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PubMed2002

Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study.

BACKGROUND AND PURPOSE: The objective of this study was to assess the effect of therapeutic moderate hypothermia on excitatory amino acids and metabolism by applying cerebral microdialysis in patients suffering from space-occupying middle cerebral artery infarction. METHODS: This was an open, prospective, observational study of 12 patients undergoing moderate hypothermia (33 degrees C) as rescue therapy for large, life-threatening middle cerebral artery infarction. Microdialysis probes were placed concomitantly with intracranial pressure (ICP) measuring devices in the frontal lobe of the infarcted and/or noninfarcted hemisphere. Using the CMA 600 Microdialysis Autoanalyzer, we analyzed glutamate, glycerol, pyruvate, and lactate. RESULTS: According to follow-up cranial CT scans, 3 different compartments of microdialysis measurements could be defined. First, noninfarcted brain tissue had stable dialysate concentrations but a significant effect of hypothermia on glutamate (2.6 versus 3.6 micromol/L), lactate (1.8 versus 3 mmol/L), and pyruvate (50 versus 95.8 micromol/L). Second, measurements from peri-infarct tissue had a significant effect of hypothermia on glutamate (4.8 versus 12.6 micromol/L), glycerol (58 versus 82 micromol/L), lactate (0.7 versus 1.3 mmol/L), and pyruvate (13.3 versus 36.8 micromol/L). Third, dialysate concentrations obtained from irreversibly damaged tissue were excessive for glutamate (453 micromol/L), glycerol (1187 micromol/L), lactate (12 micromol/L), and pyruvate (4 micromol/L). In this extreme compartment, no effect of hypothermia was observed. CONCLUSIONS: Cerebral microdialysis is a safe and feasible bedside method for neurochemical monitoring indicating normal brain tissue, potentially salvageable brain tissue, and irreversibly damaged areas in stroke. We could demonstrate that hypothermia decreases glutamate, glycerol, lactate, and pyruvate in the "tissue at risk" area of the infarct but not within the infarct core. Thus, future treatment strategies for life-threatening stroke should be guided by close neurochemical monitoring.

Adult↗
PubMed2005

In vivo microdialysis for PK and PD studies of anticancer drugs.

In vivo microdialysis technique has become one of the major tools to sample endogenous and exogenous substances in extracellular spaces. As a well-validated sampling technique, microdialysis has been frequently employed for quantifying drug disposition at the desired target in both preclinical and clinical settings. This review addresses general methodological considerations critical to performing microdialysis in tumors, highlights selected preclinical and clinical studies that characterized drug disposition in tumors by the use of microdialysis, and illustrates the potential application of microdialysis in the assessment of tumor response to cancer treatment.

Animals↗
PubMed2000

[Peripheral tissue microdialysis technique in unrestrained, conscious animals].

The microdialysis procedure had been developed in the past 2 to 3 decades to determine levels of drug and endogenous compounds in several organs under physiological conditions. Advantages of microdialysis include: minimal stress on the experimental animals; studies may be done in unrestrained, conscious animals, and multiple determination can be made without concern for excess blood loss from small animals; and measurements can be made of drug and/or metabolites at multiple sites in the animal. By employing the microdialysis technique, I developed the method of multiple sampling for a long term period from an animal under the freely moving condition. In addition, I developed a novel microdialysis probe that was applied to several peripheral tissues and/or organs. In this paper, I will describe the fundamental procedure for peripheral tissues and/or organs such as the jugular vein and liver, using subcutaneous and ocular microdialysis sampling in unrestrained, conscious animals.

Animals↗
PubMed2005

Continuous in vivo monitoring of blood diffusible calcium using on-line microdialysis sampling coupled with flame atomic absorption spectrometry.

