Search

Indocyanine green (ICG) retention test is widely used for preoperative evaluation of liver function. OATP1B3 (gene symbol: SLCO1B3) is the major transporter for hepatic ICG uptake. We previously demonstrated that the individuals with a homozygous SLCO1B3 null allele revealed markedly impaired ICG clearance. However, the effect of heterozygosity of this variant on ICG clearance remains unknown. We compared the results of ICG retention rate at 15 min (ICG-R15) and hepatic OATP1B3 expression among individuals whose SLCO1B3 genotype was determined. Although OATP1B3 expression was significantly lower in the heterozygosity than the wild-type, the ICG-R15 results were comparable; 8.4 ± 3.4 (mean ± SD) % in the heterozygosity and 8.7 ± 6.0% in the wild-type. A homozygous individual revealed markedly high ICG-R15 (79.8%) and lacked OATP1B3 expression. In conclusion, the individuals with a heterozygous SLCO1B3 null variant had similar ICG clearance capacity to those with the wild-type despite decreased hepatic OATP1B3 expression.

BackgroundThe indocyanine green (ICG) clearance test is the main method of evaluating the liver reserve function before hepatectomy. However, some patients may be allergic to ICG or the equipment of ICG clearance test was lack, leading to be difficult to evaluate liver reserve function. We aim to find an alternative tool to assist the clinicians to evaluate the liver reserve function for those who were allergic to the ICG or lack of equipment before hepatectomy.MethodsWe retrospected 300 patients to investigate the risk factors affecting the liver reserve function and to build an equivalent formula to predict ICG 15 min retention rate (ICG-R15) value.ResultsWe found that the independent risk factors affecting ICG clearance test were total bilirubin, albumin, and spleen-to-non-neoplastic liver volume ratio (SNLR). The equivalent formula of the serological index combining with SNLR was: ICG-R15 = 0.36 × TB (umol/L) − 0.78 × ALB(g/L) + 7.783 × SNLR + 0.794 × PT (s) − 0.016 × PLT(/109) − 0.039 × ALT (IU/L) + 0.043 × AST (IU/L) + 23.846. The equivalent formula of serum index was: ICG-R152 = 24.665 + 0.382 × TB (umol/L) − 0.799 × ALB(g/L) − 0.025 × PLT(/109) + 0.048 × AST(IU/L) − 0.045 × ALT(IU/L). And the area under the ROC curve (AUC) of predicting ICG-R15 ≥ 10% was 0.861 and 0.857, respectively.ConclusionWe found that SNLR was an independent risk factor affecting liver reserve function. Combining with SNLR to evaluate the liver reserve function was better than just basing on serology.

Objective. To study the correlations and discrepancies between Child-Pugh system and indocyanine green (ICG) clearance test in assessing liver function reserve and explore the possibility of combining two systems to gain an overall liver function assessment. Design. Retrospective analysis of 2832 hepatocellular carcinoma (HCC) patients graded as Child-Pugh A and Child-Pugh B with ICG clearance test being performed was conducted. Results. ICG retention rate at 15 minutes (ICG15) correlates with Child-Pugh score, however, with a large variance. Platelet count improves the correlation between Child-Pugh score and ICG15. ICG15 can be estimated using the following regression formula: estimated ICG15 (eICG15) = 45.1 + 0.435 × bilirubin − 0.917 × albumin + 0.491 × prothrombin time − 0.0283 × platelet (R2=0.455). Patients with eICG15 >20.0% who underwent major hepatectomy had a tendency towards more posthepatectomy liver failure (4.1% versus 8.0%, p=0.09) and higher in-hospital mortality (3.7% versus 8.0%, p=0.052). They also had shorter median overall survival (5.10±0.553 versus 3.01±0.878 years, p=0.015) and disease-free survival (1.37±0.215 versus 0.707±0.183 years, p=0.018). Conclusion. eICG15 can be predicted from Child-Pugh parameters and platelet count. eICG15 correlates with in-hospital mortality after major hepatectomy and predicts long-term survival.

