The Use of Human Albumin for the Treatment of Ascites in Patients with Liver Cirrhosis: Item of Safety, Facts, Controversies and Perspectives

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1 Current Drug Safety, 2011, 6, The Use of Human Albumin for the Treatment of Ascites in Patients with Liver Cirrhosis: Item of Safety, Facts, Controversies and Perspectives Antonio Facciorusso, Maurizio Cosimo Nacchiero, Rosa Rosania, Giulio Laonigro, Nunzio Longo, Carmine Panella and Enzo Ierardi * Department of Medical Sciences, Section of Gastroenterology, University of Foggia, Italy Abstract: Albumin constitutes approximately one half of the proteins in the plasma and plays a pivotal role in modulating the distribution of fluid between body compartments. Hence it is commonly employed in cirrhotic patients in association with diuretics for the treatment of ascites. Nevertheless, its usefulness is controversial in this condition and well-stated only in some circumstances. The item of safety of the drug appears to be convincing due to the accurate cautions in the course of its preparation. Side effects are described in literature only as sporadic events. Indeed, albumin administration is effective to prevent the circulatory dysfunctions after large-volume paracentesis and renal failure and after Spontaneous Bacterial Peritonitis (SBP). Finally albumin represents, associated with vasoconstrictors, the therapeutic gold standard for the hepatorenal-syndrome (HRS). Physiopathological bases of the therapeutic use of albumin in hepatic cirrhosis consist in both hypoalbuminemia and portal hypertension consequences. In fact, cirrhotic patient with ascites, in spite of hydrosaline retention, shows an effective hypovolemia with peripheral arterial vasodilatation and increase in heart rate. Therefore the effectiveness of albumin administration in the treatment of ascites is due to its plasma volume expander property as well as its efficacy in restoring plasmatic oncotic pressure. Trials are in progress in order to define the effectiveness of the prolonged home-administration of human albumin in the treatment and prevention of ascites. Finally, it has been recently demonstrated that the binding, transport and detoxification capacities of human albumin are severely reduced in cirrhotics and this impairment correlates with the degree of liver failure. Therefore, the next challenge will be to determine whether the alterations of non-oncotic properties of albumin are able to forecast mortality in cirrhotics with ascites and exogenous albumin chronic administration will be effective in predicting and preventing such alterations. Keywords: Albumin, ascites, liver cirrhosis, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS). INTRODUCTIVE REMARKS Albumin constitutes approximately one half of the proteins in the plasma and accounts for about 70% of its oncotic pressure. It plays, therefore, a pivotal role in modulating the distribution of fluid among body compartments [1,2]. Moreover, albumin exerts other biological activities such as molecule and drug carrier, free radical scavenger, and anti-inflammatory action; these properties may be relevant under several pathologic circumstances [1]. It is currently known that its considerable and enduring capacity to expand central blood volume in cirrhosis compared to common plasma-expanders [3,4,5,6], thus it should be broadly employed in the clinical practice in association with diuretics for the treatment of ascites. Furthermore, several controlled randomized trials have shown that albumin administration is effective in preventing the circulatory dysfunctions which may occur after a largevolume paracentesis affecting ex vacuo fluid mobilization [7] as well as renal failure after Spontaneous Bacterial Peritonitis (SBP) [8]. Finally albumin associated to *Address correspondence to this author at the Gastroenterology Section, Department of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, Foggia, Italy; Tel: ; Fax: ; enzo.ierardi@fastwebnet.it vasoconstrictors, represents the therapeutic gold standard for Hepatorenal-Syndrome (HRS) [9,10]. PATHOPHYSIOLOGICAL BASES OF ALBUMIN THERAPY The main pathophysiological basis of the therapeutic use of albumin in hepatic cirrhosis consists in the hypoalbuminemia, due to hepatic synthesis impairment; albumin lack associated to portal hypertension leads to a relevant hydroelettrolitic imbalance in several ways. The efficacy of albumin administration in restoring normal haematic values is an obvious notion whilst the effect on portal hypertension is more easily understandable. The more currently reliable hypothesis recognizes as initial abnormality the sinusoidal release of vasodilator molecules such as nitric oxid (NO) in association with hyperglucagonemia and other vasoactive peptides, may induce splanchnic and systemic vasodilatation. This condition would result in a sequence of events directed to an attempt of compensation by the organism, with the result of further enhancement of the underlying pathological process [11]. In detail we observe: 1. a decrease in effective arterial blood volume; 2. a decrease in renal perfusion and in glomerular filtration rate (GFR); /11 $ Bentham Science Publishers

