Neurocrit Care (2014) 21:152–162 DOI 10.1007/s12028-013-9884-4 ESSENTIALS AND BASICS Cerebral Microdialysis in Traumatic Brain Injury and Subarachnoid Hemorrhage: State of the Art Marcelo de Lima Oliveira • Ana Carolina Kairalla • Erich Talamoni Fonoff • Raquel Chacon Ruiz Martinez • Manoel Jacobsen Teixeira • Edson Bor-Seng-Shu Published online: 26 September 2013 Ó Springer Science+Business Media New York 2013 Abstract Cerebral microdialysis (CMD) is a laboratory Introduction tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is Cerebral microdialysis (CMD) is a well-established labo- inserted into the interstitium of the brain. A solute is slowly ratory tool that provides on-line analysis of the brain infused into the catheter at a constant velocity. The fen- biochemistry via a thin fenestrated dialysis catheter that is estrated membranes at the tip of the catheter permit free inserted into interstitium of the brain [1, 2]. Prior to the diffusion of molecules between the brain interstitium and development of CMD in 1970 [1], dextran-filled sacks the perfusate, which is subsequently collected for labora- were inserted into the brains of dogs and the fluid contained tory analysis. The major molecules studied using this there was studied afterwards. The first publication using method are glucose, lactate, pyruvate, glutamate, and microdialysis in humans was a 1987 study investigating glycerol. The collected substances provide insight into the interstitial glucose in adipose tissue. CMD has been used to neurochemical features of secondary injury following study the human brain since 1990, and it has been used in traumatic brain injury (TBI) and subarachnoid hemorrhage neurosurgical intensive care since 1992 [3]. (SAH) and valuable information about changes in brain The catheter acts as a blood capillary in the tissue and is metabolism within a short time frame. In this review, the useful for analyzing the chemical composition of the authors detail the CMD technique and its associated interstitial fluid. The catheter permits the study of the main markers and then describe pertinent findings from the lit- neurochemical features of brains in normal states as well as erature about the clinical application of CMD in TBI and pathological states, such as traumatic brain injury (TBI) [2– SAH. 4] and subarachnoid hemorrhage (SAH) [4]. Markers that are currently studied and are important in the pathophysi- Keywords Microdialysis Á Metabolism Á Brain injury Á ology of brain injury and ischemia include the following: Monitoring Á Subarachnoid hemorrhage Á Critical care energy substrates (glucose), brain glucose metabolism products (lactate, pyruvate), by products of cell membrane degeneration (glycerol), and excitatory neurotransmitters (glutamate). Despite improvements in clinical management, SAH and TBI remain significant clinical problems with high M. de Lima Oliveira Á A. C. Kairalla Á E. T. Fonoff Á morbidity and mortality rates. Early aggressive and ade- & M. J. Teixeira Á E. Bor-Seng-Shu ( ) quate treatment has been found to yield long-term Division of Neurological Surgery, Hospital das Clinicas, School of Medicine, University of Sa˜o Paulo, Rua Loefgreen, functional improvements. Cerebral ischemic and nonis- 1.272 – Vila Clementino, Sa˜o Paulo, SP 04040-001, Brazil chemic events are the core mechanisms that lead to e-mail: [email protected] secondary brain damage following TBI and SAH, and they are major causes of increased intracranial pressure (ICP) R. C. R. Martinez Discipline of Surgical Technique, Department of Surgery, and unfavorable prognoses [4–6]. CMD monitoring sys- School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil tems permit precocious on-line monitoring of cerebral 123 Neurocrit Care (2014) 21:152–162 153 ischemic markers in patients with TBI and SAH. Within a intraparenchymal pressure device, a microdialysis probe, a short time, early target therapy can be established to reduce multiparameter sensor (for continuous measurement of O2, secondary brain damage in at-risk patients [4, 5]. Jugular CO2, pH and temperature), and a lumen to puncture the venous saturation (SjvO2) and brain tissue oxygen satura- ventricle if necessary [10]. More than one catheter can be tion (PtbO2) can be used to detect secondary insults, used in different areas of the brain, typically the perile- although they are not considered markers of early tissue sional area and an unaffected brain area on the opposite ischemia [5, 7]. In this review, the authors describe the side. The catheter is routinely positioned 2-cm deep in the CMD technique and its associated markers in detail and right frontal region, close to white matter brain areas par- then summarize pertinent findings from the literature ticularly in patients suffering TBI with diffuse injury. If regarding the clinical application of CMD in TBI and SAH. required, the catheter may be positioned within at-risk tissue, such as the penumbral area surrounding the vascular