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Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1α (IL-1α) and IL-1β in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1α, IL-1β, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (± SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1α 19.7 ± 7.6%, IL-1β 23.9 ± 10.5%, and IL-1ra 20.9 ± 6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1α 5.6 ± 14.8 pg/mL, IL-1β 10.4 ± 14.7 pg/mL, and IL-1ra 2796 ± 2918 pg/mL. IL-1ra was consistently much higher than IL-1α and IL-1β. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1β and increasing IL-1ra (Spearman r = 0.59, p = 0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r = −0.57, p = 0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1β ratio, were associated with better outcome (Mann Whitney, p = 0.018 and p = 0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1β in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.

Background Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1–4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method. Methods Four pigs aged 2–3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2–3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels. Results In a linear mixed-effect model of standard CMD glucose (mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 ( p  < 0.001) for Loke MD glucose (mM), with an intercept at − 0.19 ± 0.15 ( p  = 0.20). The model showed a conditional R 2 at 0.81 and a marginal R 2 at 0.72. In a linear mixed-effect model of standard CMD lactate (mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 ( p  = 0.01) for Loke MD lactate (mM), with an intercept at 0.33 ± 0.21 ( p  = 0.25). The model showed a conditional R 2 at 0.47 and marginal R 2 at 0.17. Conclusions The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

Background The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products. Objective To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference ( R ) product either to itself or to a different test ( T ) product. Methods In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R ) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum plasma concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80–1.25. Results The positive control products ( R vs. R ) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products ( T vs. R ) were sensitively discriminated not to be bioequivalent. Conclusions dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n  = 40 (20 subjects in this study).

Cerebral microdialysis in rodents represents a robust and versatile technique for quantifying the pharmacologically relevant unbound fraction of drugs in the brain. When this unbound fraction is simultaneously determined in plasma, it facilitates the calculation of the corresponding unbound plasma‐to‐brain partition coefficient (Kp,uu) for a given compound in vivo. This coefficient is critical for understanding the penetration and distribution of drugs across the blood–brain barrier (BBB). However, obtaining valid and accurate microdialysis data can be particularly challenging for hydrophobic drugs due to their pronounced non‐specific interactions with the components of the microdialysis system. The present study reports the outcomes of comprehensive microdialysis investigations in rodents, focusing on three hydrophobic compounds: actinomycin D, selinexor, and ulixertinib. These compounds exhibited varying degrees of non‐specific binding to the surfaces of the microdialysis apparatus, leading to low recovery rates and substantial carry‐over effects. To diminish these limitations, strategies such as surface coating and the use of optimized materials were employed to enhance the reliability of the microdialysis system. To ensure the robustness and reproducibility of microdialysis‐related research outcomes, our experimental findings were supplemented with a narrative literature review. This review encompassed keyword‐driven PubMed‐indexed publications on microdialysis from 1970 to 2024, providing a broader context for the challenges and solutions associated with the technique. By integrating empirical results with practical recommendations, this study offers a comprehensive resource aimed at advancing the application of cerebral microdialysis in preclinical drug development, particularly for compounds with challenging physicochemical properties.

Knowing how biomarker levels vary within biological fluids over time can produce valuable insight into tissue physiology and pathology, and could inform personalised clinical treatment. We describe here a wearable sensor for monitoring biomolecule levels that combines continuous fluid sampling with in situ analysis using wet-chemical assays (with the specific assay interchangeable depending on the target biomolecule). The microfluidic device employs a droplet flow regime to maximise the temporal response of the device, using a screw-driven push-pull peristaltic micropump to robustly produce nanolitre-sized droplets. The fully integrated sensor is contained within a small (palm-sized) footprint, is fully autonomous, and features high measurement frequency (a measurement every few seconds) meaning deviations from steady-state levels are quickly detected. We demonstrate how the sensor can track perturbed glucose and lactate levels in dermal tissue with results in close agreement with standard off-line analysis and consistent with changes in peripheral blood levels. Continuous real-time measurement of biomarker levels in body fluids offers many exciting possibilities. Here, the authors develop an integrated wearable droplet microfluidic sensor that combines continuous sampling of tissue fluid with in situ analysis using wet-chemical assays.

