The package inserts of albumin solutions for restoration and maintenance of circulating blood volume and volume deficiency in Europe follow the SPCs developed by the EMA and endorsed by the national health authorities that came into effect on 1 February 2019
Albumin is the most abundant plasma protein in the human body, alone constituting about 55% of the total protein content of plasma. lt comprises a single polypeptide chain of 585 amino acids with a molecular weight of 66,500 Daltons, and is synthesised entirely by the liver. Of the total content of albumin (about 250–350g for a healthy 70kg adult), approximately 40% is located in the intravascular compartment, and its half-life is about 20 days.1
Albumin is a multi-functional protein with both colloidal and pharmacological activity. The exchange of fluids between the intravascular and extravascular compartments is basically governed by the levels of hydrostatic and oncotic pressure and the degree of capillary membrane permeability. Albumin‘s colloidal activity is essential in maintaining fluid balance between the intravascular and interstitial compartments. Because it is the predominant plasma protein, albumin accounts for approximately 75–80% of plasma colloid osmotic pressure (COP). Due to the presence of several histidine residues with an acid dissociation constant very similar to the plasma pH, albumin is an excellent buffer in plasma as well as the main extravascular buffer able to donate positive and negative charges in case of alkalosis and acidosis, respectively (see Table 1).
In addition, albumin is endowed with diverse biologically specific capabilities such as ligand binding, antioxidant, free radical-scavenging and anti-inflammatory activity, inhibition of apoptosis and cell signalling.1
Albumin specifically binds to a wide array of endogenous ligands, including metabolites, lipids, hormones, metal ions and high-affinity endothelial cell albumin receptors.2 Ligand binding itself may serve multiple purposes such as transport, sequestration and transcytosis. Additionally, albumin binds numerous administered drugs and in many cases can modify their bioavailability and pharmacokinetics.3 For example, albumin administration results in increased effects of loop diuretics by augmenting drug delivery to the renal tubule.4
Evidence concerning these non-oncotic pharmacological properties of albumin continues to accumulate rapidly. Albumin plays a modulating role in haemostasis due to binding between sulfhydryl groups of albumin and nitric oxide (NO), thus slowing the inactivation of NO, which exhibits anti-aggregating effects on platelets and has vasodilator properties.5 Albumin contributes to the maintenance of normal permeability of capillaries to macromolecules and solutes and restricts the increase in the course of inflammation. This function is due to the presence of albumin within the capillary wall and might be directly derived both from its high negative charge, resulting in electrostatic repulsion of negatively charged molecules, and from space-occupying effects.6
Indirect action on the microcirculation could be mediated by binding with arachidonic acid, a molecule that increases capillary permeability. Furthermore, albumin inhibits the adhesion of human neutrophils to endothelial cells.7
In general, fluid therapy is used for replenishing fluid losses, to restore effective circulation as well as to correct acid-base and electrolyte disturbances. This is accomplished with two categories of substance: crystalloid and colloids. The crystalloid solutions distribute easily into the extracellular space, are used for maintenance as well as replacement of blood volume and serve as a vehicle for drug delivery. Crystalloids should have a composition similar to extracellular fluid.
A disadvantage is that they have a short duration of action. Colloids are solutions that contain larger and heavier molecules, which procure an increase in COP and are able to increase the volume of plasma by attracting water from the extracellular spaces. Colloids in clinical use are classified as natural (plasma and human albumin) or artificial or semi-synthetic solutions. The individual coiloids differ in their abilities to expand plasma volume depending on the COP of each fluid. Human albumin solutions are available both at low (4%, 5%) and high concentrations (20%, 25%) and exert a COP of about 20 and 70 mmHg, respectively, the latter being the highest COP solution available. Synthetic colloids have been proposed as an alternative to crystalloids but they may have serious side effects.
Human albumin may therefore be preferentially used in cases where a sustained action on the blood volume is required or when there is a contraindication for non-protein colloids.
Indications and clinical benefits of human albumin
Evidence-based use of albumin solutions in fluid therapy has been shown in acute conditions such as expansion of plasma volume for maintenance of effective circulatory blood volume (volume resuscitation) as weil as in some chronic conditions with low serum albumin. Hypoalbuminemia is a known prognostic factor for adverse outcome and administration of albumin solution has been shown to reduce morbidity.8,9 Its use is also considered appropriate in the exchange of large volumes of plasma.10
Current consensus and recommendations
Regarding volume resuscitation, current consensus and guideline recommendations are controversial. Studies confirm that the volume effect of albumin is superior to that of crystalloids.11 The exclusive use of crystailoids is nevertheless proposed by some experts in the field; crystalloids as a first choice followed by colloids as a second choice is recommended by others. The issue of which type of colloid should be used (artificial or natural) is controversial too, including when (early versus late) and where (emergency, ICU, surgery). However, clinical trials have confirmed longstanding safety concerns regarding the widespread use of artificial colloids. In contrast, human albumin solutions have been confirmed to be safe and effective in various clinical indications; in particular some complications in cirrhosis of the liver and in intensive care medicine, where the subgroup of patients with severe sepsis or septic shock has been shown in the SAFE study, and subsequent clinical trials and meta-analyses, to derive significant survival benefit.
Before having been abandoned because of higher costs and conflicting results of meta-analyses in the late 1990s, albumin solutions had been used in various clinical indications on the basis of different levels of evidence (Table 2). Subsequently, large-scale clinical trials have been performed. Their results are now available, confirming the safety of human albumin, and which also provide high-grade levels of evidence for its modern therapeutic use.
