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Dilutional Hyponatremia in Patients With Cirrhosis and Ascites
Almudena Porcel, MD;
Fernando Díaz, MD, PhD;
Paloma Rendón, MD;
Manuel Macías, MD;
Leopoldo Martín-Herrera, MD, PhD;
José A. Girón-González, MD, PhD
Arch Intern Med. 2002;162:323-328.
ABSTRACT
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Objectives To analyze the predisposing factors, modifications of vasoactive systems,
and prognosis of patients with cirrhosis and hyponatremia.
Patients and Methods Fifty-four patients with hyponatremia (serum sodium level of <130
mEq/L after 5 days of hyponatremic diet and no diuretic therapy). Twenty cirrhotic
patients served as controls. We measured plasma renin activity and levels
of plasma aldosterone, norepinephrine, and antidiuretic hormone. Follow-up
identified the development of hepatorenal syndrome and death.
Results A higher percentage of patients with hyponatremia had decreased liver
size, higher levels of plasma renin activity, and higher serum concentrations
of aldosterone and norepinephrine. Renal insufficiency was detected in 31
of them (57%). Precipitating factors (hemorrhage or infections) were detected
in 27 patients (50%). Incidence of hepatorenal syndrome and death were higher
in patients with spontaneous development of hyponatremia (n = 23 [85%] and
n = 25 [93%], respectively) than in patients with precipitating factors (n
= 15 [56%] and n = 12 [44%], respectively) and cirrhotic controls (n = 1 [5%]
and n = 5 [25%], respectively) (P<.001). Results
of multivariate analysis showed that Child-Pugh index, presence of hepatocarcinoma,
and serum concentration of urea were associated with mortality. After excluding
those patients with kidney failure at the time of admission, only Child-Pugh
index and norepinephrine concentrations were independent predictors of mortality.
Conclusions Hyponatremia is an alteration in patients with advanced liver disease.
Although survival is significantly reduced in patients with spontaneous development
of hyponatremia, a reduced sodium concentration cannot be considered as a
independent predictor of the risk for death.
INTRODUCTION
AN ACTIVATION of the renin-angiotensin-aldosterone system and the sympathetic
nervous system and a nonosmotic release of vasopressin frequently develop
in patients with cirrhosis. This sequence of events results in enhanced renal
water and sodium retention, ascites, impaired free-water excretion, and, frequently,
hepatorenal syndrome.1-2 Hepatorenal
syndrome is characterized by a marked reduction in renal blood flow and glomerular
filtration rate in the absence of histological abnormalities in the kidney
and other known causes of renal failure. It is associated with an extremely
short survival.3 Decreased liver size, increased
plasma renin activity (PRA), and dilutional hyponatremia have been considered
predictors of hepatorenal syndrome in these patients.3-4
Precipitating factors of hepatorenal syndrome have been described, eg, gastrointestinal
tract hemorrhage or bacterial infections.4-5
Dilutional hyponatremia is considered to be the consequence of a higher
rate of renal retention of water in relation to sodium, due to a decrease
in free-water clearance.6 Although accepted
as an intermediate event in the sequence that leads to hepatorenal syndrome,
the incidence of hyponatremia in patients with cirrhosis has received little
attention.7 Clinical or analytical data that
could predict the development of hyponatremia and the course of patients with
cirrhosis and hyponatremia are also unknown or only poorly analyzed in short
series of cases.7-10
The present prospective study reports the results of a follow-up analysis
in a series of cirrhotic patients with ascites. We investigated the incidence,
predictive factors, and prognosis of dilutional hyponatremia in these patients.
PATIENTS AND METHODS
SAMPLE SIZE
To determine the sample size, we assumed a confidence level of 95%,
with a power of 80%. We predicted a finding of 30% hyponatremia in the cirrhotic
patients we attended, on the basis of previous data.3, 6-7
Because the percentage of patients with precipitating factors of hepatorenal
syndrome approached 50%,3 we predicted that
half of the patients with hyponatremia had precipitating factors and that
the other half were patients with spontaneously developed hyponatremia. Thus,
the ratio of cirrhotic patients with hyponatremia to patients without hyponatremia
was 1:2. A minimum of 20 cirrhotic control subjects and 40 cirrhotic patients
with hyponatremia (20 with hyponatremia preceded by precipitating factors
and 20 with spontaneously developed hyponatremia) were therefore needed.
