyzed. Multivariate analysis of our data only identified bacterial infections as an independent factor predictive of early rebleeding. Several prospective and retrospective studies with multivariate analyses have been performed to identify factors predictive of early death after gastrointestinal bleeding However, it is difficult to draw firm conclusions because of (1) differences in the study populations, i.e., patients with cirrhosis 15-17'.9 2, or portal hypertension in generalls; (2) the causes of gastrointestinal bleeding, i.e., rupture of esophageal varices only.3'17'.9-21 or upper gastrointestinal bleeding1<*8; (3) the study duration, i.e., 5 daysj s 30 days, *~'1<19 and 45 dayslt'2-21; and (4) the variables tested. Bacterial infections were analyzed as a prognostic factor in only one study2~; they were more frequent in the patients who died but did not correlate with 45-day mortality. The severity of liver disease correlated with mortality in most studies, as judged on the basis of the Child-Pugh score/5 ascitesj <17 encephalopathyj 8'19'21 prothrombin time,.9'2~ and bilirubinemia. 17 Signs reflecting the gravity of bleeding were also prognostic: the number of packed red cell units 21 and the presence of shock on admission, iv'is'2 Our results indicate that bacterial infections only influence the mortality rate through their link with the gravity of liver disease, which was the only factor with prognostic value for mortality. This probably explains why routine antimicrobial chemotherapy after gastrointestinal bleeding, even though it significantly reduces the incidence of bacterial infections, does not significantly affect the mortality rate. 8-1 However, it is possible that a minor prognostic role of bacterial infections was not identified in our study because of a lack of statistical power. The relationship between gastrointestinal bleeding and bacterial infection in cirrhotic patients has been well established, although its nature is not well understood. It is particularly difficult to determine if gastrointestinal bleeding is a cause or an effect of bacterial infection. Indeed, bacteriological samples can only be taken after admission for a bleeding episode. The generally accepted hypothesis is that infection is secondary to gastrointestinal bleeding, thereby justifying routine antimicrobial prophylaxis. 6 However, the alternative hypothesis, that infection triggers bleeding, is just as valid because, in our study, (1) almost all the infections documented in the first few days were diagnosed on the basis of the earliest bacteriological samples and (2) infections were the only major factor predictive of early rebleeding. The numerous circulatory and blood coagulation derangements induced by infection (reviewed by Beal and Cerra 22 and Hewett and Roth 23) in cirrhotic patients might well concur to trigger variceal bleeding. In this way, it would be useful to evaluate if long-term antibacterial prophylaxis reduces the incidence of gastrointestinal bleeding in cirrhotic patients. References 1. Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology 1984;4: Gin@s P, Quintero E, Arroyo V, Ter@s J, Bruguera M, Rimola A, Caballeria J, Rod@s J, Rozman C. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987;7: Wyke RJ. Problems of bacterial infection in patients with liver disease. Gut 1987; 28: Barnes PF, Arevalo C, Chan LS, Wong SF, Reynolds TB. A prospective evaluation of bacteremic patients with chronic liver disease. Hepatology 1988; 8: Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol 1993; 18: Rimola A, Bory F, Teres J, Perez-Ayuso RM, Arroyo V, Rodes J. Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology 1985;5: Pauwels A, Chami N, Guivarch P, Debenes B, Florent 6, Levy VG. Facteurs pr@dictifs des infections survenant au d@cours des h@morragies digestives hautes (HDH) du cirrhotique (abstr). Gastroenterol Clin Biol 1990;14:A Soriano G, Guarner C, Tomas A, Villanueva C, Torras X, Gonzales D, Sainz S, Anguera A, Cusso X, Balanzo J, Vilardell F. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1992; 103: Blaise M, Pateron D, Trinchet JC, Levacher S, Collignon A, Beaugrand M, Pourriat JL. Systemic antibiotic therapy prevents bacterial infections in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1994;20: Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Florent C, Levy VG. Antimicrobial prophylaxis after gastrointestinal hemorrhage for cirrhotic patients with a high risk of infection (abstr). Hepatology 1992; 16:123A. 11. Bleichner G, Boulanger R, Squara P, Sollet JP, Parent A. Frequency of infections in cirrhotic patients presenting with acute gastrointestinal haemorrhage. Br J Surg 1986; 73: Runyon BA, Umland ET, Merlin T. Inoculation of blood culture bottles with ascitic fluid: improved detection of spontaneous bacterial peritonitis. Arch Intern Med 1987; 147: Pugh RNH, Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60: Sayegh R, Bernuau J, Rueff B, Benhamou JP. The risk of early recurrence of gastrointestinal bleeding in cirrhosis is related to the degree of liver failure. J Hepatol 1985;(Suppl 1):$ Heresbach D, Bretagne JF, Raoul JL, Chaperon J, Piette C, Siproudhis L, Gastard J, Gosselin M. Pronostic et facteurs pronostiques de I'h@morragie par rupture de varice chez le cirrhotique I'@re de la scl@rose endoscopique. Gastroenterol Clin Biol 1991; 15: Poynard T, Chaput JC, Mary JY, Scolaro M, Buffet C, Etienne JP. Analyse critique des facteurs li@s ~ la mortalit@ au trenti@me jour

7 1834 BERNARD ET AL. GASTROENTEROLOGY Vol. 108, No. 6 dans les h6morragie digestives hautes du cirrhotique. Gastroenterol Clin Biol 1980;4: Pagliaro L, D'Amico G, Malizia G, Tine F, Traina M, Vizzini G, Pasta L. Prognostic factors for short-term survival in variceal bleeding. In: Burroughs AK, ed. Methodology and reviews of clinical trials in portal hypertension. Amsterdam: Excerpta Medica/ Elsevier, 1987: Melchior JC, Poupon RE, Verrier J, Merrer J, Moncorge C, Simon N. Analyse des facteurs li6s ~ la mortalit6 pr6coce au cours des h~morragies digestives dues ~ I'hypertension portaie. Gastroenterol Clin Biol 1987; 11: Garden O J, Motyl H, Gilmour WH, Utley R J, Carter DC. Prediction of outcome following acute variceal haemorrhage. Br J Surg 1985; 72: Prindiville T, Miller M, Trudeau W. Prognostic indicators in acute variceal hemorrhage after treatment by sclerotherapy. Am J Gastroenterol 1987;82: Le Moine O, Adler M, Bourgeois N, Delhaye M, Devi~re J, Gelin M, Vandermeeren A, Van Gossum A, Vereerstraeten A, Vereerstraeten P, Cremer M. Factors related to early mortality in cirrhotic patients bleeding from varices and treated by urgent sclerotherapy. Gut 1992;33: Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA 1994;271: Hewett JA, Roth RA. Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 1993;45: Received September 1, Accepted February 22, Address requests for reprints to: Dominique Valla, M.D., Service d'h6patologie, H6pital Beaujon, 100 Boulevard du G6n~ral Leclerc, Clichy Cedex, France. Fax: (33)