THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Ascites and Spontaneous Bacterial
Peritonitis in Fulminant Hepatic Failure
Radha K. Dhiman, M.D., Govind K. Makharia, M.D., Sanjay Jain, M.D., and Yogesh Chawla, M.D.
Departments of Hepatology and Internal Medicine, Postgraduate Institute of Medical Education and
Research, Chandigarh, India
OBJECTIVE: Although presence of ascites has been reported
in patients with fulminant hepatic failure (FHF), spontane-
ous bacterial peritonitis (SBP) has not been studied in a
large group of such patients. Hence, the present study was
conducted to evaluate the prevalence and prognostic signif-
icance of ascites and SBP in FHF patients.
METHODS: Two hundred ninety-eight consecutive patients
(mean age 32.9 ⫾ 14.8 yr) with FHF were studied. There
were 133 (44.6%) men and 165 (55.4%) women. Acute viral
hepatitis accounted for 91.6% of the patients and were
analyzed in the present study.
RESULTS: Ascites was clinically detected in 79 (28.9%)
patients. The patients with ascites were older (p ⫽ 0.005),
had longer jaundice– encephalopathy interval (p ⬍
0.0000001), lesser grade of encephalopathy on admission
(p ⫽ 0.0000043), and a lower incidence of raised intracra-
nial pressure on admission (p ⫽ 0.0007). Patients with
ascites had significantly lower serum albumin (p ⫽ 0.021),
ALT (p ⫽ 0.0005), AST (p ⫽ 0.00017), and PT (p ⫽ 0.002)
on admission than in patients without ascites. Multivariate
logistic regression analysis showed that jaundice– encepha-
lopathy interval (ⱖ14 days) and serum albumin (ⱕ2.5 g/dl)
were the only independent predictors of ascites. SBP was
detected in 14 (17.7%) patients (neutrocytic culture positive,
4; neutrocytic culture negative, 9; and monomicrobial
bacterascites, 1). Escherichia coli was identified in three
patients. Survival was no different between patients with
and those without ascites and also between patients with and
those without SBP.
CONCLUSIONS: Ascites is a frequent accompaniment of
FHF and is complicated by SBP. Jaundice– encephalopathy
interval of 14 days or more and serum albumin (ⱕ2.5 g/dl)
on admission predicts the development of ascites in these
patients. (Am J Gastroenterol 2000;95:233–238. © 2000 by
Am. Coll. of Gastroenterology)
INTRODUCTION
Although ascites is an important feature of decompensated
chronic liver disease, it has been reported infrequently in
patients with severe acute hepatitis (1, 2). Portal hyperten-
sion has been implicated in the pathogenesis of ascites both
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00750-9
in cirrhosis of the liver as well as in fulminant hepatic failure
(FHF) (2– 4). Spontaneous bacterial peritonitis (SBP) is a
well-recognized complication of ascites in cirrhotic patients.
Recent prospective studies have shown the prevalence of
SBP in cirrhotic ascites as 15% to 25% (5– 8). SBP has also
rarely been reported in patients with FHF with ascites (9,
10). Recently, Chu et al. (1) reported SBP in 31.7% of
patients with severe acute hepatitis and ascites. However,
the majority of patients in this series had underlying chronic
liver disease. There is no large study in the literature on the
occurrence of ascites and SBP in FHF and its prognostic
significance. The current study was performed to evaluate
the prevalence and prognostic significance of ascites and
SBP in patients with FHF due to acute viral hepatitis.
MATERIALS AND METHODS
For the purpose of this study, acute liver failure or FHF was
defined according to the criteria of O’Grady et al. (11), that
is, onset of hepatic encephalopathy occurring within 12 wk
of onset of jaundice and further subclassified depending on
the interval between the onset of jaundice and the onset of
encephalopathy into hyperacute (HALF; interval 0 –7 days),
acute (ALF; interval 8 –28 days), and subacute liver failure
(SALF; interval 29 days to 12 wk) (11, 12). A viral etiology
was presumed when a history of exposure to drugs or toxins
was absent. A typical prodromal illness was present in the
majority of patients. Patients with a history of intake of
hepatotoxic drugs and absence of viral markers were diag-
nosed as having drug-induced FHF. Patients who consumed
⬎50 g/day of alcohol for 5 yr and those with evidence of
chronic liver disease based on clinical, biochemical, or on
abdominal ultrasound examination or at autopsy were ex-
cluded. Standard criteria were used for the diagnosis of
Wilson’s disease (13), whereas the diagnosis of malignant
infiltration of liver leading to FHF was confirmed at au-
topsy.
