Hepatic Indocyanine Green Clearance Research Articles

Susceptibility of hepato-splanchnic perfusion to intra-abdominal pressure in peritoneal dialysis patients.

The impact of peritoneal filling on hepato-splanchnic perfusion during peritoneal dialysis has not been fully elucidated yet. Measurements were done in 20 prevalent peritoneal dialysis patients during a peritoneal equilibration test (PET) with 2L of standard dialysate. Data were obtained in the drained state at baseline (T0), after instillation (T1), and after 2 h of dwell time (T2). Intra-abdominal pressure (IAP) was measured by Durand's approach. The hepatic clearance index (KI) of indocyanine-green (ICG) was determined as an indirect measure of hepato-splanchnic blood flow. Cardiac index (CI), heart rate (HR), and total peripheral resistance index (TPRI) were derived from continuous arterial pulse analysis. Fluid volume overload (VO) was evaluated by multifrequency bioimpedance analysis. Ejection fraction (EF) was obtained from echocardiographic examination. IAP was 5.8 ± 3.5 mmHg at baseline (T0), rose to 9.4 ± 2.8 mmHg after instillation of dialysate (T1), and further to 9.7 ± 2.8 mmHg after 2 h of dwell time (p < 0.001). KI slightly declined from 0.60 ± 0.22 L/min/m2 at T0 to 0.53 ± 0.15 L/min/m2 at T1 (p = 0.075), and returned to 0.59 ± 0.22 L/min/m2 at T2 (p = 0.052). CI, HR, and TPRI did not change significantly. In five patients with an EF < 40% KI was significantly lower at T1 (0.42 ± 0.12 L/min/m2; p = 0.039), and further decreased at T2 (0.40 ± 0.04 L/min/m2; p = 0.016) compared to patients with normal EF (T1: 0.58 ± 0.15 L/min/m2 and T2: 0.67 ± 0.22 L/min/m2). Overall, hepatic clearance of ICG as a marker of hepato-splanchnic blood flow is not affected by the filling of the peritoneal cavity.

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.

Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90minutes after ingestion of 1000-mg metformin (n=16) or placebo (n=16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time×group interaction, P=0.008). In patients with baseline HVPG ≥12mm Hg clinically significant improvements in HVPG (HVPG <12mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P=0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.

A physiologically based model of hepatic ICG clearance: Interplay between sinusoidal uptake and biliary excretion

Although indocyanine green (ICG) has long been used for the assessment of liver function, the respective roles of sinusoidal uptake and canalicular excretion in determining hepatic ICG clearance remain unclear. Here this issue was addressed by incorporating a liver model into a minimal physiological model of ICG disposition that accounts of the early distribution phase after bolus injection. Arterial ICG concentration–time data from awake dogs under control conditions and from the same dogs while anesthetized with 3.5% isoflurane were subjected to population analysis. The results suggest that ICG elimination in dogs is uptake limited since it depends on hepatocellular uptake capacity and on biliary excretion but not on hepatic blood flow. Isoflurane caused a 63% reduction in cardiac output and a 33% decrease in the ICG biliary excretion rate constant (resulting in a 26% reduction in elimination clearance) while leaving unchanged the sinusoidal uptake rate. The terminal slope of the concentration–time curve, K, correlated significantly with elimination clearance. The model could be useful for assessing the functions of sinusoidal and canalicular ICG transporters.

The effect of chronic captopril administration on hepatic blood flow of the rat

The effect of chronic captopril administration on indocyanine green (ICG) clearance and hepatic extraction has been studied in the rat using the intact liver for ICG clearance and the isolated perfused liver for ICG extraction. The captopril was added to the drinking water to give a calculated daily intake from 0-45 mg kg-1. Hepatic clearance of ICG was dose related from 16.5 +/- 2.4 (control) to 7.2 +/- 1.6 mL min-1 kg-1, respectively. The hepatic extraction of ICG was not significantly different (37 +/- 6%) from the control value in groups on 4 and 45 mg kg-1 daily. Since ICG clearance and extraction are dependent on hepatic blood, a change in ICG clearance without a change in the extraction reflects a similar change in the hepatic blood flow. This remained unchanged at daily captopril intakes of 1 and 4 mg kg-1 and decreased when the daily intake was 10 mg kg-1 or higher. If these results in the rat are applicable to man, the chronic administration of therapeutic doses of captopril (0.5-2 mg kg-1) will not affect the hepatic blood flow.

