Recruitment of extravascular fluid by hyperoncotic albumin

  • Zdolsek M, Hahn RG, Zdolsek JH.
  • Acta Anaesthesiol Scand. 2018;62:1255–60.

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?

absorption of isotonic salt solutions [from the extravascular space] by the blood vessels is determined by this osmotic pressure of the serum proteins.

Starling’s principle suggests the rate of fluid movement is dependent on the differences in hydrostatic pressure and colloid pressure across the capillary walls. The equation suggests that increasing the plasma albumin concentration will, in turn, mobilise fluid from the interstitial fluid volume into the blood volume (Starling, 1896).

Mobilising fluids are a key part of fluid resuscitation in intensive care and is vital during the de-escalation stage in order to promote organ recovery and avoid the harmful effects of oedema (Heughan et al., 1972; Hunt et al., 1975; Prien et al., 1990; Gosain & Gamelli, 2005; Lindahl et al., 2013). With diuretic therapy often being ineffective, and Starling’s principle suggesting increasing plasma albumin can mobilise extravascular fluids, hyperoncotic fluids such as albumin have often been administered to patients in this stage of fluid resuscitation.

However, a more recent version of the Starling principle suggests plasma oncotic pressure is less important than previously thought, that interstitial forces are not negligible, and that the presence of the endothelial glycocalyx (EG) is key to determining fluid transfer (Woodcock et al., 2012). This revision has raised questions surrounding the efficacy of albumin for fluid recruitment.

Despite this revision there is still much debate surrounding the efficacy of albumin use for fluid recruitment. Hoping to take a more in-depth look at the physiology behind this phenomenon, Zdolsek et al. investigated plasma volume expansion using a mass balance to calculate the degree of fluid recruited from interstitial and intracellular fluid spaces.


An infusion of 3 mL/kg of 20% albumin was administered over 30 minutes to 15 healthy volunteers. Preceding the study participants were asked to fast from midnight and then instructed to have a light breakfast and glass of clear liquid 1.5 hours prior to the infusion to help ensure euhydration. Plasma blood volume and fluid recruited from extravascular and intracellular spaces were monitored from 0–300 minutes after the start of infusion.

Increase in plasma volume expansion

The maximum plasma volume expansion, (15.8% ± 5.1%), was achieved later than expected: approximately 50 minutes after starting the infusion/20 minutes after the infusion ended (Figure 1). Zdolsek et al. have hypothesised this delay is due to the gel structure of the interstitium. In the same way that this filament meshwork binds to and prevents fluid flowing to the feet when a person is standing, a lack of larger ‘free’ fluid spaces in healthy individuals might also explain the slow fluid transfer from the tissues to the blood volume observed in this study.

Change in plasma volume expansion* from 0–300 minutes after starting albumin infusion (Zdolsek et al., 2018).

Figure 1. Change in plasma volume expansion* from 0–300 minutes after starting albumin infusion (Zdolsek et al., 2018). *Plasma volume expansion derived from change in blood haemoglobin concentration both during and after infusion.

Key findings

While it’s clear that fluid was recruited to the blood plasma volume, in line with the Starling principle, had the fluid been recruited from the intracellular spaces?

By drawing blood and measuring urine outputs, Zdolsek et al. were able to calculate the fluid recruitment from the extravascular to the intravascular space per mL of 20% albumin (Recruitment Efficiency, RE). At 300 minutes the total recruitment from the tissues amounted to  3.4 ± 1.2 mL fluid/mL of infused 20% albumin. This key finding, that 3.4 times the infused volume was recruited into the circulating blood supports the traditional view of recruitment efficacy of 20% albumin based on the Starling principle. Furthermore, 19% of this fraction was recruited from the intracellular volume (figure 2).

Recruited fluid per mL after infusion of 20% albumin when analysed at 300 minutes. The fraction of the recruited fluid that originated from the intracellular space is shown in blue.

