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

Abstract

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.

Physiological and Biochemical Basis of Clinical Liver Function Tests

“…It is now the most widely used quantitative liver function test in the clinical setting. 31 ICG is a tricarbocyanine dye that binds to albumin 32,33 , alpha-1lipoproteins 28 , and β-lipoproteins. 32 It distributes uniformly in the blood within 2-3 minutes after intravenous injection of 25 mg or 50 mg ICG (dissolved in 5 mL or 10 mL sterile water, respectively).…”

“…36 Under normal conditions, ICG has a high hepatic extraction rate, and its uptake is rate-limited by blood flow. 15,33 Additionally, the clearance of ICG from the blood is similar to that of various endogenous and exogenous substances such as bilirubin, hormones, drugs, and toxins. The ICG clearance test therefore reflects several important functional parameters of the liver, including blood flow-dependent clearance and transporter capacity.…”

Vascular assessment of liver disease—towards a new frontier in MRI

“…13 Exclusive hepatic extraction and photometric properties of ICG have yielded less invasive ICG plasma disappearance rate and ICG 15-min retention rate (ICG-R15), which measure hepatic parenchymal function rather than liver blood flow and are potentially subject to error. 14,15 …”

Surgical resection of localized hepatocellular carcinoma: patient selection and special consideration

“…Indocyanine green (ICG) is a metabolically inert dye. It does not get metabolized or degraded in blood, is solely and actively excreted by hepatocytes, and is not reabsorbed via the enterohepatic pathway; hence, it is an ideal marker for liver function assessment 70–74. ICG is injected at a dosage 0.5 mg/kg intravenously; serum retention of ICG >15% at 15 minutes is generally considered inadequate75 although it has been reported that the safety cutoff can be as high as 20% for a Child-Pugh A patient 76.…”