What is the role of albumin supplementation in sepsis, considering its cost and potential benefits?

Cost-Effectiveness of Albumin Supplementation in Sepsis

Albumin supplementation in sepsis is not cost-effective as first-line therapy, as it provides no mortality benefit compared to crystalloids while being significantly more expensive. 1

Primary Recommendation Against First-Line Use

It is probably not recommended to use albumin as first-line treatment in sepsis or septic shock to reduce mortality or renal replacement therapy requirement (GRADE 2-). 1 The 2022 European guidelines explicitly state this recommendation based on comprehensive evidence showing no survival benefit. 1

• The largest trial (SAFE study, N=6,997) found no difference in 28-day mortality between 4% albumin and crystalloids (RR 0.99; 95% CI 0.91-1.09). 2
• The ALBIOS trial (N=1,818) showed no mortality benefit at 28 days (31.8% vs 32.0%, RR 1.00; 95% CI 0.87-1.14) or 90 days (41.1% vs 43.6%, RR 0.94; 95% CI 0.85-1.05). 3
• A 2014 systematic review of 16 trials (N=4,190) found no mortality reduction with albumin (RR 0.94; 95% CI 0.87-1.01), with trial sequential analysis entering the futility zone. 4
• A 2024 updated meta-analysis confirmed albumin cannot decrease overall, ICU, in-hospital/28-day, or 90-day mortality in septic patients. 5

Cost Considerations

Albumin is significantly more expensive than crystalloid alternatives, which is a major factor against its routine use. 6 The Surviving Sepsis Campaign explicitly states: "The lack of proven benefit and higher cost of albumin compared to crystalloid contributed to our strong recommendation for the use of crystalloids as first-line fluid for resuscitation in sepsis and septic shock." 1

Limited Second-Line Role

Albumin may be considered as rescue therapy only in septic shock patients requiring large volumes of crystalloids, though evidence remains insufficient for a strong recommendation. 1

• The 2021 Surviving Sepsis Campaign suggests (weak recommendation, moderate-quality evidence) using albumin in addition to crystalloids when patients require large volumes of crystalloids. 1, 2
• European guidelines could not issue a recommendation for albumin as second-line treatment in patients with major hypoalbuminemia and/or requiring large fluid volumes due to insufficient evidence. 1

Physiologic Benefits Without Mortality Impact

While albumin shows some physiologic improvements, these do not translate to survival benefit:

• Reduced fluid volumes required: In SAFE, albumin group received less total fluid (3,011 ± 1,924 vs 3,522 ± 2,507 mL, p<0.001). 1, 6
• Improved hemodynamics: ALBIOS showed lower cardiovascular SOFA scores (1.20 vs 1.42, p=0.03) and shorter vasopressor duration (3 vs 4 days, p=0.007). 1, 6
• Better fluid balance: Lower fluid balance at days 2-4 in albumin groups. 1, 6

Potential Subgroup Benefit

In septic shock specifically (not general sepsis), 20% albumin at high doses may provide mortality benefit, though evidence is limited. 5

• One meta-analysis found 20% albumin reduced mortality in septic shock (RR 0.89, p=0.03). 5
• High daily doses of albumin showed potential benefit (RR 0.90, p=0.03). 5
• ALBIOS subgroup analysis of septic shock patients (N=1,121) suggested benefit (OR 0.87; 95% CI 0.77-0.99), though the study was underpowered. 1

Safety Concerns

Albumin appears safe in sepsis without signals of harm, though one observational study suggested potential renal risk with 20% albumin. 1

• The CRYCO study showed higher risk of renal failure with 20% albumin in shock patients. 1
• However, no RCTs or meta-analyses have confirmed this renal risk. 1
• Albumin supplementation does not reduce microvascular permeability even when doubling serum concentrations (TER 6.7 ± 1.5%/h vs 6.4 ± 2.1%/h, p=0.550). 7

Clinical Algorithm

For sepsis/septic shock fluid resuscitation:

1. First-line: Use crystalloids exclusively (preferably balanced crystalloids). 1
2. Consider albumin only if: Patient has septic shock AND requires massive crystalloid volumes (>30-50 mL/kg) AND remains hemodynamically unstable. 1, 2
3. If using albumin: Consider 20% albumin at higher doses rather than 4-5% solutions based on emerging evidence. 5
4. Never use albumin: As routine first-line therapy or to simply correct hypoalbuminemia without hemodynamic indication. 1, 2

Key Pitfalls to Avoid

• Do not use albumin to correct hypoalbuminemia alone - serum albumin levels do not justify treatment in sepsis without hemodynamic instability requiring large volume resuscitation. 1
• Do not assume physiologic benefits equal survival benefits - improved hemodynamics and reduced fluid volumes have not translated to mortality reduction. 1
• Do not ignore cost - without proven mortality benefit, the substantially higher cost of albumin cannot be justified for routine use. 1, 6