Albumin in cirrhosis

Guidelines for fluid management in cirrhosis

Ideally, the aim of cirrhosis management should be to prevent disease progression with treatments that target pathological changes in the liver and suppress inflammation, to enable regression of fibrosis and normalisation of portal and arterial circulation^5,6. However, such treatments do not yet exist⁵. At present, management consists of prophylactic measures to prevent decompensated cirrhosis or treatment of complications to improve outcomes⁵.

Figure 3 illustrates the indications and dosage of albumin in the natural history of decompensated cirrhosis.

Figure 3. Traditional management of decompensated cirrhosis (Adapted⁸).

In the following video Alastair O’Brien, Professor of Experimental Hepatology at University College London, discusses the guidelines and evidence base for albumin as a treatment for cirrhosis, emphasising the importance of taking individual patient needs into consideration. He also describes practical considerations including the importance of monitoring blood pressure and creatinine levels.

In 2018, the European Association for the Study of the Liver (EASL) released their first clinical practice guidelines for the management of decompensated cirrhosis⁵. These guidelines are evidence-based and were developed to guide the management of this condition⁵.

According to EASL guidelines, evaluation of patients with cirrhosis and ascites should include⁸:

• Detailed patient history
• Physical examination
• Abdominal ultrasound
• Laboratory analyses

The guidelines also recommend diagnostic paracentesis for differential diagnosis in all patients with moderate-to-severe ascites, and for patients hospitalised for any cause⁸. The guidelines stipulate that ascitic fluid analyses should include evaluation of differential leukocyte counts, cultures, and protein and albumin concentrations⁸. They also recommend considering calculation of the serum-ascites albumin gradient, with a result of ≥1.1 g/dL suggesting – to a high degree of accuracy – the involvement of portal hypertension with ascites formation⁸. Finally, total protein concentration <1.5 g/dL is considered a risk factor for spontaneous bacterial peritonitis (SBP), and other tests such as carcinoembryonic antigen should be considered if appropriate for the particular patient⁸.

The standard treatment to manage grade 3 ascites is large volume paracentesis (LVP)⁸. However, this treatment confers a risk of paracentesis-induced circulatory dysfunction, also known as post-paracentesis circulatory dysfunction (PPCD)^5,8. In this condition, effective volaemia decreases as a result of plasma renin activity increasing by over 50% at 4–6 days post-paracentesis⁸. This involves a rapid decrease in abdominal pressure, an increase in venous return and an associated increase in cardiac output, which leads to a rapid decrease in peripheral vascular resistance, resulting in a decrease in effective volaemia⁸. The condition manifests as renal dysfunction, arterial hypotension, hepatic encephalopathy, dilutional hyponatraemia and reduced survival⁸.

The EASL guidelines recommend plasma volume expansion at LVP completion to prevent PPCD⁵.

Human albumin administration (8 g/L of ascites removed) has been shown to be superior to other plasma expanders or vasoconstrictors if >5 L of ascites fluid is removed, as it can reduce PPCD complications, including mortality, but has similar efficacy as saline and artificial plasma expanders if <5 L of fluid is removed^5,8

Although artificial plasma expanders have similar efficacy as human albumin if <5 L of ascites fluid is removed, expert opinion favours human albumin administration because of safety concerns with alternative plasma expanders, including side effects such as renal dysfunction and allergic reactions⁸.

With respect to liver-related complications and hospital costs over 30 days, albumin infusion following LVP has been shown to be more cost-effective, compared with less expensive plasma volume expanders⁵. In patients with grade 3 ascites, LVP combined with human albumin infusion was shown to be safer and more effective than diuretics⁵. However, diuretic therapy is required for patients receiving LVP treatment, to prevent re-accumulation of ascites⁵.

