Physiologically Based Modeling of the Effect of Physiological and Anthropometric Variability on Indocyanine Green Based Liver Function Tests

Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move toward an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a large in silico cohort of n = 100,000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step toward individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.

Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests

Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move towards an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a large in silico cohort of n=100000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step towards individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.

Assessment of hemodynamic parameters of hepatic and visceral blood flow in decompensated liver cirrhosis

The aim. To assess the hemodynamic parameters of the hepatic and visceral blood flow in patients with compensated and decompensated liver cirrhosis. Materials and methods. 290 patients with liver cirrhosis were examined: 206 had gastrointestinal bleeding, 84 had diuretic-resistant ascites. Ultrasonic scanning, Doppler sonography, esophagogastroduodenoscopy, angiography, radioisotope scintigraphy were performed to assess blood flow in the portal, splenic and superior mesenteric veins and in the hepatic, splenic and superior mesenteric arteries. Results. Change in the hepatic microcirculatory blood flow in the natural course of liver cirrhosis was characterized by decreased portal and increased arterial blood flow, “arterialization” of hepatic blood flow based on scintigraphy. Decompensation of the disease was associated with progressive reduction in both portal and arterial hepatic blood flow, which were correlated with the severity of functional liver disorders regardless of the complication nature. The portal blood flow in the natural course of liver cirrhosis was characterized by 3.5–4.5 times increased volume of visceral blood. Decompensation of the disease was accompanied by a decrease in blood flow in the portal vein as compared to the splenic and superior mesenteric veins by 1.8–2.2 and 1.5–2.7 times, respectively. Arterial blood flow in the natural course of liver cirrhosis was characterized by a relatively increased hepatic arterial flow. The ultrasound criterion of hepatic blood flow “arterialization” was an increase in hepatic-splenic arterial index, which can be used as a sign to differentiate between different forms of portal hypertension. Decompensation of the disease was characterized by an average of 8.2 % decreased arterial blood flow in the hepatic artery compared to the splenic artery in dynamics. Prognostically unfavorable signs were the progression of splenomegaly degree, the increase in the portal vein diameter with the decreased velocity characterizing the increase in congestive index by 2.4–2.6 times, the decrease in the hepatic artery diameter and velocity in it over time.Conclusions. The hepatic and visceral blood flow characteristics should be considered when choosing method of conservative, surgical or minimally invasive treatment of liver cirrhosis complications. Based on the hepatic hemodynamic characteristics, the mismatch between portal perfusion (reduced) and visceral blood flow (increased) is the essence of portal hypertension in liver cirrhosis. Accordingly, the criterion of treatment effectiveness in decompensated liver cirrhosis should be improved portal liver perfusion and (or) reduced volume of visceral blood flow.

Hepatic blood flow in adult Göttingen minipigs and pre-pubertal Danish Landrace x Yorkshire pigs

The liver receives dual blood supply from the hepatic artery and portal vein. The pig is often used as an animal model in positron emission tomography (PET) and pharmacokinetic studies because of the possibility for extensive and direct blood sampling. In this study, we compared measurements of hepatic blood flow in 10 female adult Göttingen minipigs and 10 female pre-pubertal Danish Landrace x Yorkshire (DLY) pigs. Ultrasound transit time flow meter probes were placed around the hepatic artery and portal vein through open surgery, hepatic blood flow measurements were performed, and the liver was weighed. Total hepatic blood flow was on average 363 ± 131 mL blood/min in Göttingen minipigs and 988 ± 180 mL blood/min in DLY pigs ( p < 0.001). The mean hepatic blood perfusion was 623 mL blood/min/mL liver tissue and 950 mL blood/min/mL liver tissue ( p = 0.005), and the liver weight was 0.58 kg and 1.04 kg, respectively. The mean arterial flow fraction in Göttingen minipigs was 12 ± 7% and lower than in DLY pigs, where it was 24 ± 7% ( p = 0.001). Using the gold standard for blood flow measurements, we found that both total hepatic blood flow and blood perfusion were significantly lower in Göttingen minipigs than in DLY pigs. The hepatic blood perfusion and arterial flow fraction in DLY pigs were comparable to normative values from humans. Differences in hepatic blood flow between adult Göttingen minipigs and humans should be considered when performing physiological liver studies in this model.