Aim The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. Methods Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. Results Seventy-one patients (78.9%) had Child–Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate (PDR) was positively correlated with the BSM-measured values (r = 0.886, P

Preoperative estimation of future remnant liver function is critical for major hepatic surgery to avoid postoperative morbidity and mortality. Among several liver function tests, the indocyanine green (ICG) clearance test is still the most popular dynamic method. The usefulness of ICG clearance test parameters, such as ICGR15, KICG, or PDRICG, has been reported by many investigators. The transcutaneous non-invasive pulse dye densitometry system has made the ICG clearance test more convenient and attractive, even in Western countries. The concept of future remnant KICG (rem KICG), which combines the functional aspect and the volumetric factor of the future remnant liver, seems ideal for determining the maximum extent of major hepatic resection that will not cause postoperative liver failure. For damaged livers with functional heterogeneity among the hepatic segments, fusion images combining technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin single photon emission computed tomography (99mTc-GSA SPECT) and X-ray CT are helpful to precisely estimate the functional reserve of the future remnant liver. Another technique for image-based liver function estimation, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd-EOB)-enhanced magnetic resonance imaging, may be an ideal candidate for the preoperative determination of future remnant liver function. Using these methods effectively, morbidity and mortality after major hepatic resection could be reduced.

Indocyanine green (ICG) is not new in the field of liver surgery. Early studies performed in the 1980s and 1990s revealed the value of the ICG clearance test in predicting post-hepatectomy morbidity and mortality. ICG clearance and retention tests are crucial for determining precise liver function before liver surgery and offer several benefits for safe surgery. Whereas ICG is well-known and has long history in medicine, recent progress in infrared light technology over the last decade has highlighted another feature of ICG. For example, ICG fluorescence-guided surgery may change the next generation of liver surgery. In the near future, ICG with near-infrared (NIR) light photodynamic therapy (PDT) is expected to become a new treatment method for hepatocellular carcinoma (HCC). Furthermore, several aspects of the mechanisms of ICG accumulation in HCC cells have been revealed by important basic research studies. New imaging technologies and mechanistic findings keep ICG in the spotlight. In this article, we review three recently described topics of ICG which may contribute to the development of innovative and new treatments method for HCC, fluorescence-guided surgery, mechanism of ICG accumulation in HCC cells, PDT for HCC.

Liver blood flow (Q) is often measured by constant infusion of ICG (i), concentration measurements in an artery (A) and a hepatic vein (V): Q = (A-V)/A. Some authors use ICG clearance, Cl = i/A, as a measure of Q assuming complete hepatic extraction. During the infusion, the ICG concentration often increases. The importance of this for calculated values of Q and Cl was examined, and the use of Cl as a measure of Q was reevaluated. ICG was given as 0.06-0.20 mumol/min to 52 subjects with liver disease, and about 0.20 mumol/min to 86 subjects with no liver disease. ICG concentration increased steeply during the first 90 min after start of the infusion; thereafter the increment was constant as evaluated in successive 40-min periods in eleven 320-min studies (analysis of variance P greater than 0.5); on average, 6 +/- 1% per hour (+/- SD). Q was not time-dependent (P greater than 0.5). ICG clearance decreased significantly, on average 5 +/- 2% per hour (+/- SD). Hepatic extraction fraction, (A-V)/A, (measurement period 90-130 min) was 0.34 +/- 0.21 in liver patients (+/- SD) and 0.61 +/- 0.80 in controls. Cl and Q were positively correlated in both groups but with substantial scatter. Thus, not only is the calculated ICG clearance time-dependent but the extraction fraction is further so low and variable, that any use of ICG clearance as a measure of liver flow is not justified.

