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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.

Guidelines for fluid management in sepsis and septic shock

In this video Dr Christian Wiedermann, a medical research consultant, discusses guideline recommendations for fluid use in sepsis and sepsis shock. He notes that some aspects of fluid management remain under discussion.

In patients with traumatic brain injury, albumin has been shown to increase mortality; in patients with peripheral oedema during the recovery phase, albumin may be beneficial; and in patients with sepsis, albumin has been shown to be beneficial8

The latest version of the global guidelines for adult sepsis management, published by the Surviving Sepsis Campaign (SSC) in October 2021, states that recommendations and guidelines cannot substitute for a clinician’s decision-making in the context of a patient’s unique clinical circumstances1.

The SSC is an initiative by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine (USA), with its goal being to improve mortality from sepsis16.

The 2021 version of the SSC guidelines was updated to represent broader gender and geographic diversity, and provides greater emphasis on improving after-patient care to address the challenges inherent when treating patients for the long-term impacts of sepsis17. These challenges include1:

  • Long stays in the intensive care unit
  • Physical rehabilitation
  • Cognitive and emotional issues
  • Care coordination for patients and their families that align with their goals

According to the current edition of the SSC guidelines, treatment and resuscitation should begin immediately when sepsis or septic shock are recognised, and they recommend a low threshold for commencement in suspects1. For example, some guidelines recommend that healthcare professionals ask, “Could this be sepsis?” when patients present with signs, symptoms or evidence of possible infection18,19. Although based on observational studies, this recommendation is considered a best practice, as sepsis and septic shock are medical emergencies1.

The SSC guidelines strongly recommend crystalloids as first-line fluid for resuscitation in adults with sepsis and septic shock (based on a moderate quality of evidence), and suggest balanced crystalloids over normal saline (low quality of evidence)1. They suggest administration of ≥30 mL/kg of intravenous crystalloid fluid within the first 3 hours of resuscitation for patients with sepsis-induced hypoperfusion or septic shock (weak recommendation, low quality of evidence)1, and suggest using dynamic measures such as a fluid bolus or a passive leg raise to guide fluid resuscitation rather than using static parameters or physical examination alone (weak recommendation, very low-quality evidence)1. In addition, they suggest that resuscitation is guided such that serum lactate is decreased in patients with high lactate level, and suggest using capillary refill time as an adjunct to other perfusion measures to guide resuscitation (based on low quality evidence)1.

The SSC guidelines suggest using albumin as a supplementary resuscitation fluid for haemodynamic management for patients who were administered crystalloids in large volumes1,4. This is based on weak, moderate-quality evidence1. Evidence demonstrates lower net fluid balance, higher static filling pressures and higher blood pressure at early and later time points with albumin, and limited data excludes a crystalloid infusion cut-off value, above which albumin could be considered as part of resuscitation1. While theory suggests that albumin would be better at maintaining oncotic pressure, compared with crystalloids, clear benefit for its routine use is lacking, and albumin is more costly1. However it should be noted that the use of human albumin solutions (HAS) for resuscitation require less fluid than using crystalloid solutions7.

While the SSC guidelines provide strong recommendations for crystalloids as the primary initial resuscitation fluid and albumin as a supplementary fluid, they do not provide clear recommendations regarding when to begin administration, the applicable population, optimal concentration or indications for albumin discontinuation1,4, and do not provide guidance on when to move from crystalloid to colloid during resuscitation6. While the guidelines are associated with improved outcomes, gaps in the literature preclude them from making specific recommendations in all clinically relevant areas16. As a result, an expert consensus was convened by the Chinese Society of Critical Care Medicine to address these gaps and provide recommendations of their own4. In their publication, ‘Expert Consensus on the Use of Human Serum Albumin in Critically Ill Patients’, 11 clinical issues are outlined along with recommendations that use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology4.

In response to the use of HAS in sepsis and septic shock, the panel made five recommendations which are contained in Table 14.