2 2 Current Drug Safety, 2011, Vol. 6, No. 4 Facciorusso et al. 3. a compensatory activation of sympathetic nervous system (SNS) with a consequent increase in cardiac output and renal vasoconstriction; 4. a hyperincretion of Renin-Angiotensin; 5. a secondary hyperaldosteronism; 6. a release of Adiuretin (ADH) and inhibition of Atrial Natriuretic Peptide. In the initial phase of compensated cirrhosis (without ascites or edema), the retained fluid would suppress sodium and water retention and reset fluid balance at an upper level of blood volume. In addition, there is a homeostatic increase in cardiac output as result of a decreased afterload [11]. However, as the disease progresses and initial factors became more prevalent, a progressive increased vasodilatation would be produced in the splanchnic circulation and the effective arterial blood volume is not maintained by the increased total blood volume. In these circumstances, the retention of water and sodium is harmful because it establishes a vicious circle and leakage of fluid re-uptake from splanchnic circulation to the peritoneal cavity with the final result of ascites onset. Therefore, the cirrhotic patient with ascites, in spite of hydrosaline retention, shows a marked hypovolemia with periferic arterial vasodilatation and increase in cardiac frequency. The role of portal hypertension in determining ascites is reported in Fig. (1). In account of these pathophysiological events, it is evident the effectiveness of albumin administration in the treatment of ascites, due to its volume expander property and efficacy in restoring plasmatic oncotic pressure. NON ONCOTIC PROPERTIES OF ALBUMIN In addition albumin is more than a simple plasma volume expander, being provided of additional non oncotic properties, as listed in Table 1. Table 1. Non Oncotic Properties of Albumin Non Oncotic Properties of Human Albumin 1) Scavenger (SH groups) 2) Binding and transport 3) Capillary integrity 4) Regulation of acid-base equilibrium 5) modulation of intracellular signaling 6) Antithrombosis, anticoagulation It has been recently demonstrated that the binding, transport and detoxification capacities of human albumin are severely compromised in cirrhotics and this impairment correlates with the degree of liver failure [12]. This finding should be due to a modification of the molecule ( ischemiamodified albumin ). Such modification has been detected in the course of myocardial infarction and seems to be due to an effect of a group of cytokines known as cytokines ROS (radical oxygen species). Ischemia-modified albumin, i.e. that form theoretically ineffective from the therapeutic point of view, is over 2% in severe hepatic failure, whereas its levels are normally widely lower. ITEM OF SAFETY The safety of human albumin has been investigated for over 60 years. Even from the time of its introduction in 1942, human albumin safety was a topic of great interest [13]. Through several further investigations in the 1940s and thereafter, human albumin gained the reputation of a very Fig. (1). Hemodynamic underlying the role of portal hypertension and hypoalbuminemia in ascites occurrence.

3 The Use of Human Albumin for the Treatment of Ascites Current Drug Safety, 2011, Vol. 6, No. 4 3 safe drug. Summarizing the first 35 years of clinical experience, in the report of a US National Institutes of Health consensus conference, Tullis characterized albumin safety as so high that it rarely warrants discussion [14]. This conclusion received a support from subsequent largescale pharmacovigilance studies. In a prospective study of approximately 8 x 10 4 hospitalized patients in whom serious adverse events were identified by a computerized surveillance program, no albumin associated adverse events were reported [15]. It is noteworthy that for the entire period from 1990 to the end of 2000, during which a total of 112 million albumin doses were distributed worldwide, no death related to albumin was documented [16]. Since, human albumin, considered as the most physiological solution for circulation volume loading, becomes free of viral risks during the procedure of preparation, is judged to acquire an excellent safety item. Indeed, side effects are described in literature only as sporadic events. Some anaphylactoid reactions, ranging from erythema to cardiac arrest, have been reported. However, they became very rare in the last years according to the evolution of the current techniques of purification. Moreover, renal, cardiac and respiratory complications may occur more frequently in patients with severe injuries of the heart, lungs and kidneys. Anaphylactoid reactions following albumin infusion are very rare. Fujita et al. described a case of anaphylactoid shock in a diabetic patient undergoing off-pump coronary artery