© 2015 Taylor & Francis Liver biology, liver disease and its management present a myriad of challenges to clinicians. Difficulties arise in determining liver functional capacity, which must be effectively measured in a quantitative reproducible manner. Measurement of indocyanine green (ICG) clearance, an exceptional tool that has been used for decades to assess liver function, has traditionally been cumbersome to perform. New technology now allows for rapid and noninvasive determination of ICG clearance making it clinically accessible. This adds ICG clearance measurement to the armamentarium of physiologic monitors that could be routinely used in the evaluation of patients undergoing liver surgery or in the intensive care setting.

The clearance of ICG, a known hepatic blood flow marker was investigated in rats in order to examine whether DDB-S influences hepatic blood flow. The effect of DDB-S on the protein binding and blood-to-plasma partition of ICG was measured. The steady-state plasma concentration of ICG was monitored before and after co-administration of various concentration of DDB-S, and ICG clearance was estimated from the steady-state concentration and the infusion rate of ICG. There was no significant difference in protein binding and blood-to-plasma partition of ICG with and without addition of DDB-S (10, 20, and 40 microg/mL). When ICG was infused into DDB-S pretreated rats, the steady-state concentrations of ICG decreased and the calculated ICG clearance increased. However, no dose-dependency of ICG Css on DDB-S Css was observed. Since DDB-S did not affect the protein binding and blood-to-plasma partition of ICG, the increased clearance of ICG with co-administration of DDB-S seems to be due to the increased hepatic blood flow by DDB-S.

Background. The most significant risk following major hepatectomy is postoperative liver insufficiency. Current preoperative assessment of the future liver remnant relies upon assumptions which may not be valid in the setting of advanced resection strategies. This paper reports the feasibility of the ALIIVE technique which assesses the liver remnant with ICG clearance intraoperatively during vascular exclusion. Methods. 10 patients undergoing planned major liver resection (hemihepatectomy or greater) were recruited. Routine preoperative assessment included CT and standardized volumetry. ICG clearance was measured noninvasively using a finger spectrophotometer at various time points including following parenchymal transection during inflow and outflow occlusion before vascular division, the ALIIVE step. Results. There were one case of mortality and three cases of posthepatectomy liver failure. The patient who died had the lowest ALIIVE ICG clearance (7.1%/min versus 14.4 ± 4.9). Routine preoperative CT and standardized volumetry did not predict outcome. Discussion/Conclusion. The novel ALIIVE technique is feasible and assesses actual future liver remnant function before the point of no return during major hepatectomy. This technique may be useful as a check step to offer a margin of safety to prevent posthepatectomy liver failure and death. Further confirmatory studies are required to determine a safety cutoff level.

The purposes of this study were 1) to examine changes in the indocyanine green (ICG) clearance by feeding and 4-day fasting in dry cows, and (2) to investigate the relationship between ICG clearance and blood chemistry profile in postpartum cows. In 3 dry cows, post-feeding ICG half-life (T(1/2)) was shorter than the pre-feeding value, and post-fasting T(1/2) was longer than pre-feeding and post-feeding values. In 16 lactating cows, T(1/2) value at 2 weeks postpartum showed positive correlations with AST, T-Bil and γ-GTP. These results suggested that ICG clearance correlated with T-Bil and liver enzymes can be sensitive and accurate diagnostic marker for impaired liver function in dairy cows. In addition, ICG clearance is greatly affected by feeding and fasting.

症例は63歳の男性. 腹部超音波検査で肝S6を中心に腫瘍陰影を認めた. 蛋白合成能, 凝固系能などの肝予備能検査と比較し, R15 (ICG R15) は20%と高値を示した. 血中ICG消失曲線では, 通常の肝硬変ではみられない高い2ndピークを認め, 門脈系-大循環シャントの存在が推察された. 腹部血管造影では, 肝後区域にhyper vascularな腫瘍陰影が存在し, 周囲に娘結節を多数認めた. また, 肝動脈-門脈シャントが存在し, 門脈圧の上昇が示唆された. そのために門脈の左右分岐より末梢は造影されず, 脾静脈系から下大静脈への大きな側副血行路が存在した. 肝動脈後区域枝に塞栓術を行ったところ, 血中ICG消失曲線の高い2ndピークは消失し, R15も12%に改善した. 血中ICG消失曲線の特徴から, 質的な病態を推察し, 正確な肝細胞予備能を把握することが可能であった.

