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Caironi P, et al. "Albumin replacement in patients with severe sepsis or septic shock". The New England Journal of Medicine. 2014. 370(15):1412-1421.
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Clinical Question

Among patients with severe sepsis or septic shock, does administration of albumin 20% solution to maintain serum albumin level ≥3 g/dL (≥30 g/L) reduce all-cause mortality at 28 days when compared to no albumin?

Bottom Line

Among patients with severe sepsis or septic shock, daily administration of albumin to maintain serum albumin ≥3 g/dL was not associated with a reduction in all-cause mortality at 28 days when compared to no albumin.

Major Points

Selection of volume for resuscitation in ICU patients was addressed in the 2004 SAFE trial, which compared albumin and crystalloids. In the severe sepsis subgroup in SAFE, albumin demonstrated a non-significant trend towards lower all-cause mortality at 28 days with albumin (P=0.09). A 2006 pilot trial by Dubois et al.[1] suggested that daily IV albumin administration for serum albumin <3.1 g/dL (<31 g/L) may improve SOFA score (for organ function) for critically ill hypoalbuminemic patients. A large randomized controlled trial to evaluate for benefit of albumin in patients with severe sepsis or septic shock was lacking.

The 2014 Albumin Italian Outcome Sepsis (ALBIOS) trial randomized 1,818 patients with severe sepsis or septic shock at 100 Italian ICUs in an unblinded fashion to albumin or no albumin. Those in the albumin group received an initial bolus and then daily administrations of IV albumin to maintain the serum albumin ≥3 g/dL (≥30 g/L). Both groups were treated with crystalloids as needed. There was no difference in all-cause mortality at 28 days and 90 days. Patients treated in the albumin group had a shorter duration on vasopressors or inotropes and improved cardiovascular parameters early in their ICU course. There was no difference in overall SOFA scores between the two groups though the albumin group had lower average cardiovascular dysfunction (SOFA CV subscore 1.20 vs. 1.42) but higher coagulation and liver dysfunction (0.65 vs. 0.50 and 0.28 vs. 0.20, respectively). The authors explain that the coagulation and liver dysfunction was due to "a higher serum bilirubin and a lower platelet count" rather than being a reflection of clinically-significant physiologic parameters. A subgroup analysis of the secondary outcome of 90 day all-cause mortality demonstrated a survival advantage for albumin therapy in those in septic shock at enrollment. However, this finding should be used for hypothesis-building purposes given its post-hoc nature. Strangely, no analysis of the primary outcome for this subgroup was presented by the authors.[2]


Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[3]

  • Recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in sepsis and septic shock (strong recommendation, moderate quality of evidence)
    • Suggest using albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement when patients with septic shock require substantial amounts of crystalloids (weak recommendation, low quality of evidence)
  • Suggest using balanced crystalloids or saline for fluid resuscitation in sepsis and septic shock (weak recommendation, low quality of evidence)


  • Multicenter, open-label, randomized trial
  • N=1,818
    • Albumin (n=910)
    • No albumin (n=908)
  • Setting: 100 ICUs in Italy
  • Enrollment: 2008-2012
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality at 28 days


Inclusion Criteria

  • Suspected or proven infection in ≥1 site (lung, abdomen, GU tract, blood, skin/soft tissue, CNS, bones, joints, cardiac system, or indwelling catheter)
  • ≥2 of the following:
    • Core temperature ≥38\B0C or ≤36\B0C
    • HR ≥90 BPM
    • RR ≥20 breaths/minute, PaCO2≤32 mmHg or use of mechanical ventilation for an acute problem
    • WBC ≥12,000/mL or ≤4,000/mL or immature PMNs >10%
  • ≥1 severe, acute organ dysfunction related to sepsis with SOFA score >1 for respiratory, hematologic, hepatic, or renal systems or CV score of 1, 3, or 4[4]

Exclusion Criteria

  • Age <18 years
  • "Terminal state"
  • Known adverse reaction to administration of albumin
  • Severe sepsis or septic shock after proven or suspected clinically active head injury
  • NYHA class III or IV heart failure
  • Conditions in which albumin is indicated including cirrhosis with ascites, intestinal malabsorption syndrome, nephrotic syndrome, burns
  • Religious objection to administration of blood products
  • Inclusion in other experimental studies

Baseline Characteristics

From the albumin group. Comparisons are albumin vs. no albumin.

  • Demographics: Age 70 years, female 39.9%
  • Baseline health data: BMI 27 kg/m2, HR 105 BPM, MAP 74 mmHg, CVP 10.0 mmHg, UOP 50 mL/hr, lactate 2.3 mmol/L, serum albumin 2.41 g/dL (24.1 g/L), Hgb 10.9 g/dL (109 g/L), ScvO2 73% (interquartile 65-79%) vs. 73% (68-80%; P=0.02)
    • Mechanical ventilation: 78.5%
    • SAPS II score: 48 (out of 163, higher indicate more severe baseline illness)
    • Modified[5] SOFA score: 8 (out of 20, higher scores indicate more severe organ dysfunction)
      • Shock: 62.6% (score of 3 or 4 on CV component of SOFA score)
      • Amount of dysfunction (P=0.04 for number of patients with organ dysfunction; 903 vs. 909 patients)
        • 1 organ: 20.8% vs. 22.9%
        • 2 organs: 40.0% vs. 33.4%
        • 3 organs: 26.1% vs. 27.3%
        • 4 organs: 9.9% vs. 12.7%
        • 5 organs: 3.2% vs. 3.6%
  • Reason for ICU admission: Medical 56.6%, elective surgery 7.6%, emergency surgery 35.8%
  • PMH: Liver disease 1.4%, COPD 12.5%, CKD 4.9%, immunodeficiency 12.7%, ischemic or congestive heart disease 16.5%
  • Fluids administered in prior 24 hours:
    • Albumin: 16.9%
    • Synthetic colloids: 50.1%