STUDY POPULATION
During a 6-month period, 155 patients were hospitalized for different
complications of the cirrhosis of liver and ascites at the Digestive Diseases
Unit of the Hospital Universitario Puerta del Mar, Cádiz, Spain. Fifty-four
of them presented with dilutional hyponatremia, whereas the sodium concentration
was within reference range in the remainder (n = 101). Those patients with
dilutional hyponatremia constituted our study population.
Dilutional hyponatremia was defined as a serum sodium level of lower
than 130 mEq/L after 5 days of a diet containing 50 mEq/d of sodium, restricted
water ingestion (<500 mL/d), and no diuretic therapy.5
Other known causes of hyponatremia (ie, digestive losses, salt-losing nephropathy,
Addison disease, osmotic diuresis, postobstructive renal insufficiency, congestive
heart failure, nephrotic syndrome, inappropriate antidiuretic hormone [ADH]
secretion secondary to neoplasms, hypothyroidism, pulmonary diseases, or central
nervous system diseases) were excluded by clinical and/or analytical methods.11 Primary causes of admission of these patients were
digestive hemorrhage due to hypertensive gastropathy (n = 4 [7%]) or esophageal
varices (n = 6 [11%]); ascites (n = 8 [15%]); pleural effusion (n = 2 [4%]);
hepatorenal syndrome (n = 4 [7%]); hepatic encephalopathy (n = 11 [20%]);
infectious diseases, including spontaneous bacterial peritonitis, primary
bacteremia, and pneumonia (n = 16 [30%]); and hepatocarcinoma (n = 3 [6%]).
Apart from these primary causes of admission, all patients with hyponatremia
presented with ascites.
Twenty consecutive patients with cirrhosis and ascites were randomly
selected as controls. Primary causes of admission of controls were digestive
hemorrhage due to hypertensive gastropathy (n = 3 [15%]) or esophageal varices
(n = 6 [30%]); ascites (n = 7 [35%]); infectious diseases, including spontaneous
bacterial peritonitis and pneumonia (n = 3 [15%]); and hepatocarcinoma (n
= 1 [5%]). Characteristics of the study population are shown in Table 1.
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Table 1. General Characteristics of the Study Population*
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Informed consent was obtained from each patient, and the study was approved
by the Research and Ethics Committee of the hospital.
STUDY SCHEDULE AND MEASUREMENTS
After admission, a detailed history was obtained, and a physical examination
was performed. Diuretic therapy was withdrawn in patients and controls. The
causes of admission were initially treated only if they acutely compromised
the liver (eg, digestive hemorrhage, liver encephalopathy and infections).
After hemodynamic stabilization, patients were prescribed a diet that included
sodium ingestion of 50 mEq/d and restricted water ingestion (<500 mL/d).12 On day 5, a 24-hour urine sample was collected to
measure electrolyte concentration. On day 6, after overnight fasting, an antecubital
vein was catheterized. Blood samples were obtained to measure serum levels
of electrolytes, urea, and creatinine and to perform standard liver function
tests. After 2 hours of bed rest, blood pressure was measured, and blood samples
were collected in iced tubes containing EDTA and sodium azide. After centrifugation
at 4°C, the plasma was immediately frozen at -30°C until assay
for PRA and concentrations of plasma aldosterone (PAC), ADH, and norepinephrine
(NE) using commercially available kits. Plasma renin activity was determined
by means of radioimmunoassay (Clinical Assays; Baxter, Cambridge, Mass) of
generated angiotensin I after 30 minutes of incubation at a pH of 7.4 and
37°C, under conditions to inhibit further conversion of angiotensin I
(reference range, 400-2300 pg/mL per hour [308.8-1775.6 pmol/L per hour]).
We measured levels of PAC (Aldoctk-2-P2714; Sorin Biomedica Diagnostics, Barcelona,
Spain; reference range, 3.5-15.0 ng/dL [0.08-0.42 nmol/L]), ADH (Bühlman
Laboratories, Basel, Switzerland; reference range, <1 pg/mL [<0.9 pmol/L]),
and NE (IBL Laboratories, Hamburg, Germany; reference range, 150-370 pg/mL
[0.9-2.2 nmol/L]) by means of radioimmunoassay. Methods used for these investigations
have been described in detail elsewhere.9, 13-14
On day 6, time-motion, 2-dimensional, and Doppler abdominal ultrasonographic
examinations were performed using an ultrasonoscope (Hitachi EUB-525; Hitachi
Medical Corp, Tokyo, Japan) with 2.5- and 3.5-MHz transducers. Liver size,
determined by means of ultrasonography, was considered to be normal if the
longitudinal diameter of the right liver lobule was 10 to 15 cm. The resistive
index of the renal arteries was calculated by the analysis of Doppler signals
obtained from arcuate arteries at the corticomedullary junction of the left
kidney. The resistive index is defined by the following ratio15:
Only 2 trained observers (P.R. and M.M.) performed the ultrasonographic
studies, to avoid interobserver variations. Three individual sets of measurements
were obtained from each ultrasonographic study, and the results were averaged.
