Modifications of blood volume alter the disposition of markers of blood volume, extracellular fluid, and total body water

Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine describe intravascular mixing and tissue distribution after i.v. administration. These models characterized physiologic marker disposition in four awake, splenectomized dogs while they were normovolemic, volume loaded (15% of estimated blood volume added as a starch solution), and mildly and moderately hypovolemic (15 and 30% of estimated blood volume removed). ICG-determined blood volumes increased 20% during volume loading and decreased 9 and 22% during mild and moderate hypovolemia. Dye (ICG) dilution cardiac output (CO) increased 31% during volume loading and decreased 27 and 38% during mild and moderate hypovolemia. ICG-defined central and fast peripheral intravascular circuits accommodated blood volume alterations and the fast peripheral circuit accommodated blood flow changes. Inulin-defined extracellular fluid volume contracted 14 and 21% during hypovolemia. Early inulin disposition changes reflected those of ICG. The ICG and inulin elimination clearances were unaffected by altered blood volume. Neither antipyrine-defined total body water volume nor antipyrine elimination clearance changed with altered blood volume. The fraction of CO not involved in drug distribution had a significant effect on the area under the antipyrine concentration-versus-time relationships (AUC) in the first minutes after drug administration. Hypovolemia increased the fraction of CO represented by nondistributive blood flow and increased the antipyrine AUC up to 60% because nondistributive blood flow did not change, despite decreased CO. Volume loading resulted in a smaller (less than 20%) antipyrine AUC decrease despite increased fast tissue distributive flow because nondistributive flow also increased with increased CO.     

The concordance of early antipyrine and thiopental distribution kinetics

Studies of factors affecting the initial disposition of drugs with a rapid onset of effect following i.v. administration have used antipyrine as a surrogate for lipophilic drugs because it lacks cardiovascular effects. The present study tested the assumption that antipyrine is a useful surrogate for the flow-dependent tissue distribution of the lipophilic drug thiopental by comparing the recirculatory pharmacokinetic models of antipyrine and thiopental disposition after concomitant administration to five dogs anesthetized with 1.5% halothane. The pharmacokinetics of indocyanine green, a marker of the intravascular behavior of antipyrine and thiopental, and antipyrine in these dogs was nearly identical to that described previously in dogs anesthetized with 1.5% halothane but not given thiopental. The total volume of distribution of the highly lipophilic drug thiopental was more than 60% larger than that of antipyrine, 53 versus 33 liters, respectively. Nonetheless, the initial distribution kinetics of the two drugs, including the pulmonary tissue volume and the volume of the nondistributive pathway as well as the clearance to it, were nearly identical. As a result, the fraction of cardiac output involved in distribution of the two drugs to peripheral tissues was similarly identical, although the distribution of cardiac output between clearance to the rapidly equilibrating tissues and clearance to the slowly equilibrating tissues differed slightly. This study validates the assumption that antipyrine is a useful surrogate for lipophilic drugs in pharmacokinetic studies in which physiologic stability is desirable to meet the assumption of system stationarity.     

The Effects of Lansoprazole on the Disposition of Antipyrine and Indocyanine Green in Normal Human Subjects

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.     

The relationship between alfentanil distribution kinetics and cardiac output.

The relationship between cardiac output and the tissue distribution of alfentanil was investigated in seven healthy volunteers. Subjects were given 10 micrograms/kg alfentanil and 0.5 mg/kg indocyanine green. Arterial blood samples were obtained at baseline, 1 minute, every 1/2 minute until 5 minutes, and then every minute until 15 minutes after the drug injection was begun. Subsequent samples were collected to 6 hours. Cardiac output was measured continuously by use of thoracic bioimpedance. Alfentanil pharmacokinetics were modeled with both a standard three-compartment model and a four-compartmental model based in part on the two-compartmental pharmacokinetics of indocyanine green. The sum of intercompartmental clearances for both the three- and four-compartment models were significantly correlated with the measured cardiac outputs, r = 0.93 and r = 0.88, respectively. These findings indicate that the intercompartmental clearance (i.e., tissue distribution) of alfentanil is largely determined by cardiac output (i.e., tissue blood flow).     

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.     

Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 +/- 0.76 ml/min/kg; mean +/- SE; n = 17) compared with normal subjects (18.17 +/- 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (0.178 +/- 0.014 ml/min/kg; n = 17) and indocyanine green (6.19 +/- 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 +/- 0.048 ml/min/kg; n = 5; 41.72 +/- 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanism, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.     

Cardiac output and its distribution in peritonitis

Cardiac output and its distribution were studied in rats made septic by an i.p. injection of live E. coli bacteria and in controls given an equivalent amount of saline. The E. coli injection was followed by signs of severe shock in eight of 12 rats. Control animals all survived with only minor changes in cardiac output and peripheral hemodynamics. Blood flow in shocked animals was characterized by a reduction of cardiac output, while myocardial and cerebral flows were not reduced. The intact circulation to the brain and to the heart in the shocked rats was at the expense of kidney, spleen, and skin blood flows.     

Effect of propranolol on hepatic blood flow in patients with cirrhosis

The effect of propranolol on systemic and hepatic hemodynamics was studied in patients with cirrhosis. One hour after 40 mg propranolol by mouth as well as during continuous oral dosing at doses that reduced heart rate 25%, cardiac output and the hepatic venous pressure gradient fell significantly, whereas arterial pressure and hepatic blood flow did not change significantly. In six patients with cirrhosis and surgical end-to-side portacaval shunts, cardiac output and the hepatic venous pressure gradient also decreased 15 minutes after intravenous propranolol (5 mg), whereas hepatic blood flow did not change significantly. In the patients with surgical shunts, systemic vascular resistance rose significantly but hepatic arterial vascular resistance fell. Our data show that in patients with cirrhosis, propranolol induces an increase in the fraction of cardiac output reaching the liver.     

Increased Clearance of Antipyrine and d-Propranolol after Phenobarbital Treatment in the Monkey: RELATIVE CONTRIBUTIONS OF ENZYME INDUCTION AND INCREASED HEPATIC BLOOD FLOW

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.     

Effect of experimental hemorrhagic shock on hepatic drug elimination.

OBJECTIVE: Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. DESIGN: Prospective, controlled, non-randomized crossover trial. INTERVENTIONS: Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. MEASUREMENTS: Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. MAIN RESULTS: For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS: The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.     

The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic lever disease.

The pharmacokinetics after oral administration of 1,200 mg antipyrine and intravenous administration of 0.5 mg/kg indocyanine green have been investigated in 6 normal subjects and in 20 patients with chronic liver disease of varying etiology. Severe impairment of liver function associated with a decrease in serum albumin, elevation in serum bilirubin, or prolongation in prothrombin time correlated with a fall in the clearance of both drugs. The clearance of the two drugs correlated well in normal subjects and in patients with chronic liver disease. The presence of a surgical portacaval anastomosis was associated with a lower indocyanine green clearance for comparable clearance of antipyrine. The concept of functioning hepatic parenchymal mass is proposed as a common rate-limiting parameter for the elimination of the two drugs.     

Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease: plasma noradrenaline splanchnic blood flow and mixed venous oxygen saturation at rest and during exercise

To study the mechanisms by which acute beta-adrenergic blockade may change the activity of the sympathetic nervous system we have measured haemodynamic responses including splanchnic blood flow in twenty-three patients with ischaemic heart disease at rest and during supine exercise before and after i.v. injection of 0.039 mmol (10 mg) dl-propranolol. After propranolol both at rest and on exercise blood pressure, cardiac output and heart rate decreased, while splanchnic vascular resistance increased; mixed venous oxygen saturation decreased whilst arterial oxygen saturation and oxygen uptake were unchanged. Plasma noradrenaline increased after propranolol, values correlating with mixed venous oxygen saturation and splanchnic vascular resistance, both at rest and during exercise before and after propranolol, only at rest was there any correlation with arterial blood pressure. The increase in sympathetic nervous activity after propranolol may be due to a reduction in cardiac output and thereby alteration of the metabolic state (oxygen or related factors) in tissues. Afferent neural signals from the tissues may play a significant role in the regulation of sympathetic nervous activity.     