bypass after 5% human serum albumin infusion, reverted with norepinephrine [17]. In particular it is documented an increased risk of anaphylactic reactions after albumin infusion in patients with ahaptoglobinemia [18,19]. However, it is well stated that the risk of anaphylactoid reactions with albumin is much lower than that of gelatins and dextrans, and similar to that of starches [20]. In fact, the presence of the prekallicreine activator (fragments of Hageman s factor), able to cause hypotension due to bradikinine production, is very rare in albumin solutions. Nephrotoxicity of human albumin administration has been rarely described [21]. Rozich et al. reported a case of hyperoncotic renal failure in a patient with refractory ascites treated with 25% human albumin at unusually very high doses (1800 gr) in 72 h [21]. Supplemental albumin added to a standard non-albumin resuscitation regimen has been shown to significantly impair heart work in seriously injured patients [22]. The role of calcium dynamics in this myocardial depression was analyzed in 94 injured patients. Albumin resuscitated patients had normal total protein and serum albumin levels and higher total calcium (TC) levels, however, they had a significantly lower ionic calcium (Ca++) and Ca++/TC. This suggests that supplemental albumin binds serum Ca++ causing an increase in TC but a reduction in Ca++ and Ca++/TC. The fall in Ca++ and Ca++/TC seems to be responsible, in part, for heart failure and pulmonary edema in albumin resuscitated patients. In summary, albumin safety appears to be a well stated topic with rare possibility of occurring adverse events, which seem to be related to the poor general conditions of the patient more than the chemical properties of the drug. THERAPEUTIC USE OF ALBUMIN IN ASCITES MANAGEMENT The treatment with a low sodium diet and diuretics is effective in mobilizing and preventing ascites in cirrhosis in the initial phases of unbalance, but it has several limitations. First, the mobilization of ascites with diuretics is a slow process. Furthermore, approximately 10% of patients cease to respond to diuretics within a few years (ascites is defined as refractory when 3 or more therapeutic paracentesis per month during at least 2 consecutive months are needed). Second, diuretic treatment is frequently associated with complications, such as hepatic hencefalopaty, hyponatremia and pre-renal failure. In 1987 the demonstration that largevolume paracentesis only if associated with plasma volume expansion is a rapid, effective, and safe treatment of ascites in cirrhosis has considerably simplified the treatment of patients admitted to the hospital with tense ascites [23]. Indeed, many studies indicate that marked changes in circulatory function occur after therapeutic paracentesis [24]. Immediately after paracentesis, circulatory function improves, with a marked increase in cardiac output and stroke volume, a reduction in cardiac filling pressure, and a suppression of the renin- angiotensin and sympathetic nervous systems hyperactivity [23]. These effects, which persist for approximately 12 hours, are followed by opposite hemodynamic changes, including a reduction in cardiac output to baseline value and a marked activation of the reninangiotensin and sympathetic nervous system activity even over the corresponding levels before the paracentesis itself. Renal function also improves during the first hours after paracentesis and may worsen 24 to 48 hours after the procedure. The impairment of circulatory function induced by paracentesis is not related, as proposed initially, to a decrease in circulating blood volume secondary to a rapid reaccumulation of ascites, but to an accentuation of the arterial vasodilatation already present in these patients which constitutes, as above reported, the first step of the process leading to the formation of ascites. The exact mechanism of the whole phenomenon is not completely known even if it may be revealed by a sensitive marker, i. e. plasmatic renin activity. Paracentesis-induced circulatory dysfunctions adversely affect the clinical course of the disease due to an increased incidence of hyponatremia (3.8% vs 17%) as well as a renal impairment (0% vs 11%) compared with a control group, i. e. cirrhotics without ascites [3]. In a well-known study, Gines et al. compared albumin administration to plasma expanders during evacuative paracentesis [3] demonstrating that, when the amount of ascitic fluid removed is less than 5 L, the incidence of circulatory dysfunctions is similar among patients treated with albumin and those treated with synthetic plasma expanders (16% vs 18%). However, when the amount is between 5 and 9 L, the incidence of circulatory dysfunctions is higher among patients receiving synthetic plasma expanders (19% vs 30%, p<0,04). Differences are particularly marked when the volume of the paracentesis is greater than 9 L. In this last case, the incidence of