Figure 2: Recruited fluid per mL after infusion of 20% albumin when analysed at 300 minutes. The fraction of the recruited fluid that originated from the intracellular space is shown in blue. ICV, intracellular volume; RE, recruitment efficiency; V, volunteer.

Urine outputs

Hyperoncotic albumin has been associated with increased plasma volume, reduction in creatine concentration and doubled urine flow rate in previous studies (Greenough et al., 1988). Interestingly in this study, while creatinine concentration did decrease significantly a strong linear correlation was observed between urinary output and the amount of recruited extravascular fluid (R2 = 0.88, p<0.001).

Table 1: Laboratory data from baseline and 300 minutes following the infusion of hyperoncotic albumin

Table 1: Laboratory data from baseline and 300 minutes following the infusion of hyperoncotic albumin

Based on the reduction in concentration in the urinary creatinine a doubled urine flow rate might be expected (Greenough et al., 1988). However, Zdolsek et al. found that participants with lower urinary output had a higher plasma volume expansion at 300 minutes than those with a larger urinary excretion. This result is unusual for albumin infusion and is more typical of crystalloid, however, colloids have been shown to have a slightly dehydrating effect which may be the case for 20% albumin as urinary excretion exceeded the infused volume by a factor of 2–3.

One concern of administering diuretic therapy to patients in the de-escalation stage of fluid resuscitation is the risk of developing hypovolaemia. In this current study, hypovolaemia wasn’t reported and therefore the dehydrating effect can be explained by the recruitment of fluid from the extravascular space. In this case, plasma volume expansion was not associated with hypovolemia risk.

Colloid osmotic pressure

The revised Starling principle suggests that recruitment of interstitial fluid can only occur through the lymphatics and not by raising the colloid osmotic pressure. In contrast to this newer theory, Zdolsek et al. found the results had a closer resemblance to the original Starling principle, where colloid osmotic pressure was increased significantly following albumin infusion at 60 minutes (p<0.001), with a slight decrease from 60 to 300 minutes (p<0.03). This increase upon infusion and a slight decrease over time is also reflected in the increase in plasma volume expansion. As mentioned earlier, these results are also in line with the Starling principle where the recruitment efficiency is proportional to the difference in colloid osmotic pressure, and a slight reduction can be caused by hydrostatic pressure. 

It seems this 19th century theory may not be one to be forgotten just yet, and although this study doesn’t reflect true clinical practice in surgical patients and the additional challenges that may be faced from endothelial barrier damage, it offers an insight into the ongoing debate of fluid transfer physiology. Further studies of a larger scale, are required to validate the results in a clinical setting, considering the limitations such as emptying the bladder prior to the hemodynamic adjustment period, and losses through diuresis and evaporation.

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Gosain A, Gamelli RL. Role of the gastrointestinal tract in burn sepsis. J Burn Care Rehabil. 2005;26:85–91.

Greenough A, Greenall F, Gamsu RH. Immediate effects of albumin infusion in ill premature neonates. Arch Dis Child. 1988;63:307–9.

Heughan C, Ninikoski J, Hunt TK. Effect of excessive infusion of saline solution on tissue oxygen transport. Surg Gynecol Obstet. 1972;135:257–60.

Hunt TK, Linsey M, Grislis H, Sonne M, Jawetz E. The effect of differing ambient oxygen tensions on wound infection. Ann Surg. 1975;181:35–9.

Lindahl AE, Stridsberg M, Sjöberg F, Ekselius L, Gerdin B. Natriuretic peptide type B in burn intensive care. J Trauma Acute Care Surg. 2013;74:855–61.

Prien T, Backhaus N, Pelster F, Pircher W, Bünte H, Lawin P. Effect of intraoperative fluid administration and colloid osmotic pressure on the formation of intestinal edema during gastrointestinal surgery. J Clin Anesth. 1990;2:317–23.

Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol. 1896;19:312–26.

Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108:384–94.

Zdolsek M, Hahn RG, Zdolsek JH. Recruitment of extravascular fluid by hyperoncotic albumin. Acta Anaesthesiol Scand. 2018;62:1255–60.


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