Initial Distribution Volume Research Articles

Antagonism of rapacuronium using edrophonium or neostigmine: pharmacodynamics and pharmacokinetics

We have studied the pharmacodynamics and pharmacokinetics of rapacuronium (Org 9487) in 70 healthy patients. Neuromuscular transmission was monitored using TOF stimulation of the ulnar nerve and mechanomyography of the adductor pollicis muscle. Half of the patients were given a single dose of rapacuronium 1.5 mg kg-1 and the remainder rapacuronium 1.5 mg kg-1 with three incremental doses of 0.5 mg kg-1, each given when T1/T0 had recovered to 25%. In all patients, neuromuscular block was antagonized using neostigmine 0.05 mg kg-1 or edrophonium 1.0 mg kg-1 (allocated randomly), 2 min after the final dose of rapacuronium. All patients developed complete block after rapacuronium 1.5 mg kg-1. Mean onset time was 66 (SD 24) s. In patients who received an antagonist 2 min after the first dose of rapacuronium, time to recovery of T1/T0 to 25% was similar after neostigmine (9.8 (3.8) min) and edrophonium (10.3 (4.3) min): in patients who received incremental doses of rapacuronium, spontaneous recovery of T1/T0 to 25% after the first dose was 18.9 (4.7) min. In those who received an antagonist 2 min after the first dose of rapacuronium, times to recovery of T4/T1 to 0.7 were also similar after neostigmine (23.7 (7.7) min) and edrophonium (29.1 (10.7) min). After three incremental doses of rapacuronium, there was a longer time to recovery of T1/T0 = 25% after neostigmine compared with edrophonium (5.1 (1.0) vs 3.3 (1.3) min; P < 0.05) but more rapid recovery to T1/T0 = 75% (10.1 (2.9) vs 16.8 (10.1) min; P < 0.05) and T4/T1 = 0.7 (19.8 (6.3) vs 35.1 (10.4) min; P < 0.05). A three-compartment pharmacokinetic model was justified. Typical values for clearance and initial volume of distribution (V1) were 4.4 ml kg-1 min-1 and 94.8 ml kg-1, respectively. In females, clearance was decreased by 38.5% compared with males and V1 was decreased by 25% in patients aged more than 65 yr.

Pharmacokinetics of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency

To characterize the pharmacokinetic profile of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency. Lanreotide was administered by intravenous bolus (7 microg/kg) to 12 patients with severe chronic renal insufficiency and to 12 healthy subjects. Lanreotide serum levels were determined by a radioimmunoassay procedure from time 0 until 24 hours after the administration. The main pharmacokinetic parameters were estimated by a noncompartmental treatment of data. The total serum clearance of lanreotide was found to be significantly lower in patients with severe chronic renal insufficiency than in healthy subjects (mean +/- SEM values of 0.138 +/- 0.017 L/hr/kg versus 0.244 +/- 0.027 L/hr/kg; P < .005). The initial lanreotide concentration, the elimination half-life, the area under the curve from time zero to 24 hours, and the area under the curve from time zero to infinity were significantly greater in patients with severe chronic renal insufficiency than in healthy subjects (307.45 +/- 79.19 ng/mL versus 127.18 +/- 22.65 ng/mL [P < .05]; 2.39 +/- 0.33 hours versus 1.32 +/- 0.20 hours [P < .005]; 62.55 +/- 9.73 ng/mL x hr versus 32.09 +/- 3.23 ng/mL x hr [P < .005]; and 62.95 +/- 9.78 ng/mL x hr versus 32.30 +/- 3.23 ng/mL x hr [P < .005], respectively). The initial volume of distribution, but not the volume of distribution at steady state, was significantly lower in patients with severe chronic renal insufficiency (0.040 +/- 0.008 L/kg versus 0.092 +/- 0.020 L/kg [P < .05] and 0.110 +/- 0.018 L/kg versus 0.172 +/- 0.046 L/kg [difference not statistically significant], respectively). The mean residence time was similar in both groups (0.77 +/- 0.06 hours versus 0.65 +/- 0.14 hours [difference not statistically significant]). A reduction in the total serum clearance and a decrease in the initial volume of distribution of lanreotide were observed in patients with severe chronic renal insufficiency treated with one intravenous bolus dose of 7 microg/kg lanreotide.

PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases

The proinflammatory cytokine, tumour necrosis factor α (TNFα) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNFα are modulated by the...

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer.

