This article is a review and summary of the current opinion of albumin in fluid management. It links the physiology of fluid management and resuscitation to clinical findings and trial data. The article suggests that in certain situations, such as sepsis, or when there is a high risk of renal injury, albumin is a fluid replacement option that should be considered.
Shock, or tissue hypoperfusion, is associated with a significant mortality risk; fluid resuscitation is a cornerstone of management, and generous early fluid replacement is associated with improved survival. Conversely, an excessively positive fluid balance is also associated with poor outcomes. Mortality rates are more than doubled with either excessive or inadequate volume replacement. A balanced approach, treating the shocked state with rapid initial fluid replacement, before restricting fluids to maintain an overall negative balance is increasingly advocated. The debate over optimal fluid management continues, despite many large randomised controlled trials on the subject, and an increasing emphasis is placed on the role of the microvascular circulation.
Any fluid administered will distribute its volume across the intravascular, extravascular (interstitial) and intracellular spaces. The nature of this distribution is dependent on the electrolyte and oncotic properties of the fluid (figure 1). The equilibrium between the intravascular and interstitial spaces is regulated by the vascular endothelium – impermeable to large molecules, it is freely crossed by fluid and electrolytes. Active transfer of larger molecules (such as albumin) occurs at this level, but even in severe disease states where the endothelium becomes damaged and ‘leaky’, the oncotic gradient is maintained (although may be reduced).
The glycocalyx is a layer of glycosaminoglycans a few micrometres thick. It is the luminal layer of the endothelium, has anticoagulant and antioxidant properties, and is another determinant of permeability. Albumin has been noted to congregate alongside the glycocalyx – further enhancing the osmotic gradient. The equilibrium between the interstitial and intracellular spaces is driven by the osmotic forces acting across the cellular membrane.
Figure 1. Schematic distribution of fluids across intravascular, interstitial and intracellular spaces. H2O and 5% glucose are distributed quickly across all compartments; NaCl and other crystalloids remain within the intracellular volume better, but do move into the interstitium; colloids primarily remain in the intravascular space, but in conditions where endothelial permeability is increased, they may distribute into the interstitium (adapted from Vincent et al., 2016).
It is the oncotic and osmotic gradients that can be used to explain the plasma-expanding properties of fluids. Isotonic solutions, such as 0.9% saline, will distribute across the intravascular and extravascular spaces – resulting in plasma expansion that is less than their volume. Colloid solutions create a plasma expansion that is greater than their infused volume, by promoting diffusion into the intravascular space. An example determined by measuring haematocrit in healthy volunteers showed that 200 ml of 20% albumin solution corresponds to a dilutional effect corresponding to 800 ml of increased intravascular volume after 60 minutes. This expansion was largely maintained for 240 minutes. The effect is determined by leakage and metabolism of the colloid protein.
It has previously been a theoretical concern that in states of endothelial permeability, albumin extravasation will cause an enhanced flattening of the oncotic gradient. This has not been borne out by practical data; in lab-based sepsis models, the plasma-expanding capacity of albumin solution remains three times higher than crystalloid. Clinical data show that the serum levels of albumin remain higher in patients who receive albumin solution – demonstrating that it remains in the circulating volume, at least in part. Randomised controlled trials have demonstrated that in severe sepsis, the plasma-expanding properties of albumin are lower than in physiological conditions – but remain higher than crystalloids. The duration of the plasma-expanding effect is also markedly longer with albumin than other colloids (reduced by 30%, but persistent at 6 hours after infusion with albumin); gelatin (2 hours) and hydroxyethyl starch (HES) (4 hours).
The microcirculatory associated changes due to sepsis relate to heterogeneous perfusion of small vessels. Fluid therapy has a beneficial effect on the micro- as well as the macrocirculation. The optimal fluid composition is not clear, and experimental data have been clearly in favour of colloids, however this has not been borne out by clinical studies. The role of the glycocalyx may assume increasing importance in time; clinical studies are exploring the extent to which fluid therapies can protect or restore it.
Several large randomised controlled trials have caused a re-evaluation of colloids and crystalloids in critically ill patients in recent years. An increased need for renal replacement therapy and the negative mortality effect of HES has pushed practice away from colloids. Albumin still plays a role in critically ill sepsis patients – significantly reducing mortality over saline as demonstrated in a subset of patients with severe sepsis. Mortality benefits have also been suggested by correcting hypoalbuminaemia – although this has yet to be definitively demonstrated.
Unlike HES, albumin does not have any negative effect on renal function. A post-hoc analysis demonstrated that it may actually have a protective effect. In patients with critical illness (including cirrhosis), hyperoncotic human albumin solution reduced the incidence of acute kidney injury (AKI), while HES increased it. In established AKI, lower serum albumin levels were a predictor of increased mortality. Patients with cirrhosis and tense ascites, hepatorenal syndrome or spontaneous bacterial peritonitis we found to have better renal protection with albumin – albumin administration during large volume paracentesis led to significantly fewer cardiovascular exacerbations. These findings are suggested to reflect the physiological properties of albumin – acting as an acid-base buffer, transporting water-insoluble molecules, and providing an antioxidative and anti-inflammatory effect.
