Initial Distribution Volume Research Articles

Biological heat and mass transport mechanisms behind nanoparticles migration revealed under microCT image guidance

Background and objectivesBlood perfusion, infusion rate, distribution and heating induced redistribution of magnetic nanoparticles inside tumour interstitium governs the heating protocol designs. This study aims to answer three important questions: Why do magnetic nanoparticles redistributes? What causes their migration? Why it is important to be included in priori-treatment planning simulations? Our aim is to test how the regulation of magnetic nanoparticles affects the temperature distribution and how this temperature change modifies tumour microenvironment. We have tested our hypothesis for two cases: (1) when the nanoparticles are lying in close proximity to the flank position of tumour i.e. near the interface of tumour and healthy tissue and (2) when the nanoparticles are located near the skin surface of tumour. Materials and methodsSAS® and MATLAB programs are used to average micro-CT cross-sectional slices containing three-dimensional clusters of pixels corresponds to nanoparticles as a SAR file and Concentration distribution file import to the COMSOL-Multiphysics® 5.2 FEA software for evaluation of temperature distribution and its resulted collateral thermal damage. The volumetric heat generation rate (qMNH‴) is kept ∼ 0.37 W for infusion rate of 4 μL/min. Pennes bioheat equation is three-way coupled with traditional Arrhenius thermal damage model, modified concentration equation in which heat source term (SAR) varies in a directly proportional relationship with Concentration distribution. All variables i.e. Diffusion coefficient, porosity, blood perfusion, metabolic heat generation are varying as a function of thermal damage for a coupled biophysics problem. ResultsThermal signatures of cell-death were evaluated for two case scenarios. The initial distribution volume is 188.46 mm3. On compare and contrast, 6.24% larger thermal diffusion is seen at outer extremities case than at the interface. However, the treatment times are 12.90% (1.13 fold more) to achieve a Ω ≥ 4.6 with ΔT=10°C for latter case. On evaluation of “Source maps” (before heating) with “Destination maps” (after heating) suggests migration of nanoparticles from the regions of higher concentration to the regions of lower concentration due to cell-necrosis induced enhancement in tumour interstitial space. Thermal-diffusion of nanoparticles suggests an increase in redistribution volumes by 23.44% and 26.30% respectively during 99.6% transformation of cancerous cells. This study precisely elucidate qualitative and quantitative aspects of this issue. One of the possible reasons of nanoparticle migration is that the dead cells release intracellular solution after the rupturing of cell membrane. We speculate that five-fold increase in diffusion coefficient of nanoparticles might have played a significant role in particle migration. ConclusionsCNIDC (Cell necrosis induced diffusivity change) and CNIPE (Cell necrosis induced porosity enhancement) may be the two intricate mechanisms that promotes nanoparticles migration.

Revisiting transient coarsening kinetics: a new framework in the Lifshitz-Slyozov-Wagner space

Phase coarsening in multiphase materials is a fundamental and crucial process in the study of microstructure evolution, for which a thorough understanding of kinetics can make a significant contribution to material processing and performance design. In this work, a new framework in the dimensionless Lifshitz-Slyozov-Wagner space is developed to study the kinetics of transient coarsening co-controlled by interface and matrix diffusion. The dynamic equations for individual particles are derived from the thermodynamic extremal principle, in consideration of energy dissipations by matrix diffusion, interface migration/reaction, and trans-interface diffusion. The effects of initial particle size distribution and finite volume fractions are clarified. Different from the conventional viewpoints, the time for transient coarsening is found to change non-monotonically with the width and tail length of the initial distribution. The ultralong transient coarsening with ‘quasi-steady’ distributions can occur for systems initiated from both the ‘wide & long tail’ and ‘narrow & short tail’ distributions. Furthermore, this work proves the existence of a unique attractor state for the steady stage and reveals the numerical origin of ‘quasi-steady’ distributions, which answers Brown's unsolved puzzle for years [LC Brown. Acta Metall 1989;37:71]. Finally, an increase in volume fraction is shown to directly shorten the transient stage dominated by single mechanism (matrix diffusion or interface), but indirectly delay the transition from the interface-dominated state to the diffusion-controlled stage. These findings not only offer new insights into the previous observations in microgravity experiments [VA Snyder, J Alkemper, PW Voorhees, Acta Mater 2001;23:699], but also theoretically describe the limiting coarsening behaviors at ultrahigh volume fractions [H Yan, KG Wang, ME Glicksman. Acta Mater 2022;117964].