The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m(2)) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m(2)) and then continuous infusion (600 mg/m(2)) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL(mean)) and initial volume of distribution (V), were as follows: the male subgroup showed a CL(mean) value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.

Estimation of the initial distribution volume of glucose by an incremental plasma glucose level at 3 min after i.v. glucose in humans.

The initial distribution volume of glucose (IDVG) could be a clinically useful indicator of the central extracellular fluid (ECF) space volume, namely the interstitial fluid volume status of highly perfused organs. In this study, we determined the formula of IDVG using incremental plasma glucose levels after i.v. glucose. One hundred and fifty patients admitted to the general intensive care unit of the University of Hirosaki hospital were entered into this prospective study which was conducted in two stages. In the first stage 300 data points from 100 patients were used to measure the IDVG (3 determinations for each patients). This utilized a one compartment model to describe the incremental plasma glucose decay curve following an intravenous bolus injection of glucose which, in turn, was used to derive the parameters of an equation for IDVG prediction following a single plasma sample. The second stage was a validation of the equation using a separate data set (150 points) from a further 50 patients. A one phase exponential decay model was well-fitted for the IDVG-postadministration glucose level curve, and indicated that the incremental glucose level at 3 min after i.v. glucose was best-correlated to the IDVG compared with those at 1, 2, 4, 5 and 7 min postadministration. The formula of the IDVG was obtained from the curve: IDVG=24.44xe-0.0298xDeltaGL+2.70, where DeltaGL=incremental glucose level at 3 min after i.v. glucose. Another 150 samples showed that the measured-IDVG from a one compartment model and predicted-IDVG from the formula were 7.24+/-1. 63 and 7.27+/-1.52 l, respectively, and that there was a significant correlation between the two IDVGs (r=0.966, P<0.0001). Using an incremental glucose level at 3 min after i.v. glucose, we have established the reliable formula for determination of the IDVG which could be a clinically useful indicator of the central ECF volume.

Standardized Uptake Value and Influx

Useful characterizing parameters have been derived from historical positron emission tomography (PET) standardized uptake values (SUV) and influx constants K. Meta-analysis was performed on 30 multipatient PET oncological studies providing same patient SUVs and K’s. Averaged results for fluorine-18 fluorodeoxyglucose (FDG) and l-methionine respectively were: SUV vs. K correlation coefficients = 0.89 and 0.80; SUV/K ratios = 192 and 63 minutes as average tracer clearance times T in these populations. For cancers, coefficients of variation (CV) for K’s were 0.61 and 0.46, notably larger than the CVs (0.50 and 0.40) for SUVs. A Monte Carlo simulation model, matching these results, represents 1/T as (an effective tracer clearance rate) × (its initial distribution volume). We conclude that T is a characteristic tracer clearance time that is independent of cancer type. A measurement model is introduced that might help improve protocols. The higher CVs of K’s vs. SUVs is worth noting clinically when seeking an effective diagnostic marker. Also, SUV conversions to K can provide some quality assurance in K measurements.

A population approach to the forecasting of amikacin plasma and urinary levels using a prescribed dosage regimen.

We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill patients who received amikacin intravenously. Fourteen subjects (577 serum amikacin concentrations, 167 urine measurements) were studied to obtain data for population modeling, while 5 patients (267 serum amikacin concentrations, 68 urine measurements) were studied for the assessment of predictive performance. The population analysis was performed using serum and urine amikacin measurements; the renal clearance of amikacin was expressed as a function of creatinine clearance. A two-compartment model was fitted to the population data by using NONMEM. The population characteristics of the pharmacokinetic parameters (fixed and random effects) were estimated using the FOCE method. The population pharmacokinetic parameters with the interindividual variability (CV%) were as follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model which relate the amikacin renal clearance to the creatinine clearance, initial volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h, 104%), steady state volume of distribution (55.2 l, 64.1%) and urinary elimination (67.5%, 36.3%). The Bayesian approach developed in this study accurately predicts amikacin concentrations in serum and urine and allows for the estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in the prediction.

Detection of histamine-induced capillary protein leakage and hypovolaemia by determination of indocyanine green and glucose dilution method in dogs.