In cirrhotic patients with ascites, the therapeutic goal of treatment with albumin is not only limited to the maintenance of COP but also to improving effective circulating blood volume because splanchnic vasodilation reduces blood volume at the central level with activation of the renin–angiotensin system, sodium retention and development of ascites.12 The appearance of refractory ascites, that is, resistant to the administration of diuretics, represents an established indication for the use of albumin, when large volume paracentesis is performed leading to improved morbidity and mortality.12 In cirrhotic patients, additional indications include spontaneous bacterial peritonitis (1.5g/kg on day 1 and 1g/kg on day 3) and hepato-renal syndrome in association with vasoconstrictors (1g/kg on day 1 then 20–40g/day for 2 weeks).12
Severe sepsis and septic shock are characterised by micro-vascular leakage into the interstitium due to increased capillary permeability, production of pro-inflammatory cytokines and severe hypovolaemia. This results in a reduction in blood pressure and insufficient blood supply to major organs, with the risk of developing multiple organ failure.
Volume resuscitation by intravenous administration of crystalloids and albumin, combined with vasoactive amines and early surgical and/or antibiotic therapy of infection, are crucial in the treatment of severe sepsis and septic shock. Artificial colloids are harmful in these situations. Updated guidelines14 suggest the use of albumin in the presence of at least one the following conditions:
- evidence of increased capillary permeability (pulmonary oedema and/ or oedema peripheral);
- failure to respond to the initial administration of at least 2l of crystalloid given in the first three hours.
In surgical patients, according to guidelines used by some hospitals, the use of albumin may be indicated in patients undergoing major surgery (liver resection >40%, large bowel resection) if, after normalisation of blood volume, serum albumin is <2g/dl.9,15 The use of albumin in cardiac surgery is recommended in various guidelines for both filling of the heart–lung machine and to reduce oedema perioperatively.16,17 The synthetic colloids have been shown to increase postoperative bleeding and number of reoperations in several clinical studies and meta-analysis.18 Burns In burns, albumin is not the therapy of first choice in the first 24 hours, when crystalloids are to be used. In accordance with guidelines, albumin solutions are associated with crystalloids when burns cover more than 30% body surface area and with albumin levels less than 20g/l or when crystalloid therapy was not effective in the correction of hypovolemia.19
Plasmapheresis For plasmapheresis, human albumin is primarily recommended compared with crystalloids or synthetic colloids, when the plasma exchange procedure concerns large plasma volumes (>20ml/kg in one sitting, or >20ml/kg per week in case of repeated procedures). Crystalloid and albumin/crystalloid combinations are cost-effectiveness alternatives for plasmapheresis at smaller volumes.18
Ovarian hyperstimulation syndrome
In ovarian hyperstimulation syndrome, use of albumin solutions in nine randomised controlled trials decreased the odds of ovarian hyperstimulation syndrome compared with placebo.21 In the literature, results are mixed and additional evidence is needed to conclusively state that albumin administration is beneficial.
Appropriate use of albumin solutions in hospitals is subject to guideline recommendations and control. Considering the latest publications on the tolerability of the synthetic colloids and their risk of adverse reactions, recommendations for colloids‘ use will increasingly differentiate between natural and artificial, in particular when volume resuscitation in intensive care and surgery is concerned. Current guidelines strongly recommend the inclusion of albumin solutions in the circulatory support in certain critically ill patients and in complications of cirrhosis of the liver.
- Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic potential. Hepatology 2005;41:2111–19.
- Rabbani G, Ahn SN. Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo. Int J Biol Macromol 2019;123:979–90.
- Bertucci C, Domenilo E. Reversible and covalent binding of drugs to human serum albumin: methodological opproaches and physiologcial relevance. Curr Med Chem 2002;9:1463–81.
- Inoue M et al. Mechanism of furosemide resistance an analbuminemic rats and hypoalbuminemic patients. Kidney Int 1987;32:198–203.
- Keaney JF Jr et al. NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest 1993;91:1582–9.
- Demling RH. Effect of plasma and interstitial protein content and tissue edema formation. Curr Stud Hemotol Blood Transfus 1986;53:36–52.
- Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 2002;55:820–9.
- Wiedermann CJ, Wiedermann W, Joannidis M. Hypoalbuminemia and acute kidney injury: a meta-analysis of observational clinical studies. Intens Care Med 2010;36:1657–65.
- Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomzied, controlled trials. Crit Care Med 2004:32:2029–38.
- Schwartz J et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher 2016;31:149–62.
- Orbegozo Cortés D et al. Crystalloids versus colloids: exploring differences in fluid requirements by systematic review and meta-regression. Anesth Analg 2015;120:389–402.
- Bernardi M et al. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. J Hepatol 2012;55:1172–81.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406–60.
- Rhodes A et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304–77.
- Haynes GR, Navickis RJ, Wilkes MM. Albumin administration: what is the evidence of clinical benefit? A systematic review of randomized controlled trials. Eur J Anaestheslol 2003;20:771–3.
- Russell JA, Navickis RJ, Wilkes MM. Albumin versus crystalloid for pump priming in cardiac surgery: meta-analysis of controlled trials. J Cardiothorac Vasc Anesth 2004;18:429–37.
- Kingeter AJ et al. Association between albumin administration and survival in cardiac surgery: a retrospective cohort study. Can J Anaesth 2018;65:1218–27.
- Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2012;144:223–30.
- Cochran A et al. Burn patient characteristics and outcomes following resuscitation with albumin. Burns 2007;33:25–30.
- Cartotto R, Greenhalgh D. Colloids in acute burn resuscitation. Crit Care Clin 2016;32:507–23.
- Youssef MA et al. Intra-venous fluids for the prevention of severe ovarian hypersimulatian syndrome. Cochrane Database Syst Rev 2011;16:CD001302.