Indocyanine green (ICG) was given intravenously (0.5 mg kg-1) to seven healthy male volunteers in random order during a control session and a session in the sauna bath. The sauna bathing session consisted of three 10 min. stays in the sauna (temperature 85-95 degrees, relative humidity 25-30%), separated by two 5-min. periods of resting at 22 degrees. Blood samples were taken for 60 min. in order to calculate ICG plasma clearance (CI), volume of distribution (Vss) and elimination half-life (t1/2 beta). The mean +/- S.E.M. values of ICG plasma clearance, Vss and t1/2 beta for the control session and the sauna bathing session were 0.47 +/- 0.08 1 min.-1 versus 0.39 +/- 0.04 1 min.-1, 2.4 +/- 0.4 1 versus 2.3 +/- 0.2 1 and 3.9 +/- 0.3 min. versus 4.4 +/- 0.3 min., respectively. No statistically significant differences in the CI, t1/2 beta or Vss of ICG were detected between the control and sauna bathing sessions. The results suggest that short-term exposure to high ambient temperatures during sauna bathing does not affect hepatic blood flow. Consequently, short-term hyperthermia and associated changes in hepatic blood flow are assumed to have little, if any, effect on the hepatic clearance of drugs.

An instrument to measure hepatic function was developed as a medical application of optoelectronic technology. The study of Indocyanine green (ICG) clearance in blood is clinically used for the estimation of hepatic function. Multiple blood samplings, however, subject the patients to mental and physical stress. Furthermore, although it is necessary with this method to correctly measure the blood sampling time after ICG injection, it is difficult to accurately measure this time in an actual test. Thus, a measuring method without blood sampling has been desired. Although some preliminary studies employing a non-invasive method were undertaken, there were still problems for clinical usage. Therefore, in this paper, a description of an instrument for the non-invasive measurement of ICG clearance using an optical sensor attached to the fingertip is presented, and a calibration method before ICG injection is proposed to solve the problem of changing blood volume. Next, the results of the clinical evaluation of 470 cases are presented. Using this newly developed instrument, the values of ICG tests correlated well with the values calculated from the conventional blood sampling method.

Whereas imaging studies such as CT or MRI allow volumetric assessment of the liver segments, only indirect information is provided concerning the quality of the liver parenchyma and its actual functional capacity. Assessment of liver function is therefore crucial in the preoperative work-up of patients who require extensive liver resection and in whom PVE is considered. As the regenerative capacity of the liver is related to the quality of liver parenchyma, the success of PVE largely depends on parameters of liver function. This chapter deals with several tests for the measurement of liver function. Passive liver function tests include biochemical parameters and clinical grading systems such as the Child-Pugh and MELD scores. Dynamic quantitative tests of liver function can be based on clearance capacity tests such as the ICG clearance test, galactose elimination capacity, and lidocaine clearance test. Although widely used, discrepancies have been reported of the ICG clearance test in relation with clinical outcome. Nuclear imaging studies have the advantage of providing simultaneous morphologic (visual) and physiologic (quantitative functional) information of the liver. In addition, regional (segmental) differences in liver function can be determined. The use of SPECT-CT cameras enables measurements of volume and function of the future remnant liver. 99mTc-galactosl serum albumin (GSA) scintigraphy and 99mTc-mebrofenin hepatobiliary scintigraphy potentially identify patients at risk for post-resectional liver failure who might benefit from PVE. Bioenergetic tests are based on the energy state of the liver and the availability of ATP. The caffeine clearance test, aminopyrine breath test and MEGX test measure the microsomal or cytosolic capacity of the liver. As there is not one test that can measure all the components of liver function, liver functional reserve remains to be estimated from a combination of clinical parameters and quantitative liver function tests.

