Abstract
The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology as well as in hepatobiliary surgery. Indocyanine green (ICG) is a widely applied test compound that is used in clinical routine to evaluate hepatic function. Important questions for the functional evaluation with ICG in the context of hepatectomy are how liver disease such as cirrhosis alters ICG elimination, and if postoperative survival can be predicted from preoperative ICG measurements. Within this work a physiologically based pharmacokinetic (PBPK) model of ICG was developed and applied to the prediction of the effects of a liver resection under various degrees of cirrhosis. For the parametrization of the computational model and validation of model predictions a database of ICG pharmacokinetic data was established. The model was applied (i) to study the effect of liver cirrhosis and liver resection on ICG pharmacokinetics; and (ii) to evaluate the model-based prediction of postoperative ICG-R15 (retention ratio 15 min after administration) as a measure for postoperative outcome. Key results are the accurate prediction of changes in ICG pharmacokinetics caused by liver cirrhosis and postoperative changes of ICG-elimination after liver resection, as validated with a wide range of data sets. Based on the PBPK model, individual survival after liver resection could be classified, demonstrating its potential value as a clinical tool.
Highlights
Determining liver function is a crucial task in hepatology, e.g., for liver disease diagnosis or evaluation of pre- and postoperative functional capacity of the liver
Based on the plasma time course of Indocyanine green (ICG), pharmacokinetic parameters are calculated as a proxy for liver function, the most common parameters being: (i) ICG retention ratio 15 min after administration (ICG-R15) [%]; (ii) ICG plasma disappearance rate (ICG-PDR) [%/min]; (iii) ICG-clearance [ml/min]; and (iv) ICG half-life (ICG-t1/2) [min]
Important questions for the evaluation of liver function with ICG in the context of HPB surgery are (i) how liver disease, especially cirrhosis, alter ICG elimination, and (ii) if postoperative survival can be predicted from preoperative ICG measurements
Summary
Determining liver function is a crucial task in hepatology, e.g., for liver disease diagnosis or evaluation of pre- and postoperative functional capacity of the liver. A comprehensive characterization of the status of a patient and their liver is routinely performed before liver surgery such as partial hepatectomy. This includes among others anthropometric factors (e.g., age, sex, body weight), static liver function tests (e.g., ALT, AST, albumin, bilirubin, INR, prothrombin time), cardiovascular parameters (e.g., cardiac output, blood pressure, hepatic blood flow) and lifestyle factors (e.g., smoking, medication) as well as volumetric. After intravenous administration ICG is taken up exclusively by the liver and excreted unchanged into the bile. It is not reabsorbed by the intestine and does not undergo enterohepatic circulation (Wheeler et al, 1958). Reduced elimination of ICG by the liver is directly reflected by these parameters (Sakka, 2018)
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