Table 1. Recommendations on the use of human serum albumin in sepsis and septic shock by an expert panel convened by the Chinese Society of Critical Care Medicine4. HAS, human albumin solution

  Recommendation Grade, recommendation, evidence level
Recommendation 1 HAS is safe as a resuscitation fluid for patients with sepsis, and its use in this setting may reduce mortality Grade 2+, weak recommendation
Recommendation 2 If haemodynamic instability persists in patients with septic shock after 30 mL/kg crystalloid resuscitation, consider initiating HAS infusion Expert opinion
Recommendation 3 In patients with sepsis, both low- (4% or 5%) and high-concentration (20% or 25%) HAS can be used for fluid resuscitation Expert opinion
Recommendation 4 In patients with sepsis, HAS infusion can be discontinued when serum albumin levels reach
≥30 g/L and haemodynamics are stable
Grade 2+, weak recommendation
Recommendation 5 When using antibiotics with a high protein-binding rate in patients with sepsis, HAS supplementation is recommended for improving drug pharmacokinetics and pharmacodynamics Grade 2+, weak recommendation

In patients with persistent signs of hypoperfusion and volume depletion after initial resuscitation, the SSC guidelines do not make a recommendation on whether to use restrictive or liberal fluid strategies within the first 24 hours of resuscitation because there is insufficient evidence1. However, they state that for most patients, continuous fluid administration will be required after initial resuscitation1. This administration should be weighed against the risk of fluid accumulation and potential harm associated with fluid overload1 – overload being defined as a 10% increase in fluid accumulation compared to baseline body weight3. Potential risks include: acute kidney injury progression, issues associated with prolonged ventilation, and increased mortality1

When managing patients with complex sepsis, the SSC guidelines state the importance of conducting a detailed initial assessment and to continuously monitor and re-evaluate the patient’s response to treatment1. By conducting careful assessment of the status of intravascular volume and organ perfusion, and using these levels to guide fluid administration following the initial resuscitation, over- and under-resuscitation may be avoided1. In some settings, advanced haemodynamic monitoring may not be available. In such cases, other signs of tissue perfusion can be used, including skin mottling, capillary refill time and temperature of the extremities – all have been validated and demonstrated to be reproducible surrogates1. If using capillary refill time during resuscitation, however, it is important to consider any underlying pathology or relevant pathological processes, and provide comprehensive and frequent patient evaluation to help predict/recognise fluid overload early1.

Fluid selection in sepsis and septic shock

In this video Dr Christian Wiedermann, a medical research consultant, discusses key considerations and challenges when managing patients with sepsis or septic shock who require intravenous fluid therapy. He outlines the risks of fluid overload, the evidence for increased mortality risk and highlights the importance of attempting to reduce overaccumulation when administering fluid for resuscitation.


According to research, the type of intravenous fluid administered during resuscitation impacts a patient's outcomes3

Selection of fluid should be grounded in the concept of treating fluids as drugs: each with indications, contraindications and possible side effects3. This concept has been labelled ‘the 4 Ds of fluid therapy’5.

The 4 Ds of fluid therapy5:


The 4 Ds of fluid therapy

According to the 4 Ds, healthcare professionals should consider the following aspects when considering the optimal fluid therapy for their patient5:

  • Drug
    • The different compounds available (crystalloids versus colloids; balanced versus unbalanced; synthetic versus blood-derived; intravenous versus oral)
    • The pH, electrolyte composition, osmolality, tonicity and levels of other metabolically active compounds
    • The patients’ clinical factors (e.g. underlying conditions, liver or kidney failure)
    • The reason for fluid administration, of which there are four indications: resuscitation, maintenance, replacement and nutrition, or a combination
  • Dose
    • There is a well-established risk of excessive fluid overload, so the dose decision should consider the fluid’s pharmacokinetics and pharmacodynamics
  • Duration
    • The longer the delay in treatment, the greater the risk of microcirculatory hypoperfusion and subsequent organ damage from ischaemia-reperfusion injury
    • The best prognosis may lie in combining early adequate and late conservative fluid management, and late conservative fluid therapy may be more important than early adequate fluid therapy
  • De-escalation
    • Fluid therapy duration should be as short as possible, and the volume tapered once shock is resolved
    • Without a trigger to stop fluid resuscitation there is a greater risk of fluid overload

ROSE concept

The second concept relevant to fluid selection in sepsis is that a different strategy is required for each phase of illness3. In sepsis, there are four dynamic phases of sepsis management, helpfully referred to as ‘ROSE’ (Figure 1)3.


Figure 1. The ROSE model (Adapted3,5). The different fluid phases during shock image is licensed under CC BY 4.0 / image redrawn with detail added for clarity.

The figure illustrates the fluid phases during shock and shows how a patient’s cumulative fluid volume status evolves across the four phases of resuscitation: (1) resuscitation, (2) optimisation, (3) stabilisation and (4) evacuation. A fifth phase, hypoperfusion, may occur if de-resuscitation is overly aggressive5. HIT refers to the events that occur during shock: HIT 1 refers to the initiating event (e.g. sepsis, burns); HIT 2 refers to ischaemia and reperfusion; HIT 3 refers to a phase of de-resuscitation, which usually results from global increased permeability syndrome; HIT 4 refers to haemodynamic deterioration and hypoperfusion in patients who enter phase 55.