Indocyanine green (ICG) is widely used for its clearance test in the evaluation of liver function. Gadoxetate disodium (Gd-EOB-DTPA) is a targeted MR contrast agent partially taken up by hepatocytes. The objective of this study was to evaluate the feasibility of an estimation of the liver function corresponding to plasma disappearance rate of indocyanine green (ICG-PDR) by use of the signal intensity of the liver alone in Gd-EOB-DTPA enhanced MR imaging (EOB-MRI). We evaluated fourteen patients who had EOB-MRI and ICG clearance test within 1 month. 2D-GRE T1 weighted images were obtained at pre contrast, 3 min (equilibrium phase) and 20 min (hepatobiliary phase) after the intravenous administration of Gd-EOB-DTPA, and the mean signal intensity of the liver was measured. The correlation between ICG-PDR and many parameters derived from the signal intensity of the liver in EOB-MRI was evaluated. The correlation coefficient between ICG-PDR and many parameters derived from the signal intensity of the liver in EOBMRI was low and not significant. The estimation of the liver function corresponding to ICG-PDR by use of the signal intensity of the liver alone in EOB-MRI would not be reliable.

Indocyanine green (ICG) clearance has been used, since the 1950s, as an indicator of dynamic liver function. The emergence of static liver function tests together with imaging and histology, has reduced the use of ICG measurements in the clinical setting. During the last two decades, methods to assess the hepatosplanchnic circulation and liver function have been the focus of intense investigation. The monitoring of this regional circulation has been shown to be the best predictor of outcome in critically ill patients [1]. As technologies advance, two mains goals can be identified concerning hemodynamic monitoring: The first is to make measurements using non-invasive tools in order to eliminate the risks associated with invasive monitoring; the second is to find a single measurement that could predict patient status. The same points are currently needed in regional hemodynamic monitoring. This chapter briefly considers ICG clearance physiology and its various methods of measurement, reviews the indications for ICG clearance measurement, and defines the current interests and limits of this technique with regard to hepatic functional impairment in critically ill patients with sepsis, liver disease, or after major hepatic surgery and liver transplantation.

The indocyanine green (ICG) clearance test has been used to assess the reserve of hepatic function. This method is based on the spectrometric measurement of its plasma concentration at maximum wavelength of 805nm, which requires a spectrophotometer and associated maintenance. We established an ICG clearance test using a Toshiba 200FR automatic chemistry analyzer that can be tuned to a wavelength of approximately 805nm. Five pooled sera spiked from 0 to 4.0mg/dL were analyzed for linearity test and precision was determined at five levels in the range 0.1–2.0mg/dL. The ICG retention rate at 15min (R15) was determined for 38 patients using a conventional method and our method. The ICG clearance test using the automatic chemistry analyzer showed good linearity, and precision ranged from 0.3% to 1.0% for within-run CVs and from 0.6% to 4.7% for total CVs. The degree of agreement between the two methods was also acceptable (mean difference of 1.5%). It is expected that the ICG test using the automatic chemistry analyzer can replace the conventional ICG clearance test, considering the excellent agreement, good precision and linearity over a clinically relevant range.

As a medical application of optoelectronic technology, an instrument to measure liver function was developed. For the estimation of liver function, Indocyanine green (ICG) is widely used as a tracer clinically. A description of an instrument for noninvasive measurement of ICG clearance and the results of the clinical evaluation of about 470 patients are presented. In in vivo measurement, to solve the problem of changing blood volume, the authors propose a novel calibration method before ICG injection. Using this instrument, called an ICG clearance meter, the value of ICG tests correlated well with the values calculated from the conventional blood sampling methods. >

211 INDOCYANINE GREEN CLEARANCE (ICG) AS A PREDICTOR OF 2-YEARS CLINICAL DECOMPENSATION AND MORTALITY IN PATIENTS WITH COMPENSATED LIVER CIRRHOSIS A. Lisotti, F. Azzaroli, F. Buonfiglioli, P. Cecinato, M. Montagnani, R. Arena, C. Calvanese, P. Simoni, S. Belvisi, A. Porro, A. Cucchetti, A. Colecchia, D. Festi, R. Golfieri, G. Mazzella. Hospital S. Orsola-Malpighi, Bologna, Italy E-mail: lisotti.andrea@gmail.com