Two hundred ninety-eight consecutive patients with FHF
were studied. There were 133 (44.6%) men and 165 (55.4%)
women. The mean age was 32.9 ⫾ 14.8 yr (range 12– 82 yr).
Acute viral hepatitis accounted for 91.6% of the patients. All
22 (7.2%) patients with drug-induced hepatitis and FHF
were related to antitubercular regimens containing rifampi-
234 Dhiman et al. AJG – Vol. 95, No. 1, 2000

Table 1. Etiology of 298 Patients With Fulminant Hepatic
Failure
Viral hepatitis
Drug induced
Acute Budd-Chiari syndrome
Wilson’s disease
Malignant infiltration
cin and isoniazid (Table 1). To study a homogenous group,
only 273 (91.6%) patients with FHF complicating viral
hepatitis were analyzed (Tables 1 and 2). Hepatitis B virus
was implicated in 47% of patients. There were 181 (66.3%)
patients with HALF, 71 (26%) with ALF, and 21 (7.7%)
with SALF.
The grade of encephalopathy at the time of admission and
the peak grade during hospitalization were noted (14). The
diagnosis of increased intracranial pressure was based on
presence of bradycardia, hypertension (⬎150/90 mm Hg),
increased muscle tone, unequal or abnormally reacting pu-
pils, neurogenic hyperventilation, myoclonus, and sponta-
neous decerebrate posturing (15, 16). The clinical diagnosis
of ascites was made by the presence of shifting dullness of
fluid in abdomen or by the presence of fluid thrill. Ultra-
sound examination of the abdomen was performed in 87
patients when clinical signs for ascites were ambiguous or
where there was a suspicion of underlying chronic liver
disease. Abdominal paracentesis was performed if any ev-
idence of peritonitis, such as fever, peripheral leukocytosis,
or ileus, developed. The diagnosis of SBP was based on the
presence of ascitic fluid PMN count ⱖ250/mm3 (17). Cul-
ture-negative neutrocytic ascites (CNNA) was defined as
ascitic fluid infection in which the PMN count was 250/mm3
or more, with no growth of ascitic fluid culture (17–20).
273 (91.6%) Monomicrobial bacterascites was diagnosed if the PMN
22 (7.4%) count was ⬍250/mm3 and ascitic fluid culture was positive
1 (0.33%) for a single organism (17, 21). Ascitic fluid culture was
1 (0.33%)
1 (0.33%) performed by inoculation of a blood culture bottles with 10
ml of ascitic fluid at bedside. Ascitic fluid protein level and
white cell counts were noted. Renal failure was defined as a
daily urine amount of ⬍300 ml and serum creatinine of
⬎3.4 mg/dl (300 ␮mol/L) in the absence of hypovolemia
(22). The other laboratory parameters studied on admission
were white blood cell count, PT, serum bilirubin, ALT,
AST, albumin, and creatinine.
All patients were given standard supportive treatment (12,
23). In all patients, hepatic encephalopathy was managed
with a standard protocol of no protein by mouth, oral anti-
biotic (1 g of ampicillin every 6 h) (24) and lactulose either
orally or by retention enema. Cerebral edema was managed
by parenteral mannitol (20%) and, when appropriate, hy-
perventilation. Fresh frozen plasma was infused for bleeding
manifestations as and when required. Appropriate antibiot-
ics were given for sepsis. Fluids and electrolytes were main-
tained throughout the illness. SBP was treated with intrave-
nous cefotaxime or ciprofloxacin for 10 days.
Statistical Analysis
The results are given as mean ⫾ SD. The data were analyzed
using the Mann-Whitney U test or Fisher’s exact test as
appropriate. A p value ⬍ 0.05 was taken as significant.
