Commercial preparations of albumin have been in use from the 1940s. The first protein to be extracted from human plasma, it was extensively used in the battles of World War II and subsequently, in civilian practice. A major controversy erupted and continues to surround the use of albumin since the publication of the systematic review by the Cochrane Injuries Group in 1998.1 The authors performed a meta-analysis on a mixed group of patients including surgical, trauma, sepsis, and burns and demonstrated an overall significant increase of mortality with the use of albumin, compared to alternative fluids. The study was limited by a vastly heterogeneous group of patients; besides, albumin was compared to several different types of fluids. Furthermore, many of the studies were several decades old, with practices that may not have been contemporaneous. Predictably, this report drew sharp reactions from the medical community and from the mainstream media. There was a considerable decline in the usage of albumin solutions in the following years, especially in UK intensive care units.
Albumin may seem close to being the ideal intravenous fluid to fill the intravascular compartment based on the Starling hypothesis, considering its colloid osmotic pressure and molecular size. Let us examine if this assumption is really true.
According to the Starling hypothesis, fluid filtration occurs across the arterial end of capillaries to the interstitium across a hydrostatic pressure gradient. On the venous side, the reverse movement was proposed to occur, from the interstitium back into the capillaries, driven by the higher colloid osmotic pressure of the plasma. However, it has been clearly established that there is no fluid reabsorption into the capillaries as believed previously; the filtered fluid is cleared by the lymphatic system.2 According to the new approach, the endothelium is lined by a layer of glycoproteins and proteoglycans, constituting the glycocalyx (Fig. 1). The glycocalyx layer is bound to proteins, mainly, albumin, and constitutes a barrier to the movement of fluid out of the capillaries along the hydrostatic gradient. There is a sub-glycocalyx space at the gap between the endothelial cells, where fluid movement occurs; this space is devoid of protein, and hence, cannot exert a colloid osmotic pressure. Hence, contrary to the Starling hypothesis, fluid movement cannot occur from the interstitium back into the capillaries.
Fig. 1: The glycocalyx layer lines the inside of the capillary endothelium and acts as a barrier to fluid filtration. Filtration occurs through the gap (colored white) between endothelial cells (colored brown). The capillary lumen is separated from the interstitium at the gaps by the glycocalyx (colored green) and the subglycocalyx space (arrow). The subglycocalyx space is devoid of protein, and hence, cannot facilitate reabsorption of filtered fluid back into the capillary lumen
The glycocalyx layer gets disrupted in critical illness, including sepsis, trauma, and postoperative patients. Once the glycocalyx breaks down, colloidal solutions, including albumin can filter through the capillary endothelium and distribute within the interstitial space. This is why, contrary to conventional wisdom, the volume of fluid required to fill the intravascular compartment is nearly equal with crystalloids and colloids, including albumin, in contrast to the predicted 3:1 ratio. Once the glycocalyx disintegrates, both types of fluid leak out, regardless of the colloid osmotic pressure or molecular size. Albumin may have other putative benefits including anti-inflammatory and free radical scavenging effects, which may be beneficial in critically ill patients.
Do these purported physiological advantages of albumin translate to clinical benefits? The Saline versus Albumin Fluid Evaluation (SAFE) Study compared the administration of 4% albumin to normal saline in 6,977 patients in a randomized controlled trial.3 There was no difference overall in the 28-day mortality, requirement for ventilator support and renal replacement therapy. The duration of ICU and hospital stays were also similar. On subgroup analysis, there was a non-significant trend towards reduced 28-day mortality in patients with severe sepsis. On the contrary, the mortality risk was higher in the subgroup of trauma patients; the risk of death was mainly due to the increased mortality among patients with traumatic brain injury who were administered albumin. The SAFE study was primarily designed to test the hypothesis that the use of 4% albumin does not increase 28-day mortality compared to normal saline. The sample size was calculated based on an assumed mortality of 15% and to test a 3% difference in mortality between groups. The study mortality was nearly 21% in both arms. Although not meant to demonstrate a significant difference in clinical outcomes, the sample size was adequate to detect any clinical outcome benefit with albumin use.
The Albumin Italian Outcome Sepsis (ALBIOS) study was conducted to specifically investigate outcome benefits with the use of albumin in patients with severe sepsis, considering its anti-inflammatory and free radical scavenging properties. Along with crystalloids, 20% albumin was administered in the study arm, targeting a serum albumin level of 30 g/L; the control group received crystalloids alone.4 No difference was observed in the 28 or 90-day mortality; however, there was a statistically significant, one day difference in the duration of vasopressor support. On non-predefined subgroup analysis, there was a trend towards improved survival at 90 days in the albumin group.
The Early Albumin Resuscitation during Septic Shock study (EARSS) evaluated the use of 100 ml of 20% albumin, administered 8 hourly for the first 72 hours after the diagnosis of septic shock in a multicentre, randomized, placebo-controlled study in France.5 The preliminary findings, reported only in an abstract form, did not reveal any improvement in 28-day survival with the use of 20% albumin. The full report of this study is still awaited.
It may seem that the theoretical advantages of albumin use as an intravenous colloid do not translate to improved clinical outcomes in a general critically ill population. There is no evidence so far that it may improve outcomes in severe sepsis. However, it may offer clinical benefit in specific subgroups of patients, including in spontaneous bacterial peritonitis,6 as replacement fluid during abdominal paracentesis,7 and as combination therapy, with terlipressin in Type I hepato-renal syndrome.8
The bottom line
- Transcapillary leak of fluid occurs due to disruption of the glycocalyx layer in critically ill patients. Colloid solutions including albumin, are distributed into the interstitial space similar to crystalloids.
- Albumin-based resuscitation use does not improve clinical outcomes in a general critically ill population.
- Therapeutic use of albumin targeting a serum level of 30/L does not improve outcomes in septic patients.
- Specific subgroups of patients with liver disease may benefit from albumin use.
- Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 317, 235–240 (1998).
- Adamson, R. H. et al.Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J. Physiol. 557, 889–907 (2004).
- A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. N. Engl. J. Med.10 (2004).
- Caironi, P. et al.Albumin Replacement in Patients with Severe Sepsis or Septic Shock. N. Engl. J. Med. 370, 1412–1421 (2014).
- Chapentier, Mira. Efficacy and tolerance of hyperoncotic albumin administration in septic shock patients: the EARSS study [abstract]. Intensive care medicine, 37(Supplement 2): S115-438. 2011; 37, 438
- Salerno, F., Navickis, R. J. & Wilkes, M. M. Albumin Infusion Improves Outcomes of Patients With Spontaneous Bacterial Peritonitis: A Meta-analysis of Randomized Trials. Clin. Gastroenterol. Hepatol. 11, 123-130.e1 (2013).
- Bernardi, M., Maggioli, C. & Zaccherini, G. Human Albumin in the Management of Complications of Liver Cirrhosis. in Annual Update in Intensive Care and Emergency Medicine 2012(ed. Vincent, J.-L.) 421–430 (Springer Berlin Heidelberg, 2012). doi:10.1007/978-3-642-25716-2_39
- Italian Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver 49, 471–483 (2017).