Echo-Doppler measurements of portal venous blood flow in intrahepatic branches and indocyanine green (ICG) clearance after continuous i.v. infusion as measure for liver blood flow were compared to evaluate the increase in splanchnic blood flow after food intake. It was shown that both methods assessed the changes in flow in a similar manner. Changes in blood flow in intrahepatic portal vein branches measured with echo-Doppler adequately predicted the change in ICG concentrations. Hence, echo-Doppler measurements of hepatic portal blood flow in intrahepatic branches can be used to estimate changes in total liver blood flow.

In a recent study, Carlisle et al. determined the hepatic blood flow in 10 healthy volunteers, measuring the blood flow in the portal vein and proper hepatic artery by means of duplex sonography [1]. We examined the portal vessels of 5 healthy volunteers by duplex sonography (3 male, 2 female, 25-29 years). At the same time, we determined the global hepatic blood flow in the same individuals using indocyanine green (ICG) clearance [2] and compared the results of both examinations. In addition, we studied with both methods the effect of propranolol 80 mg p.o. given to the same volunteers. Our mean values without medication measured by duplex sonography showed a good correlation with the results published by Carlisle et al. [1] (Table 1). One hour after the administration of propranolol, significant changes (P

The indocyanine green (ICG) clearance test has been used to assess the reserve of hepatic function. This method is based on the spectrometric measurement of its plasma concentration at maximum wavelength of 805 nm, which requires a spectrophotometer and associated maintenance. We established an ICG measurement method using a Hitachi 7180 automatic chemistry analyser that can be tuned to a wavelength of approximately 800 nm. The retention rate of ICG at 15 min was determined for 41 patients using a conventional method and our method. The ICG clearance test using the automatic analyser showed excellent agreement. It is expected that the ICG test using the automatic analyser can replace the conventional ICG clearance test.

AIM: To investigate whether the non-invasive real-time Indocynine green (ICG) clearance is a sensitive index of liver viability in patients before, during, and after liver transplantation. METHODS: Thirteen patients were studied, two before, three during, and eight following liver transplantation, with two patients suffering acute rejection. The conventional invasive ICG clearance test and ICG pulse spectrophotometry non-invasive real-time ICG clearance test were performed simultaneously. Using linear regression analysis we tested the correlation between these two methods. The transplantation condition of these patients and serum total bilirubin (T. Bil), alanine aminotransferase (ALT), and platelet count were also evaluated. RESULTS: The correlation between these two methods was excellent (r2 = 0.977). CONCLUSION: ICG pulse spectrophotometry clearance is a quick, non-invasive, and reliable liver function test in transplantation patients.

The purposes of the present investigation were (i) to directly compare in man, indocyanine green (ICG) plasma concentrations analyzed by high performance liquid chromatography (HPLC) vs. spectrophotometry; (ii) to evaluate whether the pharmacokinetic parameters generated for ICG from a clinical study are assay-dependent; (iii) to examine whether the method of pharmacokinetic analysis affects the magnitude of any assay-related differences observed in ICG's pharmacokinetic parameters; and (iv) to evaluate whether assay methodology and/or method of pharmacokinetic analysis affect the conclusions derived from a clinical study employing ICG as a marker for hepatic blood flow (HBF). Plasma samples obtained from a clinical study designed to assess the effects of cimetidine and posture on HBF were analyzed by spectrophotometry and HPLC. The spectrophotometric method overestimated ICG plasma concentrations when compared to HPLC. This finding is consistent with the observations of others suggesting the presence of a chemical impurity in the commercial ICG preparation. Data generated by the spectrophotometric method produced lower ICG clearance and HBF estimates and a longer ICG half-life regardless of the method of pharmacokinetic analysis. The method of pharmacokinetic data analysis had no effect on any pharmacokinetic parameter. The experimental conclusions derived from the clinical study were not affected by either analytical methodology or method of data analysis.

