Albumin in fluid management Learning Zone

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Albumin in cirrhosis

Declaration of sponsorship CSL Behring

Read time: 45 mins

Last updated:27th Apr 2023

Published:27th Apr 2023

Fluid needs in cirrhosis

Liver diseases, specifically cirrhosis, have been recognised as very important but underestimated health issues¹

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Chronic liver disease is very common², with an estimated 1.5 billion people having this condition in 2017³. The most common causes of chronic liver disease are alcoholic and non-alcoholic fatty liver disease, chronic viral hepatitis, genetic predisposition, autoimmune disorders and some drugs. Chronic inflammation and fibrosis result in progressive deterioration of liver function and can lead to cirrhosis². In cirrhosis, regenerative hepatic nodules replace the normal liver architecture, eventually resulting in liver failure¹. Progression to cirrhosis does not occur in all patients with liver disease, but is responsible for approximately half of all deaths from liver disease globally and is the 11th most common cause of death worldwide¹.

In the following video, Alastair O’Brien, Professor of Experimental Hepatology at University College London, discusses the increasing prevalence of liver disease and highlights fluid resuscitation as the cornerstone of management. Professor O’Brien defines compensated versus decompensated cirrhosis and introduces albumin and the benefits of treatment for people with cirrhosis.

Decompensated cirrhosis

Improving the understanding of fluid resuscitation in decompensated cirrhosis is key to decreasing morbidity and mortality⁴

Cirrhosis is typically asymptomatic until portal pressure increases and liver function worsens. In the asymptomatic phase, known as ‘compensated cirrhosis’, the disease may remain undetected for years while continuing to progress, and the person may enjoy a good quality of life during this phase⁵.

Portal hypertension triggers a chain of events that lead to sodium and fluid imbalances (Figure 1), culminating in acute decompensation. This is associated with potentially life-threatening complications including ascites, gastrointestinal bleeding, infection, particularly spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy^4,6–8.

The physiological cascade of events in cirrhosis

Figure 1. The physiological cascade of events in cirrhosis (Adapted⁴).

Decompensated cirrhosis is systemic, characterised by an increase in circulating chemokines and pro-inflammatory cytokines, and involves multiple organs and systems⁵. In 30% of cases there is rapid progression to extra-hepatic organ failure, often involving the kidneys, and acute-on-chronic liver failure (ACLF), which is associated with systemic inflammation and a high 28-day mortality rate^6–8.

The detrimental effects of cirrhosis can also be attributed to decreased synthesis of albumin as well as alterations to the structure of albumin resulting from the pro-inflammatory and pro-oxidant states⁶.

Median survival reduces from 12 years in compensated cirrhosis to approximately 2 years in decompensated cirrhosis⁵

It is now known that decompensated cirrhosis is a protracted pro-oxidant and pro-inflammatory condition caused by systemic spread of pathogen-associated molecular patterns (PAMPs) from the gut and damage-associated molecular patterns (DAMPs) from the diseased liver, with these mechanisms driving acute decompensation⁸. Given the non-oncotic properties of albumin, which may counteract pathophysiological mechanisms, long-term administration of human albumin is emerging as a disease-modifying treatment in this condition, extending its function in decompensated cirrhosis beyond volume expansion⁸.

Experimental models reveal the mechanisms of albumin that contribute to its immunomodulatory properties⁸. For instance, albumin binds a range of offending molecules in cirrhosis such as PAMPs and DAMPs, it regulates cytokine production and release, and regulates antigen-presenting cell functions⁸. These mechanisms have been observed in people with decompensated cirrhosis whereby albumin reduces the levels of some cytokines⁸. Further, the ability of albumin to bind the interstitial matrix and interact with the sub-endothelial space is an important function that helps preserve endothelial functions⁸.

Albumin synthesis and function in cirrhosis

In liver disease, albumin synthesis, structure and function are altered. In cirrhosis in particular, albumin synthesis can decrease by half and in the decompensated setting patients experience protein malnutrition⁴.

In cirrhotic patients, the cumulative effects of decreased albumin synthesis, impaired precursor intake and increased proteolysis leads to global hypoalbuminaemia, which reduces effective circulating volume and oncotic pressure, causing renal sodium and water retention with ascites and anasarca, making resuscitation more difficult⁴.