Given these findings, the EASL guidelines recommend the following treatment for patients with large or grade 3 ascites⁵:

• LVP as first-line therapy, completely removing ascites in one session
• To prevent PPCD, treat with LVP and then administer plasma volume expansion
• For patients undergoing LVP of >5 L of ascites, perform plasma volume expansion by infusing human albumin (8 g/L of ascites removed)
• For patients undergoing LVP of <5 L of ascites, treat with human albumin
• Following LVP, provide diuretics at the lowest dose possible to prevent re-accumulation of ascites
• Perform LVP in patients with acute kidney injury (AKI) or SBP when needed

In patients with refractory ascites, the EASL guidelines recommend LVP plus albumin (8 g/L of ascites removed) as first-line treatment⁵. In the case of hypervolaemic hyponatraemia, the guidelines suggest human albumin administration, but note that supporting data are very limited⁵. In patients with SBP, the guidelines recommend human albumin administration (1.5 g/kg at diagnosis and 1 g/kg on day 3). However, routine use of human albumin in other infections is not recommended⁵.

Renal impairment commonly develops in patients with ascites⁸. Acute renal impairment, defined as AKI, can occur in decompensated cirrhosis, with pre-renal AKI being the most common form⁸. Plasma volume expansion is used to correct the condition⁸. If a particular form of AKI, hepatorenal syndrome (HRS-AKI), is diagnosed, albumin treatment should be started in addition to vasoconstrictors (mainly terlipressin), having found to improve or resolve the condition in 50–60% of cases⁸. 

SBP can lead to HRS-AKI, liver function deterioration, hepatic encephalopathy and serious circulatory dysfunction⁸. However, early detection and prophylaxis with human albumin can reduce mortality from 30% down to 10%⁸. Unfortunately, there is a high rate of recurrence for patients recovering from SBP, being around 70% at one year, and their survival probability decreases to 30–50% at one year and 25–30% at two years⁸. For these reasons, prophylaxis with norfloxacin is recommended⁸. 

Fluid selection in cirrhosis

In the following video, Alastair O’Brien, Professor of Experimental Hepatology at University College London, discusses factors to consider when deciding which fluid is most appropriate to treat a person with cirrhosis. These factors include benefits, costs, evidence, and the amount of fluid to administer.

When considering fluid options, it may be useful to regard each fluid option as a drug, each with indications, contraindications and possible side effects¹⁰

It may be helpful to refer to the 4 Ds of fluid therapy (drug, dose, duration and de-escalation) when considering the most appropriate fluid therapy to treat patients with cirrhosis.

Review the 4 Ds of fluid therapy

The three categories of treatment options recommended for fluid management in cirrhosis are crystalloids, colloids and blood transfusion. Table 3 summarises the recommendations for fluid management using these options, from the EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. Please note that this table contains a summary only: for full information please refer to the EASL Clinical Practice Guidelines as well as your local treatment guidelines⁵.

Table 3. Recommended fluid management treatment options in cirrhosis⁵.

Albumin to treat cirrhosis

In cirrhotic patients, albumin has been administered because of its oncotic properties, which may increase effective circulating volume and end the physiological cascade of events. Human albumin is used for plasma expansion, to prevent and treat particular complications of cirrhosis with ascites, such as post-paracentesis circulatory dysfunction (PPCD) and renal dysfunction caused by spontaneous bacterial peritonitis (SBP)⁸. Recent evidence indicates that long-term human albumin administration in patients with decompensated cirrhosis is associated with a reduced incidence of complications, lower mortality rate, improved ascites management, has a favourable safety profile and is cost-effective⁸. Therefore, human albumin may be considered as an option for treating patients with cirrhosis and ascites⁸. However, it is important to note that the long-term administration of human albumin in patients with decompensated cirrhosis has been debated for decades and long-term benefits have not been clearly established¹¹.

Figure 4 highlights the many uses of albumin in cirrhosis.

Figure 4. Uses of albumin in cirrhosis (Adapted)⁹. AKI, acute kidney injury; MAP, mean arterial pressure; SBP, spontaneous bacterial peritonitis

Treating decompensated cirrhosis with long-term albumin administration

The results of an open-label randomised trial, the ANSWER study, revealed that long-term administration of human albumin improved 18-month survival in patients with decompensated cirrhosis (Kaplan-Meier estimates 77% vs 66%; P=0.028), reducing the mortality hazard ratio by 38% (0.62, 95% confidence intervals 0.40–0.95)^8,12. Analysis revealed that human albumin was the sole factor that protected patients from all-cause mortality⁸. Paracentesis, the incidence of refractory ascites, SBP and other cirrhotic complications were also significantly reduced by 30–67.5% with administration of human albumin. Further, patients administered human albumin had fewer hospitalisations and spent approximately half the amount of time in hospital than those who received standard medical treatment only⁸.