Changes in the Initial Distribution Volume of Glucose in Endotoxin-induced Septic Pig Models

Changes in the Initial Distribution Volume of Glucose in Endotoxin-induced Septic Pig Models

Pretherapeutic first-in-human targeting trial of anti-hK2 antibody h11B6: A potential molecular vector for alpha-particle radioimmunotherapy.

122 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has focused to date on targeting prostate specific membrane antigen, an approach associated with salivary gland toxicity and variable lesion expression. New targets are needed. Human kallikrein-2 (hK2) is overexpressed in most prostate cancer, with minimal normal tissue expression or serum secretion. Humanized monoclonal antibody (mAb) h11B6 exclusively targets hK2 in pre-clinical studies. This phase 0 study (NCT04116164) is a first-in-human trial of [111In]-DOTA-h11B6 to determine the hk2-targeting potential of h11B6. Objective: The purpose of this ongoing protocol is to characterize the biodistribution of [111In]-DOTA-h11B6 and determine a suitable mAb mass that targets mCRPC with minimal non-tumor targeting. Methods: Patients with progressive mCRPC were enrolled. A single slow bolus infusion of 2 mg [111In]-DOTA-h11B6 (nominally 185 MBq [111In]), was administered IV with or without 8 mg h11B6. Patients were observed for adverse events (AE) for at least 2 weeks. Serial gamma camera imaging including at least one SPECT/CT scan was performed up to 8 days post-administration. Serial blood samples were obtained over 2 weeks to determine serum radioactivity and h11B6 protein levels. Dosimetry for normal organs was estimated using OLINDA-EXM. Results: Results for the first 6 patients are summarized in Table. Treatment was tolerated in all patients with no AEs and no evidence of enhanced accumulation in any organ including salivary glands. Initial volume of distribution appeared confined to the vascular compartment. Slow clearance of radioactivity from the vascular compartment was observed with gradual targeting to skeletal and non-skeletal lesions in all patients. Conclusions: h11B6 is a novel mAb that targets hK2, localizes to bone and soft tissue metastases, has no significant normal tissue uptake, and spares salivary glands. An IND for a phase I therapeutic study using [225Ac] has been secured. Clinical trial information: NCT04116164. [Table: see text]

Assessment of population-based input functions for Patlak imaging of whole body dynamic 18F-FDG PET

BackgroundArterial blood sampling is the gold standard method to obtain the arterial input function (AIF) for quantification of whole body (WB) dynamic 18F-FDG PET imaging. However, this procedure is invasive and not typically available in clinical environments. As an alternative, we compared AIFs to population-based input functions (PBIFs) using two normalization methods: area under the curve (AUC) and extrapolated initial plasma concentration (CP*(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated CP*(0). The aim of this study was to validate IDIF and PBIF for FDG oncological WB PET studies by comparing to the gold standard arterial blood sampling.MethodsThe Feng 18F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0–60 min) or CP*(0), estimated from an exponential fit. CP*(0) is also described as the ratio of the injected dose (ID) to initial distribution volume (iDV). iDV was modeled using the subject height and weight, with coefficients that were estimated in 23 subjects. In 12 oncological patients, we computed IDIF (from the aorta) and PBIFs with scaling by the AUC of the IDIF from 4 time windows (15–45, 30–60, 45–75, 60–90 min) (PBIFAUC) and estimated CP*(0) (PBIFiDV). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak Ki values.ResultsThe IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and Ki comparison, 30–60 min was the most accurate time window for PBIFAUC; later time windows for scaling underestimated Ki (− 6 ± 8 to − 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIFAUC(30–60), and PBIFiDV were 0.91, 0.94, and 0.90, respectively. The bias of Ki was − 9 ± 10%, − 1 ± 8%, and 3 ± 9%, respectively.ConclusionsBoth PBIF scaling methods provided good mean performance with moderate variation. Improved performance can be obtained by refining IDIF methods and by evaluating PBIFs with test-retest data.

