ICG Concentration Research Articles

Measurement of Indocyanine Green Dye Is Improved by Use of Polyethylene Glycol to Reduce Plasma Turbidity

Indocyanine Green (ICG; CardioGreen®; Akorn Inc.) is a sterile, water-soluble dye that is used clinically as a dilution indicator for studies involving the heart, liver, lungs, and circulation. When ICG is infused intravenously into the bloodstream, it rapidly binds to plasma proteins and thereby is confined to the vascular space (1)(2). ICG is removed exclusively by the liver at the rate of 18–24% per minute (2), so the elimination of ICG follows an exponential curve with a half-life of ∼150–180 s (3). The concentration of ICG is determined spectrophotometrically with undiluted plasma samples at 805 nm. Substances that alter the absorbance of the plasma interfere with the accuracy of the measurements. Background opacity or turbidity of plasma is predominantly linked to the non-albumin fraction of the plasma proteins and is manifested by variation in the background absorbance reading. The manufacturer of ICG states that ICG binds primarily (95%) to albumin, with lesser binding to α2-globulins. Therefore, the accuracy of measuring ICG may be improved by first removing the non-albumin fraction of the plasma proteins. Zweens and Frankena (4) used polyethylene glycol (PEG) to precipitate the non-albumin fraction of the plasma proteins in a study involving another dilution indicator, Evan’s blue dye. Evan’s blue dye, like ICG, attaches primarily to albumin, but it is measured at a different wavelength. The authors showed that the variable background absorbance of plasma at 620 nm was virtually eliminated by mixing plasma samples with equal volumes of a 240 g/L solution of PEG (mean molecular …

Optimal solder and power density for diode laser tissue soldering (LTS)

Laser tissue soldering (LTS) using albumin and indocyanine green dye (ICG) is an effective technique utilized in various reconstructive surgical procedures. The purpose of this study was to describe in vivo and in vitro temperature profiles of an albumin-based solder while varying ICG concentration and laser power density (PD), and to describe immediate and short-term tensile strength measurements and histology of tissue with variable ICG concentrations and PD. ICG ranged from 0.31 to 20 mg/mL while PD ranged from 3.2 to 63.7 W/cm(2). Direct solder temperature measurements were obtained at 5-second intervals during laser activation. Differential temperature measurements were determined within the dermis of rat skin and the overlying solder. Eighteen rats were subjected to 2.0-cm incisions (n = 113) created on the dorsal skin followed by closure with LTS at varying PD and ICG concentrations. ICG concentrations included 0.31, 2.5, and 20 mg/mL, while PD ranged from 8.0 to 63.7 W/cm(2). Tensile strength (TS) profiles were measured immediately and 10 days post-operatively. Histological examination was performed at the time of sacrifice. Temperature profiles of the ICG/albumin solder differed significantly only at the highest concentration of ICG (20 mg/mL), but showed statistically significant variability at different laser PD. Using solder color changes as an endpoint of LTS, average peak solder temperature ranged from 69 degrees C at a PD of 8.0 W/cm(2), 105 degrees -120 degrees C at PD 15.9-31.8 W/cm(2), and > 200 degrees C at PD > or = 47.7 W/cm(2). Peak intradermal temperatures remained below 50 degrees C at all PDs. Varying ICG concentration only had an effect on the immediate TS of wounds at the lowest power densities. Increasing PD resulted in statistically significant increases in immediate TS up to a PD of 23.9 W/cm(2) at an ICG concentrations of 0.31 and up to a PD of 15.9 W/cm(2) at a concentration of 2.5 mg/mL. Statistically insignificant decreases in 10-day would strength resulted from higher PD. Power densities > or = 23.9 W/cm(2) showed significant thermal injury upon histologic examination. Power density, not ICG concentration, is the primary determinant of solder and tissue temperature during LTS. Effective and reproducible laser tissue soldering may be achieved primarily by power density control when using diode laser and ICG-based albumin solder. Alterations in PD show the most direct and predictable effects on the healing properties of skin closed by LTS. Optimal laser wound closure occurs with an ICG of 2.5 mg/mL and at a PD between 15.9 and 23.9 W/cm(2).