  • Patients were stratified by time meeting severe sepsis criteria to one of two groups:
    • Albumin - Following randomization, administration of 300 mL albumin 20% solution then albumin 20% solution IV daily to maintain serum albumin concentration ≥3 g/dL (≥30 g/L)for days 1-28 or until discharge from ICU (whichever came first)
    • No albumin - No albumin administered
  • Early fluids were administered according to an EGDT protocol
  • Crystalloids were administered as deemed necessary by an attending physician
  • Synthetic colloids use was disallowed
  • All other treatment as directed by the attending physician


Comparisons are albumin vs. no albumin. RR is relative risk.

Primary Outcome

All-cause mortality at 28 days
31.8% vs. 32.0% (RR 1.00; 95% CI 0.87-1.14; P=0.94)

Secondary Outcomes

All-cause mortality at 90 days
41.1% vs. 43.6% (RR 0.94; 95% CI 0.85-1.05; P=0.29)
New organ failure
None: 44.5% vs. 45.5%
1 organ: 33.9% vs. 34.1%
2 organs: 15.6% vs. 14.6%
3 organs: 4.8% vs. 4.3%
4 organs: 1.2% vs. 1.3%
5 organs: 0.1% vs. 0.1%
Average daily SOFA score during the study period
6.00 vs. 5.62 (P=0.23)
CV: 1.20 vs. 1.42 (P=0.03)
Respiratory: 2.00 vs. 2.00 (P=0.63)
Renal: 0.83 vs. 0.75 (P=0.15)
Coagulation: 0.65 vs. 0.50 (P=0.04)
Liver: 0.28 vs. 0.20 (P=0.02)
Length of stay
ICU: 9 vs. 9 days (P=0.42)
Hospital: 20 vs. 20 days (P=0.65)

Additional Analyses

Renal replacement therapy
24.6% vs. 21.4% (P=0.11)
21.9% vs. 22.7% (P=0.71)
Duration of mechanical ventilation
6 vs. 6 days (P=0.50)
Time to suspension of vasopressors or inotropes
3 vs. 4 days (P=0.007)
Heart rate
After hour 6: 97 vs. 101 BPM (P<0.001)
Day 1: 94 vs. 99 BPM (P<0.001)
Day 2: 89 vs. 92 BPM (P<0.001)
Day 3: 86 vs. 89 BPM (P=0.01)
Day 4: 86 vs. 87 BPM (P=0.49)
Day 5: 86 vs. 86 BPM (P=0.96)
Day 6: 86 vs. 86 BPM (P=0.95)
Day 7: 85 vs. 87 BPM (P=0.04)
After hour 6: 79 vs. 77 mmHg (P<0.001)
≥65 mmHg: 86.0 vs. 82.5% (P=0.04)
Day 1: 81 vs. 80 mmHg (P=0.02)
Day 2: 84 vs. 84 mmHg (P=0.52)
Day 3: 87 vs. 86 mmHg (P=0.43)
Day 4: 87 vs. 86 mmHg (P=0.82)
Day 5: 87 vs. 87 mmHg (P=0.97)
Day 6: 87 vs. 86 mmHg (P=0.07)
Day 7: 87 vs. 86 mmHg (P=0.24)

Subgroup Analysis

For all-cause mortality at 90 days

Time of enrollment in regards to meeting inclusion criteria
<6 hours: 40.6% vs. 40.6% (RR 1.00; 95% CI 0.82-1.22; P=0.99)
6-24 hours: 41.3% vs. 45.0% (RR 0.92; 95% CI 0.81-1.05; P=0.20)
Septic shock at enrollment, post-hoc
No: 37.0% vs. 32.7% (RR 1.13; 95% CI 0.92-1.39; P=0.25)
Yes: 43.6% vs. 49.9% (RR 0.87; 95% CI 0.77-0.99; P=0.03)


  • Open label design
  • Albumin concentration differed from that used in the SAFE study
  • Lower-than-expected 28 day mortality may have resulted in underpowering of the study
  • The minority of patients were enrolled during early severe sepsis


  • Italian Medicines Agency

Further Reading

  1. Dubois MJ, et al. "Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective, randomized, controlled, pilot study." Critical Care Medicine. 2006;34(10)2536-2540.
  2. Kane SP. "Really NEJM? Shocking Failure of the Peer Review Process for the ALBIOS Trial." Published 2014-03-20. Accessed 2014-03-25.
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  4. SOFA Scoring, supplemental appendix.
  5. SOFA scoring was modified for this trial to include respiratory, coagulation, liver, cardiovascular, and renal components only. Cerebral failure -- measured by GCS -- was not performed. MAP for cardiovascular subscore of 1 was decreased to 65 mmHg to correlate more closely with EGDT.