The pharmacokinetics of the Fab fragment of a humanized anti‐cocaine monoclonal antibody and its effects on cocaine’s distribution in mice

There is currently no FDA approved treatment for cocaine abuse. Our laboratory has created a humanized anti‐cocaine monoclonal antibody (mAb), h2E2, that has high affinity and specificity for cocaine and is cleared slowly in rodents. The mAb h2E2 sequesters cocaine in the plasma and prevents cocaine entry into the brain in rodents. The antigen binding portion, the Fab fragment, of h2E2 has the same high affinity and selectivity as its whole mAb counterpart. The Fab fragment should also sequester cocaine into the plasma compartment but is expected to have a more rapid clearance than the intact mAb. This study elucidated the pharmacokinetics of the Fab fragment and its effects on cocaine’s pharmacokinetics in mice. Catheterized mice were injected with Fab (80 mg/kg, i.v., pH=7.4, PBS) (n=8) and blood samples collected from the tip of the tail at designated time points over three days. Fab concentrations in blood samples were quantified using an ELISA assay. Two groups of catheterized mice were injected under mild restraint with Fab (82 mg/kg, i.v. pH= 7.4, PBS, generated by enzymatic digestion of whole mAb h2E2) or vehicle (PBS, pH=7.4). One hour later, mice were injected with an equimolar dose of cocaine HCl (0.56 mg/kg, i.v.). At 8 time points between 0.75 and 60 min, mice were decapitated, and trunk blood was collected. Sodium pentobarbital (50 mg/kg, i.p.) was administered 3 minutes prior to decapitation. For the 0.75 and 1.5‐minute time points, cocaine was injected into anesthetized rats. Blood (typically 0.5–2 mL) was placed into 2‐mL polypropylene tubes and then centrifuged at 5000 g for 3 minutes. Plasma was pipetted into polypropylene microcentrifuge tubes and rapidly frozen on dry ice and stored at −80°C until LC‐MS/MS analysis. This experiment was performed three times. Total cocaine concentrations were quantified using LC‐MS/MS. The pharmacokinetic profile of the Fab fragment in mice was described by a 2‐compartment model (Figure 1). The Fab fragment has a mean distribution half‐life (t1/2α) of 16.7 minutes and a terminal elimination half‐life (t1/2β) of 7.1 hours (Figure 1). In the presence of the Fab fragment, cocaine concentrations in the plasma increased by 4.5‐fold compared to vehicle animals (Figure 2). The initial volume of distribution of cocaine decreased approximately 4.5‐fold in the presence of Fab. The Fab fragment increases the concentration of cocaine in the plasma by approximately 4.5‐fold compared to vehicle controls. Although the data is not shown, it is hypothesized that the Fab fragment, like its mAb counterpart, prevents cocaine from crossing the blood‐brain barrier and entering the brain. With a 24‐fold decrease in elimination half‐life (7.1 hours) compared to the intact h2E2 (7.8 days) and predicted rapid urinary excretion, the Fab fragment may be useful for the treatment of cocaine overdoses.Support or Funding InformationThis work is supported by the National Institutes of Health, National Institute on Drug Abuse grant number U01DA039550 (to ABN).The pharmacokinetics of the Fab fragment in male miceFigure 1The pharmacokinetics of cocaine in the presence of the Fab fragmentFigure 2

Effect of remifentanil and midazolam on ED95 of propofol for loss of consciousness in elderly patients: A randomized, clinical trial.

Background:Older people are more vulnerable to hemodynamic instability caused by propofol due to their decreased initial distribution volume and increased sensitivity to propofol. Midazolam or remifentanil can often be coadministered because of their synergistic or additive effects with propofol as well as amnesic properties and the blockade of sympathetic stimulation. However, no study has confirmed the appropriate dose of propofol for loss of consciousness in aged patients when administered with other drugs, including opioids or benzodiazepines.Methods:Patients >65 years scheduled for general anesthesia were enrolled. The patients were randomized into 3 groups using a computer-generated randomization table. Patients in group P (propofol) received only propofol for loss of consciousness, those in group PR (propofol–remifentanil) received remifentanil before propofol, and those in group PMR (propofol–midazolam–remifentanil) received remifentanil and midazolam before propofol. After propofol administration, loss of both eyelash reflex and verbal response represented success. The 95% effective dose of propofol for loss of consciousness in each group, which was the primary outcome, was determined using a modified biased coin up-and-down method.Results:In total, 120 patients were randomized into the 3 groups (n = 40). The 95% effective dose of propofol for loss of consciousness was 1.13, 0.87, and 0.72 mg/kg in groups P, PR, and PMR, respectively. The mean blood pressure (MBP) in group PMR was more significantly decreased before propofol injection (P = .041) as well as 2 minutes (P = .005) and 3 minutes after propofol administration (P<.001), compared with group P, but there were no intergroup differences at other time points.Conclusions:The effective dose of propofol for loss of consciousness in elderly patients could be decreased by 23% and 36% when remifentanil pretreatment was used without and with midazolam, respectively. However, the decrease in MBP was greater with remifentanil and midazolam pretreatment than with propofol alone. These findings suggest that pretreatment with midazolam for propofol infusions with remifentanil in elderly patients should be cautiously used, due to hemodynamic instability during induction.