Experimental study of liver dysfunction evaluated by direct indocyanine green clearance using near infrared spectroscopy.

Blood clearance of indocyanine green (ICG) is an objective test of liver function. Hepatic ICG clearance can now be measured directly using near infrared spectroscopy (NIRS). The aim of this study was to evaluate measurement of hepatic ICG clearance by NIRS in an animal model of acute hepatic dysfunction. New Zealand white rabbits (n = 36) underwent laparotomy for liver exposure. Hepatic blood flow and microcirculation were measured along with hepatic ICG concentration by NIRS. Hepatic ICG clearance was measured in groups of six animals after reduction of the hepatic blood flow by hepatic artery occlusion and portal vein partial occlusion, lobar ischaemia and reperfusion (I/R), colchicine administration and bile duct ligation. Hepatic ICG uptake and excretion rates were calculated by a non-linear least square curve fitting method from the ICG concentration-time curve. There was a significant positive correlation between hepatic ICG rate of uptake and both hepatic blood flow and microcirculation (r = 0.79, P = 0.0001; r = 0.59, P = 0.005 respectively). I/R resulted in a significant reduction of both the rates of ICG uptake (mean(s.d.) 0. 85(0.59) min-1; P = 0.0002 versus control) and ICG excretion (0. 020(0.006) min-1; P = 0.02 versus control). Colchicine decreased the rate of hepatic ICG excretion (0.030(0.010) min-1; P = 0.02 versus control) as did bile duct ligation (0.002(0.001) min-1; P = 0.01 versus control). Measurement of hepatic ICG clearance by NIRS is a promising technique for assessing hepatic parenchymal dysfunction and may have application in liver surgery and transplantation.

Effect of liver blood flow and function on hepatic indocyanine green clearance measured directly in a cirrhotic animal model.

Peripheral blood clearance of indocyanine green (ICG) has been used as a test of liver function but gives little information on biliary excretion. Hepatic ICG uptake and clearance can be measured directly by near-infrared spectroscopy (NIRS). Direct ICG measurement has not previously been correlated with liver blood flow and function in cirrhosis. Two groups of New Zealand white rabbits (n = 12) underwent laparotomy for liver exposure. Cirrhosis was induced by feeding animals (n = 6) with a high-cholesterol (2 per cent) diet for 16 weeks. Hepatic blood flow and microcirculation were measured. Hepatic ICG concentration was measured directly using NIRS probes on the liver surface. From the ICG concentration-time curve, hepatic ICG uptake and excretion rates were calculated by a non-linear least square curve fitting method. There was a significant reduction in ICG uptake rate (mean(s.d.) 0.300(0.130) versus 2.040(0.420) min-1; P = 0.0001) and ICG excretion rate (0.007(0.009) versus 0.227(0.096) min-1; P = 0. 002) in cirrhotic animals. The hepatic ICG uptake rate correlated with hepatic blood flow and flow in the microcirculation (r = 0.81, P = 0.002; r = 0.92, P < 0.001, respectively). The hepatic ICG excretion rate was significantly associated with indicators of impaired liver function including bilirubin (r = - 0.86, P = 0.0004), aspartate aminotransferase (r = - 0.81, P = 0.001) and lactate dehydrogenase (r = - 0.83, P = 0.0008). ICG uptake measured directly by NIRS reflects the reduced liver blood flow and perfusion in cirrhosis and its excretion correlates with the degree of liver parenchymal dysfunction. This technique may allow a more accurate method of liver function assessment than peripheral blood ICG clearance.

Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis.