The discrepancy between measurements was less than 10% in every case.
Precipitating factors of hyponatremia were considered when a complication
of cirrhosis of liver, usually a complication of portal hypertension, was
chronologically related to hyponatremia.
Renal failure at the time of enrollment was diagnosed when the serum
creatinine level was greater than 1.5 mg/dL (>132.6 µmol/L). Hepatorenal
syndrome was defined as a nonreversible deterioration of renal function using
the following criteria: (1) In patients without renal failure at enrollment,
hepatorenal failure was diagnosed when the serum urea or serum creatinine
level increased by more than 50% to higher than 30 mg/dL (10.7 mmol/L) or
1.5 mg/dL (132.6 µmol/L), respectively. (2) In patients with preexisting
renal failure, an increase in the serum urea or serum creatinine level by
more than 50% from baseline was required for a diagnosis of hepatorenal failure.16
The mean (SD) follow-up of patients with and without hyponatremia was
similar (patients with hyponatremia, 141 ± 101 days [range, 5-330 days];
cirrhotic controls, 161 ± 107 days [range, 4-300 days]). Seventeen
patients with hyponatremia (31%) and 2 cirrhotic controls (10%) died during
their first hospitalization (P = .11). The remaining
patients were followed up closely throughout the illness by staff members
of the unit. All patients were asked to attend the outpatient clinic at regular,
2-month intervals. Plasma and urine electrolyte levels were measured, and
liver and standard renal function tests were performed at clinic visits or
whenever a complication occurred.
STATISTICAL ANALYSIS
Unless otherwise indicated, data are presented as mean ± SD.
The data from 2 independent groups were compared using the Mann-Whitney test.
The significance of variables within each group were tested by means of the
Wilcoxon matched-pairs signed rank test. For qualitative variables,  2 with Yates correction or Fisher exact test was used. A P value of less than .05 was considered significant.
The cumulative probability of survival after admission was calculated
using the Kaplan-Meier method. Curves were statistically compared using the
Mantel-Cox test. The relation of hyponatremia to hepatorenal syndrome or mortality
was assessed, and the odds ratios (ORs) with 95% confidence intervals (CIs)
were determined. Multivariate analysis was performed via stepwise logistic
regression, using mortality as the dependent variable.
RESULTS
CHARACTERISTICS OF PATIENTS WITH HYPONATREMIA
Forty-four of 155 consecutive patients presented with dilutional hyponatremia
(34.8%) after stabilization of acute causes of admission. We detected no differences
between patients with hyponatremia and controls in the percentages of patients
previously treated with diuretics or in the doses of diuretics they received.
Among the patients with hyponatremia, 13 (24%) received spironolactone alone
and 21 (39%), with furosemide, compared with 2 (10%) and 8 (40%), respectively,
of 20 cirrhotic controls. The mean dosage of spironolactone was 146 ±
66 mg/d for patients vs 124 ± 15 mg/d for controls. Mean dosage of
spironolactone plus furosemide was 157 ± 53 plus 39 ± 15 mg/d,
respectively, for patients vs 150 ± 84 plus 38 ± 10 mg/d, respectively,
for controls. Patients with hyponatremia presented with a significantly higher
prevalence of ascites before the onset of the study, higher serum concentrations
of urea, and a higher prevalence of decreased liver size. The causes of the
cirrhosis and serum and urine concentrations of potassium were similar in
patients and controls (Table 1).
The following precipitating factors were detected in 27 patients (50%
of all patients with hyponatremia): infection in 17 patients (spontaneous
bacterial peritonitis in 8, pneumonia in 5, and primary bacteremia in 4);
digestive hemorrhage in 9 patients (variceal hemorrhage in 5 and hypertensive
gastropathy in 4); and pneumonia plus hemorrhage due to hypertensive gastropathy
in 1 patient. Twelve (44%) of these patients died as a result of the precipitating
factors (infection in 7 patients, digestive hemorrhage in 4 patients, and
infection and hemorrhage in 1 patient). Serum sodium concentrations returned
to the reference range in the remaining 15 patients, who survived the precipitating
factors. Hyponatremia persisted in the 27 patients in whom it developed spontaneously,
in the absence of precipitating factors.
