Transfusion dosing targets; Concentration vs potency (a case for oxygen delivery-based metrics)

Abstract

Abstract INTRODUCTION: Blood transfusions are used to treat anemia when oxygen (O2) delivery to tissues is compromised or when the body's compensatory cardiovascular response poses risk. Traditionally, transfusion decisions have relied heavily on hemoglobin (Hb) concentration thresholds, under the assumption that Hb levels directly reflect the body's oxygenation status. However, this approach overlooks variations in the actual O2 delivery capacity between a patient's own red blood cells and those stored from donors, as well as among different blood product types. While assessing how well a patient tolerates anemia remains important, there is also a critical need to evaluate the functional potency of transfused blood in terms of its potential O2 delivery. Currently, no standardized metric exists to guide this more nuanced assessment. METHODS: We developed an in vitro metric to predict the O2 delivery potency for blood products (fresh whole blood; fWB, stored whole blood; sWB in citrate phosphate dextrose adenine solution; CPDA-1, and stored RBC concentrate; sRBCc in additive solution 1; AS-1). O2 uptake and delivery was modeled across physiologic O2 gradients by integrating data from matched O2 association (high pH ~ lung) and dissociation curves (low pH ~ tissue); HEMOX analyzer - simulating circulatory O2 uptake in the lung and delivery to tissue. These data were used to compute a novel O2 delivery potency metric, lung to tissue O2 flux (L-TOF), which we propose as a quantifiable predictive measure of O2 delivery potency. RESULTS: Using L-TOF, we quantified O2 delivery potency of sWB (CPDA-1) and sRBCc (AS-1), determining that equipotent transfusion from day 0 to 26 ± 2 (sWB), or 42 ± 1 (sRBCc) would require an increase in 'dose’ of 163% for sWB (735 ± 82.4 mL of day 26 sWB was equipotent to 450 ± 0.0 mL of fWB) or 158% for sRBCc (476 ± 21.6 mL of day 42 sRBCc was equipotent to 300 ± 0.0 mL of fresh RBCs). L-TOF was further employed to measure post-transfusion blood mixtures, utilizing a novel benchtop human massive transfusion (HMT) model, enabling direct comparison of O2delivery effectiveness between fWB, sWB, and simple crystalloid/colloid (normal saline; NS). A 50% volume transfusion with NS (1:1 fWB:NS) did not affect L-TOF (mL O2/gram Hb), as Hb O₂ carriage remains unchanged by dilution, but reduced L-TOF (mL O2/liter blood) by 50%, due to lost O2 carrying capacity. In contrast, a 1:1 fWB:sWB transfusion reduced L-TOF (mL O2/gram Hb) ~17%, due to storage lesion–related loss of allosteric effectors, resulting in a 17% drop in L-TOF (mL O2/liter blood). CONCLUSION: L-TOF introduces the concept of pharmacodynamic potency to blood products, which we suggest is long overdue. L-TOF not only enables direct comparison of O2 delivery potency between blood products (fWB, sWB, and sRBCc) but can also be used to predict O2 delivery potency of post-transfusion blood mixtures (using our novel benchtop HMT model). Ultimately, transfusion decision making based solely on Hb concentration does not account for the significant variability in O₂ delivery potency between donor and recipient RBCs, which L-TOF reveals, i.e., sWB and sRBCc have reduced potency compared to fWB, requiring higher doses to achieve similar effects - potentially increasing side effects. Ultimately, L-TOF offers a valuable tool for optimizing transfusion dosing based on functional effectiveness rather than static thresholds, in addition to filling an important knowledge gap by offering a predictive readout of transfusion quality.