Phases of sepsis management3,5:


  • Aggressive resuscitation aimed at rescuing the patient’s life


  • Diligent fluid titration to optimise organ perfusion


  • Aim to stabilise the fluid balance to a neutral daily balance


  • Aim to evacuate fluids that may have accumulated without being too aggressive with fluid removal, to avoid phase 5

Watch the following video featuring Dr Christian Wiedermann, to learn about the different types of fluids, their functions and routes of administration. Dr Wiedermann also provides an overview of crystalloids and colloids and recommendations for their use.

There are three broad categories of fluid options: colloids, crystalloids and blood products. Colloids and crystalloids for resuscitation in sepsis patients, including recommendations for their use in sepsis and septic shock, are summarised in Tables 2 and 3, respectively.

Table 2. Colloid fluid options for resuscitation in sepsis including recommendations and key points1,3,20–22. EMA, European Medicines Agency; PRAC, Pharmacovigilance Risk Assessment Committee; SSC, Surviving Sepsis Campaign. *Mekeirele et al., 2022; Evans et al., 2022; Moeller et al., 2016; §Marx et al., 2021; ** GENIUS. 2022. 

• Synthetic colloids (especially hydroxyethyl starches) should not be used in sepsis,
   burns or renal failure patients*
• In patients with low serum albumin levels (<3 g/dL) albumin 4% could be considered for those with
   severe sepsis, and albumin 20% could be considered in a subset of patients with septic shock*
Types of colloids
Human albumin
• Individual trials demonstrate a trend towards mortality reduction, and an
   analysis shows pooled relative risk is 0.92 (CI: 0.84–1.00; P=0.046)*
• The SSC guidelines suggest administering albumin in patients who received
   large volumes of crystalloids over crystalloids alone
Hydroxyethyl starches (HES)
• Strong evidence indicates negative effects of synthetic colloids†
• According to the EMA’s PRAC, starches must not be used in patients with sepsis,
   septic shock, burn injuries or renal failure
• The SSC guidelines strongly advise against using HES
• According to a systematic review, may increase anaphylaxis risk and
   increased renal failure, bleeding and mortality
• The GENIUS trial aimed to confirm/refute the above, but was terminated in 2021§**
• The SSC guidelines have a weak recommendation against gelatin use for acute resuscitation,
   given its increased adverse effects, inconclusive mortality effects
   and the availability of cheaper alternatives
• Limited data on effectiveness and complications*
• Cheaper alternatives with favourable safety profiles are available*

Table 3. Crystalloid fluid options for resuscitation in sepsis including recommendations and key points1,3. EMA, European Medicines Agency; PRAC, Pharmacovigilance Risk Assessment Committee; SSC, Surviving Sepsis Campaign. *Evans et al., 2022.

• Cover a range of fluid types with varying properties
• Appear as effective as human albumin and are less expensive than colloids,
   therefore are used more generally in septic shock* 
• The SSC guidelines strongly recommend crystalloids as first-line fluid for resuscitation1
• According to available data, in patients with sepsis and septic shock, isotonic balanced crystalloids
   (not saline) should be the fluid of choice 
• Excessive administration of (ab)normal saline could contribute to hyperchloremic metabolic acidosis

Review human serum albumin products approved for use in fluid replacement therapy

Blood products are not usually administered as fluid resuscitation in septic shock3 and the Surviving Sepsis Campaign recommends blood transfusion only if haemoglobin levels fall below 7 g/dL, but transfusion practice should always be tailored to the patient’s individual needs1.

Key considerations that may help guide optimal fluid choice include3,5,16:

  • Indications
  • Reference to guideline recommendations
  • Comparison between the options that are available
  • Patient-specific factors
  • Context-specific circumstances

Watch this video for Dr Wiedermann’s key take aways for healthcare professionals managing patients with sepsis and septic shock who require intravenous fluid therapy.

When considering the optimal resuscitation fluid, it is important that patients are given the opportunity to make informed decisions about their care and treatment in partnership with their clinician, when possible, with their individual needs and preferences considered23. This extends to decisions post-intensive care and in hospital discharge planning1. Goals of care and prognosis should be discussed with patients and their families, preferably with goals of care discussed within 72 hours of diagnosis, and palliative care principles should be integrated within the treatment plan when appropriate1.

Learn about fluid needs and fluid selection in liver disease


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