Significantly higher PRA and PAC levels were detected in patients with
hyponatremia with or without precipitating factors, compared with controls.
In patients with hyponatremia without precipitating factors, significantly
higher concentrations of plasma NE were detected than in controls. Plasma
values of ADH were similar in all 3 groups (Table 2). The more enhanced concentrations of these hormones were
detected in patients with renal insufficiency (data not shown).
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Table 2. Plasma Renin Activity and Serum Concentrations of Aldosterone
and Norepinephrine in the Study Population
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Because renal failure could modify the results, a comparative analysis
of patients without kidney failure and controls was performed. Excluding those
patients with renal insufficiency present at the time of admission, differential
characteristics between hyponatremic (n = 23) and nonhyponatremic (n = 13)
subjects were maintained. Previous ascites was present in 20 patients (87%)
vs 7 controls (54%) (P<.05). In a comparison of
patients and controls, serum urea levels were 39 ± 11 vs 29 ±
11 mg/dL (P<.01); serum sodium levels, 123.7 ±
3.8 vs 135.8 ± 3.7 mEq/L (P<.001); urinary
sodium levels, 5 ± 3 vs 54 ± 47 mEq/24 hours (P<.01); PRA, 11 000 ± 5200 vs 4700 ± 5700 pg/mL
per hour (260.7 ± 123.2 vs 111.4 ± 135.1 pmol/L per hour) (P<.05); PAC levels, 86.5 ± 22.0 vs 28.7 ±
34.5 ng/dL (2.3 ± 0.6 vs 0.8 ± 0.9 nmol/L) (P<.001); and renal resistive index, 0.67 ± 0.24 vs 0.63 ±
0.20 (P = .03).
FOLLOW-UP
Hepatorenal syndrome developed in 1 cirrhotic control (5%), 15 patients
with hyponatremia with precipitating factors (56%) (OR, 23.75 [95% CI, 2.76-1050.91]; P<.001 vs cirrhotic controls), and 23 patients with
hyponatremia without precipitating factors (85%) (OR, 109.25 [95% CI, 10.10-4723.50]; P<.001 vs cirrhotic controls; and OR, 4.60 [95% CI,
1.09-22.70]; P<.05 vs patients with precipitating
factors). The cirrhotic control in whom hepatorenal syndrome developed presented
with a serum sodium level of 130 mEq/L at the time of inclusion in the study.
Hepatorenal syndrome did not develop in any patient with a serum sodium of
greater than 130 mEq/L.
Death occurred in 5 cirrhotic controls (25%), 12 patients with a precipitating
factor (44%) (OR, 2.40 [95% CI, 0.59-10.78]; P>.05
vs cirrhotic controls), and 25 patients without a precipitating factor (93%)
(OR, 37.50 [95% CI, 5.44-389.54]; P<.001 vs cirrhotic
controls; and OR, 15.63 [95% CI, 2.77-153.72]; P<.001
vs patients with precipitating factors). Survival curves of these groups are
presented in Figure 1.
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Survival of cirrhotic patients without hyponatremia (cirrhotic controls)
and cirrhotic patients with hyponatremia, without and with precipitating factors.
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Differential characteristics between patients who died and survivors
are presented in Table 3. A multivariate
analysis of factors potentially associated with mortality showed that the
Child-Pugh index, presence of hepatocarcinoma, and serum concentration of
urea were associated with mortality, whereas the levels of serum or urine
sodium and vasoactive hormones were not (Table 4). After excluding those patients with kidney failure at
the time of admission, only the Child-Pugh index and NE concentrations were
independent predictors of mortality (Table
4).
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Table 3. Differential Characteristics of Cirrhotic Patients Grouped
in Function of Their Mortality*
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Table 4. Multivariate Analysis of Variables Implicated in Mortality
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COMMENT
Our work has analyzed the incidence, associated findings, and prognosis
of dilutional hyponatremia in cirrhotic patients with ascites. One third of
patients hospitalized for complications of cirrhosis present with hyponatremia.3, 6-7 However, the percentage
of cirrhotic patients admitted to a hospital with hyponatremia is dependent
on the admission criteria.
Several characteristics were demonstrated in our patients with hyponatremia.