Results from the Pilot-PRECIOSA and INFECIR-2 trials indicated that patients with decompensated cirrhosis who were treated with albumin showed reductions in cardiocirculatory dysfunction and systemic inflammation¹³. In an exploratory cohort, administration of albumin at 1.5 g/kg weekly for 12 weeks demonstrated significant immunomodulatory effects¹³. While the investigation cohort consisted of a low number of patients, the results suggest that treating decompensated cirrhosis with albumin improves markers of systemic inflammation, which may explain the improvements demonstrated by albumin therapy in this setting¹³. The Pilot-PRECIOSA study indicates the importance of the dose of albumin administered, as patients given the low dose (1 g/kg every fortnight) did not experience the same beneficial effects as those given the high dose⁸. Similarly, a post hoc analysis of the ANSWER study found that normalised serum albumin concentration at one month had a close association with survival, surpassing 90% when reaching a concentration of 4.0 g/dL⁸.

In this video Professor O’Brien shares his key take aways for healthcare professionals who manage patients with cirrhosis who require intravenous fluid therapy. He highlights the importance of close and careful monitoring post-infusion.

In the ATTIRE trial, patients with decompensated cirrhosis were treated with albumin or standard care for up to 14 days, and the results demonstrated that albumin infusions to achieve a target level of 30 g/L or more was not more beneficial than standard care. The PRECIOSA trial is currently underway to evaluate the effects of long-term albumin infusion (up to 12 months) in patients with decompensated cirrhosis and ascites^14,15.

Further research is needed to help optimise the administration of human albumin in clinical practice, namely⁸:

• Optimal dose and schedule
• The role of human albumin concentration during treatment
• Whether human albumin may have a role in acute cirrhotic complications
• Understanding which patient populations would derive the greatest benefit
• When stopping administration of human albumin may be appropriate

In addition, more research is required into the effectiveness of albumin, compared with saline, for general surgical patients with decompensated cirrhosis⁴.

When considering fluid treatment options, it is important to work in collaboration with the patient, taking into account their individual needs and preferences and giving them the opportunity to make an informed choice about their treatment¹⁶.

References

1. Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N. Liver cirrhosis. The Lancet. 2022.
2. Sharma A, Nagalli S. Chronic Liver Disease. StatPearls [Internet]. 2021.
3. Moon AM, Singal AG, Tapper EB. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clinical Gastroenterology and Hepatology. 2020;18(12):2650-2666.
4. Maynard E. Cirrhosis and Fluid Resuscitation. Surgical Clinics of North America. 2017;97(6):1419-1424.
5. Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, et al. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. Journal of Hepatology. 2018;69(2):406-460.
6. Bernardi M, Angeli P, Claria J, Moreau R, Gines P, Jalan R, et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020;69(6):1127-1138.
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9. Jagdish RK, Maras JS, Sarin SK. Albumin in Advanced Liver Diseases: The Good and Bad of a Drug! Hepatology. 2021;74(5):2848-2862.
10. Mekeirele M, Vanhonacker D, Malbrain MLNG. Fluid Management in Sepsis. Springer Nature Singapore; 2022. p. 199-212.
11. Paolo Caraceni PADPMB. AISF-SIMTI position paper on the appropriate use of albumin in patients with liver cirrhosis: a 2020. 2022.
12. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. The Lancet. 2018;391(10138):2417-2429.
13. Fernández J, Clària J, Amorós A, Aguilar F, Castro M, Casulleras M, et al. Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis. Gastroenterology. 2019;157(1):149-162.
14. China L, Freemantle N, Forrest E, Kallis Y, Ryder SD, Wright G, et al. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis. New England Journal of Medicine. 2021;384(9):808-817.
15. NCT03451292. Effects of Long-Term Administration of Human Albumin in Subjects With Decompensated Cirrhosis and Ascites (PRECIOSA). 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03451292.
16. NICE. Patient-centred care | Intravenous fluid therapy in adults in hospital | Guidance | NICE. https://www.nice.org.uk/guidance/cg174/chapter/Patient-centred-care. Accessed 2 Jul 2022.