Indocyanine green: Intracellular uptake and phototherapeutic effects in vitro

Indocyanine green (JCG; absorption peak in human plasma 805 nm) was investigated for ICG-mediated phototherapy in vitro. The cellular uptake of ICG (1 μM-50 μM) into HaCaT keratinocytes after an incubation period of 24 h increased up to an intracellular ICG concentration of 12.1 ± 1.3 nmol per 10 6 cells. To examine dose dependent phototoxic effects in vitro, keratinocytes were incubated with 0 μM-50 μ M ICG for 24 h and irradiated by a diode laser (805 nm) with different energy densities (0, 12, 24, 48 J cm −2). All applied ICG concentrations except for 5 μM yielded a cell killing effect in combination with irradiation depending significantly on ICG concentration and light dose. Cell viability for dark control and cells incubated with 50 μM ICG and irradiated with 48 J cm −2 was 0.82 ± 0.15 and 0.07 ± 0.02, respectively. Sodium azide (100 mM), a quencher of reactive oxygen species, inhibited significantly the cell killing using 50 μM ICG and 24 J cm −2. Taken together, photoactivation of ICG by irradiation with a diode laser was shown to induced effectively cell killing of HaCaT keratinocytes. Moreover, this effect was inhibited by sodium azide, thus irradiation of ICG might induce a photodynamic reaction.

Effects of altitude (4300 m) on the pharmacokinetics of caffeine and cardio-green in humans.

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardio-green (ICG) were examined in eight healthy males (23-35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg. kg-1) was administered as an intravenous bolus and caffeine (4 mg. kg-1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in a caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g.l-1.min-1), and increased clearance (117 vs 86 ml.min-1.70 kg-1). In ALT the area under the curve the ICG significantly decreased (85 vs 207 mg.l-1.min-1) and the volume of distribution and clearance increased (5.2 vs 2.4 l and 532 vs 234 ml.min-1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.

New method for measuring ICG Rmax with a clearance meter.

The maximal removal rate of indocyanine green (ICG Rmax) is considered to be an important parameter of hepatic function. However, the method of analysis has some flaws, and an abnormal value is obtained for about 15% of patients. We developed a new method of measuring the ICG Rmax with a clearance meter (RK-1000) that continuously measured the ICG concentration using a fingertip optical sensor. Twenty patients were examined. The histologic diagnosis was as follows: normal for 10, cirrhosis in 6, hepatitis in 4. The ICG concentration was measured in vivo continuously with the RK-1000. To obtain the Rmax by the Michaelis-Menten model, the ICG concentration in the VLDL compartment was subtracted from the values obtained by the RK-1000 because ICG binds to various serum proteins and its rate of removal in the VLDL compartment differs from that in other protein compartments. The removal velocity was calculated and a Michaelis plot obtained. Then Rmax was calculated from the reciprocal of the y-intercept of a Lineweaver-Burk plot. The Rmax in subjects with liver disease was significantly lower than in those with normal liver. It is concluded that our new method of measuring ICG Rmax with the RK-1000 reflects liver function appropriately.

Indocyanine green disposition in healthy dogs and dogs with mild, moderate, or severe dimethylnitrosamine-induced hepatic disease

Summary Disposition kinetics of indocyanine green (icg) were used to evaluate hepatic function in healthy Beagles (group 1; n = 6) and Beagles with progressive hepatic disease induced by oral administration of dimethylnitrosamine, a hepatospecific toxin. Three classes of hepatic disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of icg was studied 3 weeks following the last dose of toxin. A rapid iv injection of 0.5 mg of icg/kg was administered and serum samples were obtained at certain intervals during 60-minute periods. Serum icg was analyzed by use of visible spectrophotometry. Disposition kinetics were determined from serum icg concentrations vs 15- and 60-minute time curves and compared between one another and among groups. Data based on 60-minute time curves were not significantly different from those based on 15-minute curves. Area under the curve for icg was greatest in group 3. Clearance of icg was decreased and mean resident time was increased in groups 3 and 4, compared with those in groups 1 and 2. When disposition data (60 minutes) were normalized for differences in hepatic weight among dogs, group-3 mean resident time was significantly greater than that of group 4. This study supports the diagnostic benefits of using icg disposition kinetics as a method of evaluating hepatic function in dogs with progressive liver disease.

A 52-week chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in dogs

A chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

胆汁中ICG濃度測定(ICG Bmax)による減黄効果判定

胆汁中ICG濃度測定(ICG Bmax)による減黄効果判定

Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man.

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.

The influence of taurocholate and dehydrocholate choleresis on plasma disappearance and biliary excretion of indocyanine green in the rat.

The pharmacokinetics of indocyanine green (ICG; 3.9 μmoles/kg and 12.9 μmoles/kg) were investigated in rats given infusion of either saline, taurocholate (106 μmoles/h) or dehydrocholate (106 or 268 μmoles/h). During the infusion of saline and taurocholate the plasma concentration of ICG decreased in a mono-exponential manner. However, with dehydrocholate the clearance of ICG from plasma showed two phases with different half lives. The half life of the rapid component (2.2 min) was about the same as the one found in the control experiments.