| | Randomized trial comparing human albumin and hydroxyethyl starch 6% as plasma expanders for treatment of patients with liver cirrhosis and tense ascites following large volume paracentesisReceived 11 December 2009; accepted 11 January 2010. published online 26 February 2010. Abstract Background and study aimsCirrhosis is the commonest cause of ascites accounting for almost 85% of all cases. Approximately 10% of patients with cirrhosis develop diuretic-resistant tense ascites that requires other therapeutic interventions. Large-volume paracentesis with plasma expander infusion, mainly albumin, has been used for the management of ascites in cirrhotic patients. We aimed at investigating whether human albumin can be substituted by a less expensive plasma expander, hydroxyethyl starch 6% following paracentesis. Patients and methodsOne-hundred and thirty-five patients (60% with cirrhosis and schistosomal periportal fibrosis combined, 26.7% with posthepatitic cirrhosis and 13.3% with schistosomal periportal fibrosis) with tense ascites were randomized to treatment by one-session of a nearly-total paracentesis plus intravenous human albumin (68 patients) or hydroxyethyl starch 6% (67 patients). These were given at a dose of 8 g/l of ascitic fluid removed. The two groups were compared for incidence of complications, recurrence of massive ascites after hospital dismissal and survival rate. ConclusionsHydroxyethyl starch 6% is safe and as effective as human albumin in protecting patients treated with nearly-total paracentesis from developing renal and electrolyte complications. Transient hypotension following paracentesis was, however, commoner in the hydroxyethyl starch group. Introduction  Ascites is considered as one of the most common complications of liver cirrhosis and is usually associated with a poor quality of life and poor long-term outcome [1], [2], [3], [4], [5]. Removal of ascites by paracentesis is an effective line of treatment, but this may lead to hypovolaemia, which may persist for months in some patients [6], [7], [8]. Human albumin is used as an intravascular volume expander. It is the major plasma protein and constitutes around 50% of the cell free protein in healthy individuals. It is produced exclusively in the liver, and therefore its concentration is reduced with hepatic dysfunction [9]. It is responsible for 80% of the colloid osmotic pressure of plasma; therefore, the intravenous administration of albumin is associated with a rapid increase in the circulating blood volume. However, albumin is more than a simple plasma volume expander, it has many other physiological functions including the binding and transport of a wide variety of water insoluble endogenous and exogenous substances, metals, and drugs [10], [11]. Human albumin is also quantitatively the most important circulating antioxidant [12]. Because of its high cost, human albumin cannot be routinely prescribed and synthetic colloids are often used for plasma expansion. In the literature, there is a major controversy about using albumin in cases of ascites. A randomized study stated that albumin is the most effective plasma expander [13]. Other investigators in their randomized controlled trial showed that albumin in addition to antibiotics led to a significant reduction in mortality and renal failure in cases of cirrhotic patients with spontaneous bacterial peritonitis [14]. In contrast, many other randomized trials showed no benefit of albumin in preventing postparacentesis complications in comparison to synthetic colloids [15], [16], [17], [18], [19]. The aim of this clinical prospective randomized trial was to compare the efficacy of human albumin with the less expensive synthetic plasma expander, hydroxyethyl starch 6% after paracentesis regarding the incidence of complications, prevention of postparacentesis circulatory dysfunction (as estimated through changes in the activity of the renin–angiotensin system), recurrence of ascites after hospital dismissal and survival rate. Patients and methods Study design Patients were admitted to Internal Medicine Department, Mansoura University Teaching Hospitals in Egypt between April 2008 and February 2009. Patients with cirrhosis and tense ascites were included if they needed to receive a plasma expander for paracentesis for ascites. The criteria for inclusion were cirrhotic patients with tense ascites with absolute unresponsiveness to low-sodium diet and maximal tolerated doses of diuretic therapy. The diagnosis of cirrhosis was based on standard clinical and biochemical criteria, diagnosis of oesophageal varices at endoscopy or collateral circulation at ultrasonography and histological analysis of liver biopsy whenever possible. To assess the degree of hepatic failure, the Child–Pugh score was adopted. Exclusion criteria included: Serum bilirubin level more than 5mg/dl, prothrombin activity less than 40%, urinary sodium excretion more than 10mEq/day, severe hyponatraemia (<125mEq/l), serum creatinine more than 2mg/dl, platelet count less than 40.000/mm3, gastrointestinal haemorrhage within the preceding 3months, sepsis, hepatic encephalopathy, hepatic malignancy, terminal cardiac or respiratory diseases and patients treated with propranolol for primary or secondary prophylaxis of portal hypertensive bleeding. The study was approved by the Local Ethics Committee, and all patients gave a written informed consent before enrollment to participate in the trial. Baseline assessment