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients.

Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V1/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V1/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients.

Effects of cardiac output on the initial distribution volume of glucose in the absence of fluid gain or loss in pigs.

Thirteen pigs were anesthetized and allocated to either the modified cardiac output group (m-CO group, n=10) or the control group (control group, n=3). In the m-CO group, CO was sequentially modulated from high CO (high CO) to two grades of low CO (low CO-1 and low CO-2) with dobutamine and propranolol with lidocaine, respectively, in the absence of any apparent change in basal fluid volume status. Thermodilutional CO and IDVG were measured at each CO condition. The IDVG was measured according to a one-compartment model with 2g glucose. The same parameters were measured in the control group using the same time schedule as for the m-CO group but without inotropes and at a stable CO state. Thereafter, 250ml of 10% dextran were infused over 15min to compare the effects of a preload-dependent increase in CO on IDVG measurements to the effects of the pharmacological modification of CO. Data were expressed as the mean±SD. Statistical analysis was performed with repeated measures ANOVA followed by Dunnett's test. Pearson's correlation test was also used. A P value of <0.05 was considered to indicate statistical significance. In the m-CO group, where CO increased to 147.2±26.7% of the baseline CO value in the high CO state and decreased to 65.9±11.0 and 37.3±14.4% of the baseline CO value in the low CO-1 state and the low CO-2 state, respectively, the IDVG did not change as CO was modified. IDVG significantly increased in response to volume loading of dextran in the control group. There was no correlation between the IDVG and CO in the m-CO group when there was no fluid gain or loss (r=0.097, n=40, P=0.554), but the IDVG was well correlated with CO in the control group with volume loading (r=0.764, n=18, P=0.0002). This study suggests that the IDVG is dependent on the central extracellular fluid volume and not on cardiac output.

Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis

CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway.

Degree of peripheral vasodilation induced by dexmedetomidine and midazolam in patients undergoing lower extremity surgery

Objective To evaluate the degree of peripheral vasodilation induced by dexmedetomidine and midazolam in the patients undergoing lower extremity surgery. Methods One hundred patients of both sexes, aged 27-64 yr, with body mass index of 20-30 kg/m2, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, undergoing elective lower extremity surgery under epidural anesthesia, were randomly divided into 4 groups(n=25 each): dexmedetomidine group(group D), compensatory volume expansion+ dexmedetomidine group(group CVE+ D), midazolam group(group M), and compensatory volume expansion + midazolam group(group CVE+ M). In D and CVE+ D groups, dexmedetomidine was infused over 5 min in a loading dose of 0.5 μg/kg, followed by an infusion of 0.3-0.6 μg·kg-1·h-1 until Observer's Assessment of Alertness/Sedation (OAA/S)score reached 3.In M and CVE+ M groups, midazolam was injected over 5 min in a dose of 0.05 mg/kg, followed by an infusion of 0.03-0.10 μg·kg-1·h-1 until OAA/S score reached 3.In CVE+ D and CVE+ M groups, compensatory volume expansion was performed at the same time as dexmedetomidine and midazolam were infused, 6% hydroxyethyl starch 130/0.4 and sodium chloride solution was infused intravenously at a rate of 0.5 ml·kg-1·min-1, and the total volume infused was 7 ml/kg.Before injection of dexmedetomidine or midazolam, and when OAA/S score reached 3, arterial blood samples were collected to determine the blood glucose concentration.Then 50% glucose 10 ml was injected intravenously, and 3 min later, arterial blood samples were collected again to determine the blood glucose concentration.According to the initial distribution volume of glucose, the degree of glucose dilution was determined to reflect the degree of peripheral vasodilation. Results The degree of peripheral vasodilation was(8.5±0.5)%, (8.4±0.4)%, (0.9±0.5)% and(0.8±0.5)% in D, CVE+ D, M and CVE+ M groups, respectively.There was no significant difference in the degree of peripheral vasodilation between D and CVE+ D groups, and between M and CVE+ M groups. Conclusion The degree of peripheral vasodilation induced by dexmedetomidine is about 8.5%, and by midazolam is only about 0.9% in the patients undergoing lower extremity surgery. Key words: Dexmedetomidine; Midazolam; Conscious sedation; Peripheral vasodilation