First, hyponatremia occurs predominantly in patients with a reduced liver
size. The predictive value of a decreased liver size with reference to the
hepatorenal syndrome or to survival has previously been demonstrated.3, 17 Second, most of our patients with
hyponatremia had previously presented with ascites. Third, blood pressure
was significantly decreased, and PRA, concentrations of PAC and NE, and renal
resistance index were significantly elevated in our patients with hyponatremia,
with values approaching those detected in patients with functional renal insufficiency.3 These findings could be the consequence of an arterial
vascular underfilling secondary to peripheral arterial vasodilation (spontaneous
or after bacterial infection)4 or to hypovolemia
due to hemorrhage. Hyponatremia appeared in the patients with renal insufficiency
(31 patients [57%]) or with normal renal function (23 patients [44%]). The
Child-Pugh index (when all hyponatremic patients were considered) and causes
of cirrhosis were similar in our patients with or without hyponatremia.
Hyponatremia is assumed to be a consequence of an impaired free-water
secretion, and nonosmotic secretion of ADH has been considered to play a pathogenic
role.1-2,6 Although
significantly higher PRA and concentrations of PAC and NE were detected in
our patients with hyponatremia, plasma levels of ADH were similar in our hyponatremic
patients and nonhyponatremic controls. Plasma ADH concentrations in patients
with cirrhosis have been reported to vary from the reference range to increased
concentrations and have not been consistently elevated.8-9,18-20
This variation has been attributed to measurement methods,8
to episodic secretion of ADH,20-21
and to prolonged ADH half-life.9 Likewise,
ADH concentrations did not correlate with serum sodium levels.8
The existence of other putative mechanisms implicated in impaired free-water
excretion (eg, prostaglandins and atrial natriuretic peptide) might also be
considered.10, 22
In half of our patients, hyponatremia followed a complication (gastrointestinal
tract bleeding or bacterial infection) that could have precipitated activation
of the vasoactive systems.4 The recovery of
normal levels of natremia was detected in every patient who survived those
precipitating events.
Spontaneously developed hyponatremia affected our patients with advanced
liver cirrhosis. The Child-Pugh index and systolic and diastolic blood pressure
of these patients were significantly higher compared with those of patients
with hyponatremia induced by precipitating factors. However, analyzed plasma
concentrations of vasoactive hormones were similar in patients with spontaneous
hyponatremia and in those with hyponatremia induced by precipitating factors.
No patient with spontaneous development of hyponatremia had a serum sodium
concentration within the reference range.
This study has analyzed the possible role of hyponatremia as a prognostic
factor in these patients. Although the survival of patients with hyponatremia
induced by precipitating factors was similar to that of cirrhotic patients
without hyponatremia, the survival of patients with spontaneously developed
hyponatremia was significantly lower. The median survival after the diagnosis
of spontaneous hyponatremia was 111 days. Most of these patients (23 [85%])
died owing to hepatorenal syndrome.
However, multivariate analysis showed that the Child-Pugh index, presence
of hepatocellular carcinoma, and serum levels of urea were associated with
mortality, whereas serum sodium level was not. In cirrhotic patients without
renal insufficiency, a decreased liver size, increased PRA, and dilutional
hyponatremia have been considered predictors of hepatorenal syndrome and mortality.3-4 However, the presence of kidney failure
and/or hepatocarcinoma significantly shortens the survival of cirrhotic patients,3, 23-24 thus minimizing the
possible role of hyponatremia as a prognostic factor. The survival of our
patients with spontaneous hyponatremia was intermediate, between that of patients
with hepatorenal failure and that of cirrhotic patients with ascites and no
hyponatremia.3, 23 Moreover, after
excluding patients with renal failure, only the Child-Pugh index and NE concentration
were independent predictors of the risk for death. These variables have been
shown to be useful in the assessment of prognosis in cirrhotic patients.3, 23, 25
CONCLUSIONS
Hyponatremia is an analytical alteration in patients with reduced liver
function and activation of hemodynamic mechanisms. Survival is significantly
reduced in patients with spontaneous development of hyponatremia. However,
a reduced sodium concentration is not an independent predictor of the risk
for death.
AUTHOR INFORMATION
Accepted for publication April 19, 2001.
This study was supported by grant FIS 99/1323 from Fondo de Investigación
Sanitaria, Ministerio de Sanidad, Consumo, Madrid.
Corresponding author and reprints: José A. Girón-González,
MD, PhD, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar,
c/Ana de Viya 21, 11009, Cádiz, Spain (e-mail: joseantonio.giron{at}uca.es).
From the Servicio de Aparato Digestivo (Drs Porcel, Díaz, Rendón,
Macías, and Martín-Herrera) and the Servicio de Medicina Interna
(Dr Girón-González), Hospital Universitario Puerta del Mar,
Cádiz, Spain.
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