and follow up data collection A total of 135 patients were enrolled in the trial. All patients were subjected to history taking and thorough clinical examination. Baseline clinical and laboratory data included age, sex, cause and severity of liver disease, previous treatment, comorbidities, core temperature, body weight, dry body weight, arterial blood pressure, heart rate, serum creatinine and sodium concentrations, other investigations (e.g. angiography, CT scan, abdominal ultrasonography, upper gastrointestinal endoscopy) and ongoing treatment. Tests for cognitive function were done and liver biopsy was done in only 22 patients. On admission, patients were kept on a low-sodium diet (50mEq/day) and bed rest regimen. Diuretic administration was discontinued at least 5days before paracentesis. No vasoactive drugs were allowed before or during the study. Urinary volume and urinary sodium were recorded daily. The allowed oral fluid intake did not exceed 1.5l/day. Biochemistry On day 5, 24-h urine volume was collected to measure the electrolyte concentration. On day 6, after overnight fasting from food, blood samples were obtained to measure serum electrolytes, complete blood picture, serum creatinine, standard liver function tests, hepatitis B and hepatitis C markers. After 2h of bed rest, blood samples were collected, then after centrifugation at 4°C, plasma was immediately frozen at −30°C until it was assayed for plasma renin activity (PRA) and plasma aldosterone concentration (PAC), then paracentesis was done. Randomization and treatment protocol Before paracentesis, patients were randomized to one of the two treatment groups based on random numbers generated by the SAS V6.12 statistical software (SAS Institute, Cary, NC) in a 1:1 ratio. Group I: Consisted of 68 patients who were treated with paracentesis and simultaneous intravenous albumin administration (8g/l of ascitic fluid removed) using 20% human albumin solution, half of the required albumin was given during paracentesis and the other half was given 6–8h after paracentesis to avoid acute intravascular fluid overload [20]. Group II: Consisted of 67 patients who were treated with paracentesis and simultaneous intravenous infusion of poly O-2-hydroxyethyl starch, average molecular weight (MW)=200,000, molar substitution (MS)=0.45–0.55, in isotonic sodium chloride solution, Hemohes 6% (HES 6%). B. Braun Melsungen AG. 34209 Melsungen, Germany). The infusion was given in a schedule similar to that of the above mentioned albumin infusion (using a solution containing 6g per 100ml of the solution) [21]. Data on colloid administration included indication, dose and volume of ascetic fluid removed. Serum creatinine and sodium levels were measured and recorded before and after colloid administration. Data were collected at each scheduled visit (2, 4, and 6months) or during any hospitalization that occurred between two scheduled visits. Paracentesis All patients were treated with one-session nearly-total paracentesis using routine and traditional procedures for spontaneous drainage (without suction pump) in the left lower abdominal quadrant. Under strict sterile conditions, slow aspiration of the peritoneal fluid was performed over 4–8h till paracentesis was considered complete when drainage became intermittent despite gentle mobilization of the peritoneal cannula or left side tilting of the patient’s bed. Ascitic fluid samples were taken during paracentesis for routine investigations (culture, cell count and biochemistry). Body weight, mean arterial blood pressure (MAP), heart rate, urine output and cognitive functions were assessed just before and after paracentesis, then every morning in the following week. Serum electrolytes, serum creatinine, liver function tests, complete blood picture, urinary sodium and potassium, PRA and PAC were measured at 48h, and on the 6th day after paracentesis. After peritoneal fluid mobilization, patients remained hospitalized for 7days without diuretic therapy. Patients were then discharged from hospital on diuretic therapy with dose adjustments according to the individual response to maintain patients with no or minimal ascites. Follow up The follow up period started at the end of the first hospitalization. Patients were examined in the outpatient clinic at least weekly during the first month, monthly for the next two months and bimonthly thereafter. Patients in whom tense ascites developed during the follow up period were treated with large-volume paracentesis and the same plasma expander assigned at inclusion. Study outcomes The end points planned in the protocol were as follows: (a) death, (b) recurrent episode of massive ascites, (c) renal impairment, (d) hepatic encephalopathy, (e) portal hypertensive bleeding and (f) any other cirrhosis-related complication. Results Of the 135 patients included, 106 were men (78.5%) and 29 were women (21.5%), with age range between 43 and 52years. The aetiology of liver cirrhosis (based on histological analysis of liver biopsies in only 31 patients and on clinical and laboratory data and ultrasonography) was cirrhosis combined with fibrosis in 81 patients (60%). Posthepatitic cirrhosis was diagnosed in 36 patients (26.7%): 28 cases with chronic hepatitis C virus infection (HCV) and eight cases had chronic hepatitis B virus infection (HBV). Pure schistosomal periportal fibrosis was the cause of liver disease in 18 patients (13.3%) based on histological examination of hepatic