A direct, rapid and continuous in vivo monitoring of diffusible calcium in the blood of living rabbits has been developed using microdialysis sampling coupled on-line with flame atomic absorption spectrometry. Microdialysates perfused through implanted microdialysis probes were collected with a sample loop on an injection valve and directly introduced into the flame atomizer by a carrier solution. An ultrapure saline solution (0.9% NaCI, pH 7.2) was used as the perfusion solution at a flow rate of 20 microI min(-1) via the microdialysis probe. A 0.1% La solution in 0.5% HNO3 solution was employed as the carrier solution at a nebulizer uptake flow rate of 2.5 ml min(-1). The interval for each determination was 2.5 min (2 min of sampling time, 20 s of read time and 10 s of washing time). The performance characteristics of the on-line microdialysis-FAAS system were validated as follows: linearity range, 0 - 100 mg l(-1); detection limit (3a, n = 7), 3.66 mg l(-1); precision (RSD, n = 50), 6.2%. For the evaluation of analytical accuracy, the proposed on-line method was compared with the in vivo no net flux method. The use of an on-line microdialysis-FAAS system permitted the in situ, dynamic and continuous in vivo monitoring of diffusible calcium in the blood of the living rabbits after CaCl2 administration with a temporal resolution of 2.5 min.

Animals↗
PubMed1996

Topics in xenobiochemistry--application of microdialysis techniques in pharmacokinetic studies.

The principle of the microdialysis technique, the microdialysis system and its application to pharmacokinetic studies is discussed. By applying the microdialysis technique to pharmacokinetic studies the number of animals needed can be substantially reduced, because the technique involves a sampling technique which does not withdraw body fluid and so does not disturb blood homeostasis. Therefore, there are no limiting factors to the amount of samples taken from one animal. The utility offered by the microdialysis technique will have a bearing on future pharmacokinetic studies and it is to be expected that the importance of microdialysis in pharmacokinetic studies will grow in the future.

Animals↗
PubMed2001

Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound.

OBJECT: When evaluating the results of intracerebral microdialysis, the in vivo performance of the microdialysis probe must be considered, because this determines the fraction of the interstitial concentration obtained in the microdialysis samples. The in vivo performance is dependent on several factors, for example, the interstitial compartment's diffusion characteristics, which may vary during the course of the acute brain injury process. In the present study the authors investigated the method of controlling the in vivo performance by using urea, which is evenly distributed in all body fluid compartments, as an endogenous reference compound and by comparing the urea levels in three compartments: the brain (CNS), abdominal subcutaneous tissue (SC), and blood serum (BS). METHODS: Sixty-nine patients with traumatic brain injury or cerebrovascular disease were included in the study. In 63 of these patients a CNS probe was used, an SC probe was used in 40, and both were used in 34. Urea was measured by enzymatic methods, at bedside for the microdialysis samples and in routine clinical laboratory studies for the BS samples, with the probe calibrated to give identical results. The correlation coefficient for CNS/SC urea was 0.88 (2414 samples), for CNS/BS urea it was 0.89 (180 samples), and for SC/BS urea it was 0.98 (112 samples). CONCLUSIONS: Urea levels in the CNS, SC, and BS were highly correlated, which supports the assumption that urea is evenly distributed. The CNS/SC urea ratio can therefore be used for monitoring the CNS probe's in vivo performance. Fluctuations in other substances measured with microdialysis are probably caused by biological changes in the brain, as long as the CNS/SC urea ratio remains constant.

Adipose Tissue↗
PubMed2000

In vivo brain microdialysis as a tool in studies of neuroprotective effects of cyclosporin A in acute excitotoxicity.