Although plasma norepinephrine (NE) increases and hepatocellular function is depressed during early sepsis, it is unknown whether gut is a significant source of NE and, if so, whether gut-derived NE helps produce hepatocellular dysfunction. We subjected rats to sepsis by cecal ligation and puncture (CLP), and 2 h later (i.e., early sepsis) portal and systemic blood samples were collected and plasma levels of NE were assayed. Other rats were enterectomized before CLP. Hepatocellular function was assessed with an in vivo indocyanine green (ICG) clearance technique, systemic levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined, and the effect of NE on hepatic ICG clearance capacity was assessed in an isolated, perfused liver preparation. Portal levels of NE were significantly higher than systemic levels at 2 h after CLP. Prior enterectomy reduced NE levels in septic animals. Thus gut appears to be the major source of NE release during sepsis. Enterectomy before sepsis also attenuated hepatocellular dysfunction and downregulated TNF-alpha, IL-1beta, and IL-6. Perfusion of the isolated livers with 20 nM NE (similar to that observed in sepsis) significantly reduced ICG clearance capacity. These results suggest that gut-derived NE plays a significant role in hepatocellular dysfunction and upregulating inflammatory cytokines. Modulation of NE release and/or hepatic responsiveness to NE should provide a novel approach for maintaining hepatocellular function in sepsis.

Effects of LPS on transport of indocyanine green and alanine uptake in perfused rat liver.

Lipopolysaccharide (LPS) initiates cholestasis. Whether this process is mediated by tumor necrosis factor-alpha (TNF-alpha) and whether the cholestatic response to LPS is associated with intrahepatic accumulation of possibly toxic substances are under debate. To study these questions the hepatic uptake and biliary excretion of indocyanine green (ICG) was examined in the isolated perfused rat liver 18 h after intravenous treatment of rats with either saline, 1 mg/kg body wt LPS, or LPS and intraperitoneal pentoxifylline (POF) (n = 6 in each group). POF inhibits TNF-alpha release after LPS administration. LPS induced a typical acute-phase response with increased mRNA for acute-phase proteins, reduced albumin mRNA, and increased hepatic uptake of alanine. Intrinsic hepatic clearance of ICG in controls (1.01 +/- 0.05 ml. min(-1). g liver(-1)) was similarly decreased by LPS alone (0.62 +/- 0.04 ml. min(-1). g(-1); P = 0.002 vs. control) or combined with POF (0.66 +/- 0.06 ml. min(-1). g(-1)). A kinetic analysis indicated that LPS reduced both uptake and excretion processes in a balanced manner, so that intrahepatic ICG content was unaffected or even slightly reduced, as confirmed by measurement of ICG contents in the perfused livers. In livers from parallel-treated nonperfused rats, mRNA for the organic anion transporting protein-1 (Oatp1, which is likely to mediate ICG uptake) was unaffected by LPS, whereas the concentration of Oatp1 protein was reduced. Thus LPS induced an acute-phase response that included downregulation of ICG uptake by reduction of Oatp1 protein concentration, possibly at a posttranscriptional level. TNF-alpha appears not to be the mediator because POF did not modify these LPS effects.

Hepatic ICG removal in the pig depends on plasma protein and hematocrit: Evidence of sinusoidal binding disequilibrium and unstirred water layer effects

