Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Abstract

Abstract.Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review

“…The association between lesion size and biomarker levels was also barely mentioned (66). Together, these conditions make it difficult to accurately generate a precise half-life due to the constant influx/efflux of the proteins to the serum compartment (20). Furthermore, some studies suggest peak times of biomarkers as related to time after trauma (73, 102, 112, 115).…”

“…We believe that this description is inaccurate as we are not looking at protein decay in a single space; instead it is probably a combination of influx and efflux between bodily compartments with ongoing release from the injured brain, where actual clearance is one of many actors (20). Thus, we have used the term “effective serum half-life” to describe that concentration dynamics is presumably more accurate as this is not a process with constant decay (i.e., as is true in theory for a biological half-life).…”

“…Blood–brain barrier (BBB) disruption (17) or release independent of BBB integrity (18) as well as passage through the newly discovered glymphatic system (19) have been suggested as possible routes. Presumably, these proteins are first released in the brain extracellular space, a component difficult to access for repeated sampling (20), before being transported to the cerebral spinal fluid (CSF) [where a passive diffusion from CSF to blood the first 24 h after injury has been suggested (21)] and/or subsequently into serum where it is most easily sampled. However, there are several factors that may influence this transport and thus the availability in serum, including clearance, redistribution, protein stability, and ongoing release from the damaged brain (22).…”

Monitoring the Neuroinflammatory Response Following Acute Brain Injury

“…The brain compartment, or specifically the extracellular space of the brain, is accessible by using a microdialysis (MD) catheter. The MD catheter possesses a semipermeable membrane that is able to extract proteins like cytokines directly from the extracellular fluid (ECF) when inserted into the injured brain (13, 45). …”

“…MD is commonly used in the NCCU for metabolic monitoring of the injured brain, recovering small metabolites such as lactate, pyruvate, glucose and glycerol from the ECF (45). For these metabolites, the relative recovery is circa 70% from catheters inserted into the brain, using a flow rate of 0.3 µl/min (60).…”