The validity of the ICG clearance method for the measurement of THBF in abnormal circulatory states remains questionable. In this study THBF measured by this method is compared with the electromagnetic flow technique in a canine spetic model. Good correlation is demonstrated between the two in normal control animals. However, in the septic animals the ICG underestimated the electromagnetic flow result by 20%. This is true in both the high and the low cardiac output septic shock pictures that emerge. In the septic animals, the total hepatic blood flow as measured by the ICG was almost equal to the portal vein flow alone measured by the electromagnetic flowmeters suggesting that this was the quantity it was measuring in this abnormal state. Pathophysiologic mechanisms that may explain the discrepancy are given.

Summary. The results from simultaneous measurements of indocyanine green (ICG) plasma clearance and hepatic blood flow (HBF) in subjects without hepatic dysfunction duringchanges in HBF induced pharmacologically or by food stimulation, are reported. A linear relation is established between the relative changes in HBF and that of ICG clearance (r= 0·94), but the changes are not identical, and therefore the changes in HBF cannot be accurately predicted from that of ICG plasma clearance. The reason behind the lack of identity of the changes lies in the complicated kinetics of dye removal by the liver. The hepatic venous catheterization technique is the only method when physiologically correct values for hepatic blood flow or changes therein are wanted.

Previous animals studies have demonstrated a fall in liver blood flow associated with acute rejection after liver transplantation. To study the relationship between rejection and liver blood flow in humans after liver transplantation indocyanine green (ICG) clearance was measured serially in 7 patients with clinical and histological features of acute rejection. There was a consistent pattern of satisfactory initial ICG clearance that fell in association with acute rejection and rose with successful treatment of the episode of rejection. In one patient there was no improvement in ICG clearance after treatment with additional immunosuppression, and she subsequently required retransplantation for chronic rejection. The volume of distribution of ICG was also estimated and fell considerably during the first weeks after transplantation. These results show that rejection is associated with a reduction in ICG clearance that may be due to a fall in liver blood flow, and that graft ischemia and rejection may therefore be interrelated, and important in one another's etiology.

The changes in the energy charge (ATP + 0.5 ADP)/(ATP + ADP + AMP) levels of the remnant liver were studied in relation to changes in the incorporation rate of methyl-3H-thymidine into DNA, the blood ratio of acetoacetate/beta-hydroxybutyrate and indocyanine green (ICG) clearance in 70% hepatectomized rabbits. The energy charge levels of the remnant liver decreased rapidly to 0.767 from 0.856 of normal, despite a marked enhancement of mitochondrial phosphorylative activity, concomitant with the fall in blood ketone body ratio, before a maximal increase of DNA synthesis after hepatectomy. Blood ketone body ratio was correlated with hepatic energy charge (r = 0.696, p less than 0.01). After a maximal increase of DNA synthesis, hepatic energy charge levels and the blood ketone body ratios increased gradually to normal levels, concomitant with a rise in ICG clearance. Energy charge levels of the remnant liver can be evaluated by the blood ketone body ratio.

The effect of Prostaglandin E2 (PGE2) on hepatic blood flow and bile excretion has been only partially investigated. We studied in the rat the effect of PGE2 on indocyanine green (ICG) clearance, bile flow and ICG recovery in the bile. PGE2 administered to rats at a rate of 2 micrograms/kg/min had no effect on ICG clearance as compared to vehicle-treated rats (14.6 +/- 2.5 Vs, 16.9 +/- 2.5 ml/min/kg) and on bile flow (1.23 +/- 0.15 Vs. 1.24 +/- 0.11 microliters/min/gm liver). However, ICG excretion in bile was significantly increased as compared to a vehicle-treated group, 0.48 +/- 0.09 and 0.25 +/- 0.02 micrograms/microliters bile, respectively (P less than 0.005). This effect of PGE2 on ICG recovery in bile was found to be dose-dependent, and when PGE2 was administered at a rate of 1 microgram/kg/min, bile ICG decreased to 0.33 +/- 0.10 microgram/microliter bile. The effect of PGE2 on bile ICG is not due to an increased extraction of ICG by the liver since using the isolated perfused rat liver, the mean ICG extraction rate over a 20 minute period, with and without PGE2 infusion, was very similar, 33 +/- 3.5 and 37 +/- 6.2 percent, respectively. The lack of effect of PGE2 on ICG clearance and extraction and on bile flow, with an increase in biliary excretion of ICG, suggests a decreased hepatic storage of ICG induced by PGE2 possibly due to an accelerated rate of ICG excretion from the hepatocytes to the bile canaliculi.