Figure 2 illustrates the effects of liver disease on albumin synthesis and function.

Albumin in liver disease

Figure 2. Albumin in liver disease (Adapted⁹). ACLF, acute-on-chronic liver failure; ESLD, end-stage liver disease; HNA, human nonmercaptalbumin; PGE2, prostaglandin E₂; TNF_α, tumour necrosis factor alpha.

Ascites

Cirrhosis is responsible for approximately 80% of ascites cases in developed countries^5,8. Five to 10% of patients with compensated cirrhosis develop ascites, which is the most common complication of decompensation⁵. Ascites signals a significant worsening of prognosis and requires chronic treatment. Its clinical manifestations impact a person’s ability to work and socialise, can lead to hospitalisation, and can cause further complications such as abdominal hernias, restrictive ventilatory dysfunction, spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS)^5,8. Learn more about guideline recommendations for treatment of decompensated cirrhosis.

With the onset of ascites, 5-year survival reduces from approximately 80% in compensated patients to around 30% in decompensated cirrhosis⁵

The 1-year mortality rate of cirrhosis with ascites is approximately 40%, the 2-year mortality rate is about 50%, and the 5-year mortality rate around 70%⁸. It is therefore important that patients with ascites are assessed for liver transplantation⁸.

Ascites is graded according to the amount present (Table 1) and classified according to treatment responsiveness (Table 2)⁸.

Table 1. Ascites grades and characteristics⁸.

Grade	Characteristics
Grade 1	Mild: only detectable by ultrasound
Grade 2	Moderate: moderate abdominal distension
Grade 3	Large or gross: severe abdominal distension

Table 2. Ascites treatment classifications⁸.

Responsive ascites
Can be fully mobilised or confined to grade 1 with diuretic therapy, which may involve dietary sodium restriction
Recidivant ascites
Recurs at least three times within 12 months despite satisfactory diuretic dosage and dietary sodium restriction
Refractory ascites
Diuretic-resistant Cannot be mobilised, or prevention of early recurrence not possible due to inadequate response to diuretic treatment and sodium restriction Diuretic-intractable Cannot be mobilised, or prevention of early recurrence not possible due to diuretic-induced complications impeding the use of an effective dose of diuretic

Complications of ascites that further worsen prognosis include SBP, which is established by a neutrophil count of >250/µL in the ascitic fluid and hepatorenal syndrome (HRS)⁸.

Fluid resuscitation in decompensated cirrhosis

While it is important to determine volume status in cirrhosis, this can be difficult because up to half the extracellular fluid may be in the extravascular space, evidenced as ascites and oedema⁴. Further, while a patient may appear total volume expanded, they may in fact be intravascularly volume-depleted and therefore at risk of HRS⁴. In a postoperative patient with liver disease, over-resuscitation risks ascites and hyponatraemia, which are hard to treat⁴.

Management of hypervolaemic hyponatraemia

In decompensated cirrhosis, portal hypertension leads to increases in plasma volume, which can lead to significant hypervolaemic hyponatraemia⁴. Hyponatraemia (defined as sodium <130 mmol/L) is an independent predictor of mortality, and the initial step is to determine whether the patient is hypo- or hypervolaemic⁴.

Hypovolaemic hyponatraemia often occurs secondary to overdiuresis. It is less common than hypervolaemic hyponatraemia, and its hallmark symptoms are low serum sodium in the absence of ascites and oedema. Administration of normal saline and withholding diuretics is the initial management step in this condition. Albumin use in this setting is not supported by evidence⁴.

Hypervolaemic hyponatraemia occurs when antidiuretic hormone is over-secreted, resulting in unbalanced water and sodium retention⁴. Restriction of free water to <1000 mL/day is the primary treatment, with no data supporting saline administration. The European Association for the Study of the Liver guidelines support albumin use in this setting for volume expansion⁴. After over-resuscitation with crystalloid in a perioperative patient, iatrogenic hypervolaemic hyponatraemia may occur; therefore, careful fluid administration and free water restriction are necessary as a preventive measure⁴.