The influence of binding protein concentration and hematocrit on hepatic uptake of indocyanine green (ICG) was studied in anesthetized pigs during constant infusion of ICG. By exchange transfusions, we either substituted plasma protein with dextran 70 (n = 8) or changed hematocrit (n = 8). Intrinsic hepatic clearance of ICG, K, was calculated from plasma flow rate and concentrations in peripheral artery and liver vein after correction for extrahepatic distribution. By analyzing the relative change of K versus either the protein dilution factor or the change in plasma volume fraction (1-hct), we evaluated four current models for hepatic uptake of protein-bound substances even though a number of model parameters were unknown (parameter-free testing). Protein dilution factors (unitless) of 0.506 +/- 0.027, 0.673 +/- 0.011, and 0.749 +/- 0.028 were associated with inverse K ratios of 0.621 +/- 0.025, 0.758 +/- 0.021, and 0.817 +/- 0.013. These data rejected the traditional hypothesis that ICG uptake is proportional to the unbound concentration. They were compatible with development of binding disequilibrium along the sinusoidal lumen, an unstirred water layer close to the hepatocyte surface, or facilitated uptake from the bound pool. A plasma volume ratio [(1-hct2)/(1-hct1)] of 1.14 +/- 0.02 was associated with a K ratio of 1.07 +/- 0.02 (P = .01). Only sinusoidal binding disequilibrium predicted this finding, whereas an additional unstirred water layer effect could not be excluded. The observations could be simulated by a model that included both of these effects. Thus, neither the relative changes of K nor the absolute K values required the assumption of facilitated uptake from the bound pool. The parameter-free design presented may be useful with other ligands in intact animals. (Hepatology 1997 Sep;26(3):679-90)

Nontraditional effects of protein binding and hematocrit on uptake of indocyanine green by perfused rat liver.

We used a novel parameter-free approach to study the role of protein binding in the hepatic clearance of indocyanine green (ICG) from reconstituted pig blood by perfused rat liver. Either perfusate total plasma protein concentration or hematocrit was changed. By analyzing protein concentration ratios or plasma volume ratios relative to ratios of intrinsic hepatic clearance of ICG (K), it was possible to evaluate current models of hepatic uptake of protein-bound ligands without precise knowledge of some of the model parameters. A four-fold increase in the total plasma protein concentration produced only a 36% decrease in K. This was substantially less than predicted by the traditional model, where K is proportional to the free concentration of ligand. Because an unstirred water layer effect could not by itself account for the observations, the effects of binding disequilibrium in the sinusoids or uptake directly from the bound pool had to be considered. To discriminate, hematocrit was increased from 15% to 29%, causing a 20% decrease in the sinusoidal plasma volume. A significant reduction in K strongly suggested a sinusoidal binding disequilibrium effect. The dissociation rate constant predicted by this model was confirmed by in vitro measurement, further supporting this interpretation. The simple experimental design and its parameter-free evaluation provide a new tool for investigating the hepatic uptake of protein-bound ligands.

Direct measurement of hepatic indocyanine green clearance with near-infrared spectroscopy: Separate evaluation of uptake and removal

We continuously measured hepatic absorbance of indocyanine green (ICG) using near-infrared (NIR) spectroscopy after intravenous bolus injection in rabbits. Hepatic ICG concentration was obtained by subtracting out the absorbance of hemoglobin and other pigments within the liver. Two exponential rate constants, the first reflecting the dye uptake from plasma to the hepatocytes, and the second representing the dye removal from the liver by cytoplasmic transport and biliary excretion, were determined by fitting the time-course curve of hepatic ICG concentration to a two-compartment model with irreversible transfer between the two compartments, as defined by the double-exponential equation: [ICG]liver(t) = -A exp(-alpha t) + B exp(-beta t). The results showed that treatment with bilirubin, a competitive inhibitor of ICG uptake, caused a decrease in alpha. Treatment with either colchicine, which is toxic to microtubules, or with ouabain, an inhibitor of Na+,K+-ATPase, caused a decrease in beta. These results were compatible with the kinetic model. This new method was then used in liver-injured rabbits inflicted with hemorrhagic shock and ischemia-reperfusion, to show that the first rate constant is primarily affected by hepatic microcirculatory condition, and the second refers closely to parenchymal liver damage. In another series of partial liver ischemia- reperfusions, it was possible to simultaneously and separately monitor the ICG profiles of post-ischemic and nonischemic areas. Thus, the kinetic analysis of hepatic ICG concentration curves, as directly measured by NIR spectroscopy, led to the separate evaluation of different clearance process of ICG in the liver, suggesting the advanced utility as a comprehensive liver function test. (Hepatology 1996 Jan;23(1):137-44)

Direct measurement of hepatic indocyanine green clearance with near-infrared spectroscopy: Separate evaluation of uptake and removal