Constitutional excretory defect of indocyanine green (ICG) is characterized by the selective impairment of plasma ICG clearance. We studied binding patterns of ICG to plasma proteins and plasma ICG kinetics in three patients and one relative. Binding patterns of ICG to plasma proteins were modified in subjects with the ICG excretory defect. However, plasma disappearance rates of ICG bound to various protein fractions were not significantly different from each other, except for one case. In the kinetic study of ICG hepatic uptake rates (a values) were decreased, and hepatic reflux rates (b values) were increased in ICG excretory defect and liver cirrhosis. However, a values were unchanged and b values were clearly increased in ICG excretory defect, while a values decreased and changes in b values were slight in liver cirrhosis after loading with a large dose of ICG. These results suggest that active transport of ICG in the hepatic cell membrane is selectively lost in the ICG excretory defect.

Controversy exists as to whether H2-receptor antagonists decrease hepatic blood flow. This study examined the effect of single doses of cimetidine 300 and 600 mg po on apparent hepatic blood flow as estimated by indocyanine green (ICG) clearance. A double-blind, repeated-measure study was performed in nine supine healthy men. Following an overnight fast, placebo or cimetidine was administered one hour prior to ICG 0.5 mg/kg iv. Plasma samples were obtained serially for a period of 20 minutes following dye administration and stored at −70° until high performance liquid chromatographic analysis. Cimetidine had no apparent effect on mean ± SD ICG clearance following placebo, cimetidine 300 mg, and cimetidine 600 mg (366 ± 66 vs. 336 ± 55 vs. 350 ± 58 ml/min/m2, respectively; NS). Corresponding values for estimated hepatic blood flow were 632 ± 109, 580 ± 103, and 617 ± 112 ml/min, respectively; NS. No statistically significant changes in ICG half-life or volume of distribution at steady state occurred as a function of treatment. Contrary to previous reports, single-dose cimetidine administration appeared to have no appreciable effect on hepatic blood flow. These results implicate cimetidine binding to the cytochrome P-450 system as the sole mechanism responsible for inhibition of the systemic clearance of co-administered drugs metabolized by the liver.

• Multiple system failure is often the final result of severe infection that cannot be controlled. The changes that may occur in remote organs and cells in the early stages of sepsis and that may initiate this process have not been defined. To study this, indocyanine green (ICG) clearance, serum enzyme levels, and reticuloendothelial (RE) function were measured during various stages of sepsis, which was produced in rats by cecal ligation and puncture (CLP). The clearance of ICG decreased significantly during the early stages of sepsis (five hours after CLP) at a time when there was no change in the serum enzyme levels or RE function. Ten hours after CLP, RE function was depressed, and serum enzyme levels were elevated. Progressive changes in RE function and serum enzyme levels occurred in the late stages of sepsis (16 hours after CLP). Since unaltered hepatic adenosine triphosphate levels have been previously found, even ten hours after CLP, humoral factor(s) may be responsible for altered ICG clearance in the early stages of sepsis. Thus, hepatocellular dysfunction occurred early in the course of sepsis and was manifested by a deficit in a plasma membrane active transport process (ICG clearance). Indocyanine green clearance provided an extremely sensitive early indication of a hepatic abnormality. ( Arch Surg 1982;117:151-157)