Variables found significant were then dichotomized for best
discrimination between the FHF patient with ascites and

Table 2. Clinical and Laboratory Data of Patients With FHF With Ascites and Those Without Ascites
Parameters FHF With Ascites FHF Without Ascites p Value
Number 79 (28.9%) 194 (71.1%)
Age (yr) 36.7 ⫾ 17.0 30.6 ⫾ 13.5 0.005
Sex (M:F) 32:47 92:102 NS
Grade of encephalopathy
1&2
3&4
Jaundice–encephalopathy
31 (39.2%)
48 (60.8%)
16.8 ⫾ 18.6
26 (13.4%)
168 (86.6%)
5.7 ⫾ 6.9
} 0.0000043

⬍0.0000001
interval (days)
Raised intracranial pressure 20 (25.3%) 94 (48.5%) 0.0007
Gastrointestinal bleed 28 (35.4%) 63 (32.5%) NS
Type of liver failure
Hyperacute
Acute
Subacute
Survival
35 (44.3%)
26 (32.9%)
18 (22.8%)
22 (27.8%)
146 (75.3%)
45 (23.2%)
3 (1.5%)
68 (35.1%)
} 0.0000001

NS
Bilirubin (mg/dl) 19.0 ⫾ 11.0 16.7 ⫾ 10.6 NS
ALT (IU/L) 69.2 ⫾ 34.3 99.2 ⫾ 80.5 0.0005
AST (IU/L) 68.3 ⫾ 37.6 102.6 ⫾ 91.5 0.00017
Albumin (g/dl) 2.8 ⫾ 0.5 3.0 ⫾ 0.6 0.021
Prothrombin time (s) 38.7 ⫾ 24.4 47.8 ⫾ 29.0 0.002
Creatinine (mg/dl)
Mean 1.93 ⫾ 2.21 1.68 ⫾ 1.50 NS
ⱖ3.5 9 (11.4%) 15 (7.7%) NS
White blood cells (⬍4,000 or ⬎18,000/mm3) 24 (30.4%) 55 (28.4%) NS
Bilirubin, normal 0.6 –1.0 mg/dl; ALT, normal 2–15 IU/L; AST, normal 2–20 IU/L; albumin, normal 3.5–.5 g/dl; prothrombin time, control 12 s; creatinine, normal 0.6 –1.4 mg/dl.
AJG – January, 2000 Ascites and SBP in Fulminant Hepatic Failure 235

those without ascites by the construction of receiver-oper- Table 3. Multiple Logistic Regression Analysis
ating characteristic curves (25, 26). To identify independent Regression
predictors of ascites, we used multivariate analysis, logistic Factors on Admission Coefficient t p Value
regression technique (12, 27). Jaundice–encephalopathy interval 1.608 4.13 ⬍0.001
(ⱖ14 days)*
Albumin (ⱕ2.5 g/dl)† 0.744 2.4 0.025
RESULTS Grade 1 or 2 encephalopathy‡ 0.720 1.85 NS
ALT (⬍60 IU/L)§ 0.703 1.76 NS
Ascites was clinically detected in 79 (28.9%) patients.
AST (⬍80 IU/L)㛳 0.484 1.33 NS
These patients were older than those without clinically de- Absence of raised intracranial 0.388 1.08 NS
tectable ascites (36.7 ⫾ 17.0 vs 30.6 ⫾ 13.5 yr, p ⫽ 0.005). pressure**
Patients with ascites had a significantly longer interval be- Prothrombin time (ⱕ40 s)†† 0.311 0.86 NS
tween onset of jaundice and onset of encephalopathy (p ⬍ Age (⬎40 yr)‡‡ 0.257 0.66 NS
0.0000001). They also had a lesser grade of encephalopathy Constant 0.821
on admission (p ⫽ 0.0000043) and lower incidence of raised * If jaundice– encephalopathy interval is ⱖ14 days, value is 1, otherwise it is 0; † if
serum albumin level is ⱕ2.5 g/dl, value is 1, otherwise it is 0; ‡ if grade of
intracranial pressure on admission (p ⫽ 0.0007), suggesting encephalopathy is ⱕ2, value is 1, otherwise it is 0; § if ALT is ⬍60 IU/L, value is 1,
a less stormy course and longer duration of illness. Ascites otherwise it is 0; 㛳 if AST is ⬍80 IU/L, value is 1, otherwise it is 0; ** if raised
intracranial pressure is absent, value is 1, otherwise it is 0; †† if prothrombin time is
was significantly more common in patients with SALF (18 ⱕ40 s, value is 1, otherwise it is 0; ‡‡ if age is ⬎40 yr, value is 1, otherwise it is 0.
