The pathogenesis of kernicterus, although complex and multifactorial, is ultimately dependent on a central nervous system tissue bilirubin exposure capable of inducing neurotoxicity and resultant bilirubin encephalopathy [1]. The risk of bilirubin encephalopathy, in turn, is driven by the magnitude of the total body (i.e., intravascular plus extravascular) bilirubin load (TBBL) and the level of diffusible unbound bilirubin available to enter the central nervous system [2, 3]. As highlighted by Ahlfors “The greater the bilirubin load, the higher the total and unbound bilirubin levels, tissue bilirubin level, and likelihood of toxicity” [2].

However, a quantitative analysis of the relationship between the TBBL and its tissue bilirubin component to the risk of bilirubin encephalopathy is difficult to carry out in clinical practice. This is because although the total serum bilirubin (TSB), unbound bilirubin level, and the intravascular component (plasma volume x TSB) of TBBL can be measured, the extravascular tissue bilirubin fraction (Tissue B) of TBBL cannot. For infants who have undergone an exchange transfusion (ET), however, the pre-exchange Tissue B can be estimated. The mathematical equations to make this estimate were worked out decades ago in the independent exchange transfusion studies on neonates of Valaes [4], and Sproul and Smith [5]. Both studies detailed bilirubin clearance during ET in hyperbilirubinemic human neonates including bilirubin equilibration between intravascular and extravascular compartments [4, 5]. Sproul and Smith used tracer dilution techniques (Cr51-labeled red blood cells and I131-labeled human serum albumin) in their investigation [5]. However, the relatedness of their individual insights has been overlooked. We show that when combined their heretofore separate equations provide a method to quantitatively estimate the pre-exchange Tissue B and TBBL in neonates who have undergone an ET.