The mitochondrial permeability transition (MPT) resulting from calcium-induced opening of cyclosporin A (CsA)-sensitive megachannels, leading to deenergisation of mitochondria and release of pro-apoptotic cytochrome c, has been implicated in the pathomechanism of excitotoxic neurodegeneration. The aim of this work was to test neuroprotective potential of CsA in the model of N-methyl-D-aspartate-(NMDA)-induced excitotoxicity in vivo, and to verify utility of microdialysis of the rabbit hippocampus in vivo for these mechanistic studies. In vitro experiments demonstrated that the early rapid phase of Ca(2+)-induced swelling of isolated brain mitochondria, and of accompanying cytochrome c release, was strongly inhibited by 0.5 microM CsA. In the in vivo experiments 1 mM NMDA was applied for 20 min to the hippocampus in a control, or 5 microM CsA-containing dialysis medium via transhippocampal microdialysis probes, and changes in extracellular Ca2+ concentration and in NO release were monitored. Application of NMDA induced a prolonged decrease in the extracellular concentration of Ca2+, reflecting influx of Ca2+ to stimulated neurones. CsA only slightly enhanced this effect. NMDA induced also release of NO to the dialysis medium. Morphological examination 30 min after NMDA application visualised swelling of dendritic mitochondria and cisternae of endoplasmatic reticulum of pyramidal neurones in the CA1 sector of the hippocampus in the vicinity of microdialysis probes. CsA prevented mitochondrial swelling. After 24 h degeneration of the CA1 pyramidal neurones close to a microdialysis probes was observed, which was partially prevented in CsA-treated rabbits. These results indicate that the mechanism of CsA nuroprotection may be at least in part ascribed to prevention of MPT. Microdialysis of the rabbit hippocampus combined with NMDA excitotoxicity appeared to be useful in mechanistic studies of CsA neuroprotection.

Animals↗
PubMed2001

Effect of capillary efflux transport inhibition on the determination of probe recovery during in vivo microdialysis in the brain.

Intracerebral microdialysis probe recovery (extraction fraction) may be influenced by several mass transport processes in the brain, including efflux and uptake exchange between brain and blood. Therefore, changes in probe recovery under various experimental conditions can be useful to characterize fundamental drug transport processes. Accordingly, the effect of inhibiting transport on probe recovery was investigated for two capillary efflux transporters with potentially different membrane localization and transport mechanisms, P-glycoprotein and an organic anion transporter. Fluorescein/probenecid and quinidine/LY-335979 were chosen as the substrate/inhibitor combinations for organic anion transport and P-glycoprotein-medicated transport, respectively. Probenecid decreased the probe recovery of fluorescein in frontal cortex, from 0.21 +/- 0.017 to 0.17 +/- 0.020 (p < 0.01). Quantitative microdialysis calculations indicated that probenecid treatment reduced the total brain elimination rate constant by 3-fold from 0.37 to 0.12 (ml/min. ml of extracellular fluid). In contrast, the microdialysis recovery of quinidine, delivered locally to the brain via the probe perfusate, was not sensitive to P-glycoprotein inhibition by systemically administered LY-335979, a potent and specific inhibitor of P-glycoprotein. Recovery of difluorofluorescein, an analog of fluorescein, was also decreased by probenecid in the frontal cortex but not in the ventricle cerebrospinal fluid. These experimental observations are in qualitative agreement with microdialysis theory incorporating mathematical models of transporter kinetics. These studies suggest that only in certain circumstances will efflux inhibition at the blood-brain barrier and blood-cerebrospinal fluid barrier influence the microdialysis probe recovery, and this may depend upon the substrate and inhibitor examined and their routes of administration, the localization and mechanism of the membrane transporter, as well as the microenvironment surrounding the probe.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

[Use of the in vivo microdialysis technique in basic and clinical research].

Microdialysis is in vivo technique that permits monitoring of local concentrations of metabolites and drugs at specific sites in the body that makes it an attractive tool for the basic and clinical research. Microdialysis entered the experimental studies of the brain, and later also of the peripheral tissues such as adipose and muscle tissues, kidney, lung, eye, skin, and blood. There are several critical factors in the experimental implementations of microdialysis: the probe, the perfusion solution, tissue integrity, and the sensitivity of microdialysate analysis method. When the experimental conditions are optimised to give valid results, microdialysis can provide numerous data from the relatively small number of individual subjects. It can bring about detailed clinical information reflecting free metabolite and drug concentrations in studied tissues and/or in plasma. With the progress of analytical methods, applications and importance of the microdialysis technique in clinical and pharmacokinetic research and diagnostics will increase.

Humans↗
PubMed2003

[Subcutaneous microdialysis: a simple technique for monitoring the extracellular biochemical environment. Combination with capillary electrophoresis and laser-induced fluorescence detection].