Influence of interapplicator distance on multibipolar radiofrequency ablation during physiological and interrupted liver perfusion in an in vivo porcine model

Radiofrequency ablation (RFA) is a curative treatment option for early stage hepatocellular carcinoma (HCC). Vascular inflow occlusion to the liver (Pringle manoeuvre) and multibipolar RFA (mbRFA) represent possibilities to generate large ablations. This study evaluated the impact of different interapplicator distances and a Pringle manoeuvre on ablation area and geometry of mbRFA. 24 mbRFA were planned in porcine livers in vivo. Test series with continuous blood flow had an interapplicator distance of 20 mm and 15 mm, respectively. For a Pringle manoeuvre, interapplicator distance was predefined at 20 mm. After liver dissection, ablation area and geometry were analysed macroscopically and histologically. Confluent and homogenous ablations could be achieved with a Pringle manoeuvre and an interapplicator distance of 15 mm with sustained hepatic blood flow. Ablation geometry was inhomogeneous with an applicator distance of 20 mm with physiological liver perfusion. A Pringle manoeuvre led to a fourfold increase in ablation area in comparison to sustained hepatic blood flow (p < 0.001). Interapplicator distance affects ablation geometry of mbRFA. Strict adherence to the planned applicator distance is advisable under continuous blood flow. The application of a Pringle manoeuvre should be considered when compliance with the interapplicator distance cannot be guaranteed.

Effects of propofol and sevoflurane on hepatic blood flow: a randomized controlled trial

Background Maintaining adequate perioperative hepatic blood flow (HBF) supply is essential for preservation of postoperative normal liver function. Propofol and sevoflurane affect arterial and portal HBF. Previous studies have suggested that propofol increases total HBF, primarily by increasing portal HBF, while sevoflurane has only minimal effect on total HBF. Primary objective was to compare the effect of propofol (group P) and sevoflurane (group S) on arterial, portal and total HBF and on the caval and portal vein pressure during major abdominal surgery. The study was performed in patients undergoing pancreaticoduodenectomy because - in contrast to hepatic surgical procedures - this is a standardized surgical procedure without potential anticipated severe hemodynamic disturbances, and it allows direct access to the hepatic blood vessels. Methods Patients were randomized according to the type of anesthetic drug used. For both groups, Bispectral Index (BIS) monitoring was used to monitor depth of anesthesia. All patients received goal-directed hemodynamic therapy (GDHT) guided by the transpulmonary thermodilution technique. Hemodynamic data were measured, recorded and guided by Pulsioflex™. Arterial, portal and total HBF were measured directly, using ultrasound transit time flow measurements (TTFM) and were related to hemodynamic variables. Results Eighteen patients were included. There was no significant difference between groups in arterial, portal and total HBF. As a result of the GDHT, pre-set hemodynamic targets were obtained in both groups, but MAP was significantly lower in group S (p = 0.01). In order to obtain these pre-set hemodynamic targets, group S necessitated a significantly higher need for vasopressor support (p < 0.01). Conclusion Hepatic blood flow was similar under a propofol-based and a sevoflurane-based anesthetic regimen. Related to the application of GDHT, pre-set hemodynamic goals were maintained in both groups, but sevoflurane-anaesthetized patients had a significantly higher need for vasopressor support. Trial registration Study protocol number is AGO/2017/002 – EC/2017/0164. EudraCT number is 2017–000071-90.Clin.trail.gov,NCT03772106, Registered 4/12/2018, retrospective registered.

Hepatic blood flow and oxygen tension in different types of liver damage and hyperoxia

