Clinical microdialysis in neuro-oncology: principles and applications

Abstract

Clinical microdialysis allows a discrete volume of the brain to be sampled for neurochemical analysis of neurotransmitters, metabolites, biomarkers, and drugs. The technique can be safely used in humans intraoperatively, in the intensive care unit, and in ambulatory settings. Microdialysis probes, micropumps, and analytical equipment are commercially available and have been used extensively for neurochemical monitoring in traumatic brain injury, stroke, and subarachnoid hemorrhage. There has been very limited use of microdialysis in neuro-oncology, but this technique has great promise in the study of the basic neurochemistry of brain tumors, alterations in neurochemistry in response to therapy, and the pharmacokinetics of chemotherapeutic agents. Microdialysis probes may also be used to deliver drugs while simultaneously permitting monitoring of neurochemical changes induced by this therapy.

Figure 1.. The basic principles of cerebral microdialysis. Artificial cerebrospinal fluid is slowly pumped into the microdialysis probe using a microsyringe pump capable of pumping very low volumes of fluid. The wall of the probe is semi-permeable to small molecules which diffuse from the extracellular space of the brain into the dialysate fluid. The analyte molecules must diffuse through the extracellular space, but their diffusion pathways are geometrically complex; the tortuosity of the extracellular space can restrict diffusion. Ultimately, the amount of analyte that is collected for analysis depends on the permeability of the probe's membrane, the concentration of the analyte, the flow rate of the perfusate, and the tortuosity of the extracellular space.

Figure 2.. Current generation microdialysis probes have concentrically arranged tubing. The outer tube is composed of a rigid semi-permeable membrane. The perfusate is pumped into this space, where equilibration with the extracellular space of the brain occurs. After equilibration, the perfusate fluid, now containing analytes, is collected in a centrally located tube, which stores the fluid for later collection and analysis. (Modified from Dr. Urban Ungerstedt with permission)

Figure 3.. The complex geometry of the extracellular space restricts diffusion of analytes to the probe. The degree of restriction of diffusion can be measured and expressed mathematically as the tissue tortuosity. Measurements in glioblastoma multiforme generally show greater tortuosity which restricts diffusion; therefore, apparent analyte concentrations will be lower in tumor than in normal brain.

Figure 4.. A variety of molecules can be obtained using microdialysis. Specific neurochemlcal signatures of pathological processes such as Ischemia, membrane breakdown, excitotoxicity, and membrane breakdown have been validated, and those Indicated In Italics can be measured with commercially available analytical equipment.