Pharmacokinetics of pergolide after intravenous administration to horses.

To determine the pharmacokinetics of pergolide after IV administration to horses. 8 healthy adult horses. Pergolide mesylate was administered IV at a dose of 20 μg/kg (equivalent to 15.2 μg of pergolide/kg) to each horse, and blood samples were collected over 48 hours. Pergolide concentrations in plasma were determined by means of high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined on the basis of noncompartmental methods. After IV administration of pergolide, mean ± SD clearance, elimination half-life, and initial volume of distribution were 959 ± 492 mL/h/kg, 5.64 ± 2.36 hours, and 0.79 ± 0.32 L/kg, respectively. With an elimination half-life of approximately 6 hours, twice-daily dosing may be more appropriate than once-daily dosing to reduce peak-trough fluctuation in pergolide concentrations. Further pharmacodynamic and pharmacokinetic studies of pergolide and its metabolites will be necessary to determine plasma concentrations that correlate with clinical effectiveness to determine the therapeutic range for the treatment of pituitary pars intermedia dysfunction.

ブドウ糖初期分布容量（initial distribution volume of glucose, IDVG）が減圧症の水分管理に有用であった1例

ブドウ糖初期分布容量（initial distribution volume of glucose, IDVG）が減圧症の水分管理に有用であった1例

Basic and clinical assessment of initial distribution volume of glucose in hemodynamically stable pediatric intensive care patients.

BackgroundInitial distribution volume of glucose (IDVG), which is not associated with significant modification of glucose metabolism, has been proposed as an indicator of the central extracellular fluid volume status in adults. However, data on IDVG in children are lacking. This study examined pharmacokinetic data on IDVG in children and compared IDVG with other clinical variables.MethodsIn total, 128 daily data sets from 60 consecutive pediatric intensive care patients (body weight ≥8.0 kg), consisting mostly of children undergoing cardiovascular surgery, were studied. Either 1 or 2 g of glucose based on body weight (approximately 0.1 g/kg) was administered. IDVG could not be determined from ten data sets from eight children because of body movement-associated glucose fluctuation during measurement. In the remaining 113 data sets from 55 children, IDVG was determined by applying the one-compartment model. Approximated IDVG based on the incremental plasma glucose level at 3 min postinjection (1-point IDVG), and approximated IDVG based on incremental plasma glucose levels at 3 and 5 min postinjection (2-point IDVG), were also calculated. Postoperative daily IDVG and the relationship between IDVG and cardiac output or circulating blood volume (CBV) were evaluated when data were available.ResultsConvergence was assumed in each glucose clearance curve. Mean indexed IDVG (IDVGI) of the first measurement in 55 children was 144 ± 22 (SD) mL/kg, which was associated with a plasma glucose disappearance rate (Ke-glucose) of 0.094 ± 0.033/min. Bias and precision were smaller between 2-point IDVG and standard IDVG than between 1-point IDVG and standard IDVG (−0.02 ± 0.13 L versus 0.07 ± 0.20 L, p <0.001). Postoperative IDVGI in 37 children after cardiovascular surgery increased daily on postoperative days 1–2 (p ≤0.011). Linear correlations were observed between IDVGI and indexed cardiac output (r = 0.588, n = 28, p <0.001) and between IDVGI and indexed CBV (r = 0.547, n = 25, p = 0.0047).ConclusionsIDVG is a potential marker of fluid volume status in children, even though body movement-associated glucose fluctuation is a major limitation. Two-point IDVG is preferable to 1-point IDVG for approximated IDVG.

