Fluid management in sepsis: The potential beneficial effects of albumin

  • Vincent JL, De Backer D, Wiedermann CJ.
  • J Crit Care. 2016 Oct;35:161–7.

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.

Albumin in sepsis

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.

Albumin and kidney injury

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:

  • fluid overload in critically ill patients
  • pulmonary oedema in acute lung injury
  • increased central venous pressure in critical illness
  • renal transplant.

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.

Explore the Fluid Management Knowledge Centre to discover more about the role of fluid therapy in cardiac surgery, critically ill patients, liver cirrhosis, and more.

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