We continuously measured hepatic absorbance of indocyanine green (ICG) using near-infrared (NIR) spectroscopy after intravenous bolus injection in rabbits. Hepatic ICG concentration was obtained by subtracting out the absorbance of hemoglobin and other pigments within the liver. Two exponential rate constants, the first reflecting the dye uptake from plasma to the hepatocytes, and the second representing the dye removal from the liver by cytoplasmic transport and biliary excretion, were determined by fitting the time-course curve of hepatic ICG concentration to a two-compartment model with irreversible transfer between the two compartments, as defined by the double-exponential equation: [ICG]liver(t) = -A exp(-alpha t) + B exp(-beta t). The results showed that treatment with bilirubin, a competitive inhibitor of ICG uptake, caused a decrease in alpha. Treatment with either colchicine, which is toxic to microtubules, or with ouabain, an inhibitor of Na+,K(+)-ATPase, caused a decrease in beta. These results were compatible with the kinetic model. This new method was then used in liver-injured rabbits inflicted with hemorrhagic shock and ischemia-reperfusion, to show that the first rate constant is primarily affected by hepatic microcirculatory condition, and the second refers closely to parenchymal liver damage. In another series of partial liver ischemia-reperfusions, it was possible to simultaneously and separately monitor the ICG profiles of post-ischemic and nonischemic areas. Thus, the kinetic analysis of hepatic ICG concentration curves, as directly measured by NIR spectroscopy, led to the separate evaluation of different clearance process of ICG in the liver, suggesting the advanced utility as a comprehensive liver function test.

Enhancement of unbound clearance of ICG by plasma proteins, demonstrated in human subjects and interpreted without assumption of facilitating structures

The kinetics of hepatic removal of protein-bound substances were studied in nine human subjects with various liver diseases by the use of indocyanine green as a model substance. Intrinsic hepatic clearance of indocyanine green was measured by means of a constant infusion of indocyanine green and concentration measurements of indocyanine green in arterial and hepatic venous plasma samples. During the indocyanine green infusion, 1-1.51 of dextran-70 was given whereby a stable dilution of the plasma protein concentration by a factor of 0.6-0.8 was obtained. In each of the subjects, the intrinsic clearance of indocyanine green increased after the protein dilution (range 11-64%). Elimination of ethanol (not protein bound), similarly assessed, was not significantly changed. The traditional hypothesis that unbound clearance (intrinsic clearance divided by the free fraction of the ligand) is independent of protein concentration was refuted since in each of the subjects the protein dilution was followed by a reduction of the unbound clearance of ICG (P < 0.005, n = 9). We examined whether these observations imply some special mechanism (e.g. a hepatocyte protein receptor) by which the unbound clearance is enhanced by the binding protein(s). The previously developed pseudofacilitation model--describing the effects of ligand-protein diffusion and dissociation in an unstirred plasma layer near the hepatocyte--was extended to the case of a mixture of binding proteins, and parameter-free bounds were derived to predict the response of intrinsic clearance to protein dilution. The observed changes of the intrinsic clearance values did not violate these bounds (P < 0.002, n = 9). Thus no facilitating mechanisms are necessary to account for the observed deviations from the traditional hypothesis.

Hemodynamic evaluation of octreotide in patients with hepatitis B-related cirrhosis

The hemodynamic effects of octreotide were studied in 20 patients with hepatitis B-related cirrhosis. In patients receiving a 100-μg bolus and a 100-μg/h infusion, heart rate, cardiac index, and systemic vascular resistance showed no significant changes, whereas right atrial pressure, pulmonary capillary wedge pressure, and inferior vena cava pressure decreased significantly after octreotide infusion compared with basal values. In contrast, in patients receiving a 50-μg bolus and a 50-μg/h infusion, all the systemic hemodynamic values were unaffected. In both groups of patients receiving two different doses of octreotide, the estimated hepatic blood flow, hepatic indocyanine green clearance, and wedge hepatic venous pressure were significantly reduced at 60 minutes after octreotide administration compared with basal values, whereas the hepatic venous pressure gradient remained unchanged. It is concluded that the two different doses of octreotide administration result in the reduction of the wedge hepatic venous pressure and the hepatic blood flow of a similar magnitude, whereas the hepatic venous pressure gradient is unaffected. Octreotide induces discrepant systemic hemodynamic response; this effect is dose related.