of 21 patients, 85.7%), than in patients in ALF (26 of 71
patients, 36.6%) and HALF (35 of 181 patients, 19.3%) significant difference between patients with and those with-
(p ⬍ 0.0000001). Although 22.8% of patients with clinically out SBP, except the serum albumin was significantly lower
detectable ascites had SALF, only 1.5% of patients without (p ⫽ 0.017) and number of patients with white blood cell
ascites had SALF (Table 2). Patients with ascites had sig- counts of ⬍4,000 or ⬎18,000/mm3 were significantly
nificantly lower serum albumin (p ⫽ 0.021), ALT (p ⫽ higher (p ⫽ 0.016) in patients with SBP (Table 5).
0.0005), AST (p ⫽ 0.00017), and prothrombin time (p ⫽ A total of 24 (8.8%) patients had renal failure. The
0.002) on admission than in patients without ascites (Table prevalence of renal failure on admission was not higher in
2). patients with ascites or in patients with SBP (Tables 2 and
Variables found significant on univariate analysis were 5). The incidence of GI bleeding was not significantly dif-
then dichotomized for best discrimination between FHF ferent in patients with or without ascites and those with and
patients with ascites and those without ascites by constrict- without SBP (Tables 2 and 5).
ing receiver-operating characteristic curves. The best cut-off Ninety of 273 (33%) patients with FHF because of viral
level for age was ⬎40 yr, grade of encephalopathy ⱕ2, hepatitis survived. Seventy-three (40.3%) patients with
jaundice– encephalopathy interval ⱖ14 days, ALT ⬍60 IU, HALF survived as compared to 13 (18.3%) with ALF and
AST ⬍80 IU, albumin ⱕ2.5 g/dl, and prothrombin time four (19.0%) with SALF, and the difference was statistically
ⱕ40 s. Multivariate analysis, with logistic regression tech- significant (p ⫽ 0.0014). However, there was no significant
nique, was applied to the following factors found to be difference in survival between patients with and those with-
significant, on univariate analysis: age, grade of encepha- out ascites (27.8% vs 35.1%, p ⫽ not significant). Among
lopathy, jaundice– encephalopathy interval, presence of the patients with ascites, those without SBP did not have a
raised intracranial pressure, ALT, AST, albumin, and PT. higher survival (SBP 28.5% vs no SBP 27.7%, p ⫽ not
Jaundice– encephalopathy interval (ⱖ14 days) and serum significant).
albumin (ⱕ2.5 g/dl) were found to be the only independent
predictors of development of ascites (Table 3). DISCUSSION
A total of 14 (17.7%) patients proved to have SBP (cul-
ture positive 4, CNNA 9, and monomicrobial bacterascites Ascites, although regarded as an infrequent feature in FHF
1). A total of five microorganisms were isolated from ascitic (1, 2), in the present study it was detected in 79 (28.9%) of
fluid in these patients, including one patient with normal Table 4. Characteristics of Ascitic Fluid
ascitic polymorphonuclear leukocytes count (Table 4). All
episodes of SBP were spontaneous. Three of these 14 pa- SBP SBP
Present Absent
tients had evidence of aspiration pneumonia. There was no Parameters (n ⫽ 14) (n ⫽ 44)
evidence of clinical, ascitic fluid analysis, or radiological
Total proteins (g/dl) 0.79 ⫾ 0.39 1.05 ⫾ 0.88
data suggesting secondary peritonitis. The mean concentra- Polymorphonuclear leukocytes 1384 ⫾ 1977* 39 ⫾ 50*
tion of total proteins in ascitic fluid was not significantly counts (/mm3)
different between patients with and those without SBP. Microorganisms Escherichia coli (n ⫽ 3)†
Polymorphonuclear leukocytes count in ascites were signif- Staphylococcus
icantly higher in patients with than those without SBP (p ⬍ aureus (n ⫽ 1)
0.0000001) (Table 4). Enterobacter sp (n ⫽ 1)
The clinical and laboratory parameters did not show any * p ⬍ 0.0000001; † one patient had only bacterascites.
