| Abstract|| |
There are several indications for the use of albumin in patients with decompensated cirrhosis and its role has existed in clinical practice for many decades. While the drug enjoys immense popularity, it yet attracts intensive debate amongst clinicians and pharmacologists alike. Regardless of its pharmacological properties, its clinical use in cirrhotic patients has its fair share of proponents and opponents. At present, in the setting of cirrhosis this debate centers around the treatment of spontaneous bacterial peritonitis, in patients with ascites treated with large volume paracentesis, and in those with hepato-renal syndrome. With the evolving evidence it has become imperative to shed old dogmas and address this issue in the light of evidence-based medicine. This article gives a representative view of albumin use in the above conditions across both sides of the clinical divide.
Keywords: Albumin, ascites, circulatory dysfunction, cirrhosis, hepatorenal syndrome, large volume paracentesis, spontaneous bacterial peritonitis
|How to cite this article:|
Sanai FM, Marotta PJ. Albumin use is beneficial in cirrhotic patients. Saudi J Gastroenterol 2007;13:200-3
The use of albumin in clinical practice has existed for many decades. Albumin was classically used in hospitalized cirrhotic patients with tense ascites to increase serum albumin, thereby enhancing the renal response to diuretics. It is currently the most effective plasma expander available owing to its high oncotic activity and prolonged half-life in the intravenous compartment. It plays a pivotal role in distributing fluids between the compartments. Apart from its oncotic properties, albumin is recognized for its capacity of molecular transportation and free radical scavenging, for its ability to modulate capillary permeability, neutrophil adhesion and activation and for its hemostatic effects.
The role of albumin administration in the setting of decompensated cirrhosis warrants better understanding of the pathophysiologic considerations of ascites and the complicating renal impairment. A reduction in the effective arterial blood volume is the recognized principle of hemodynamic disturbance in cirrhosis.  This reduction in effective blood volume with arterial hypotension activates the renin-angiotensin-aldosterone system (RAAS), which in turn stimulates the kidney to retain sodium and water. , In addition, renal perfusion pressure is reduced, thereby leading to decreased renal blood flow. Compensatory splanchnic vasoconstriction further reduces renal perfusion with its consequent reduction in the glomerular filtration rate. 
From its initial period of induction in the 1950s, the drug enjoyed immense popularity in the treatment of decompensated cirrhosis. Subsequently, the publication of two meta-analyses within the last decade vastly questioned the benefit of using albumin in critically ill patients. These two trials showed that patients treated with albumin either fared worse  or at best had no survival advantage.  However, the methodology of these two trials seriously lack in their selection of trials, namely, the combination of heterogeneous trials and the absence of a plausible mechanism to explain albumin-associated excess mortality. In addition, the first meta-analysis evaluated no trials in cirrhotic patients.  However, these meta-analyses dampened the enthusiasm for albumin administration; it also generated a huge amount of incursive research.
The issues of safety, efficacy and survival that were raised by these meta-analyses have since been addressed in patients with end-stage cirrhosis who are receiving albumin. It has been found to reduce complications, avert hemodynamic derangements and prevent the development of renal impairment. A subsequent meta-analysis examining indication-based outcomes found reduced morbidity, length of stay and treatment cost in those receiving albumin for the treatment of cirrhotic complications. 
A major limitation of clinical trials is the undue reliance on survival as an endpoint. Improved survival has been elusive in cirrhotic patients who are undergoing large volume paracentesis (LVP) and receiving albumin to prevent circulatory dysfunction. However, this evidence is elusive not for lack of effectiveness of the drug but for lack of trials conducted to address this issue. In contrast, there is evidence that survival may be improved in other settings of decompensated cirrhosis. Further, clinically relevant outcomes such as morbidity, length of stay and costs of care should also be considered when the clinical utility of albumin is appraised.
However, the issue that must be addressed is what specific conditions benefit from the intravenous infusion of albumin? Recently, evidence has accumulated that promotes the role of albumin in several specific indications. There is ample evidence to support the use of albumin in the management of (1) spontaneous bacterial peritonitis (SBP), (2) paracentesis-induced circulatory dysfunction (PICD) and (3) hepato-renal syndrome (HRS)-1,2. This article will deal with the case in favor of administering albumin in the abovementioned conditions.
| Albumin in Patients with SBP|| |
SBP in the setting of decompensated cirrhosis is a frequent occurrence and has been studied in extensive detail. The inflammatory response in the abdominal cavity increases the local release of cytokines that pass into the systemic circulation, impairing the hemodynamics and leading to severe hemostatic activation of the endogenous vasoconstrictor systems and renal failure. ,,,,,, This development of renal failure is the most sensitive predictor of survival in patients with SBP. 