Microdialysis is a simple technique that allows monitoring endogenous or exogenous substances in any extracellular compartment. It has many useful experimental and clinical applications. The sampling of the extracellular fluid of the subcutaneous compartment is especially useful for metabolic evaluation in critically ill patients, pharmacokinetic studies and blood glucose monitoring. We built a subcutaneous microdialysis probe, with a cellulose hollow fiber (13,000 molecular weight cut off, 200 microns outside diameter) glued to stainless steel tubing (26 ga. outside diameter). It was implanted in the subcutaneous tissue of a critically ill child or anesthetized mice to obtain amino acids patterns by means of capillary electrophoresis with laser induced fluorescence detection (CE-LIFD). The probe was also implanted in ambulatory volunteers to monitor glucose. The results confirmed that subcutaneous microdialysis is a very simple, inexpensive and not aggressive method with advantages over repeated venipuncture sampling and endovenous microdialysis sampling. The present report shows that subcutaneous microdialysis with the proper analytical technique can be used to monitor the chemical composition of the interstitial compartment in very different preclinical or clinical conditions.

Adolescent↗
PubMed2005

Metabolic stress during hypoglycaemia clamp assessed by microdialysis.

AIM: Microdialysis allows the biochemical analysis of interstitial fluids as a bedside procedure. This technique is of interest to evaluate the glucose dependent metabolism in hypoglycaemic patients. It was the aim to perform subcutaneous and blood microdialysis during hypoglycaemic clamp experiments in 12 healthy young men to reveal basis data for critical care microdialysis practice. METHODS: The hyperinsulinaemic clamp was induced with a continuous infusion of 1.5 mU min(-1) kg(-1) insulin (H-insulin, Hoechst, Frankfurt, Germany). A 20% dextrose solution simultaneously was infused at a variable rate to control blood glucose levels. For hypoglycaemia blood glucose levels were reduced to 40 mg/dL for a 30 min period. Glucose, lactate, pyruvate and glycerol concentrations were semicontinuously measured. RESULTS: The absolute concentrations of glucose and glycerol in blood vs subcutaneous microdialysate were significant different during observation. Until the end of hypoglycaemia, glucose concentration in both compartments declined in parallel, followed by an increase thereafter. During the clamp the subcutaneous glycerol increased threefold, whereas blood glycerol rose with a delay of 15 min and increased only twofold. After the clamp in both compartments glycerol values normalized. The lactate-pyruvate-ratio persisted in normal range throughout the examination. CONCLUSIONS: In our experiment subcutaneous lipolysis increased faster and more profound than blood microdialysis. We propose the microdialysis technique as an additional monitoring tool in hypoglycaemia patients.

Adult↗
PubMed1994

Quantitative approaches to in vivo brain microdialysis.

The microdialysis technique has been widely used for the study of extracellular chemical events in various tissues. Until recently, however, little was known about the sampling characteristics of dialysis probes in vivo. The purpose of this review is to describe several theoretical models of in vivo microdialysis that consider both the diffusional resistances encountered in vivo and the effects of various active processes, such as metabolism, release and uptake, and transport across the blood brain barrier. The relevance of the models to practical in vivo microdialysis experiments is discussed. Several microdialysis techniques that quantitatively estimate extracellular analyte concentrations are also reviewed. These techniques are discussed in relation to the theoretical models, together with a discussion of the experimental factors that affect in vivo microdialysis experiments.

Animals↗
PubMed1996

An intravascular microdialysis sampling system suitable for application in continuous biochemical monitoring of glucose and lactate.

Direct sensor implantation for continuous biochemical monitoring has proved disappointing, but microdialysis sampling devices can serve as a biocompatible patient-sensor interface. We propose a novel "MiniShunt" extracorporeal microdialysis sampling circuit designed to sample core blood, and report the performance of different microdialysis probe membrane types and sizes with pumped and non-pumped blood flow in anaesthetised dogs. Discrete microdialysate and plasma samples collected during glucose and lactate monitoring were analysed with a YSI analyzer and showed microdialysis efficiency (% relative recovery) in excess of 95% for both analytes using fibres of greater than 70 mm2 internal surface area. Pumped veno-venous extracorporeal blood microdialysis sampling of this type could provide a suitable interface for future multi-analyte on-line biosensor applications in critically ill patients.