The plasma volume of histamine-induced protein capillary leakage may be overestimated when this is determined using the indocyanine green (ICG) dilution method (Vd-ICG), since this dye binds to plasma proteins. The initial distribution volume of glucose (IDVG) has been shown to indicate the central extracellular fluid volume including plasma. Accordingly, the overestimation would be detected by a higher Vd-ICG/IDVG ratio. Our study was intended to examine whether the simultaneous measurement of these two variables can evaluate histamine-induced protein leakage and associated hypovolaemia. Prospective animal study. Institutional animal research laboratory. Twenty-four anaesthetized and ventilated mongrel dogs. Anaesthetized animals were mechanically ventilated and received infusions of normal saline (n = 8), histamine 50 microg/kg per h (n = 8), or histamine 100 microg/kg per h. The Vd-ICG and IDVG were calculated using a one-compartment model by simultaneous administration of ICG 0.5 mg/kg, and glucose 100 mg/kg followed by serial arterial blood sampling. In both histamine groups, a significant elevation of haematocrit and a decrease of plasma albumin concentration were found (p<0.05). Although the IDVG decreased following histamine administration (p<0.05), the Vd-ICG remained unchanged. The Vd-ICG/IDVG ratio increased in a dose-dependent manner after histamine administration (p<0.05), but remained unchanged following normal saline administration. The results suggest that the Vd-ICG/IDVG ratio and the IDVG are useful in evaluating the magnitude of the leakage and hypovolaemia.

Elimination of methoxyacetic acid and ethoxyacetic acid in rat

1. The pharmacokinetics of methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) have been determined in the male and female rat following bolus intravenous administration at 100 mg/kg. The plasma-concentration data of MAA fitted well to a one-compartment model, and the plasma-concentration data of EAA to a two-compartment model. 2. The elimination half-life of MAA estimated from plasma data was higher in females (18.6 ± 2.0 h) than in males (13.2 ± 0.4 h). There was no difference in the elimination half-lives estimated from urine data. The apparent volume of distribution was lower in the male than in the female rat estimated from plasma data only, while AUC, total and non-renal clearances and the relative amount MAA excreted unchanged in urine was similar in the male and female rat. 3. Clearance of EAA is higher than of MAA, and this appears as a result of metabolic capacity. The elimination half-lives of EAA were similar in the male and female rat, 9.4 ± 3.7 and 10.5 ± 2.6 h respectively. AUC was higher in the female compared with the male rat. The fraction of EAA eliminated during the distribution phase was 44.0 ± 15.4 and 41.0 ± 17.4% in the male and female rat respectively. The initial volume of distribution, the apparent volume of distribution, total and non-renal clearance are higher in the male compared with the female rat.

Detection of capillary protein leakage by glucose and indocyanine green dilutions during the early post-burn period

Overestimation of the plasma volume determined by the indocyanine green (ICG) dilution method (PV-ICG) may occur after burns, since this dye has the potential of extravasation in the presence of the capillary protein leakage. Assuming that the initial distribution volume of glucose (IDVG) consistently indicates the extracellular fluid volume of highly perfused organs including plasma, overestimation of the PV-ICG can be detected by a higher PV-ICG IDVG ratio. The present study was designed to test whether a higher PV-ICG IDVG ratio is observed within 24 h post-burn compared to the subsequent days. Ten severely burned adult patients admitted to the ICU were studied through the 2nd post-burn day. The daily IDVG and PV-ICG were calculated using a one compartment model by simultaneous administration of glucose, 5 g, and ICG, 25 mg. Although the IDVG increased on the 1st post-burn day ( p < 0.05), the PV-ICG remained unchanged. The PV-ICG IDVG ratio within 24 h post-burn was significantly higher than that on the 1st post-burn day ( p < 0.01). Results indicate that overestimation of the PV-ICG can occur within 24 h post-burn and suggest that simultaneous measurement of the IDVG and the PV-ICG would help predict the generalized capillary protein leakage after burns.

Ratio of indocyanine green and glucose dilutions detects capillary protein leakage following endotoxin injection in dogs

This study was designed to determine whether endotoxin-induced generalized capillary protein leakage can be detected using the ratio of indocyanine green (ICG) and glucose dilutions. Plasma volume determined by the ICG dilution method (Vd-ICG) and the initial distribution volume of glucose (IDVG) were assessed simultaneously before and after either the administration of lipopolysaccharide (LPS) 0.3 mg kg-1 or equal amounts of isotonic saline in two groups of eight dogs, using a one-compartment model after simultaneous infusions of both ICG 0.5 mg kg-1 and glucose 100 mg kg-1. The IDVG has been shown to indicate the extracellular fluid volume of highly perfused organs including plasma. All post-treatment values decreased compared with the pre-treatment values (P < 0.05), except Vd-ICG in the LPS group, even though the post-treatment total plasma protein concentration of the LPS group decreased significantly compared with the pre-treatment value (P < 0.05). The post-treatment Vd-ICG/IDVG ratio of the saline group remained unchanged compared with that of the pre-treatment, and the post-treatment ratio of the LPS group increased significantly (P < 0.01). It can be concluded that overestimation of the Vd-ICG can occur after endotoxin injection, which can be detected by simultaneous measurements of the Vd-ICG and the IDVG.