4 4 Current Drug Safety, 2011, Vol. 6, No. 4 Facciorusso et al. paracentesis induced circulatory dysfunction is 52% among patients receiving synthetic plasma expanders (p<0,02). Conclusive remarks of this relevant study are: a) Paracentesis-induced circulatory dysfunction is frequent when the plasma volume is not expanded; b) plasma volume expansion with albumin almost totally prevents paracentesis-induced circulatory dysfunction; c) among patients with an ascitic fluid volume of less than 5 L, the incidence of paracentesis-induced circulatory dysfunction is low and independent of the type of the plasma expander ; d) when the amount of ascitic fluid volume removed is over 5 L, the incidence of circulatory dysfunctions increases with the volume of paracentesis in patients receiving synthetic plasma expanders but not in those receiving albumin. The main aspects of the study are summarized in Fig. (2). Fig. (2). Post-paracentesis circulatory dysfunctions detected by Gines. et al. (Gastroenterology 1996; 111: ) Rate of postparacentesis circulatory dysfunction according to the plasma expander used and the volume of ascitic fluid drained. P < 0.04 and P < 0.02 compared to patients receiving albumin. ALBUMIN DOSES IN THE TREATMENT OF ASCITES The amount of albumin given in most centers after a paracentesis is 8 g/l of ascitic fluid removed. On the contrary the dosage in the chronic use of this drug is still a matter of debate. Studies performed when human albumin became available failed to show a clear usefulness in cirrhotics with hydroelectrolitic unbalance. However, these investigations were not controlled studies and included a small number of patients [25,26]. The problem concerning the use of albumin as chronic therapy in cirrhotics has been debated in Italy since 1998, when the Commissione Unica del Farmaco (CUF), i. e. the Italian Drug Commission, amended its Note 15 to limit the payment of the drug only to the out-of-hospital prescriptions for patients with ascites and plasma albumin concentration equal to or lower than 2,5 g/dl. Note 15 was further modified in 2001 by removing hypoalbuminemia as a prerequisite to have the reimbursement by the National Health Service on the basis of some Italian studies published or performed between 1999 and 2001 [27,28]. Indeed, an important new piece of information derived from the Albumin Delphi Study, involving 68 centers throughout Italy, that stated the efficacy of albumin administration in out-of-hospital cirrhotics with ascites independently from the starting value of serum albumin [27]. The aim of the study was to define a consensus among Italian physicians with regard to the use of albumin in patients with decompensated cirrhosis and ascites. All controversial issues related to the use of albumin were identified by the experts' board and proposed to the 68 participating hepatology centres through two subsequent questionnaires. About 77% of the experts involved considered likely that albumin administration could shorten hospital stays or could reduce the number of hospital admissions. The results of the study, along with a socioeconomic analysis, were presented to the Italian Drug Commission, which subsequently removed the specific hypoalbuminemia level as a prerequisite for having the drug reimbursed by the National Health Service [27]. However, the lack of further randomized controlled trials and the high cost of the human albumin is the reason that albumin infusion is not usually included among the therapeutic options for difficult-to-treat ascites. In fact, the guidelines published by the American Association for the Study of the Liver (AASLD) do not mention albumin as a possible therapeutic tool in ascites except when administered to prevent the circulatory dysfunctions after large-volume paracentesis. In summary, the lack of economical analysis about the real cost/benefit ratio makes the efficacy of homeadministration of albumin in cirrhotics with ascites doubtful. For this reason a large multicentric randomized controlled trial is in progress powered by the Agenzia Italiana del Farmaco (Italian Drug Agency: AIFA) and by the Associazione Italiana Studio Fegato (Italian Association for the Study of the Liver: AISF). The objectives of this study are to define the effectiveness of the prolonged homeadministration of human albumin during 24 months associated with diuretic therapy in the treatment of liver cirrhosis with non complicated ascitic decompensation. The primary outcome will be the possibility of a decrease in mortality and development of refractory ascites. Secondary outcomes will be a possible reduction in diuretics dosage, number of total paracenteses, hospital admissions, and SBP and HRS occurrence. TREATMENT OF SPONTANEOUS BACTERIAL PEROTONITIS (SBP) SBP is defined as the infection of ascitic fluid without an apparent intra-abdominal source. Its prevalence SBP in hospital admitted patients with cirrhosis and ascites ranges between 10% and 30% [29, 30]. Diagnosis is established by a polymorphonuclear cell count in ascitic fluid giving a value higher than 250 cells/mm3. Therapy is mainly based