Intrahospital transfer (IHT), a routine in the management of neurocritical patients requiring imaging or interventions, might affect brain metabolism. Studies about IHT effects using microdialysis (MD) have produced conflicting results. In these studies, only the most damaged hemisphere was monitored, and those may not reflect the impact of IHT on overall brain metabolism, nor do they address differences between the hemispheres. Herein we aimed to quantify the effect of IHT on brain metabolism by monitoring both hemispheres with bilateral MD. In this study, 27 patients with severe brain injury (10 traumatic brain injury and 17 subarachnoid hemorrhage patients) were included, with a total of 67 IHT. Glucose, glycerol, pyruvate and lactate were measured by MD in both hemispheres for 10 h pre- and post-IHT. Alterations in metabolite levels after IHT were observed on both hemispheres; although these changes were more marked in hemisphere A (most damaged) than B (less damaged). Our results suggest that brain metabolism is altered after an IHT of neurocritical ill patients particularly but not limited to the damaged hemisphere. Bilateral monitorization may be more sensitive than unilateral monitorization for detecting metabolic disturbances not directly related to the course of the disease.

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.

Trace elements (TEs) status alterations in the brain have been linked to neurodegenerative diseases. However, data on TEs in living humans and in the post-traumatic conditions are scarce. Some TEs (copper - Cu, selenium - Se, zinc - Zn) are involved in essential antioxidant defence. This study aims to measure the evolution of TEs concentrations in the brain and serum of severe traumatic brain injury (TBI) patients over time. Twenty adult patients with severe TBI were monitored using cerebral microdialysis (CMD) and blood sampling within three days of intensive care unit admission. TEs levels were measured using inductively coupled plasma system coupled to mass spectrometry. TEs concentrations of chromium - Cr, Cu, cobalt - Co, manganese - Mn, molybdenum - Mo, Se, and Zn were quantified in brain interstitial fluid and serum. While serum and CMD levels did not differ significantly for Co, Mo and Mn, and modest differences was observed for Cr and Zn, significant differences were observed for Cu and Se with higher serum levels (8-10-fold higher) compared to CMD. No correlation was found between serum and brain TEs levels, except for Mo. This study provides novel TEs concentration data in living TBI patients, the largest differences between brain and serum being observed for Cu and Se, serving as a basis for further research on TEs dynamics in acute brain injury.

Background Intracerebral microdialysis is an advanced method to guide clinicians during intensive care of patients with severe acute brain injury. Using intracerebral microdialysis, markers of brain metabolism and homeostasis can be analysed. Currently, trends are considered more important in clinical decision-making than absolute values. Establishing absolute reference values in healthy brain tissue may facilitate an earlier detection of abnormal brain tissue metabolism and provide better decision support for clinicians. However, the current evidence on normal values in the uninjured human brain has not previously been summarized. The aim of this study was to summarise the literature regarding microdialysate concentrations of common markers of brain energy metabolism (glucose, lactate, pyruvate, glutamate, and glycerol) in vivo in healthy brain tissue of humans and gyrencephalic animals. Method MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science were searched for published studies that report values of microdialysis in healthy brain tissue. In order to identify unpublished studies, we searched ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and EU Clinical Trials Register. Study quality was evaluated using a pre-specified protocol. Result Out of 3257 studies identified, 39 studies were included. Six of these studies were in humans (total n  = 54), 26 in pigs/swine ( n  = 432), two on monkeys ( n  = 10), one in sheep ( n  = 15), and one in dogs ( n  = 10). We found a high degree of clinical and methodological heterogeneity in both human and gyrencephalic animal studies. Conclusion This scoping review identified studies that applied microdialysis to measure common biomarkers in healthy brain tissue. The clinical and methodological heterogeneity between the measured values was substantial, limiting any conclusions. Furthermore, the quality of several human studies was moderate at best. Methodologically comparable studies are warranted to establish reference values for markers of brain energy metabolism using intracerebral microdialysate.