Non-invasive estimation of the net influx constant using the standardized uptake value for quantification of FDG uptake of tumours.

To reduce the variability of the standardized uptake value (SUV) which is widely used to evaluate 2-[18F]fluoro-2-deoxy-d-glucose (FDG) uptake by neoplasms, net influx constant (Ki) was derived from SUV. The relationship Ki=SUV.kp.V0, where kp is the plasma clearance rate and V0 is the initial distribution volume of FDG, was utilized. A total of 71 plasma input functions were measured up to 60 min after intravenous injection of FDG in 55 patients and were analysed to obtain kp and V0. SUV and V0 were calculated based on either body weight or body surface area. To validate the Ki estimation, another group of eight patients with squamous cell carcinoma of the head and neck was included. Parametric images of the net influx constant were obtained by Patlak graphical analysis of dynamic positron emission tomography (PET) data and measured plasma input function. V0 based on body weight was 0.1627+/-0.0329 (ml/g) and showed a weak negative correlation with body weight (y=0.23356-0.00138x, r=0.591). V0 based on body surface area was 5540+/-871 (ml/m2) and had no significant correlation with body weight. kp at 50 min post injection was 0. 03272+/-0.00243 (1/min), and had no correlation with the plasma glucose concentration. A highly significant positive correlation was noted between true Ki and estimated Ki based on both body weight (y=0.0033+1.0371x, r2=0.897), and body surface area (y=0.0033+1. 0351x, r2=0.926). Ki, a better indicator of FDG uptake by tumour than SUV, is derivable non-invasively. Quantification of FDG uptake by Ki will aid standardization of diagnostic criteria of FDG PET oncology.

CAPILLARY PROTEIN LEAKAGE AND PLASMA VOLUME IN THE EARLY POST-BURN PERIOD

S131 Indocyanine green (ICG) has been used for evaluation of plasma volume (PVICG). However, Obvious capillary protein leakage has potential to modify PVICG within 24 post-burn hours, since ICG binds to plasma proteins. Recent radioisotopic studies demonstrated that extracellular glucose distribution is not affected by its metabolism [1,2]. Assuming that the initial distribution volume of glucose (IDVG) consistently indicates the extracellular fluid volume of the highly perfused organs including plasma volume (PV) [3], the PVICG/IDVG ratio (normal range: 0.30 - 0.40) would provide the magnitude of overestimation of PVICG. The purpose of the study is to evaluate PVICG by comparing with the IDVG and other routine clinical variables. METHODS: With IRB approval 10 severely burned patients admitted to the ICU within 24 hours post-burn were studied. Fluid resuscitation with crystalloids alone were performed by 24 hours post-burn. ICG 25mg and glucose 5 g were simultaneously infused over 30 sec throughout the first 3 post-burn days. Daily two estimates were calculated using a one compartment model utilizing increased plasma values 3-11 min and 3-7 min postinfusion, for PVICG and the IDVG. RESULTS: Each variable tended to indicate an increase in PV day by day, even though statistically significant change was observed only in hematocrit (Table 1). Apparent overestimation of PVICG occurred in 4 patients within 24 hours post-burn judged by clinical variables other than the IDVG, whose ratio ranged between 0.45 and 0.74. No correlation was found between two estimates on that day (r=0.15).Table 1CONCLUSIONS: In addition to capillary protein leakage in the burned tissues, obvious generalized leakage may occur in some severely burned patients within 24 hours post-burn, resulting in an overestimation of PVICG. The simultaneous determination of PVICG and IDVG is useful to evaluate the presence of the leakage.