Long-term effects of distal splenorenal shunt on hepatic hemodynamics and liver function in patients with cirrhosis: importance of reversal of portal blood flow.

We studied 23 patients with cirrhosis who had undergone retroperitoneal distal splenorenal shunt without portal-azygos disconnection more than 2 yr earlier. We investigated the suitability of the Doppler technique (ultrasound + Doppler) to assess the patency and blood flow direction through the portal vein and the distal splenorenal shunt and its correlation with the continuous thermal dilution technique. The study also assessed the influence of the distal splenorenal shunt and time after surgery on portal perfusion and liver function. Ultrasound + Doppler distal splenorenal shunt thrombosis in two patients; however, none was confirmed by continuous thermal dilution. Ultrasound + Doppler flowmetry was possible in 19 patients (83%) (mean, 1.58 +/- 0.53 L/min). Distal splenorenal shunt continuous thermal dilution measurements were performed in all patients (100%), (mean, 1.65 +/- 0.5 L/min). Good correlation was seen between them (r = 0.66). Ultrasound + Doppler of the portal vein showed a hepatopetal flow in 16 patients (69.9%). Hepatic blood flow was significantly higher in patients with hepatopetal flow (p = 0.003). Hepatic clearance and intrinsic hepatic clearance of indocyanine green were significantly lower in patients with hepatofugal flow. Patients with hepatofugal flow had a higher incidence of chronic encephalopathy. None of the patients with a follow-up of less than 4 yr exhibited hepatofugal flow, whereas 7 of the 16 patients with a longer follow-up had hepatofugal flow (43.7%). The difference was statistically significant (p = 0.04). This study suggests that ultrasound + Doppler sonography may provide useful data in the evaluation of the patency and blood flow direction through the portal vein and the distal splenorenal shunt.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined evaluation of total and functional liver plasma flows and intrahepatic shunting

A diagnostic protocol was studied, designed to evaluate the main parameters of liver circulation in man. A water solution of D-sorbitol (S) and indocyanine green (ICG) was infused intravenously in six controls and nine cirrhotics. Steady-state renal and hepatic S clearances as well as hepatic ICG clearance were calculated. In controls the values (mean +/- SD) of the independent measurements of S and ICG hepatic clearance were 978 +/- 107 and 519 +/- 142 ml/min, respectively, while in cirrhotic patients they were 554 +/- 238 and 231 +/- 90 ml/min. Owing to the kinetic properties of S, its hepatic clearance may be regarded as a measure of functional liver plasma flow (FLPF). The total liver plasma flow (TLPF) values (mean +/- SD), calculated according to Fick's principle, were 1091 +/- 157 ml/min (S method) and 1033 +/- 153 ml/min (ICG method) in controls, and 1251 +/- 554 and 1284 +/- 677 ml/min in cirrhotics. In controls, FLPF was found to be very close to TLPF. In cirrhotic patients the difference between TLPF and FLPF (ranging from 169 to 2093 ml/min when measured by S method) was considered as an approximate estimate of intrahepatic shunting. The procedure is safe and simple and may add a new dimension to the investigation of hepatic circulation.

Thermal injury decreases hepatic blood flow and the intrinsic clearance of indocyanine green in the rat.

The influence of severe thermal injury (full-thickness burns involving 50% of the body surface area) on hepatic blood flow in the rat was assessed using the tricarbocyanine dye indocyanine green (ICG). In a randomized crossover fashion, rats received sequential infusions of ICG through both the femoral vein and the portal vein, allowing the estimation of total hepatic plasma clearance and transhepatic extraction of the dye. These two parameters, along with the hematocrit, were used to calculate intrinsic hepatic clearance of ICG and hepatic blood flow. Animals were examined at 0 (control), 0.5, 12, or 24 hr following infliction of scald burns. Hepatic blood flow was decreased significantly by 0.5 hr postburn and remained approximately 20% below normal throughout the remainder of the study. The intrinsic efficiency of the liver in removing ICG from the systemic circulation was also decreased by thermal injury. The potential mechanisms involved in these two physiologic perturbations are discussed.

Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis

This study aimed to assess the effects of verapamil, a calcium-channel blocker, on porto-hepatic pressure gradient and on hepatic function as measured by the intrinsic hepatic clearance of indocyanine green (ICG) in patients with biopsy proven alcoholic cirrhosis. Hepatic venous pressures and hepatic extraction of ICG were measured before and 60 min after intravenous injection of 10 mg of verapamil in 19 consecutive patients. Hepatic blood flow and intrinsic hepatic clearance of ICG were calculated in the 10 patients whose hepatic extraction fraction was higher than 10%. No significant difference was observed when comparing porto-hepatic pressure gradient (17.72 ± 4.79 vs. 17.77 ± 4.43 mmHg), hepatic blood flow (13.47 ± 4.75 vs. 16.13 ± 7.88 ml.min −1- · kg −1) and intrinsic hepatic clearance of ICG (1.99 ± 0.54 vs. 1.97 ± 0.45 ml · min −1 · kg −1) before and after verapamil injection. We conclude that verapamil has no beneficial effect in patients with alcoholic cirrhosis.

The influence of verapamil and nifedipine on hepatic indocyanine green clearance in patients with HBsAg-positive cirrhosis and ascites.

The influence of verapamil and nifedipine on hepatic indocyanine green kinetics was studied in 12 patients with HBsAg-positive cirrhosis and ascites. Hepatic clearance and its two biologic determinants, hepatic blood flow and metabolic activity (intrinsic clearance [maximum velocity/metabolite elimination rate constant, or Vmax/km]), were determined from hepatic indocyanine green elimination at steady state in patients with cirrhosis. Acute intravenous administration 10 mg verapamil significantly increased the hepatic indocyanine green blood flow (p less than 0.05), but significantly decreased the hepatic clearance (p less than 0.05), extraction ratio (p less than 0.05) and Vmax/km (p less than 0.05). However, acute sublingual administration of 10 mg nifedipine resulted in no significant change in any parameters of hepatic elimination function. These results show that verapamil, but not nifedipine, might impair the transhepatic extraction activity of hepatocytes in patients with HBsAg-positive cirrhosis and ascites.

Methodological limitations of the use of intrinsic hepatic clearance of ICG as a measure of liver cell function.

Negligible extra-hepatic elimination of indocyanine green (ICG) makes it well suited as a liver test substance. The liver blood flow rate (Q) is estimated from concentration measurements in peripheral (A) and hepatic venous (V) blood during a constant ICG infusion rate (Inf), as Q = Inf/(A-V). Intrinsic hepatic clearance of ICG, Cli = Inf/((A-V)/ln(A/V)), is interesting because it should give a flow-independent quantitative estimate of liver cell function, utilizing the same concentration measurements. The present study was aimed to investigate possible limitations involved in the estimation and use of Cli of ICG in 41 liver patients and 20 controls. Time-dependence was studied by means of two successive 40-min infusion periods (with no significant change in Q). Cli of ICG decreased 6% per hour +/- 3% (mean +/- SD, n = 6, P less than 0.01) due to a small but significant increase of the concentrations during the infusion period. Flow-dependence was studied by measurements before and after an increment of flow of on average 51%, induced by the intake of a meal. This caused no significant change in Cli of ICG (P greater than 0.5, n = 5, Student's paired t-test). The intrinsic hepatic clearance of ICG was on average 0.75 +/- 0.26 l plasma min-1 (+/- SD, n = 20) in controls and 0.39 +/- 0.18 l plasma min-1 in liver patients (n = 41), P less than 0.001. It was positively correlated to the galactose elimination capacity, although the scatter was large (P less than 0.05, n = 56).(ABSTRACT TRUNCATED AT 250 WORDS)