territory that is most likely to be affected by vasospasm or Technique next to parenchymal traumatic lesions. Nevertheless, CMD catheters should not be placed in the contusional tissue [4]. The CMD catheter is thin (0.6 mm) and has a semiperme- Commercially available CMD catheters have a gold tip able membrane that permits the free diffusion of water and whose position can be visualized in computed tomography solutes down the concentration gradient between the sur- scans (CT) [1, 4] and can be used to determine whether the rounding interstitial fluid and the perfusate (Fig. 1)[2, 8]. catheter is located in ‘‘normal’’, pericontusional or contu- Because CMD analyzes the extracellular interstitial fluid sional tissue. ‘‘Normal’’ brain tissue should show no from the specific area where the probe is located [1], macroscopic lesions in CT scans, and pericontusional brain catheter positioning within the brain can influence the areas should occur at a distance of 0.5–1.5 cm from the results. The catheter can be inserted in a triple-lumen core of the lesion in the scans [11]. transcranial bolt alongside cerebral tissue oxygen (PtbO2) After insertion, the CMD is tunneled and sutured to the and ICP probes [9]. Some studies have employed a four- skin of the scalp and connected to a 2.5-ml syringe that is way multiparametric transcranial screw for gripping an placed into a microinfusion pump [12]. Fig. 1 The catheter consists of an inner tube and an outer tube with a semipermeable membrane in the tip. In the inner tube of the catheter, infused solution flows to the outer tube, which allows the exchange of extracellular substances by differences in fluid concentration. Later, the solution is collected at the external tip for biochemical analysis 123 154 Neurocrit Care (2014) 21:152–162 The perfusate is infused through the catheter using a microinfusion pump at a constant rate of 0.3 ll/min, which allows for sampling every 60 min [2]. Extracellular mol- ecules equilibrate across the semipermeable membrane and are eventually collected at the external tip of the CMD catheter for biochemical analysis (Fig. 1). The main markers of brain cell metabolism are collected using a standard dialysis membrane with a molecular weight cut- off of 20 kDa. Larger molecules require a 100 kDa semi- permeable membrane [2]. The recovery of biochemical markers increases with the length of the dialysis membrane that is inserted into the brain tissue. A 10-mm microdi- alysis catheter membrane and a perfusion flow rate of 0.3 ll/min permit the collection of 70–80 % of the rou- tinely used biochemical markers. Following these procedures, the concentration of the molecules in the Fig. 2 The cell uses two alternatives for energy synthesis. The dialysate and the extracellular cerebral fluid is approxi- aerobic phase requires oxygen. At this stage, glucose is converted to mately the same [2, 8]. pyruvate; pyruvate is converted to 36 ATP, water, and CO2 in the mitochondria. The anaerobic phase does not require oxygen. At this stage, glucose molecule is converted to pyruvate, resulting in only 2 ATP and lactate in the cytoplasm. This latter stage is associated with Results type 1 LPR increase Cerebral Microdialysis Markers: Glucose, Lactate, Lactate-Pyruvate Ratio, Glutamate, and Glycerol molecule produces pyruvate, which is in turn converted into lactate with a net yield of only 2 molecules of ATP Under normal circumstances, glucose is the sole source of (Fig. 3). A high concentration of lactate and a concomi- energy utilized by the brain because it is the only molecule tantly high lactate-pyruvate ratio (LPR type 1) are that can be transported across the blood–brain barrier at a subsequently observed. LPR type 1 is associated with a sufficient rate. Once glucose enters the cytoplasm of neu- shift to anaerobic metabolism due to ischemia, hypoxia or a ronal cells, it is converted to pyruvate, which enters the failure of mitochondrial oxidative phosphorylation [13– citrate cycle in the mitochondria. The majority of the net 15]. In reversible ischemia, LPR normalizes within yield of 36 ATP is produced in the mitochondrial phase of 60–90 min of CBF restoration [16–18], which allows the aerobic glucose metabolism, and glucose is ultimately accumulated lactate to be aerobically used and prevents converted to carbon dioxide and water. Alternatively, tissue damage [16, 19, 20]. It has been proposed that the glucose can be anaerobically converted to pyruvate with a brain is capable of using lactate to produce energy under net yield of only 2 ATP per glucose molecule, and part of distress and thus spare glucose [21]. the pyruvate is converted to lactate [6]. In addition to LPR is a nonspecific indicator of brain ischemia [17]. In consuming more glucose to produce less ATP, the anaer- acute brain injury without hypoxia, a reduction in glyco- obic pathway also decreases the interstitial glucose lytic pyruvate production leads to type 2 or ‘‘nonischemic’’ concentration (Fig.