236 Dhiman et al. AJG – Vol. 95, No. 1, 2000

Table 5. Clinical and Laboratory Parameters of Patients With Ascites With SBP and Those Without SBP
Parameters SBP No SBP p Value
Number 14 65
Age (yr) 34.0 ⫾ 15.7 37.2 ⫾ 17.4 NS
Sex (M:F) 5:9 27:38 NS
Grade of encephalopathy
1&2 8 (57.1%) 23 (35.4%) NS
3&4 6 (42.9%) 42 (64.6%)
Jaundice–encephalopathy interval (days) 23.722.9 15.417.4 NS
Increased intracranial pressure 3 (21.4%) 17 (26.1%) NS
Gastrointestinal bleed 6 (42.9%) 22 (33.8%) NS
Survival 4 (28.5%) 18 (27.7%) NS
Bilirubin (mg/dl) 22.5 ⫾ 13.3 18.2 ⫾ 10.5 NS
ALT (IU/L) 61.4 ⫾ 29.5 70.9 ⫾ 35.3 NS
AST (IU/L) 75.7 ⫾ 43.0 66.6 ⫾ 36.5 NS
Albumin (g/dl) 2.4 ⫾ 0.6 2.8 ⫾ 0.5 0.017
Prothrombin time (s) 28.1 ⫾ 7.2 39.8 ⫾ 26.4 NS
Creatinine (mg/dl)
Mean 1.94 ⫾ 2.39 1.86 ⫾ 1.13 NS
ⱖ3.5 3 (21.4%) 6 (9.2%) NS
White blood cells (⬍4,000 or ⬎18,000/mm3) 8 (57.1%) 6 (24.6%) 0.016
Bilirubin, normal 0.6 –1.0 mg/dl; ALT, normal 2–15 IU/L; AST, normal 2–20 IU/L; albumin, normal 3.5–5.5 g/dl; prothrombin time, control 12 s; creatinine, normal 0.6 –1.4
mg/dl.

patients with FHF due to acute viral hepatitis. The patients
with ascites were older, had significantly longer jaundice–
encephalopathy interval, had lesser grade of encephalopa-
thy, and lower incidence of increased intracranial pressure.
ALT, AST, serum albumin, and PT on admission were also
significantly lower in patients with than in those without
ascites. Multivariate analysis identified jaundice– encepha-
lopathy interval (ⱖ14 days) and serum albumin (ⱕ2.5 g/dl)
as independent predictors of development of ascites. Of the
79 patients with ascites, 14 (17.7%) developed SBP during
admission. All the episodes of SBP were spontaneous.
Portal hypertension is a universal feature of FHF, and its
frequency is much higher in patients with than in those
without ascites (2, 3, 28). Portal hypertension seems to be a
complication of FHF, and not of acute hepatitis in general,
as it has been shown that portal venous pressure is either
normal or, in a few cases, slightly raised in benign viral
hepatitis (29 –31). Lebrec et al. (3) found that the gradient
between wedged and free hepatic venous pressure was in-
creased in all 10 patients with FHF and ascites was present
in seven (70%) of them. Valla et al. (2) suggested that
sinusoidal collapse due to liver cell dropout was a major
factor in the pathogenesis of portal hypertension in acute
hepatitis. They determined the fractional area of sinusoidal
collapse on chromotrope-stained sections and sirius red-
stained collagen fiber density in liver biopsies of patients of
acute hepatitis with ascites and observed that hepatic venous
pressure gradient significantly correlated with fractional si-
nusoidal collapse area and sirius red-stained collagen fiber
density. The hepatic venous pressure gradient was higher in
patients with than in patients without ascites. The ascites
was not detectable clinically when hepatic venous pressure
gradient was ⬍6 mm Hg (2).
