This site is intended for healthcare professionals
Doctor separates blood and plasma
Albumin in fluid management Learning Zone

Albumin in sepsis and septic shock

Read time: 40 mins
Last updated:27th Apr 2023
Published:27th Apr 2023

Fluid needs in sepsis and septic shock

Introduction to albumin use in sepsis

Watch this video featuring Dr Christian Wiedermann, a medical research consultant, to learn about the roles of albumin in sepsis. Dr Wiedermann also discusses the SAFE Study and the ALBIOS trial.

Globally, sepsis and septic shock affect millions of people every year, killing one-sixth to one-third of those affected1

Sepsis is defined as a life-threatening organ dysfunction caused by the body’s dysregulated infection response, while septic shock is a subset in which the underlying abnormalities are severe enough to lead to increased mortality2. Fluid loss is a major factor in organ damage3.

To improve patient outcomes, sepsis must be identified early and managed appropriately in the first hours after development1. In patients with sepsis and septic shock, fluid management is an essential part of haemodynamic resuscitation4. Fast and effective fluid resuscitation is necessary to stabilise tissue hypoperfusion caused by sepsis1. Tissue hypoxia can then be corrected and organ function maintained when plasma volume is restored quickly and effectively4. However, haemodynamic resuscitation with fluid administration remains a therapeutic challenge with regard to the risk of fluid overload, questions about the most effective type and dose of fluid, and timing of resuscitation5.

There has been extensive research into the use of intravenous fluid therapy to treat sepsis and septic shock, with albumin solution being extensively reviewed for its use as a resuscitation fluid and to prevent hypoalbuminaemia6.

Albumin’s range of pharmacological effects, including its regulation of oncotic pressure, contributes to its role in critical care7. It is hypothesised that the potential clinical benefits of albumin use in sepsis are also related to anti-inflammatory and immunomodulatory effects, endothelial stabilisation and antibiotic transportation7. While albumin transports a range of drugs typically administered in critically ill people, in patients with hypoalbuminaemia the binding ability of albumin is often diminished, thereby potentially leading to suboptimal treatment7.

The antioxidant properties of albumin reduce re-oxygenation injury, which is of particular importance in sepsis7. In fact, most of the research into the administration of albumin combines a degree of resuscitation with a degree of supplementation or maintenance of albumin7.

Albumin derived from human plasma has a range of therapeutic applications, but the question of whether the use of human serum albumin improves the clinical prognosis of critically ill patients has been contentious because of conflicting results of meta-analyses8. Practice was largely influenced by a meta-analysis published by the Cochrane Injuries Group in 1998, which included 32 studies with a total of 1,419 patients. The study reported increased mortality rates in patients who received albumin treatment,9 which led to a significant decrease in the use of albumin10. Interestingly, a Cochrane review published in 2018 that compared crystalloids and colloids, including albumin, concluded that either choice probably makes little to no difference to mortality11.

The conflicting results of meta-analyses on the use of albumin in critically ill patients may have been due to the inclusion of heterogenous populations, including patients with traumatic brain injury, in whom albumin is associated with worse outcomes and should be avoided8,10,12

Studies of albumin use in resuscitation

To resolve the question of whether albumin worsened outcomes for critically ill patients, the SAFE trial, a large clinical trial including 6,997 patients in intensive care units, was conducted in Australia and New Zealand in 200413. This trial compared 4% human albumin with 0.9% saline as a resuscitation fluid in a heterogenous group of critical care patients. The study found no statistically significant difference in all-cause mortality at 28 days and observed similar outcomes for incidence of renal replacement therapy, length of stay and duration of mechanical ventilation. In patients with trauma, sub-group analysis showed a trend towards higher mortality in patients who received human albumin solution (HAS) (13.6% vs 10.0%; relative risk [RR] 1.36; 95% confidence intervals [CI] 0.99 to 1.86; P=0.06). Post hoc analyses suggest that albumin should be avoided in patients who have had traumatic brain injury13.

The ALBIOS trial, conducted in Italy, was the largest sepsis clinical trial to date (n = 1818), and it compared a combination of albumin and crystalloids to crystalloids alone in patients with sepsis or septic shock14,15. It did not demonstrate a difference in mortality at 28 days (RR, 1.0; 95% CI, 0.87−1.14) or 90 days (RR, 0.94; 95% CI, 0.85−1.05). Similarly, a meta-analysis of studies that included patients with sepsis did not demonstrate a significant difference in mortality (RR, 0.98; 95% CI, 0.89−1.08), or a difference in risk of new organ failures (RR, 1.02; 95% CI, 0.93 to 1.11), vasopressor-free days nor ventilator-free days1.

The EARSS Study, a multicentre, open-label, randomised trial conducted in France did not find significant differences in mortality (24.1% vs 26.3%) between patients administered 100 mL of 20% albumin every 8 h for 3 days, compared with 100 mL of 0.9% saline administered at the same intervals. However, the trial did reveal a significant reduction in catecholamine requirement in the albumin group6. It is important to note that this study has not yet undergone peer review6.  

An informal meta-analysis of the SAFE, ALBIOS and EARSS trials found that when small trials were excluded, the pooled relative risk indicated a significant decrease in mortality when albumin was administered6. These mixed results highlight the urgent need for a formal analysis, and the need for a large-scale randomised controlled trial comparing HAS with other intravenous fluid therapies in sepsis6.

Twenty experts convened for the ‘Expert Consensus on the Use of Human Serum Albumin in Critically Ill Patients’ support the use of albumin for sepsis and septic shock, and although the use of HAS is widespread for critically ill patients for albumin supplementation and fluid resuscitation, controversy remains as to the appropriate administration regimen, population and timing4.

Despite varying results, HAS continues to be used in critical care and while use of colloids has decreased overall, HAS use has in fact increased proportionally6.