Sort et al. demonstrated the benefit of albumin administration in SBP by expanding the plasma volume and preventing circulatory dysfunction.  This resulted in a 66% reduction in HRS type 1 and in-hospital mortality and further reflected in the 3-month survival. The study faced criticism of investigator bias in that albumin was administered only in those with hypovolemia, which is commonly exacerbated in the presence of infection. A recent Dutch study investigated the effect of albumin load on blood volume distribution, arterial compliance and the RAAS in patients with cirrhosis without underlying SBP.  The findings revealed a significant improvement in the effective arterial blood volume in these patients, thereby showing benefit on circulatory dysfunction independent of hypovolemia . Similar findings in a previous study in patients with SBP demonstrated that the beneficial effects of albumin on systemic hemodynamics and renal function were related to both an improvement in cardiac function and a decrease in the degree of arterial vasodilation. 
While this provided the evidence for volume expansion as being useful in the presence of SBP, it was questionable whether a similar benefit could be derived from other considerably cheaper plasma expanders. To address this issue, Fernandez et al. compared albumin and hydroxyethyl starch (HES) in patients with SBP.  The results showed that albumin - but not HES - improved the systemic hemodynamics in patients with SBP, not just by volume expansion but also due to an action on the peripheral arterial circulation through increase in the systolic volume and peripheral vascular resistance.
The previously mentioned study by Sort et al. also showed that the patients with SBP who were most likely to benefit were those with elevated baseline urea, bilirubin (>68 µmol/L) or prothrombin time >60% of the control.  The mortality rate in those patients without these features and who received albumin was 0%, while it was 4% in those who did not receive albumin. The role of the baseline renal function is not clear at present, although it cannot be ignored that the incidence of renal impairment and the mortality rate in the albumin group in this study are the lowest to be reported in any series.
The volume expansion by other plasma expanders leading to significant decreases in serum creatinine levels has also been demonstrated by infusion of other fluids. , However, albumin consistently shows better results in improving creatinine as compared with other plasma expanders. , This suggests that the beneficial effect of albumin on renal function is not achieved merely by volume expansion and there are other factors responsible for this. Detractors of albumin therapy in SBP have argued along the limited nature of clinical evidence favoring albumin; however, it is imperative to understand that at present there is no evidence against its use. Therefore, until further studies are performed in this category of patients, albumin therapy should remain as standard of care in all patients with documented SBP.
| Albumin in the Prevention of PICD|| |
At present, LVP, defined to exceed >5 L, is widely used in the treatment of ascites. When paracentesis is performed without volume expansion, it is complicated by the development of PICD that is characterized by a decrease in effective arterial blood volume and marked activation of the RAAS.  The incidence of PICD within the first 2-6 days is approximately 80% after paracentesis alone and is reduced to 35-40% by plasma expansion after the procedure.  The probability of developing PICD in patients treated with saline solution, dextran-40 or dextran-70 or polygeline depends on the amount of fluid removed, which is <20% in patients with paracentesis <6 L and ~60% with paracentesis >9 L. 
PICD has a 20% risk of developing renal dysfunction and/or hyponatremia immediately after the procedure with the risk of renal dysfunction being <5% in those without PICD.  The presence of PICD is the most important independent predictor of survival in cirrhotics receiving LVP and plasma expansion. The incidence of PICD may be reduced to 15-20%, which is similar to the nonprocedure-related incidence in cirrhotics with ascites by plasma volume expansion with albumin. 
Recent studies have shown comparable efficacy between albumin and vasoconstrictors such as terlipressin and noradrenaline in the prevention of PICD. , Given the fact that terlipressin is equally expensive and that these were small pilot trials, the use of these agents as standard therapy cannot be recommended at present. Moreover, since the mechanism of action of plasma expanders and vasoconstrictors is different, it is feasible for the role of vasoconstrictors to be more appropriate as adjuncts to plasma expanders.