Цель исследования - изучение кровотока и напряжения кислорода в печени при механическом, химическом и комбинированном поражении и курсовом воздействии гипербарической оксигенации (ГБО). Методика. Опыты выполнены на 143 белых крысах-самках массой 180-220 г. Механическое повреждение печени моделировали частичной гепатэктомией (ЧГЭ), удаляя часть левой доли печени (15-20% массы органа), химическое поражение - подкожным введением 50% раствора ССl4 на оливковом масле (0,1 мл/100 г). Инъекции делали через день на протяжении 65 сут. Для комбинированного поражения на 65-е (последние) сут введения ССl4 проводили ЧГЭ с последующей ГБО (3 ата, 50 мин, трёхкратно, через 4-8, 24 и 48 ч после ЧГЭ.) Печёночный кровоток в оперируемой левой (ЛДП) и одной из неоперируемых (средней, СДП) доле печени исследовали методом водородного клиренса. Напряжение кислорода (рО2) в печёночной ткани исследовали полярографически с платиновым электродом с поправкой на температурный коэффициент. Исследования проводили на 3-и, 7-е и 14-е сут послеоперационного (1-е, 4-е и 11-е сут постгипероксического) периода. Результаты. ЧГЭ у здоровых животных, стимулируя кровоток в обеих исследуемых долях печени, снижает рО2 только в остатке ЛДП на 3-и и 7-е сутки послеоперационного периода. На 65-е сут введения ССl4 наблюдается снижение кровотока в остатке ЛДП и СДП, соответственно, на 42% и 39%, а рО2 на 50%. Эти показатели не нормализуются к 14-м сут после отмены токсина. Применение ЧГЭ на 65-е сут введения ССl4 вызывает увеличение кровотока на 3-и и 7-е сут послеоперационного периода только в СДП, однако на 14-е сут он снижается до уровня конца затравки. Это сопровождается кратковременной нормализацией сниженного рО2 на 7-е сутки послеоперационного периода. В остатке ЛДП у животных с хроническим ССl4-гепатитом и ЧГЭ величина кровотока и рО2 не изменяется, оставаясь ниже нормы к 14-м сут после ЧГЭ. Применение ГБО у здоровых крыс с ЧГЭ устраняет стимулирующее влияние операции на кровоток в обеих исследуемых долях органа, нормализуя рО2 в остатке ЛДП и снижая его в СДП на 3-и и 7-е сут, которое устраняется к 14-м сут после ЧГЭ на фоне отсроченного стимулирующего влияния гипероксии на кровоток в этой доле печени. У животных с комбинированным поражением печени применение ГБО стимулирует увеличение кровотока в обеих исследуемых долях органа, что способствует увеличению рО2 относительно предоперационного уровня, но полной его нормализации не происходит. Стимулирующее влияние ГБО на кровоток у животных с комбинированным поражением печени сохраняется к 11-м сут постгипероксического периода. Заключение. Длительное действие на организм ССl4 снижает чувствительность печёночного кровотока к стимулирующему влиянию ЧГЭ, способствуя стойкому развитию гипоксии в повреждённой и неповреждённой при операции долях печени. Реакция кровотока и тканевого рО2 оперированной печени на ГБО находится в прямой зависимости от состояния данного органа на момент гипероксического воздействия. The aim of study was to investigate hepatic blood flow and oxygen tension in mechanical, chemical, and combined injury of the liver and during a course of hyperbaric oxygenation (HBO). Methods. Experiments were performed on 143 white female rats weighing 180-220 g. Mechanical injury of the liver was modeled with partial hepatectomy (PHE) by removing a part of the left hepatic lobe (HL) (15-20% of liver weight). Chemical injury was modeled by subcutaneous injection of 50% ССl4 in olive oil (0.1 ml/100 g). Injections were performed every second day for 65 days. For the combined injury, PHE followed by HBO (3 ATA, 50 min) was performed on day 65 (last day) of ССl4 administration. HBO was applied three times, at 4-8, 24, and 48 hours after PHE. Hepatic blood flow was studied using hydrogen clearance in the operated, left HL (LHL) and in one of unoperated, middle HL (MHL). Hepatic oxygen tension (рО2) was evaluated by polarography with a platinum electrode; data were corrected for the temperature coefficient. Studies were performed on postoperative days 3, 7 and 14 (posthyperoxia days 1, 4, and 11). Results. In normal animals, PHE stimulated blood flow in both studied hepatic lobes and decreased рО2 only in the remaining LHL on postoperative days 3 and 7. On day 65 of ССl4 administration, blood flow was reduced by 42% and 39%, respectively, in remaining LHL and MHL while рО2 was reduced by 50%. These changes were not reversed by day 14 following the toxin withdrawal. PHE performed on day 65 of ССl4 administration caused an increase in blood flow on postoperative days 3 and 7 only in MHL; however, on day 14, the blood flow decreased to the level of the end of toxin administration. This was associated with a brief normalization of the reduced рО2 on postoperative day 7. In the remaining LHL of animals with chronic ССl4-induced hepatitis and PHE, values of blood flow and рО2 did not change and remained below the normal level at 14 days after PHE. The HBO exposure of healthy rats with PHE abolished the stimulating effect of surgery on blood flow in both studied hepatic lobes, thereby normalizing pO2 in the remaining LHL and decreasing pO2 in MHL on days 3 and 7. This was reversed by postoperative day 14 due to the stimulating effect of hyperoxia on blood flow in this HL. In animals with combined injury of the liver, HBO stimulated blood flow in both studied HLs, thereby increasing рО2 above the preoperative level; however, a complete recovery did not occur. The stimulating effect of HBO on blood flow in animals with combined injury remained by day 11 of the posthyperoxic period. Conclusion. A prolonged exposure to ССl4 reduced the sensitivity of hepatic blood flow to the stimulating effect of PHE, which facilitated development of persistent hypoxia in both injured and uninjured HLs. Responses to HBO of blood flow and tissue рО2 in operated liver directly depend on the state of liver at the moment of hyperoxia exposure.