🧭 REBEL Rundown
📌 Key Points
- 🩸 No BP Boost at 24h: Early 20% albumin in sepsis didn’t significantly improve systolic BP at 24 hours compared to standard care.
- 💉 Less Fluid, Fewer Pressors: Albumin group received 725mL less fluid over 72h and needed vasopressors 7.4% less often—but the differences were small and statistically fragile.
- 🧪 Better SOFA, Same Outcomes: Slight drop in SOFA scores, but no impact on mortality, ventilation, or dialysis. Surrogate gains, not patient-centered wins.
- 💰 High Cost, Low Yield: Albumin costs over 30x more than crystalloids—without delivering meaningful clinical benefit.
- 🏥 Another ICU Myth Debunked in the ED: ICARUS joins SAFE & ALBIOS in showing no mortality benefit for albumin in sepsis—even when given early in the ED.
🤕 Case
A 74-year-old man with a history of hypertension and chronic kidney disease is brought to the ED from home by EMS. He’s febrile to 38.9°C, tachycardic to 112 bpm, and hypotensive with a BP of 84/52. His lactate is 4.1 mmol/L. He’s altered but arousable, with suspected urosepsis. After receiving empiric antibiotics, 2 liters of crystalloid, and a norepinephrine drip his BP remains low.
The ED team considers whether to administer concentrated 20% albumin early as part of his resuscitation. The team questions whether albumin could improve his hemodynamics and reduce the need for vasopressors.
What does the evidence say?
📝 Introduction
Sepsis is one of the most common emergencies we encounter, yet despite decades of research, it still carries a high burden of morbidity and mortality. Over the years, our attempts to improve outcomes have spanned the spectrum—from clearly lifesaving (like timely antibiotics)1 to largely discredited (like high-dose vitamin C).2
On paper, treatment with albumin makes sense: it’s a large protein that can boost oncotic pressure and theoretically counteract sepsis-induced capillary leak. But when tested in clinical trials—most of which were conducted in ICU settings—albumin hasn’t delivered.3, 4 No improvement in mortality, no game-changing results.
The ICARUS-ED trial5 set out to explore whether 20% albumin given during the earliest phase of sepsis care could improve systolic blood pressure at 24 hours. Let’s dive into the study.
🧾 Paper
Williams JM, et al. Intervention With Concentrated Albumin for Undifferentiated Sepsis in the Emergency Department (ICARUS-ED): A Pilot Randomized Controlled Trial. Ann Emerg Med. 2025 Jan 22: PMID: 39846907
⚙️ What They Did
📈 Results
- Total enrolled: 464 patients over 32 months (Jan 2021 – Aug 2023), averaging 14.5 patients/month
- Eligible patients: 615 retrospectively assessed as eligible during the study period
- Analyzed patients: 463 (1 patient withdrew consent after allocation to albumin arm)
- Enrollment timing: 63.5% (294 patients) were enrolled outside weekday business hours (evenings/weekends)
- Baseline characteristics: Similar between albumin and standard care groups
- Final diagnosis: Infection confirmed in 95% of patients based on discharge summaries
- Albumin levels:
- Similar between groups at baseline
- Significantly higher in the intervention group for up to 4 days post-enrollment
- Missing data: Albumin concentrations beyond baseline were variably missing (43% to 77% missing at different time points)
💥 Critical Results
- Primary Outcome — SBP at 24 hours:
Albumin: 110.5 mmHg (102–124)
Standard care: 110 mmHg (100–120)
Difference: +1 mmHg (95% CI: –2.7 to 4.7) - SBP at 6 hours:
Albumin: 108 mmHg (98–122)
Standard care: 104 mmHg (96–118)
Difference: +4 mmHg (95% CI: 0.2 to 7.8) - Total fluid at 72 hours:
Albumin: 4,275 mL (2,700–5,730)
Standard care: 5,000 mL (3,000–6,600)
Difference: –700 mL (95% CI: –1,284 to –116) - Vasopressor use (any time):
Albumin: 25.5%
Standard care: 32.9%
Difference: –7.4% (95% CI: –14.5 to 0.0)
💪 Strengths
- Clinically relevant research question: Addresses the ongoing controversy over albumin use in sepsis resuscitation, with direct relevance to emergency and critical care practice.
- Prospective, consecutive sampling: Enrolled patients consecutively rather than via convenience sampling, reducing selection bias and enhancing internal validity.
- High diagnostic specificity for sepsis: Discharge diagnoses confirmed infection in ~95% of enrolled patients, minimizing misclassification and enhancing internal validity.