Changes in initial distribution volume of glucose and extra vascular lung water index following whole lung lavage in patients with pulmonary alveolar proteinosis

Changes in initial distribution volume of glucose and extra vascular lung water index following whole lung lavage in patients with pulmonary alveolar proteinosis

The pleth variability index as an indicator of the central extracellular fluid volume in mechanically ventilated patients after anesthesia induction: Comparison with initial distribution volume of glucose

BackgroundThe pleth variability index (PVI) has been demonstrated to be a useful, noninvasive indicator of continuous fluid responsiveness. Whether PVI can be used to assess the changes of intravascular volume status remains to be elucidated.Material/MethodsUsing correlation analysis and receiver operating characteristic (ROC) curves, we sought a correlation between PVI and the initial distribution volume of glucose (IDVG), evaluating PVI as an indicator of the central extracellular fluid volume after anesthesia induction in patients undergoing elective abdominal surgery.ResultsStrong negative correlations existed between IDVG and PVI (r=−0.72), IDVG, and pulse pressure variation (PPV) (r=−0.73), and between IDVG and systolic pressure variation (SPV) (r=−0.53), P<0.01. Strong positive correlations existed between PPV and PVI (r=0.66), PVI and SPV (r=0.49), and between PPV and SPV (r=0.59), P<0.01. The areas under the ROC curve of IDVG, PVI, and SPV were significantly different from the area under a reference line. The optimal cutoff values (followed by sensitivity and specificity in parentheses) comparable to PPV over 11% as the threshold of hypovolemia were IDVG 94.5 mL/kg (75%, 100%), PVI 13% (91.7%, 77.8%), and SPV 7% (41.7%, 100%).ConclusionsOur results show that strong correlations exist among IDVG, PVI, PPV, and SPV in the evaluation of volemia. PVI can serve as a useful, noninvasive indicator of continuous central extracellular fluid volume for those patients not requiring invasive hemodynamic monitoring, but needs attention to changes in intravascular volume status for optimal fluid management.

Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice

BackgroundThe anti-diabetic drug metformin has been demonstrated to exert a protective effect against vascular complications in diabetes independent of its glucose lowering action. Since the endothelial glycocalyx has been indicated to have important vasculoprotective properties and to be vulnerable to degradation by hyperglycemic conditions, we evaluated in the current study the effect of short-term metformin treatment on whole-body glycocalyx barrier properties in a mouse model of non-insulin dependent diabetes mellitus (db/db mouse).MethodsGlycocalyx barrier properties were measured in an acute experiment in three groups of mice: 1) db/db mice without treatment serving as controls, 2) db/db mice which received metformin for two weeks in the drinking water serving as experimental group, and 3) C57Bl/6 mice serving as reference group. Animals were put under anesthesia (ketamine, medetomidine, and atropine) and carotid artery blood pressure was continuously monitored. To probe the glycocalyx a mixture of the tracers FITC-labeled 70 kDa dextrans (Dex70) or fluorescein-labeled red blood cells (RBCs) versus Texas Red-labeled 40 kDa dextrans (Dex40) was infused and blood samples subsequently collected for 30 min to determine the initial vascular distribution volume and clearance of these tracers. Urine was collected and dry-to-wet weight of heart and kidney were determined after the experiment. Group differences were tested using unpaired t-tests.ResultsMetformin treatment did not affect body weight, fasting blood glucose and arterial blood pressure. Compared to C57Bl/6 mice, db/db mice showed a diminished initial exclusion and increased vascular clearance of Dex70 versus Dex40 (P < 0.05), and both were improved by the metformin treatment (P < 0.05). While urine production was higher in the db/db mice compared to C57Bl/6 (P < 0.05), heart and kidney of the metformin treated animals showed comparable dry-to-wet weights compared to the C57Bl/6 mice.ConclusionsTwo weeks of metformin in the drinking water is associated with an improvement in glycocalyx barrier properties in db/db mice, as evidence by an enhanced exclusion and retention of 70 kDa dextrans in the vasculature. In addition, metformin improved hydration of heart and kidney. Previous reported cardiovascular benefits of metformin may well involve an improvement of the endothelial glycocalyx.