EVALUATION OF CAPILLARY PROTEIN LEAKAGE BY INDOCYANINE GREEN AND GLUCOSE DILUTIONS FOLLOWING HISTAMINE INJECTION IN DOGS

S153 Plasma histamine often increases in critically ill patients and induces generalized capillary protein and water leakage resulted in a loss of plasma volume (PV). However, there has been no clinically useful indicator to detect the systemic capillary permeability. In the presence of capillary leakage, PV determined by indocyanine green (ICG) dilution method (Vd-ICG) may be overestimated because ICG mostly binds to plasma protein. According to a recent radioisotopic study [1] and our volume challenge test [2], the initial distribution volume of glucose (IDVG) reflects the extracellular fluids volume of highly perfused organs (central-ECF) including PV. Assuming that IDVG is not affected by capillary permeability and glucose metabolism [1], the Vd-ICG/IDVG ratio would increase in the presence of protein leakage. The purpose of this study was to examine whether the ratio can detect capillary protein leakage following histamine injection in dogs. METHODS: 24 adult mongrel dogs were divided into 3 equal groups; 1) histamine 50 [micro sign]g/kg/hr, 2) histamine 100 [micro sign]g/kg/hr, 3) isotonic saline were administered. All dogs were anesthetized and mechanically ventilated. Vd-ICG and IDVG were calculated using a one-compartment model following simultaneous infusions of ICG 0.5 mg/kg and glucose 100 mg/kg before and after 90 min. each treatment. RESULTS: The post-treatment Vd-ICG of saline group decreased reflecting the volume of blood sampling, however, no changes were found in both histamine groups despite an obvious PV loss associated with hemoconcentration and hypoalbuminemia. The post-treatment IDVG of histamine groups decreased because the central-ECF volume was reduced by histamine. The Vd-ICG/IDVG ratio increased after histamine administration. (Table 1)Table 1CONCLUSION: The results suggest that the Vd-ICG/IDVG ratio is useful to detect the capillary protein leakage.

Pharmacokinetics of a Slower Clearing Tissue Plasminogen Activator Variant, TNK-tPA, in Patients with Acute Myocardial Infarction

The rapid clearance of t-PA from plasma requires administration by intravenous (I.V.) infusion. A slower clearing, fibrin-specific rt-PA variant may allow single intravenous bolus administration, thereby simplifying dosing. This study was designed to characterize the pharmacokinetics of the slower clearing, fibrin-specific tissue-plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction (AMI) following a single I.V. bolus injection. Single I.V. bolus doses of 5 to 50 mg of TNK-tPA were studied in an open-label, multicenter, dose escalation study. A total of 113 AMI patients were enrolled. Blood sampling for pharmacokinetics was conducted in eighty-two patients (72 men, 10 women), with 5 to 27 patients per dose. TNK-tPA was administered as an I.V. bolus over 5-10 s. Following I.V. bolus administration, there was a biphasic elimination of TNK-tPA from plasma. The initial phase had a mean half-life that ranged from 11 +/- 5 to 20 +/- 6 min and was followed by a terminal phase with a mean half-life that ranged from 41 +/- 16 to 138 +/- 84 min. Mean TNK-tPA plasma clearance was 125 +/- 25 - 216 +/- 98 ml/min, and the initial volume of distribution was 4.3 +/- 2 - 8.4 +/- 6 1. A decrease in TNK-tPA plasma clearance with increasing TNK-tPA dose was noted. In addition, women and patients with lower body weight or older age had a slower plasma clearance. In conclusion, TNK-tPA has a slower plasma clearance in patients with AMI than that reported for rt-PA, allowing administration as a single I.V. bolus.

Delayed antinociceptive effect following morphine-6-glucuronide administration in the rat – pharmacokinetic/pharmacodynamic modelling

This study was conducted with the aim of characterising the pharmacokinetics and pharmacodynamics of morphine-6-glucuronide (M6G), a morphine metabolite possessing agonist properties. M6G was administered to three groups of rats as either a bolus dose, a 2-h computer-controlled stepwise infusion or as two consecutive 30-min infusions given 3 h apart. Clearance and initial volume of distribution were estimated to be 27 ml/min/kg for clearance and 339 ml/kg for initial volume. Morphine could not be detected until 4 h after dosing. The antinociceptive response profile, measured using the electrical stimulation vocalisation method, showed a pronounced delay in relation to the plasma concentration profile. The peak concentrations of 12 000 ng/ml, 6270 ng/ml and 12 800 ng/ml in the bolus, the stepwise infusion and the two consecutive infusion groups gave corresponding maximal antinociceptive effects of 49%, 181% and 168%. A pharmacokinetic-pharmacodynamic model was applied to the data and the effect delay was estimated to be 1.4 h, which is considerably longer compared to morphine (0.5 h). Acute tolerance to the antinociceptive response was observed but could not be quantified due to the slowly ascending effect. Based on these results, the importance of study design for potency determination of drugs exhibiting different effect equilibration times was elucidated. Significant increases in the pCO 2 levels were observed following the stepwise infusion and the two consecutive infusions. When compared to morphine, there was a tendency of a less pronounced effect on respiration by M6G.