- Enrollment of DNR/DNI patients: Broadens applicability by including comorbid and older patients often excluded from ICU trials.
- Enrollment of ward (non-ICU) admitted patients: Captures a large, heterogeneous population of septic patients, improving generalizability.
- Clear rationale for intervention choice: Authors explicitly justified the use of 20% albumin, improving transparency and supporting reproducibility.
- Early intervention timing in the ED: Albumin was administered earlier than in prior ICU-based trials (e.g., ALBIOS, SAFE), increasing plausibility of benefit and addressing a key evidence gap.
- High protocol adherence: 95% compliance in both arms strengthens internal validity and reduces risk of bias.
- Robust enrollment of eligible patients: Approximately 75% of retrospectively eligible patients were enrolled, reducing selection bias and enhancing representativeness.
- Intention-to-treat analysis with appropriate statistical methods: Preserved randomization; used multiple imputation and regression techniques for missing data, increasing analytic rigor.
⚠️ Limitations
- Open-label design: Introduces risk of performance and ascertainment bias by treating clinicians, potentially influencing fluid, vasopressor, and support decisions.
- Small sample size: Although powered to detect a 5 mmHg difference in systolic blood pressure, the study was underpowered to detect clinically important differences in patient-centered outcomes such as mortality.
- Simplified binary outcome measures: Vasopressor use recorded as yes/no does not reflect acuity (e.g., single-agent vs. multi-pressors, low dose vs high dose), limiting interpretability of the finding.
- Potential co-intervention bias: Lack of detailed reporting on other concurrent treatments (e.g., antibiotics, source control, etc.) limits attribution of observed effects specifically to albumin.
- Imbalance in baseline organ dysfunction: Albumin group had more patients with respiratory dysfunction (20 vs 6), while the control group had more with renal dysfunction (57 vs 41), which could confound outcome comparisons.
- Baseline severity imbalance: A higher proportion of control patients met both hypotension and lactate criteria (12.9% vs 6.9%), suggesting they may have been sicker at enrollment despite similar overall characteristics.
- Statistical fragility of results: Some statistically significant findings (e.g., SBP at 6 hours, vasopressor reduction) had 95% confidence intervals close to zero, indicating weak effects.
- Short duration of follow-up (72 hours): Inadequate to capture important downstream outcomes such as late mortality, ICU readmissions, or recovery trajectory.
- Single-center trial in Australia: Findings may not generalize to other healthcare systems with different ED workflows, ICU thresholds, or resuscitation practices.
- Narrow inclusion criteria: Required SBP <90 mmHg or lactate ≥4 mmol/L; excludes many ED patients with early or less severe sepsis who may have benefited from early albumin use.
- Use of surrogate outcomes over patient-centered ones: Primary outcome (SBP at 24 hours) and many secondaries (e.g., fluid volume, SOFA scores) are physiologic measures without clear linkage to functional recovery or survival.
- Benefits did not translate into meaningful clinical outcomes: Modest SBP and SOFA improvements did not result in reduced mortality, need for organ support, or fewer ward emergencies.
- High cost of albumin: Albumin is significantly more expensive than crystalloids and synthetic colloids
🗣️ Discussion
Modest Gains, Questionable Impact
This was a well-executed, medium-sized, single-center trial that adds to the existing body of evidence suggesting albumin offers no meaningful advantage over crystalloids in the resuscitation of septic patients. While the authors demonstrated modest improvements in early hemodynamic and physiologic endpoints—slightly higher systolic blood pressure at 6 hours, lower fluid volumes at 72 hours, reduced vasopressor use, and improved SOFA scores—these benefits were either barely statistically significant, of questionable clinical relevance, or not patient-centered.
Do These Results Matter Clinically?
A 4 mmHg difference in SBP (104 vs. 108) is unlikely to change management or outcomes, especially when both values fall within an acceptable perfusion range. Similarly, a 700 mL reduction in fluid over 72 hours, while statistically significant, may not be clinically meaningful—particularly in the absence of differences in invasive ventilation, dialysis, or hypotension requiring escalation. From a critical care standpoint, a 4.3L vs. 5.0L fluid total is unlikely to move the needle.
The reduction in SOFA scores is also of uncertain value. While SOFA is a validated surrogate for organ dysfunction,6 the absence of difference in hard outcomes (mortality, ICU-level interventions, ward emergencies) raises the possibility that SOFA lacks specificity in this context, rather than indicating therapeutic benefit.1
The vasopressor findings, while directionally favorable, are similarly fragile. At all timepoints, the 95% confidence intervals included or were very close to zero, weakening confidence in a true benefit.