Pharmacokinetics of Pergolide Mesylate in Horses

AimsPergolide mesylate is the treatment of choice for equine pituitary pars intermedia dysfunction (PPID) and veterinary preparations are now licensed for this use in a number of countries. Pharmacokinetic properties of the drug have not been established completely in horses and current dosing recommendations are based upon clinical experience. This study aimed to establish the pharmacokinetic properties of the drug following intravenous administration.MethodsEight healthy Thoroughbred or Standardbred geldings were administered 0.02 mg/kg bwt pergolide mesylate via an intravenous jugular catheter. Blood samples were collected over a period of 48 h from a catheter in the contralateral jugular vein for determination of plasma pergolide concentrations. Pergolide concentrations in plasma were determined using a high‐performance liquid chromatography–tandem mass spectrometry assay. Maximum concentration of pergolide was determined directly from the data. Other pharmacokinetic parameters were determined for each horse by use of noncompartmental analysis with a commercial software program. Area under the curve was calculated by the linear trapezoidal rule. The terminal elimination rate constant and terminal half‐life were calculated by means of log‐linear regression. Initial volume of distribution, mean residence time, and clearance were calculated using standard noncompartmental formulae.ResultsSee Table . Results Mean (± s.d.) Maximum concentration (Cmax) 14.90 ± 5.02 Terminal elimination rate constant (λ) (h−1) 0.14 ± 0.06 Terminal half‐life (h) 5.80 ± 2.26 Area under the curve 0‐∞ (ng*h/ml) 18.63 ± 7.30 Mean residence time (h) 6.30 ± 2.43 Clearance (ml/h/kg bwt) 964.30 ± 460.95 Initial volume of distribution (l/kg bwt) 1.13 ± 0.39 ConclusionsVolume of distribution and half‐life for pergolide in horses are shorter than reported previously. There is no rationale for administering a loading dose of pergolide mesylate; however, based on its pharmacokinetic properties twice daily dosing with pergolide mesylate may be more appropriate than once daily dosing.Ethical animal researchApproved by the Animal Care and Ethics Committee, Charles Sturt University. Sources of funding: Internal funding. Competing interests: Although not used in the current study, David Rendle has acted as a paid speaker and consultant for Boehringer Ingelheim, manufacturers of Prascend: the licensed form of pergolide in Europe and the USA.

The effects of cardiac output on the initial distribution volume of glucose in pigs without changing the fluid volume status

The effects of cardiac output on the initial distribution volume of glucose in pigs without changing the fluid volume status

Corrected right ventricular end-diastolic volume and initial distribution volume of glucose correlate with cardiac output after cardiac surgery

Appropriate adjustment of cardiac preload is essential to maintain cardiac output (CO), especially in patients after cardiac surgery. This study was intended to determine whether index of right ventricular end-diastolic volume (RVEDVI), corrected RVEDVI using ejection fraction (cRVEDVI), index of initial distribution volume of glucose (IDVGI), or cardiac filling pressures are correlated with cardiac index (CI) following cardiac surgery in the presence or absence of arrhythmias. Eighty-six consecutive cardiac surgical patients were studied. Patients were divided into two groups: the non-arrhythmia (NA) group (n = 72) and the arrhythmia (A) group (n = 14). Three sets of measurements were performed: on admission to the ICU and daily on the first 2 postoperative days. The relationship between each cardiac preload variable and cardiac index (CI) was evaluated. A p value less than 0.05 indicated statistically significant differences. Each studied variable was not different between the two groups immediately after admission to the ICU. cRVEDVI had a linear correlation with CI in both group (NA group: r = 0.67, n = 216, p < 0.001; A group: r = 0.77, n = 42, p < 0.001), but RVEDVI had a poor correlation with CI (NA group: r = 0.27, n = 216, p < 0.001; A group: r = 0.19, n = 42, p = 0.036). IDVGI had a linear correlation with CI (NA group: r = 0.49, n = 216, p < 0.001; A group: r = 0.61, n = 42, p < 0.001), Cardiac filling pressures had no correlation with CI. Our results demonstrated that cRVEDVI and IDVGI were correlated with CI in the presence or absence of arrhythmias. cRVEDVI and IDVGI have potential as indirect cardiac preload markers following cardiac surgery.