Management of hepatorenal syndrome

HRS is defined by acute kidney injury (AKI) in cirrhosis. Albumin is used to both treat and prevent HRS, and a randomised trial demonstrated albumin’s ability to prevent HRS and to improve survival in SBP. HRS comprises two types: HRS1, which is more severe, and HRS2. In HRS1, standard treatment involves vasopressin, or a vasopressin analogue such as terlipressin, and albumin administration. HRS tends to occur in postoperative patients; therefore, it is important to investigate postoperative patients with increased creatinine for potential HRS, with aggressive treatment to help reduce mortality⁴.

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.

Traditional management 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.

Hypervolaemic hyponatraemia
Managing hypervolaemic hyponatraemia with hypertonic saline should be limited to cases with life-threatening complications, and for patients with severe hyponatraemia expecting a liver transplant within days • Once symptoms reduce, slow correction of serum sodium concentration (≤8 mmol/L per day) will help avoid irreversible neurological complications • Human albumin can be considered to treat hypervolaemic hyponatraemia, but supportive data are very limited
Acute gastrointestinal (GI) bleeding in cirrhosis
Considered a medical emergency, carrying a high risk of complications and mortality • In cirrhotic patients with upper acute GI bleed, acute variceal haemorrhage must be suspected, with treatment commencing immediately once bleeding has been confirmed clinically, with the goal of initial treatment to restore volaemia • Expeditious initiation of blood volume replacement should be considered for restoration and maintenance of haemodynamic stability for tissue perfusion and oxygen delivery. Colloids and/or crystalloids should be used, and starch should not be used. Note the use of colloids has not been demonstrated to confer benefit over crystalloids • In severe anaemia, red blood cells can improve delivery of oxygen to tissues. For most patients, a restrictive transfusion strategy is sufficient with a haemoglobin threshold of 7 g/dl for transfusion and 7–9 g/dL as a target range post-transfusion. For patients with massive haemorrhage or particular underlying conditions, the threshold for transfusion could be higher
Spontaneous bacterial peritonitis
Human albumin administration is recommended at 1.5 g/kg at diagnosis and 1 g/kg on day 3. However, routine albumin use is not recommended for other infections
Acute kidney injury (AKI)
Volume replacement should be administered in line with the cause and severity of fluid loss • Packed red blood cells are recommended for patients with acute GI bleeding, to maintain haemoglobin level of 7–9 g/dL • Crystalloids are recommended for patients with excessive diuresis or diarrhoea • Therapeutic paracentesis is recommended with human albumin infusion for patients with AKI and tense ascites • For AKI stage >1A and with no obvious cause, 20% human albumin solution at 1 g/kg (100g albumin maximum) is recommended for two days
Hepatorenal syndrome (HRS)
All patients who meet AKI-HRS stage >1A should receive expedited treatment with vasoconstrictors and albumin • Consider terlipressin plus human albumin as the first-line option to treat HRS-AKI • 20% human albumin solution at 20–40 g/day is recommended for patients with HRS-AKI ◦ Taking serial measurements of central blood volume can assist with titrating the albumin dose, thus optimising fluid balance and avoiding circulatory overload

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.

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

Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N. Liver cirrhosis. The Lancet. 2022.
Sharma A, Nagalli S. Chronic Liver Disease. StatPearls [Internet]. 2021.
Moon AM, Singal AG, Tapper EB. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clinical Gastroenterology and Hepatology. 2020;18(12):2650-2666.
Maynard E. Cirrhosis and Fluid Resuscitation. Surgical Clinics of North America. 2017;97(6):1419-1424.
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.
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.
Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol. 2021;75 Suppl 1(Suppl 1):S49-s66.
Tufoni M, Zaccherini G, Caraceni P, Bernardi M. Albumin: Indications in chronic liver disease. United European Gastroenterology Journal. 2020;8(5):528-535.
Jagdish RK, Maras JS, Sarin SK. Albumin in Advanced Liver Diseases: The Good and Bad of a Drug! Hepatology. 2021;74(5):2848-2862.
Mekeirele M, Vanhonacker D, Malbrain MLNG. Fluid Management in Sepsis. Springer Nature Singapore; 2022. p. 199-212.
Paolo Caraceni PADPMB. AISF-SIMTI position paper on the appropriate use of albumin in patients with liver cirrhosis: a 2020. 2022.
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.
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.
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.
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.
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.

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