Identifying a long standing error in single-bolus determination of the hepatic extraction ratio for indocyanine green

For approximately 50 years, hepatic clearance of indocyanine green (ICG) has been used to assess liver function. Steady-state infusion of ICG with simultaneous measurement of arterial and hepatic venous ICG concentrations provides unambiguous measures of the extraction ratio for ICG and the hepatic blood flow rate, but also requires cannulation of a hepatic vein. Transient clearance following injection of a single bolus of ICG, which typically involves only measurement of arterial ICG concentration, is a more commonly used procedure. Since drawing blood from a hepatic vein is often impossible, and, in any event can be difficult, there has been considerable interest in the claim by Grainger et al. (Clin Sci 64:207-212, 1983) that a single-bolus, two-compartment model "enabled the hepatic extraction ratio (ER(ss)) of dye to be determined solely from the plasma disappearance curve". The principal purpose of this paper is to show that the claim by Grainger et al. is not valid because it ignores the fact that a finite fraction of ICG entering the liver passes directly into hepatic veins without being sequestered in the liver. A valid relationship between ER(ss) and parameters determined from single-bolus clearance data is derived in this paper. For individuals with normally functioning livers, the single-bolus method of Grainger et al. yields an extraction ratio approximately 20% too large, but in cirrhotic patients with extensive intrahepatic shunting, the extraction ratio evaluated using the single-bolus method of Grainger et al. may be too large by a factor of two.