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Background  Guidelines recommend a restrictive red blood cell transfusion strategy based on hemoglobin (Hb) concentrations in critically ill patients. We hypothesized that the arterial-venous oxygen difference (A-V O 2diff ), a surrogate for the oxygen delivery to consumption ratio, could provide a more personalized approach to identify patients who may benefit from transfusion.    Methods  A prospective observational study including 177 non-bleeding adult patients with a Hb concentration of 7.0–10.0 g/dL within 72 h after ICU admission. The A-V O 2diff , central venous oxygen saturation (ScvO 2 ), and oxygen extraction ratio (O 2 ER) were noted when a patient’s Hb was first within this range. Transfusion decisions were made by the treating physician according to institutional policy. We used the median A-V O 2diff  value in the study cohort (3.7 mL) to classify the transfusion strategy in each patient as “appropriate” (patient transfused when the A-V O 2diff  > 3.7 mL or not transfused when the A-V O 2diff  ≤ 3.7 mL) or “inappropriate” (patient transfused when the A-V O 2diff  ≤ 3.7 mL or not transfused when the A-V O 2diff  > 3.7 mL). The primary outcome was 90-day mortality.    Results  Patients managed with an “appropriate” strategy had lower mortality rates (23/96 [24%] vs. 36/81 [44%];  p  = 0.004), and an “appropriate” strategy was independently associated with reduced mortality (hazard ratio [HR] 0.51 [95% CI 0.30–0.89],  p  = 0.01). There was a trend to less acute kidney injury with the “appropriate” than with the “inappropriate” strategy (13% vs. 26%,  p  = 0.06), and the Sequential Organ Failure Assessment (SOFA) score decreased more rapidly ( p  = 0.01). The A-V O 2diff , but not the ScvO 2 , predicted 90-day mortality in transfused (AUROC = 0.656) and non-transfused (AUROC = 0.630) patients with moderate accuracy. Using the ROC curve analysis, the best A-V O 2diff  cutoffs for predicting mortality were 3.6 mL in transfused and 3.5 mL in non-transfused patients.    Conclusions  In anemic, non-bleeding critically ill patients, transfusion may be associated with lower 90-day mortality and morbidity in patients with higher A-V O 2diff .    Trial registration  ClinicalTrials.gov,  NCT03767127 . Retrospectively registered on 6 December 2018.

Using arterial-venous oxygen difference to guide red blood cell transfusion strategy