Cost Without Clear Benefit
Albumin is significantly more expensive than crystalloid solutions, with human albumin solution costing more than 30 times as much as crystalloids such as sodium chloride or Ringer lactate, and more than twice as much as synthetic colloids like hydroxyethyl starch. The Surviving Sepsis Campaign specifically notes the high cost of albumin as a reason to avoid its routine use in most critically ill patients, given the lack of clear mortality benefit over crystalloids.1
📊 State of The Evidence
This trial adds to the existing body of evidence evaluating albumin administration in septic patients—none of which have demonstrated a clear benefit over crystalloids. Notably, prior trials were conducted exclusively in ICU settings, whereas this study assessed albumin use earlier in the emergency department.3, 4
📘 Author's Conclusion
“Early identification, trial enrollment, and intervention in ED patients with sepsis are feasible. In this pilot study, concentrated albumin given early in resuscitation did not improve blood pressure at 24 hours.However, albumin was associated with less total fluid and vasopressor requirements up to 72 hours and improved organ dysfunction. A multicenter study is indicated.”
💬 Our Conclusion
This trial adds to the growing body of evidence suggesting no clinically meaningful benefit to albumin administration in the resuscitation of septic patients. Albumin did not improve blood pressure at 24 hours, nor did it impact mortality. While small differences were observed in early SBP, fluid volume, and vasopressor use, these findings were either clinically insignificant or statistically fragile.
🎯 Case Resolution
After initial evaluation and resuscitation, you pause—then recall the ICARUS-ED trial.
Despite being well-conducted, ICARUS-ED found no significant improvement in blood pressure at 24 hours, and only modest early gains: 4 mmHg higher SBP at 6 hours, ~700 mL less fluid at 72h, and a 7% reduction in vasopressor use. These differences didn’t result in better patient-centered outcomes—no reduction in mortality, ventilation, dialysis, or ICU stay.
Given the high cost of albumin and the absence of meaningful clinical benefit, you stick with your current resuscitation plan.
🚨 Clinical Bottom Line
Based on the best available current evidence, including this trial, albumin provides no meaningful clinical benefit in the resuscitation of septic patients.
🔄 REBEL Recap
📚 References
- Evans L, Rhodes A, Alhazzani W, et al.
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.
Crit Care Med. 2021;49(11):e1063-e1143.
PMID: 34605781 - Lamontagne F et al.
Intravenous Vitamin C in Adults with Sepsis in the Intensive Care unit.
N Engl J Med 2022.
PMID: 35704292. - Finfer S, Bellomo R, Boyce N, et al.
A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
N Engl J Med. 2004;350(22):2247-2256.
PMID: 15163774 - Caironi P, Tognoni G, Masson S, et al.
Albumin replacement in patients with severe sepsis or septic shock.
N Engl J Med. 2014;370(15):1412-1421.
PMID: 24635772 - Williams JM, et al.
Intervention With Concentrated Albumin for Undifferentiated Sepsis in the Emergency Department (ICARUS-ED): A Pilot Randomized Controlled Trial.
Ann Emerg Med. 2025 Jan 22.
PMID: 39846907 - Singer M, Deutschman CS, Seymour CW, et al.
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
JAMA. 2016;315(8):801-810.
PMID: 26903338
Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)
👤 Guest Author
🔎 Your Deep-Dive Starts Here
Clinical Conundrum: What is the Utility of Procalcitonin in the ED?
Procalcitonin is a protein that is upregulated during inflammatory states. ...
REBEL Core Cast 138.0: A Simple Bedside Approach to Shock
In this episode, we will dive into a simple yet ...
The ADAPT-Sepsis Trial: Biomarker-Guided Antibiotic Duration for Hospitalized Patients with Suspected Sepsis
Antibiotic stewardship entails delivering the most appropriate antimicrobial therapy for ...
Is 7 Days Enough? Rethinking Antibiotic Duration in Sepsis — The BALANCE Trial
Current IDSA guidelines for sepsis recommend individualized durations of antibiotic ...
Clinical Conundrum: Should We Always Treat Fever in Patients with Sepsis?
Bottom Line Up Top: There doesn’t appear to be a ...
Is Pip-Tazo Harming Sepsis Patients?
Background: Patients with sepsis are routinely treated with empiric broad-spectrum ...