5 The Use of Human Albumin for the Treatment of Ascites Current Drug Safety, 2011, Vol. 6, No. 4 5 on the use of antibiotics (first of all cephalosporines and quinolones as prophylaxis), but albumin is a relevant therapeutic tool. For many years the mortality rate associated with SBP has been very high (20-30%) despite antibiotic therapy. Subsequent investigations showed a rapid deterioration of systemic hemodynamics in these patients, with a marked increase in the degree of activity of both the renin-angiotensin system and sympathetic nervous system probably as the consequence of an increased production of bacteria-derived vasodilatory substances or inflammatory cytokines [31,32]. Therefore, an appropriate administration of albumin improves the deeply compromised hemodynamics in these circumstances when there is an unbalance between plasmatic mass and circulatory system (effective hypovolemia), as explained and confirmed in several studies. In detail, a controlled randomized trial showed a significant decrease in the mortality of the patients treated with albumin [33]. The study included 126 patients with SBP who were treated with intravenous cefotaxime (63 patients) or with cefotaxime and intravenous albumin (63 patients). Albumin was given at a dose of 1.5 g/kg of body weight at the time of the diagnosis, followed by 1 g/kg of body weight from the third day. Plasma renin activity increased significantly in patients treated with cefotaxime and decreased in patients receiving cefotaxime plus albumin. Renal impairment developed in 33% of the cefotaxime group of patients versus the 10% of the cefotaxime plus albumin ones. The hospital mortality rate was 29% in cefotaxime in comparison with the 10% in cefotaxime plus albumin group. The mechanism of albumin efficacy in these patients has been recently explored in a randomized pilot study comparing the hemodynamic effects of albumin and synthetic plasma expanders in patients with SBP [4] and showing that albumin acts not only as plasma volume expander but even by reducing the degree of arterial vasodilatation, probably through a decrease of endothelial release of nitric oxyde (NO), as confirmed by the low levels of its metabolites exclusively seen in the patients treated with albumin. TREATMENT OF HEPATO-RENAL SYNDROME (HRS) HRS is a form of renal failure, exclusively of functional origin, caused by a marked vasoconstriction in the renal circulation. It may be considered as the end of the spectrum of functional renal abnormalities in liver cirrhosis ranging from ascites to hyponatremia until HRS. HRS is characterized by an extreme contraction of the diuresis, hypercreatininemia and hyponatremia evolving to the death within a few days in type I and a few months in type II (International Ascites Club, 1994). The diagnostic criteria of HRS are [34]: Cirrhosis with ascites Serum creatinine > 133 μmol/l (1,5 mg/dl) No improvement of serum creatinine after at least 2 days of diuretic withdrawal and volume expansion with albumin Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease. The initial abnormality, as above reported, would be a sinusoidal portal hypertension causing renal sodium retention and leading to a marked arterial vasodilatation located mainly in the splanchnic district. Splanchnic arterial vasodilatation results in an abnormal distribution of blood volume with reduction of effective arterial blood volume and subsequent renal sodium and water retention (secondary hyperaldosteronism). In the pre-ascitic stage the retained fluid would suppress sodium and water retention and reset fluid balance at an upper level of blood volume. However, as the disease progresses, more and more vasodilatation would be produced and a leakage of fluid from the splanchnic circulation to the peritoneal cavity is the final result (i. e. ascites). At this point, the persistent activation of renin-angiotensin-arterial system (RAAS) is followed by activation of sympathetic nervous system (SNS) and hyperincretion of adiuretin (ADH) with consequent dilutional hyponatremia and severe renal vasoconstriction that constitutes the well-known pathophysiologal basis of HRS. In conclusion volemic underfilling in systemic circulation due to the splanchnic vasodilatation determines a vasoconstrictor hyperincretion such as norepinephrine and endothelin [35,36,37] and the activation of RAAS/SNS systems [35,38] leading to renal vasoconstriction; in Fig. (3), in which the progression of the alteration of renal functionality is shown, from the figure it may be argued why volemic expansion associated with vasoconstrictors represents the core of HRS treatment. In fact such molecules act in splanchnic circulation removing the primum movens of renal vasoconstriction. The administration of Terlipressin is associated with a significant improvement in glomerular filtration rate (GFR) and reduction of serum creatinine level below 1,5 mg/dl in 42% to 92% of patients with HRS [39,40]. The contemporary