tissue in 22 patients, while in the remaining patients schistosomal periportal fibrosis was suggested by the history of previous schistosomal infestation and clinically by the manifestations of portal hypertension without evident liver cell failure and by the ultrasonographic picture of periportal fibrosis [23]. Pugh’s modification of Child’s classification was used to assess the degree of liver failure. The Child–Pugh class was 11.01±0.81 (mean±SD) versus 10.98±0.82 in groups I and II respectively (p=0.835). Table 1, Table 2 show no significant difference between the 2 groups as regards age, sex, body weight, heart rate, daily urine volume and urinary sodium excretion before paracentesis. Similarly, the aetiology and severity of liver disease (Child–Pugh grading), standard renal and hepatic function tests, PRA and PAC were not statistically different in both groups. Results during the first hospital stay Table 4 demonstrates that there were no significant differences between the two groups in the duration of hospital stay (from randomization until discharge from the hospital or death), rate and volume of ascitic fluid removed and mean duration of paracentesis. Local complications related to paracentesis were few. Ascitic fluid leakage at the site of puncture for several hours after paracentesis was recorded in one patient from group I and two patients from group II. A small subcutaneous haematoma developed in only one patient from each group. Mean arterial blood pressure decreased and heart rate increased to a similar degree in patients of the two groups at 48h and, to a lesser degree on the 6th day after paracentesis. To a similar degree, there was a significant decrease in the body weight at 2 and 6days after paracentesis in the two groups. The effect of paracentesis on biochemical parameters was shown in Table 3. Serum albumin concentration increased significantly at 2 and 6days in group I patients only, while group II patients showed no changes in this parameter. No significant changes were observed in serum bilirubin, prothrombin activity, haematocrite, platelet count, serum creatinine, blood glucose and plasma potassium and sodium levels in the two groups after paracentesis. There was a significant increase in 24h urine volume and urinary sodium excretion at 2 and 6days after paracentesis in the two groups. The effect of paracentesis on the effective intravascular volume (or postparacentesis circulatory dysfunction) was indirectly assessed by measuring PAC and PRA before paracentesis, 2days and 6days after paracentesis. The patients baseline values were comparable in the two groups. None of the mean values of the two parameters changed significantly in the two groups after paracentesis. However, postparacentesis transient hypotension occurred more frequently in group II than group I patients (23.9% versus 8.8%, p=0.018) (Table 5). | a Transient hypotensive attacks following paracentesis. |
Table 5 shows the complications in the two groups during the hospital stay. There was no significant difference between the two groups in the incidence and types of complications, although the number of complications was slightly higher in the HES group. The mortality rate during the first hospital stay was very low in the two groups. Results during the follow up period The 131 patients who were discharged from the hospital were followed up closely until the end of the study or death. Causes and number of times of readmission are showed in Table 6. There were no significant differences between the two groups as regards the number of patients requiring readmission (47.1% and 55.2% in groups I and II, respectively, p=0.343), total number of times of readmission, causes of readmission and mortality. Causes of death were hepatic encephalopathy (two cases in either group) and severe gastrointestinal bleeding (three cases in group I and four cases in group II). Discussion Ascites is one of the earliest and most common complications of patients with portal hypertension. A number of treatment modalities including sodium restriction, diuretic therapy, paracentesis, ascites ultrafiltration and reinfusion, peritoneo-venous shunting, and portosystemic anastomosis are currently used in the management of ascites. Therapeutic paracentesis is an effective and safe therapy for such patients and is commonly used by the great majority of physicians in many centers especially in patients with tense or refractory ascites [24]. It has been shown that expansion of the intravascular plasma volume with albumin at a dose of 6–8gm/l of ascitic fluid removed prevents the impairment of systemic circulation and renal function which occurs 12h after large-volume paracentesis [6], [25], [26]. A still unanswered question is whether albumin can be safely substituted by artificial plasma expanders. This is an important issue because albumin is expensive and not available in all centers. Several studies have compared between human albumin and synthetic plasma expanders and have provided discrepant results [13], [16], [21], [27]. These discrepancies in the results after therapeutic paracentesis could be ascribed to the lack of the uniformity in the criteria of patient selection and to the marked heterogeneity of patients with decompensated cirrhosis [16], [20], [25]. Most of these studies comprised a small number of cirrhotic patients and they advised more comparative studies with a large series of patients with different aetiologies of portal