Intravascular mixing and drug distribution: the concurrent disposition of thiopental and indocyanine green

The dispositions of concomitantly administered indocyanine green (ICG) and thiopental were determined in 12 patients undergoing general anesthesia and surgery. These were best characterized by a two-compartment ICG model and a four-compartment thiopental model, chiefly because of data obtained from frequent early arterial blood samples. The models had a common central volume (V1), and the peripheral ICG compartment was the subset of a peripheral thiopental compartment. The two-compartment ICG model described its mixing within the intravascular space. The traditional VC of three-compartment models of thiopental disposition is described by the present four-compartment model as an initial distribution volume, V1, codetermined by ICG as central blood volume, and a rapidly equilibrating peripheral volume, V4. The combined simultaneous ICG-thiopental model more clearly reflects physiology than do the results of earlier curve-fitting techniques and may be useful in studying the pharmacokinetic basis of altered reactivity to thiopental.     

Beta blockade increases pulmonary and systemic transit time heterogeneity: evaluation based on indocyanine green kinetics in healthy volunteers

Knowledge of factors influencing the heterogeneity of blood transit times is important in cardiovascular physiology. The aim of the study was to investigate the effect of beta-adrenergic blockade on blood transit time dispersion in awake, anxious volunteers. Recirculatory modelling of the disposition of intravascular markers using parametric forms for transit time distributions, such as the inverse Gaussian distribution, provides the opportunity to estimate the systemic and pulmonary transit time dispersion in vivo. The latter is determined by the flow heterogeneity in the microcirculatory network. Using this approach, we have analysed indocyanine green (ICG) disposition data obtained in four subjects by frequent early arterial blood sampling before and after beta-adrenergic blockade by propranolol. Propranolol decreased cardiac output from 9·3 ± 2·8 l min⁻¹ to 3·5 ± 0·47 l min⁻¹ (P<0·05). This reduction was accompanied by a 4·5 ± 0·6-fold and 2·1 ± 0·3-fold increase (P<0·001) in the relative dispersion (dimensionless variance) of blood transit times through the systemic and pulmonary circulation, respectively.     

Pulmonary extraction of [3H]bupivacaine: modification by dose, propranolol and interaction with [14C]5-hydroxytryptamine

The authors studied the single-pass pulmonary extraction of the potent local anesthetic, bupivacaine, in 21 anesthetized rabbits. Pulmonary extraction of [3H]bupivacaine and [14C]5-hydroxytryptamine (5-HT) was quantified from multiple indicator-dilution outflow curves using indocyanine green as the intravascular reference substance. Pulmonary extraction at control (n = 15; mean +/- S.D.) was 81 +/- 6 and 78 +/- 9% for [3H]bupivacaine and [14C]5-HT, respectively. The apparent volume of distribution of bupivacaine was 38 +/- 9 ml/kg compared with 12 +/- 4 ml/kg for indocyanine green. Simultaneous administration of up to 300 micrograms/kg of bupivacaine did not affect the disposition of either radiolabeled amine; however, injection of 1000 micrograms/kg of bupivacaine significantly (P less than .01) depressed pulmonary extraction of both [3H]bupivacaine and [14C]5-HT. In the presence of 1000 micrograms/kg bupivacaine, the apparent volume of distribution of [3H]bupivacaine decreased to 24 +/- 9 ml/kg (P less than .01). Fifteen minutes after administration of propranolol (100-250 micrograms/kg i.v.), [14C]5-HT removal was unchanged, but the pulmonary extraction of [3H]bupivacaine was significantly decreased to 70 +/- 12% (n = 6; P less than .01). These data suggest that bupivacaine is extensively removed as it enters the lung and that the removal process is a combination of passive diffusion and a small component of saturable specific binding. The interaction of bupivacaine with 5-HT may be part of this specific binding (i.e., endothelial cell uptake) or may have been secondary to direct effects of large concentrations of bupivacaine on membrane function.(ABSTRACT TRUNCATED AT 250 WORDS)     

An investigation of an infrared ray electronic endoscope with a laser diode light source

An infrared ray electronic video-endoscope with a laser diode light source was used to obtain information on the submucosal area. As contrast medium we employed indocyanine green, which has a light absorption peak in the infrared range. The wavelength of the laser diode was set to 810 nm as suggested by the results of the spectrophotometric study on the reflected light at fingertips after injection of ICG (3 mg/kg). Using this system we inspected the stomach under visible light and then continuously under infrared light before and after intravenous injection of ICG (2 mg/kg). A dendritic figure with fine ramifications emerged in the early stage after intravenous injection of indocyanine green, which was not seen under visible light. These features of the figure visualized by the infrared endoscope suggest that they have a close relationship with blood vessels and blood circulation beneath the mucosal surface. This infrared electronic endoscope system provides submucosal information more readily and at a lower cost than ever before, and also the infrared lighting method of this system could be applied to almost all available electronic endoscopes by modulating infrared cutting filters, so it could become a valuable clinical tool.     