Albumin treatment has also been demonstrated to reduce nephrotoxicity of some drug classes, such as aminoglycosides – where a lower serum albumin concentration was found to be a powerful predictor of the risk of AKI. Other clinical scenarios where albumin has been demonstrated to play an important role include:
The role of fluid administration in improving both the macro- and microvascular perfusion in states of critical illness is becoming increasingly emphasised, and it is clear that albumin has a part to play in this setting.
Catch-up on the debate surrounding hydroxyethyl starch use as we take you on an interactive journey through its changing fortunes. Do you think current restrictions will be enough to change clinical practice?
This position paper from the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) reviews the evidence for the use of albumin in several settings related to liver cirrhosis.
This paper presents a meta-analysis to determine the impact of resuscitation with albumin on the morbidity and mortality of adult burn patients.
This meta-analysis examines whether the dosing of albumin affects outcomes in type 1 hepatorenal syndrome (HRS).
This review article explores the relationship between low albumin levels and acute kidney injury (AKI).
This meta-analysis pooled data from three large randomised controlled trials to determine whether early goal-directed therapy (EGDT) was an effective intervention for managing septic shock.
This systematic review and meta-analysis looked at the different mortality rates of various intravenous fluids and fluid protocols when used for resuscitation in sepsis.
This Chinese randomised controlled study explores the impact that a goal-directed fluid restriction (GDFR) protocol had on outcomes during anaesthesia for brain surgery.
This review paper examines the role of albumin in chronic liver disease, assessing the evidence for its use in several key clinical areas.
This matched cohort study aimed to determine whether a goal-directed fluid therapy (GDFT) intervention, delivered intraoperatively, would reduce post-operative morbidity in patients undergoing hip revision surgery.
This study explored fluid prescribing practices in intensive care – providing a picture of how fluid resuscitation is being managed internationally.
This multicentre audit reviewed the records of 431 patients who had undergone major elective surgery. The authors sought to determine how well IV fluids were prescribed both intraoperatively and perioperatively when compared with current guidance.
This double-blinded, randomised controlled trial examined whether pre-operative administration of exogenous albumin affected rates of acute kidney injury (AKI).
This article is a review and summary of the current opinion of albumin in fluid management.
This retrospective, observational study used a propensity scoring system to match patients treated with saline with those given a balanced, calcium-free fluid.
A recent PRAC review has recommended suspension of marketing authorisations for HES solutions for infusion across the EU.
Following the European Medicines Agency’s (EMA) suspension of the marketing authorisations of hydroxyethyl starch (HES) solutions across the European Union (EMA, 2018), Roberts et al., have written an open letter addressed to the World Health Organization (WHO) Director General seeking support for the suspension of HES solutions and expanding it to a worldwide ban.
The Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) endorse the suspension of hydroxyethyl-starch (HES) solutions, due to serious risks of kidney injury and death in certain patient populations.
The hypothesis that hypertonic fluid has a dual physiological role, increasing circulatory volume while administering minimal volumes and muting the pro-inflammatory response to injury and illness, may be appealing, but is it superior to isotonic fluids in practice?
In this post-hoc, subgroup analysis (study 1) and prospective, single-centre nested cohort (study 2) from the SPLIT (0.9% saline vs. PL-148 for ICU fluid therapy) trial, the investigators hypothesised that patients receiving Plasma-Lyte 148 would require fewer blood products and have less post-operative bleeding than those receiving saline.
Acute kidney injury (AKI) affects one-fifth of major surgery patients, increasing the risk of long-term mortality. This review paper discusses recent study data, discussing the best methods for preventing postoperative AKI.
Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion.
Cirrhosis of the liver is a leading cause of mortality. For patients with decompensated cirrhosis, long-term weekly human albumin administration can act as an effective disease-modifying treatment.
In 1896 Ernest Starling published his hypothesis for fluid exchange, whereby fluid exchange exists mainly in the capillaries through a process of plasma ultrafiltration across semipermeable membranes (Starling, 1896). But is this 19th century theory something of the past?
Long-term albumin treatment for ascites associated with cirrhosis has been debated in recent years, with mixed results reported for the treatment’s efficacy. In this non-randomised prospective study, Di Pascoli and colleagues question the benefits of long-term albumin in patients with liver cirrhosis and refractory ascites, focussing on survival and emergent hospitalisations. Could this be part of the solution to the ongoing challenge of ascites in cirrhosis?
The choice of fluid administered during cardiac surgery remains a debated topic, often focussed around colloid solutions containing albumin. Conflicting results from numerous studies have left questions over albumin safety and potential to be superior to crystalloids during surgery. Kingeter et al. hoped to achieve clarity on this controversial topic in a retrospective study of cardiac surgery outcomes over a 12-year period.
Patients admitted to intensive care are often haemodynamically unstable with fluid resuscitation therapy regularly used to overcome this. The use of small volume resuscitation with 20% albumin has historically been limited compared to standard fluid resuscitation with 4–5% albumin due to safety concerns, but could those concerns be misplaced? Read more about how the SWIPE trial has provided new insights into the possibilities of using small volume resuscitation within the ICU.