hypertension. In the present work, we report data from a randomized trial with a 6months follow up period that was designed to compare outcomes in patients with cirrhosis and ascites who had been treated with either 20% human albumin or a synthetic colloid. Patients were randomized into two groups, receiving either human albumin or HES 6%. At inclusion, there were no significant differences between patients of the two groups as regards demographic, clinical, biochemical and hormonal data. Also the technique of paracentesis, volume of ascitic fluid removed, duration of paracentesis, and rate of ascitic fluid removal were more or less similar in both groups. The results of the current study confirm that nearly-total paracentesis plus intravenous albumin infusion is an effective and safe treatment for patients with refractory ascites because it was not associated with significant changes in renal and hepatic function tests. Also there were no deleterious effects on the effective intravascular volume (as evaluated by non significant changes in PRA and PAC) and with little complications. These results are in agreement with many other studies [6], [13], [16], [20]. The mechanism by which albumin administration prevents the development of renal, electrolytes and circulatory disturbances after nearly-total paracentesis was suggested to be theoretically related to the diminution of the rate of ascites reformation, an expansion of the effective circulatory blood volume or both [6]. In the present trial, patients treated with the synthetic plasma expander, HES 6% after one-session of nearly-total paracentesis had no significant changes in renal and hepatic functions, haematocrite or platelet count after treatment. Moreover, the incidence of complications and deaths during the first hospitalization in patients infused with the synthetic plasma expander were comparable with those infused with albumin. The course of the disease during the follow up period, as estimated by the number of patients readmitted to hospital, causes of readmission and survival, was almost similar in patients infused with the synthetic plasma expander when compared to those infused with albumin. Therefore, HES 6% seems to be safe and as effective as human albumin in preventing renal and electrolyte complications that may develop after the mobilization of ascites by paracentesis [13]. El Garem et al. [21] have investigated the effect of large volume (6–8l) paracentesis combined with replacement with 1l of the synthetic plasma expander, HES 6%, on the portal and splenic vein haemodynamics in 20 patients suffering from advanced liver cirrhosis and intractable ascites. They reported a significant reduction in the congestion of portal circulation with clinical improvement in all patients with no recorded complications. They concluded that HES 6% is a safe and effective plasma expander after large volume paracentesis. Unfortunately, they did not measure PRA or PAC (which reflect the effective intravascular volume) before or after treatment. Body weight showed a marked significant decrease, to a similar degree, in patients of the two groups at 2days and to a lesser degree at the 6th day after paracentesis. These changes in body weight were due to removal of ascitic fluid and then its gradual reaccumulation but did not reach its basal level. Also, the mean arterial pressure decreased and heart rate increased to a similar degree in patients of the two groups at 48h and, to a lesser degree, at the 6th day after paracentesis. These results are in agreement with previous trials [6], [20]. Pozzi et al. [25] reported that the intraabdominal pressure decreased progressively during paracentesis which is accompanied by a marked reduction in the intrathoracic, right arterial, pulmonary artery and pulmonary capillary wedge pressure. These changes in the central haemodynamics were accompanied by a progressive reduction in the mean arterial pressure, a progressive increase in the stroke index and a marked progressive decrease in the systemic vascular resistance. All haemodynamic changes produced by paracentesis were substantially preserved 24h later and can be preserved later on with the use of intravascular plasma expanders. Also, the significant increase in urine output and urinary sodium excretion at 2 and 6days after treatment could be explained by the improvement in central and renal haemodynamics after paracentesis and to the increase in atrial natriuretic peptide secretion that participates in maintenance of renal perfusion in cirrhosis [26]. The effect of therapeutic paracentesis on the effective intravascular volume in most of the previous studies and in the present study was evaluated by measuring PRA and PAC before and after treatment. Therapeutic paracentesis of more than 6l without volume expansion by albumin produces a significant increase in PRA and PAC [6], [13], [26]. In the current study, postparacentesis transient hypotension occurred more frequently in patients treated with HES 6% (23.9%) than in those treated with albumin (8.8%) (p=0.018). These results are in agreement with that of Planas et al. [15] and Gines et al. [13]. This can be explained by considering the different pharmacokinetics of the two substances. Albumin, the plasma expander of choice, persists intravascularily for longer time than the artificial colloids; its half-life in cirrhotic patients is approximately 21days [28]. 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