Ascites in FHF is common as seen in our study. Recently,
Chu et al. (1) reported 82 patients with acute severe hepatitis
with ascites either de novo or acute decompensation of
underlying chronic liver disease. In another study ascites
was reported in 24 of 25 patients with FHF (28). In our
study, the patients of FHF with ascites had significantly
longer duration of onset of encephalopathy from the onset of
jaundice, suggesting longer duration of illness and had sig-
nificantly lower albumin levels (Table 3). The longer the
duration of liver cell failure, the higher will be the chance of
developing hypoalbuminemia (32). When data on the oc-
currence of ascites in different groups of patients according
to appearance of encephalopathy from the onset of jaundice
was analyzed, it was observed that ascites was significantly
more common in patients with SALF (85.7%) than in pa-
tients with ALF (36.6%) and HALF (19.3%). This may be
due to the presence of both increased hydrostatic pressure
(portal hypertension) (2, 3) and decreased oncotic pressure
(hypoalbuminemia) due to longer duration of liver failure.
Patients with FHF are at increased risk of infection be-
cause of broadly compromised immune function including
impaired neutrophil and Kupffer cell functions and defi-
ciency of opsonins (33, 34). SBP is a well-recognized com-
plication in cirrhotic patients with ascites (6, 8). SBP de-
velops as a result of translocation of bacteria from the gut
into the ascitic fluid, which is evidenced by frequent isola-
tion of gut-derived bacteria in SBP (6, 17). The high inci-
dence of SBP in end-stage cirrhosis results from a combi-
nation of factors such as failure of Kupffer cells from the
hepatic reticuloendothelial system to efficiently screen the
portal venous blood, shunting of portal venous blood
thereby bypassing the hepatic reticuloendothelial system
and low protein ascites with less opsonin and complement
activity, which favor bacterial proliferation (33–35). In the
present study SBP was present in 14 of 79 patients (17.7%)
AJG – January, 2000
with FHF and ascites. There are only a few reports of the
occurrence of SBP in FHF in the English literature (9, 10).
Thomas and Fromkes (9) in 1982 reported two patients with
SBP in FHF (9). In the other large series of 82 patients of
severe acute hepatitis with ascites, SBP was observed in 26
(31.7%) patients, but the limitation of study was that most of
the patients had underlying chronic liver disease (1). The
present study is the largest series of patients of FHF with
ascites and SBP.
SBP has been subclassified into culture-positive neutro-
cytic ascites, culture-negative neutrocytic ascites, and mo-
nomicrobial bacterascites (17, 19 –21). CNNA accounts for
nearly one-third of patients with ascites with SBP (17, 18).
However, most of our patients had CNNA. The reason for
culture negativity in the majority of our patients may be
explained because most of the patients received oral ampi-
cillin for hepatic encephalopathy as a protocol. GI bleeding
by mechanism of translocation of bacteria due to altered
mucosal permeability caused by bowel ischemia has been
implicated as an important predisposing factor for SBP in
patients with cirrhosis (17). However, there was no signif-
icant difference in GI bleeding in patients with or without
SBP in our patients.
There was no significant difference in survival between
patients with and those without SBP. Because the mortality
was high, the severity of liver disease appeared to be a major
determining factor in survival. Abdominal paracentesis was
performed only in those patients who had evidence of peri-
tonitis such as fever, peripheral leukocytosis, or ileus. In the
absence of surveillance paracentesis it is not possible to
know whether all episodes of SBP were detected. Perhaps
some were undetected and untreated. Therefore, prospective
studies with surveillance paracentesis in detecting and treat-
ing all episodes of SBP are required to answer the effect of
occurrence of SBP on the survival in these patients.
In conclusion, ascites is a frequent (28.9%) accompani-
ment of FHF and is complicated by SBP in 17.7% of those
patients who developed ascites. An occurrence of ascites is
more frequent in patients with longer duration of liver cell
failure, i.e., patients with SALF. A jaundice– encephalopa-
thy interval of ⱖ14 days and serum albumin (ⱕ2.5 g/dl) on
admission predicts the development of ascites.
ACKNOWLEDGMENT
We thank Dr. Anil Dhawan, system analyst, Postgraduate
Institute of Medical Education and Research, Chandigarh,
for his help with statistical analysis and Ashok Kumari for
secretarial help.
Reprint requests and correspondence: Yogesh Chawla, M.D.,
Department of Hepatology, Postgraduate Institute of Medical Ed-
ucation and Research, Chandigarh 160012, India.
Received Jan. 25, 1999; accepted Aug. 20, 1999.
Ascites and SBP in Fulminant Hepatic Failure 237
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