Despite a greater efficacy of albumin over other plasma expanders in reducing the incidence of PICD when >5 L of ascites is removed, this is not translated into a survival advantage. It must be underlined here that these trials were not designed to address the issue of survival; to attain this purpose, larger randomized trials must be conducted before any firm recommendations are made. Until such trials are performed, the bulk of the indirect data favors the use of albumin as the plasma volume expander of choice in patients with massive ascites undergoing paracentesis in order to decrease the incidence of PICD, which is a known predictor of renal dysfunction that logically evolves to type 1 HRS and perhaps eventual death.
The prevention of PICD serves as the most common indication for plasma expansion. However, the enthusiasm for the routine use of albumin has been dented by its expense, thereby triggering a search for cheaper alternatives. As mentioned before, other plasma expanders have been compared with albumin for the prevention of PICD, including saline, dextran and polygeline. In these randomized trials, none of these cheaper alternatives demonstrated efficacy comparable to albumin in terms of PICD development, increase in creatinine levels and probability of hospital readmission. ,
| Albumin and the Treatment of HRS|| |
Type 1 HRS is an acute functional renal failure that complicates end-stage cirrhosis. Previous investigations in cirrhotics with ascites have shown that both the expansion of the arterial blood volume and the reduction in the arterial vasodilation are essential to improve the renal function in nonazotemic patients. 
Two types of vasoconstrictor drugs have been used for the treatment of HRS: vasopressin analogues (ornipressin and terlipressin) and a-adrenergic agonists (noradrenaline and midodrine). Vasoconstrictors have a preferential effect in the splanchnic bed and have been shown to ameliorate renal hypoperfusion. , On the other hand, the infusion of plasma expanders (including albumin) alone has marginal or no effect on the renal function in patients with HRS type 1.  Evolving strategies have advocated combined therapy to improve the circulatory function by vasoconstrictors and increasing the central blood volume with albumin.
Recent evidence shows that the combined administration of albumin and vasoconstrictors normalizes the renal function in up to 65% of patients with type 1 HRS.  Studies have also shown that the improvement in renal function is associated with a significant increase in the survival expectancy.  Investigators have questioned the role of albumin in improving the therapeutic efficacy of vasoconstrictors. A study in Spanish patients comparing albumin and terlipressin with terlipressin alone showed that combination therapy resulted in more marked improvement in both circulatory and renal functions.  The same study also showed that albumin administration was associated with improved survival. Another large retrospective multicenter study revealed that the concomitant administration of albumin was associated with a higher chance of survival and that albumin had a significant survival advantage over other plasma expanders. 
The mechanism for this efficacy may be explained partially by the reduction in the vascular compliance achieved with terlipressin, which may improve the renal effects of albumin administration. It has also been hypothesized that albumin increases the effect of terlipressin at the receptor level and in turn contributes to the enhancement of its vasoconstrictor action.
The consensus statement of a recent workshop on HRS by the International Ascites Club recommends the combined usage of vasoconstrictors and albumin as the first line of therapy for type-1 HRS.  Vasoconstrictor therapy is significantly more effective when combined with plasma expansion by albumin. This regimen improves renal function, effectively translating into greater survival rates; hence, it serves as a valuable bridge to eventual liver transplantation.
| Conclusion|| |
There are several indications for the use of albumin in patients with decompensated cirrhosis. Obviously, in patients with documented SBP, albumin has ample evidence for its usefulness and is to be considered standard of care. There is considerable evidence that PICD is associated with a poor outcome and plasma expanders, particularly albumin, vastly prevent it. The clear demonstration that albumin prevents renal impairment speaks in favor of the agent; clearly, it is a predictor of worse outcome in patients with decompensated cirrhosis and prevents the development of HRS. In addition, albumin shows greater efficacy in comparison to other plasma expanders in randomized controlled trials and has a better safety profile. The evidence in support of SBP and HRS is significant and also shows survival advantage. As such, recent guidelines from the International Ascites Club recommend the usage of albumin for all the three indications mentioned above. Further studies are required to identify the subgroups of patients who are likely to derive the greatest benefit from albumin-based treatment.
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Faisal M Sanai
Department of Medicine, Riyadh Military Hospital, P. O. Box 7897, Riyadh - 11159
Source of Support: None, Conflict of Interest: None