Evaluation of heavy water for indicator dilution cardiac output measurement

We evaluated deuterium oxide (D₂O) as a tracer for cardiac output measurements. Cardiac output measurements made by thermodilution were compared with those made by indicator dilution with D₂O and indocyanine green as tracers. Five triplicate measurements for each method were made at intervals of 30 minutes in each of 9 anesthetized, mechanically ventilated goats. Cardiac output ranged between 0.68 and 3.79 L/min. The 45 data points yielded a correlation coefficient of 0.948 for the comparison of D₂O indicator dilution cardiac output measurements with thermodilution measurements and a linear regression slope of 1.046. D₂O indicator dilution measurements were biased by –0.11±0.22 L/min compared with thermodilution measurements and had a standard deviation of ±0.12 L/min for triplicate measurements. Hematocrits ranging between 20 and 50 vol% had no effect on optical density for D₂O. D₂O is more stable than indocyanine green and approximately one-tenth the price (40 cents per injection compared with $4). The basic instrumentation cost of approximately $9,000 is an additional initial expense, but provides the ability to perform pulmonary extravascular water measurements with a double-indicator dilution technique. D₂O has potential as a tracer for the clinical determination of indicator dilution cardiac output measurements and pulmonary extravascular water measurements.This study was supported by a U.S. Veterans Administration Merit Review Grant (103). Dr Schreiner is a recipient of an American Society of Anesthesiologists starter grant (1985–86). Dr Leksell is on leave from the Dept of Anesthesia, Karolinska Hospital, Stockholm, Sweden, and is supported by grants from the Swedish Medical Research Council, Karolinska Institute, Sandoz AB, and the Swedish Medical Association.     

Monitoring global volume-related hemodynamic or regional variables after initial resuscitation: What is a better predictor of outcome in critically ill septic patients?

OBJECTIVE: Regional variables of organ dysfunction are thought to be better monitoring variables than global pressure-related hemodynamic variables. Whether a difference exists between regional and global volume-related variables in critically ill patients after resuscitation is unknown. DESIGN: Prospective diagnostic test evaluation. SETTING: University-affiliated mixed intensive care unit. PATIENTS: Twenty-eight critically ill patients. INTERVENTIONS: Using standardized resuscitation, hemodynamic optimization was targeted at mean arterial pressure, heart rate, occlusion pressure, cardiac output, systemic vascular resistance, and urine output. Primary outcome variable was in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: During resuscitation, global volume-related hemodynamic variables were measured simultaneously and compared with regional variables. At admission no variable was superior as a predictor of outcome. During resuscitation, significant changes were seen in mean arterial pressure, central venous pressure, oxygen delivery, systemic vascular resistance, total blood volume, right heart and ventricle end-diastolic volume, right ventricle ejection fraction, right and left stroke work index, intramucosal carbon dioxide pressure, gastric mucosal pH, mucosal-end tidal Pco2 gap, indocyanine green blood clearance, indocyanine green plasma clearance, and plasma disappearance rate. Multivariate analysis identified lactate, gastric mucosal pH, mucosal-end tidal Pco2 gap, mucosal-arterial Pco2 gap, indocyanine green plasma clearance, and plasma disappearance rate of dye as nondependent predictors of outcome. Patients who subsequently died had a significantly lower gastric mucosal pH, higher intramucosal carbon dioxide pressure and mucosal-end tidal Pco2 gap, and lower indocyanine green blood clearance, indocyanine green plasma clearance, plasma disappearance rate, and right ventricular end-diastolic volume index, of which gastric mucosal pH, mucosal-end tidal Pco2 gap, and indocyanine green blood clearance were the most important predictors of outcome. CONCLUSIONS: Initial resuscitation of critically ill patients with shock does not require monitoring of regional variables. After stabilization, however, regional variables are the best predictors of outcome.