Animals↗
PubMed1998

Ventromedial nucleus of hypothalamus is related to the development of cancer-induced anorexia: in vivo microdialysis study.

UNLABELLED: Based on reports that increased hypothalamic ventromedial nucleus (VMN)-serotonin (5-HT) is associated with cancer anorexia and recent findings in our laboratory that low levels of dopamine (DA) in the VMN are associated with prolonged inter meal intervals thus decreased food intake, and reports that setting up satiation is concomitant with descending levels of DA in the rostromedial hypothalamus, we hypothesized that an elevated 5-HT to low DA ratio in the VMN modulates food intake in cancer anorexia. METHODS: In Expt 1: A microdialysis cannula guide was placed stereotactically into the VMN of methylcholanthrene (MCA) sarcoma tumor-bearing (TB) Fischer rats and in non-tumor-bearing (NTB) and pair-fed (PF) controls. When TB rats manifested anorexia by a decrease in food intake, VMN-5-HT, its metabolite 5-hydroxyindolacetic acid (5-HIAA), and DA with its metabolite 3,4,-dihydroxyphenylacetic acid (DOPAC) were measured by in vivo microdialysis using HPLC during baseline, in response to food, and after feeding. In Expt 2: TB rats had tumor removed and VMN microdialysis performed 7 days later. RESULTS: Increased 5-HT release and turnover, and significantly reduced DA release with increased DOPAC occurred in TB vs NTB or PF rats. When food was offered, intake in TB rats was significantly lower than in NTB control rats. During eating, VMN-5-HT rose and peaked significantly earlier in TB vs NTB rats, while DA release was significantly reduced. With eating, the 5-HT and DA metabolism became reduced in all rats. Seven days after surgical removal of the tumor, 24 h food intake had increased to the level of controls; and when food was offered during microdialysis, intake in TB rats increased (ns relative to control), but was not yet normal. VMN microdialysis showed that 5-HT was normal at baseline, as well as during and after eating, while DA remained depressed. The metabolic turnover of 5-HT and DA was significantly lower in TB-r and PF vs NTB rats. We conclude that increased 5-HT/DA ratio is related to the development of cancer-induced anorexia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Quantitative microdialysis of ethanol in rat striatum.

We have applied a steady-state theory of microdialysis to characterize the diffusion of ethanol through a microdialysis membrane and through rat striatum. Quantitative characterization required measurement of in vitro and in vivo extraction fractions for ethanol and determination of the clearance of ethanol from brain tissue during steady-state perfusion through a microdialysis probe. Extraction fraction of ethanol was determined in vitro by perfusing a known concentration of ethanol through probes immersed in water at 37 degrees C with stirring. The in vitro extraction fraction yielded a probe permeability value of 0.046 +/- 0.004 cm/min that is comparable with an estimate from published measurements for similar dialysis membranes. The in vivo extraction fraction was determined for probes placed in the striatum. Clearance of ethanol and a brain slice concentration profile of ethanol were determined by measurement of the amount of ethanol remaining in the brain tissue during steady-state perfusion of the probe. Steady state was achieved within 10 min after beginning the ethanol perfusion in vivo, and the extraction fraction was not altered by sedation of the rat with pentobarbital. The tissue concentration profile was symmetrical around the probe track, and ethanol was detected 1 mm from the probe. The experimental clearance rate constant value obtained for ethanol (2.0 +/- 0.3 min(-1)) was higher than that expected for removal solely by loss to the blood. The tissue diffusivity for ethanol, Dt, derived from the experimental measurements was 1.2 +/- 0.2 x 10(-5) cm2/sec. This value is greater than expected for interstitial diffusion, suggesting a substantial contribution by transcellular diffusion of ethanol as well. The predicted tissue concentration profile had a higher peak value and did not extend into the tissue (0.5 mm) as much as the experimental profile (1 mm), although there was reasonable agreement between experiment and theory. Our quantitative characterization of the microdialysis behavior of ethanol in brain provides a framework for interpretation of brain microdialysis experiments using ethanol by supplying, inter alia, a means for estimating the ethanol concentration achieved in the tissue volume being sampled by the probe.

