Characterizing diffusion from microdialysis catheters in the human brain: a magnetic resonance imaging study with gadobutrol.

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across grey matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± s.d.) from catheters, but with a steep concentration drop off so that ≤ 50 % of maximum concentration was achieved at ≈ 4 mm, and ≤ 10 % of maximum was found beyond ≈ 7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol-1s-1 (mean ± s.d.); assuming gadobutrol remained extracellular thereby occupying 20 % of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 hours of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared to microdialysis period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism - the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

In-vitro gadolinium retro-microdialysis in agarose gel-a human brain phantom study.

Rationale and objectives: Cerebral microdialysis is a technique that enables monitoring of the neurochemistry of patients with significant acquired brain injury, such as traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). Cerebral microdialysis can also be used to characterise the neuro-pharmacokinetics of small-molecule study substrates using retrodialysis/retromicrodialysis. However, challenges remain: (i) lack of a simple, stable, and inexpensive brain tissue model for the study of drug neuropharmacology; and (ii) it is unclear how far small study-molecules administered via retrodialysis diffuse within the human brain. Materials and methods: Here, we studied the radial diffusion distance of small-molecule gadolinium-DTPA from microdialysis catheters in a newly developed, simple, stable, inexpensive brain tissue model as a precursor for in-vivo studies. Brain tissue models consisting of 0.65% weight/volume agarose gel in two kinds of buffers were created. The distribution of a paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) perfusion from microdialysis catheters using magnetic resonance imaging (MRI) was characterized as a surrogate for other small-molecule study substrates. Results: We found the mean radial diffusion distance of Gd-DTPA to be 18.5 mm after 24 h (p < 0.0001). Conclusion: Our brain tissue model provides avenues for further tests and research into infusion studies using cerebral microdialysis, and consequently effective focal drug delivery for patients with TBI and other brain disorders.

Quantification of pyruvate in-vitro using mid-infrared spectroscopy: Developing a system for microdialysis monitoring in traumatic brain injury patients.

Introduction: Complex metabolic disruption is a major aspect of the pathophysiology of traumatic brain injury (TBI). Pyruvate is an intermediate in glucose metabolism and considered one of the most clinically informative metabolites during neurocritical care of TBI patients, especially in deducing the lactate/pyruvate ratio (LPR) - a widely-used metric for probing the brain's metabolic redox state. LPR is conventionally measured offline on a bedside analyzer, on hourly accumulations of brain microdialysate. However, there is increasing interest within the field to quantify microdialysate pyruvate and LPR continuously in near-real-time within its pathophysiological range. We have previously measured pure standard pyruvate in-vitro using mid-infrared transmission, employing a commercially available external cavity-quantum cascade laser (EC-QCL) and a microfluidic flow cell and reported a limit of detection (LOD) of 0.1 mM. Research question: The present study was to test whether the current commercially available state-of-the-art mid-infrared transmission system, can detect pyruvate levels lower than previously reported. Materials and methods: We measured pyruvate in perfusion fluid on the mid-infrared transmission system also equipped with an EC-QCL and microfluidic flow cells, tested at three pathlengths. Results: We characterised the system to extract its relevant figures-of-merit and report the LOD of 0.07 mM. Discussion and conclusion: The reported LOD of 0.07 mM represents a clinically recognised threshold and is the lowest value reported in the field for a sensor that can be coupled to microdialysis. While work is ongoing for a definitive evaluation of the system to measuring pyruvate, these preliminary results set a good benchmark and reference against which future developments can be examined.

Monitoring Neurochemistry in Traumatic Brain Injury Patients Using Microdialysis Integrated with Biosensors: A Review.

In a traumatically injured brain, the cerebral microdialysis technique allows continuous sampling of fluid from the brain's extracellular space. The retrieved brain fluid contains useful metabolites that indicate the brain's energy state. Assessment of these metabolites along with other parameters, such as intracranial pressure, brain tissue oxygenation, and cerebral perfusion pressure, may help inform clinical decision making, guide medical treatments, and aid in the prognostication of patient outcomes. Currently, brain metabolites are assayed on bedside analysers and results can only be achieved hourly. This is a major drawback because critical information within each hour is lost. To address this, recent advances have focussed on developing biosensing techniques for integration with microdialysis to achieve continuous online monitoring. In this review, we discuss progress in this field, focusing on various types of sensing devices and their ability to quantify specific cerebral metabolites at clinically relevant concentrations. Important points that require further investigation are highlighted, and comments on future perspectives are provided.