Does the initial distribution volume of glucose reflect the shift of the central extracellular fluid volume after major surgical procedures?

Our experimental studies indicated that the initial distribution volume of glucose (IDVG) reflects the central extracellular fluid (ECF) volume status including plasma rather than glucose metabolism. The present study was designed to discover whether the IDVG follows the postoperative fluid shift from the peripheral to the central ECF compartment. Five grams of glucose and 25mg of indocyanine green (ICG) were infused simultaneously over 30 seconds through the central venous line in 21 patients following either subtotal esophagectomy or major vascular surgery. A total of 104 daily comparisons between the IDVG and plasma volume determined by the ICG dilution method (PV-ICG) were performed. Two estimates were calculated using a one compartment model utilizing plasma values from 3 to 7 minutes postinfusion for the IDVG, and from 3 to 11 minutes postinfusion for PV-ICG. Two estimates increased on the 3rd postoperative day (P<0.05), even though body weight remained unchanged. A linear correlation was obtained between two estimates (r=0.68, n=104, P<0.001). Our results demonstrate that two estimates followed the fluid shift, and suggest that the IDVG is useful to evaluate central ECF volume status following major surgical procedures.

Repeated Doses of Rocuronium Bromide Administered to Cirrhotic and Control Patients Receiving Isoflurane

Comment: As is the case for other muscle relaxants having a steroid structure, the pharmacokinetics of rocuronium are altered by liver disease. In this carefully constructed study, the authors have noted a reduction in the clinical efficacy of the initial dose, a phenomenon that may be attributed to increased volume of extracellular fluid and, hence, an increase in the initial volume of distribution. Subsequently, there is a trend toward prolongation of action during maintenance, which is best demonstrated by delayed spontaneous recovery. The time to 25% recovery was significantly prolonged, especially after successive maintenance doses. There also was reduction in the elimination constant and a prolongation of mean residence time. Perhaps of greatest significance to the clinician is the authors' observation as to the marked inter-patient variability in patients with cirrhosis. This makes it all the more important to perform careful monitoring of neuromuscular function in the patient with cirrhosis and to titrate rocuronium dosage to the patient's needs. Although it is important to reverse rocuronium in most clinical settings, it may be even more so in the patient with cirrhosis.

Comparison of the Initial Distribution Volume of Glucose and Sucrose in Volume-Challenged Dogs

&lt;i&gt;Objective:&lt;/i&gt; Sucrose has been used as an estimate of the extracellular fluid (ECF) volume. This study was designed to examine the hypothesis that the initial distribution volume of glucose (IDVG) correlates with the initial distribution volume of sucrose (IDVS) following volume challenges. &lt;i&gt;Design:&lt;/i&gt; Prospective study for comparison of two methods. &lt;i&gt;Setting:&lt;/i&gt; Animal laboratory of the University of Hirosaki School of Medicine. &lt;i&gt;Materials and Methods:&lt;/i&gt; Ten mongrel dogs of either sex, weighing 8.5-14.0 kg, were the subject of the study. Dogs were anesthetized with pentobarbital and paralyzed with pancuronium. The volume challenge was conducted with 3% dextran in lactated Ringer’s solution 30 ml · kg&lt;sup&gt;–1&lt;/sup&gt; over 30 min in 10 dogs. Thereafter, the same amount of the fluid was further administered in 8 of these 10 dogs. Before and after each volume challenge, glucose (100 mg·kg&lt;sup&gt;–1&lt;/sup&gt;) and sucrose (100 mg·kg&lt;sup&gt;–1&lt;/sup&gt;) were infused simultaneously over 30 s. The two estimates were calculated using a one-compartment model from repeated measurements of increased plasma glucose and sucrose during postinfusion. &lt;i&gt;Results:&lt;/i&gt; A linear correlation was obtained between the two estimates (r = 0.89, n = 28, p&lt; 0.0001). All dogs consistently showed that the IDVG individually followed the IDVS during changes in the latter. &lt;i&gt;Conclusions:&lt;/i&gt; Results demonstrated that the IDVG correlated with the IDVS before and after volume changes and support the hypothesis that the IDVG is useful for evaluating the ECF volume status of highly perfused tissues.