Animals↗
PubMed1992

Microdialysis administration of vasopressin and vasopressin antagonists into the septum during pole-jumping behavior in rats.

Wistar rats (n = 95) were trained in a pole-jumping apparatus (10 trials/session/day) to investigate the involvement of centrally and peripherally released endogenous AVP in their acquisition rate and to examine the feasibility of the microdialysis technique for the administration of peptides during a behavioral test. After session 1, a microdialysis probe was implanted into the septum; during sessions 2 and 3 the probe was perfused with artificial cerebrospinal fluid (aCSF) alone or containing either AVP (delivered amount via the probe: 0.2 ng) or the V1 (d(CH2)5Tyr(Me)AVP, 5.0 ng) or the V2/V1 (d(CH2)5-D-Tyr(Et)VAVP, 5.0 ng) antagonist. Administration of AVP via microdialysis into the septum failed to alter the acquisition rate of pole jumping. Also, ip application of both hypertonic saline and the AVP V1 antagonist (10 micrograms) in another experiment failed to show a significant effect upon behavior. Septal administration of the V1 or the V2/V1 antagonist via microdialysis, however, produced a significantly impaired performance. The results indicate that AVP release within the septum is involved in the acquisition of pole-jumping behavior probably mediated by the V1 receptor subtype. An additional involvement of the V2 receptor subtype, however, cannot be entirely excluded. The microdialysis technique proved to be a potent tool to administer substances concomitantly with behavioral tests.

Animals↗
PubMed1992

On-line coupling of in vivo microdialysis with tandem mass spectrometry.

The capability of interfacing in vivo microdialysis with mass spectrometry has been demonstrated. The goal of this research was to demonstrate the feasibility of real-time analysis in biological systems using microdialysis in combination with tandem mass spectrometry (MS/MS). Microdialysis sampling was accomplished by surgically implanting a small microdialysis probe into a tissue or area of interest. Molecules diffuse through the membrane of the microdialysis probe due to concentration differences. These molecules are collected in a sample loop and analyzed by tandem mass spectrometry. Sequential injections can be made in as little as 2 min. This capability is advantageous in the study of molecules with very rapid elimination rates. Tris(2-chloroethyl)phosphate (TRCP) was used as a model compound in the development of this analytical technique. As an example of an application of the microdialysis/MS/MS technique, plasma concentration vs time curves were obtained and compared with the plasma concentration profiles obtained using conventional studies. For the microdialysis/MS/MS studies, the average slope from three animals was -0.086 min-1. In comparison, the average slope from four animals from the conventional studies was -0.035 min-1.

Animals↗
PubMed1998

Characterization of microdialysis acidification for capillary isoelectric focusing-microelectrospray ionization mass spectrometry.

A microdialysis junction, based on a microdialysis membrane connecting a separation capillary and a short, sharply tapered microelectrospray emitter capillary, is demonstrated for on-line combination of capillary isoelectric focusing (CIEF) with electrospray ionization mass spectrometry (ESI-MS). The microdialysis junction provides the necessary electrical connection across the dialysis membrane for defining the electric fields needed for the CIEF separation and the electrospray process. Additionally, postseparation acidification of focused protein zones eluted from the CIEF capillary is achieved using the microdialysis junction while separation efficiency and resolution is maintained. A microelectrospray emitter produces a stable electrospray of protein analytes without the need for a makeup liquid flow and eliminates any subsequent sample dilution and reduction in MS sensitivity. The microdialysis junction is advantageous over the coaxial liquid sheath interface as evidenced by the simplicity in operation procedures, the enhancement in detection sensitivity, and the linear correlation between protein migration time and isoelectric point in CIEF-ESI-MS.

Buffers↗