Clinical applications of microdialysis monitoring

The first known application of MD in humans was reported in 1990 by Meyerson et al., who implanted MD probes in patients with Parkinson’s disease.²¹⁰ Since that time, cerebral MD has been increasingly used as a neuromonitoring tool in neurocritical patients with TBI, MMCAI, and SAH to monitor cerebral energy metabolism during the acute phase after injury or stroke onset.²⁰¹ Today, the commercially available equipment is considered to be a well standardized, safe, and powerful research tool that is clinically indicated in the management of neurocritical patients. However, before considering the use of cerebral MD as a clinical monitor after acute brain injury, it is important to understand that there are wide variations in MD variables over time after the injury, not only between different subjects, but also within individuals.^211–214

There is a large body of literature suggesting that MD monitoring can predict poor outcomes after TBI.²¹¹ There is also some evidence that MD may assist in clinical decision-making, such as in the management of CPP,²¹⁵ guidance of hyperventilation,²¹⁶ and the appropriateness of extensive surgical procedures.²¹⁷ The main aim of MD is the early detection of metabolic changes that suggest the development of tissue ischemia, as well as monitoring the effect of the therapeutic techniques applied to treat the ischemia. Thus, cerebral MD is a highly sensitive technique that can provide early metabolic information about brain energy status (glucose, lactate, and pyruvate), excitatory amino acid (glutamate) levels, and cell membrane integrity (glycerol). The determination of brain energy status can provide information about the relative contribution of the aerobic or anaerobic metabolisms in energy production. A simplified schematic of major energy pathways in the brain is shown in Figure 14.

One of the main advantages of cerebral MD monitoring after TBI is the ability to assess the cerebral delivery and utilization of glucose.²¹¹ As the primary source of energy to the brain, glucose is an important indicator of changes in brain metabolism. Glucose levels can change for several reasons: 1) ischemia (e.g., insufficient capillary blood Flow); 2) hyperemia (e.g., an increase in capillary blood flow); 3) hyper-hypoglycemia (e.g., an increase/decrease in blood glucose concentration); and 4) hypermetabolism or hypometabolism (e.g., an increase or decrease of glucose uptake into cells; a shift from aerobic to anaerobic metabolism). In addition, cerebral MD lactate has been considered for decades to be an excellent BM of oxygen limitation and therefore organ

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ischemia.⁸¹ High lactate and LPR levels indicate an increase in anaerobic metabolism due to impairment in oxidative metabolism. This phenomenon can principally result from two circumstances: 1) a lack of O2 supply resulting from a hypoxic or ischemic process and 2) a failure in mitochondrial oxidative phosphorylation. The LPR is generally regarded as a more useful clinical marker than lactate concentration alone, although both lactate and pyruvate, along with glucose, must also be reported individually for proper interpretation of bedside microdialysate monitoring.¹⁹⁵ The lactate/glucose ratio (LGR) is also a sensitive marker of tissue hypoxia/ischemia and has been interpreted to indicate increased glycolysis.^99,211 Glutamate can give information about the excitatory amino acids released into the extracellular space and about the energetic dysfunction that occurs in certain pathologies. Glycerol levels provide information about the membrane state and the level of cellular stress. Briefly, energy loss due to ischemia leads to an influx of calcium into cells, activation of phospholipases, and eventually the decomposition of cell membranes, which liberates glycerol into the ECS.⁹⁸ Glycerol is therefore a useful MD marker of tissue hypoxia and cell damage after TBI.²¹¹

One of the main advantatges of using cerebral MD is that it can help in the differential diagnosis of the distinct types of non-ischemic hypoxia. Identification of metabolic patterns can lead to the distinction of ischemia and mitochondrial dysfunction, which helps in the clinical management and therapeutic guidance of TBI patients.70,85,218,219

A summary of pathophysiological changes monitored by cerebral MD is shown in Table 5.

Table 5. Biochemical markers of secondary injury in TBI

MD marker Secondary Injury

↓ Glucose

• Hypoxia/Ischemia

• Reduced glucose supply

• Hyperglycolysis

↑ LPR

• Hypoxia/Ischemia

• Reduction in redox state

• Reduced glucose supply

• Mitochondrial dysfunction

↑ Glycerol • Hypoxia/Ischemia

• Cell membrane degradation

↑ Glutamate • Hypoxia/Ischemia

• Excitotoxicity

MD: Microdialysis; LPR: Lactate-to-pyruvate ratio. Table modified from Tisdall and Smith et al.²²⁰

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Figure 14. Simplified representation of glucose pathways in the brain. Glucose and lactate are transported from blood and ECS into the cell through GLUTs and MCTs, respectively. Oxygen can diffuse freely into the cells. Cellular ATP production is mainly performed through the glycolytic and oxidative pathway. Four stages convert glucose into ATP: glycolysis, pyruvate oxidation, KC, and ETC. For each glucose molecule, a net of 32 to 38 ATP molecules is produced. The pentose phosphate pathway takes place in the cytosol and is an alternative energy pathway that can be upregulated after injury. ECS:

Extracellular space; GLUT: Glucose transporter; MCT: Monocarboxylate transporter; O2: Oxygen; HK: Hexokinase; GAPDH: Glyceraldehid 3-phosphate dehydrogenase; LDH:

Lactate dehydrogenase; PDH: Pyruvate dehydrogenase; IDH2: Isocitrate dehydrogenase 2; SDH: Succinate dehydrogenase; FH: Fumarate hydratase; PC: Pyruvate carboxylase;

ETC: Electron transport chain; KC: Krebs cycle.

Any molecule present in the cerebral ECS that is small enough to cross the semi-permeable dialysis membrane will also be collected in the dialysate. This opens the door to the investigation of novel BMs of TBI with several applications aimed at increasing knowledge of the physiopathology among patients with acute brain lesions.

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The applications include: 1) the recovery of large molecules contained in the ECS (inflammatory molecules and OxS BMs); 2) the use of ¹³C-labeled substrates to study the fate of specific molecules through metabolic pathways; 3) monitoring the ionic profile of brain tissue in different situations; 4) studying the local effects of drugs on neurochemistry and their penetration across the BBB; and 5) developing on-line analysis systems for continuous monitoring.¹⁹⁵

Combining MD with highly sensitive analytical methods enables the investigation of individual BMs involved in the pathophysiology of acute brain injuries. Several highly sensitive immunochemical analytical methods are used to detect the neuroinflammatory and OxS profile following acute brain injury. In a previous study, our group showed that the in vivo ionic concentration can be calculated reliably from the microdialysate concentrations in patients with TBI.²²⁰ However, the main limitation of the methodology used in our proof-of-concept study on this conventional ion-selective electrode-based analyzer was its low temporal resolution. Inductively coupled plasma mass spectrometry (ICP-MS) is the best method available for analyzing metals, including ions at very low concentrations and with extremely low detection limits.²²¹