administration of albumin (1 g/kg on first day followed by 20/40 gr/day) is broadly recommended although not definitively proved in controlled trials [41]. CONCLUSIVE REMARKS As previously described, approximately 10% of cirrhotic patients with ascites per year develops refractory ascites [37]. This condition is associated with a very low survival rate (about 30% within 2 years) and a deep worsening of the quality of life [42]. Furthermore, in these circumstances there is a substantial rise in care costs because of the frequent need of hospitalization and invasive procedures (paracentesis, TIPSS). Repeated large-volume paracentesis is the most widely accepted therapy for refractory ascites, although early recurrence of fluid accumulation occurs almost invariably. Transjugular intrahepatic portosystemic shunt (TIPSS) is effective in preventing recurrence, but it can be safely performed only in selected cases, due to the risk of hepatic encephalopathy and liver failure. It should also be reminded that refractory ascites represents an indication for liver transplantation and creatininemia constitutes one of three

6 6 Current Drug Safety, 2011, Vol. 6, No. 4 Facciorusso et al. Fig. (3). Progression of the alteration of renal functionality in cirrhotics. parameters of Model for End-Stage Liver Disease (MELD), a score determining the urgent need of transplantation by indicating mortality possibility within 3 months [43]. On this basis the need for accurate statements identifying the real effectiveness of chronic albumin homeadministration with standard diuretic therapy becomes evident in order to prevent the incidence of refractory ascites recurrences; thus care costs could be reduced: indeed, the decreased number of hospitalization and invasive procedures for every occurrence of ascitic unbalance could likely overcome the higher costs of prolonged albumin administration. Thence the next challenge will be to determine, by means of controlled studies, whether the alterations of non oncotic properties of albumin are able to estimate mortality in cirrhotics with ascites and if exogenous albumin chronic administration is effective in predicting and preventing such alterations. Fig. (4). MARS system.

7 The Use of Human Albumin for the Treatment of Ascites Current Drug Safety, 2011, Vol. 6, No. 4 7 Finally, even detoxification capacities of albumin have been even used for extracorporeal depuration in the course of hepatic failure (fulminant or chronic). These systems are based on the use of a double-sided, albumin-impregnated polysulfone or a hollow-fiber dialysis membrane as a molecular adsorbent in a closed-loop dialysis circuit. Such an approach is based on the long-recognized principle that albumin molecules with free binding sites compete for toxins bound to carrier proteins in perfused blood (bilirubin, biliary salts, aromatic aminoacids). An incorporation of the 5% of human albumin in the dialysate results in the transfer of adsorbed toxins in turn from the membrane to the dialysate. The dialysate is then perfused over charcoal and resin adsorbents to remove albumin-bound toxins from the dialysate albumin and finally dialyzed to remove watersoluble toxins (NH4, etc.) in readiness for the next cycle. An example of these systems is described in Fig. (4). Despite encouraging results of such systems have been tested in recent studies [44,45,46]. In any case, only large multicenter controlled trials could provide definitive assurances about their convenience in clinics for the treatment of hepatic coma particularly in the pre-transplant setting. REFERENCES [1] Evans TW. Review article: drug-biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther 2002; 16 (suppl.5): [2] Chuang VT, Otagiri M. Recombinant human serum albumin. Drugs Today (Barc.) 2007; 43(8): [3] Gines A, Fernandez-Esparrach G, Monescillo A, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. 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8 8 Current Drug Safety, 2011, Vol. 6, No. 4 Facciorusso et al. [39] Uriz J, Gines P, Cardenas A, et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000; 33: [40] Gluud LL, Kjaer M, Taastroem A. Terlipressin for hepatorenal syndrome: a Cochrane systematic review. J Hepatol 2005; 42:206A. [41] Schiff ER, Sorrell MF, Maddrey WC. Schiff s Diseases of the Liver 10 th ed. Lippincott Williams & Wilkins. [42] Gines P, Cardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Eng J Med 2004; 350: [43] Wiesner RH, Edwards EB, Freeman RB, et al. Model for End Stage Liver Disease(MELD) and allocation of donor livers. Gastroenterology 2003;124:91-6. [44] Heemann U, Treichel U, Loock J, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 2002;36: [45] Jalan R, Sen S, Steiner C, et al. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis. J Hepatol 2003;38: [46] Kreymann B, Seige M, Schweigart U, et al. Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins. J Hepatol 1999;31: Received: July 11, 2011 Revised: October 10, 2011 Accepted: October 10, 2011