Oxygen delivery, hemodilution and transfusion in critical illness: an underrecognized safety signal in albumin randomized trials

Dear Editor,

Human albumin has been widely used for decades in critically ill patients to optimize intravascular volume and oncotic pressure¹. Beyond its volume-expanding properties, albumin exerts pleiotropic effects, including anti-inflammatory, antioxidant, and endothelial-modulating actions, which provide a strong physiological rationale for its use in sepsis and perioperative critical care¹. Although large randomized trials have demonstrated overall safety and possible benefits in selected subgroups¹, uncertainty persists regarding its net clinical effects and unintended consequences. Experimental and clinical evidence suggests that rapid fluid administration –including albumin administration– can significantly decrease hemoglobin concentration through dilutional effects, potentially limiting improvements in oxygen delivery despite increases in cardiac output². These physiological considerations highlight the importance of carefully evaluating unintended downstream effects of albumin therapy beyond traditional safety outcomes.

We read with great interest the randomized clinical trial by Sakr et al. evaluating albumin replacement therapy in septic shock (ARISS trial)³. Although the study did not demonstrate a survival benefit and concluded that albumin administration was safe, we believe that an important safety outcome –red blood cell transfusion exposure– deserves further consideration.

In ARISS, albumin administration targeting serum concentrations ≥3.0 g/dL was associated with a similar overall rate of adverse events. However, detailed reporting of transfusion-related outcomes was limited. This issue is clinically relevant, as the trial population was predominantly surgical and postoperative, a group intrinsically at higher risk of anemia and transfusion. Prolonged albumin administration (median 5 days, up to 28 days) may increase hemodilution and potentially trigger earlier transfusion. Notably, data from the supplementary material suggests a numerically higher frequency of transfusion-related interventions in the albumin group. Specifically, blood transfusion occurred in 52 patients (23.4%) in the albumin group versus 38 (17.4%) in controls at baseline and remained more frequent at 6 hours after randomization (44 [19.8%] vs 25 [11.5%]). Although these data do not specify packed red blood cell transfusion alone, they raise the prospect that albumin replacement therapy may be associated with increased transfusion requirements.

These observations are consistent with signals emerging from another randomized trial. In the ALBICS-AKI trial⁴, postoperative albumin infusion in high-risk cardiac surgery patients was associated with a significantly higher rate of transfusion compared with usual care (37.8% vs 29.9%; p=0.04).

Taken together, these findings suggest that increased transfusion exposure may represent an underrecognized safety signal of albumin therapy across critically ill and surgical populations. Even if albumin is hemodynamically well tolerated, its indirect effects through dilutional anemia and transfusion could attenuate potential physiological benefits.

We therefore propose that future randomized trials of albumin supplementation systematically report transfusion-related outcomes, including cumulative pRBC exposure, transfusion thresholds and indications, time to first transfusion, and the relationship between albumin dose and transfusion risk. Such analyses would provide important insights into the overall safety profile of albumin therapy and help refine patient selection. Importantly, transfusion exposure should not only be considered a short-term safety outcome. Growing evidence suggests that perioperative transfusion may compromise long-term outcomes, reinforcing Patient Blood Management as a value-based strategy to improve prognosis beyond the acute phase⁵.

In conclusion, transfusion exposure may represent a clinically meaningful and underreported safety outcome in albumin randomized trials. Clarifying this association could improve interpretation of current evidence and inform the design of future studies evaluating albumin supplementation in critically ill patients.