Microdialysis in Traumatic Brain Injury – Methodology and Pathophysiology

Acta Neurochir (2005) [Suppl] 95: 441–445 6 Springer-Verlag 2005 Printed in Austria

Microdialysis in traumatic brain injury – methodology and pathophysiology

P. J. Hutchinson

Academic Department of Neurosurgery and Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke’s Hospital, UK

Summary ters and brain tissue oxygen sensors) is also widely practised both for research and clinical purposes [15]. The application of clinical microdialysis to monitor changes in cerebral extracellular chemistry is now well established in several neu- Measurement of the e¤ect of fundamental derange- rosurgical units worldwide. In neuro-intensive care the technique has ments of pathophysiology such as increased ICP, re- been predominantly applied to patients with traumatic brain injury duced CBF and reduced cerebral oxygenation in terms and subarachnoid haemorrhage. There is no doubt that microdialysis has increased and continues to increase our understanding of the of the impact on cerebral metabolism is now feasible pathophysiology of these conditions. Current studies are addressing with the application of cerebral microdialysis. This has the potential role of microdialysis as a clinical monitoring technique enabled monitoring of brain injury in terms of changes assisting in the management of patients on an intention to treat basis. in the extracellular concentration of fundamental sub- This involves establishing the relationship between microdialysis and outcome, and the e¤ect of therapeutic manoeuvres on the chemistry. strates and metabolites. This manuscript describes the place of microdialysis in traumatic The microdialysis technique was first described brain injury in terms of the fundamental principles, methodology, by Ungerstedt and Pycock in 1974 [29], applied to the pathophysiology and clinical application. human brain initially to monitor neurotransmitters Keywords: Traumatic brain injury; head injury; microdialysis; in Parkinson’s disease [20] and subsequently used to cerebral metabolism; hypoxia; ischemia. monitor patients with traumatic brain injury (TBI) and subarachnoid haemorrhage in neuro-intensive care. Introduction Following trauma to the head, one of the fundamen- Principle of microdialysis tal processes that results in progression of injury is cerebral ischemia. Both the primary insult (ictus) and The principle of cerebral microdialysis is the perfu- secondary insults such as hypoxia, hypotension and sion of a fine catheter lined with semi-permeable renal seizures contribute to this process. Ischemia results in dialysis membrane [28], introduced into the cerebral reduced oxygen delivery, energy failure, and cerebral cortex either directly or via a cranial access device. edema. One of the goals of traumatic brain injury The catheter comprises an inlet tube, a shaft, a mem- management is to detect and treat these secondary in- brane and an outlet tube. The inlet tube is perfused sults in order to reduce injury progression and improve with a physiological solution such as normal saline or outcome. Ringer’s solution at very low flow rates (typically 0.1– In neuro-intensive care, measurement of intra- 2.0 ml/min i.e. approximately 0.15–3.0 ml/day) using cranial pressure (ICP) is the cornerstone of multimo- a precision pump. The solution passes down the con- dality monitoring and is recommended by US and Eu- centric shaft to the membrane where molecules di¤use ropean guidelines [5, 16]. Monitoring of cerebral blood from the extracellular space into the perfusion fluid. flow (CBF; by extrapolation of flow velocity from The solution then passes up the shaft via the outlet trans-cranial Doppler or by functional imaging) and tube into collecting vials. Standard membranes have a brain oxygenation (by jugular venous oxygen cathe- 20 kDa cut-o¤ and are applied to measure the concen- 442 P. J. Hutchinson

tration. The term ‘‘recovery’’ is applied to the propor- tion of substance in the extracellular fluid that is detected in the dialysate. ‘‘Relative recovery’’ depends on the length of the dialysis membrane, the rate of flow of the perfusion fluid, the speed of di¤usion of the substance and the properties of the membrane. Relative recovery is defined as concentration of a particular substance in the fluid as it leaves the dialysis membrane expressed as a percentage of the concentration in the extracellular fluid surrounding the membrane. It approaches 100% when the flow rate ap- Fig. 1. Fundamental substrates and metabolites monitored by proaches zero. Absolute recovery is the total amount microdialysis. Glucose is metabolised to pyruvate (glycolysis) which of substance recovered during a defined time period, enters the citric acid cycle. However, under conditions of hypoxia, pyruvate is preferentially metabolised to lactate. The lactate/ usually the sampling period. It approaches a maxi- pyruvate ratio is therefore a marker of anaerobic metabolism. Gluta- mum value at higher flow rates because the concentra- mate and glycerol are also markers of evolving injury tion gradients between the environment of perfusate/ dialysate are then maximal. In practice, long membranes (10–30 mm) and slow flow rates (0.3–2 ml/ min) are used to increase recovery rates. Longer tration of glucose as an indicator of glucose supply and 30 mm membranes enable significantly higher re- uptake, the lactate/pyruvate ratio as an indicator of covery rates than shorter 10 mm membranes but are anaerobic metabolism, glutamate as a marker of exci- more di‰cult to implant and may monitor heteroge- totoxicity and the release of glycerol from damaged neous volumes of brain. Slow flow rates while increas- cell membranes (Fig. 1). Molecular cut-o¤ membranes ing recovery, reduce the volume of dialysate available of 100 kDa can also be applied which enable the detec- for analysis in a given unit time. tion of larger proteins. The collecting vials are changed The concept of recovery can be applied to determine at set intervals of 10–60 minutes and analysed for glu- the true extracellular concentration of a particular sub- cose, pyruvate, lactate and glutamate at the bedside us- stance by varying the flow rate, while measuring the ing automated enzyme analysers and then stored for changes in concentration of substance coming out of delayed o¤-line analysis using, for example HPLC, to the catheter, and extrapolating to zero flow. Using this detect other amino acids. technique the relative recovery for the 10 mm 20 kDa cut-o¤ CMA70 catheter has been shown to be approximately 70% at 0.3 ml/min and 30% at 1.0 ml/min for Methodology of microdialysis glucose, pyruvate, lactate and glutamate [12]. There are a number of important considerations to be taken into account in terms of the clinical appli- Perfusion fluid cation of microdialysis to the human brain. These in- Ideally, the composition of the perfusion fluid should clude the concepts of recovery, the choice of perfusion be as close to the normal physiological values of the fluid, and critical appraisal of the technique. extracellular fluid. Early clinical microdialysis studies utilised normal saline. However, concerns raised from animal studies that depletion of calcium will impair Recovery neurotransmitter release have lead to introduction of The microdialysis catheter lies within the extracellu- other solutions such as CMA perfusion fluid. Despite lar space mimicking a blood vessel allowing communi- these concerns the absence of calcium from the perfu- cation with the extracellular fluid along a logarithmic sate does not appear to a¤ect the recovery of glucose, concentration gradient towards and away from the lactate, pyruvate and glutamate [12]. For the larger catheter. It is important to recognise, therefore that cut-o¤ molecular membranes it is recommended that the level of substance detected in the dialysis fluid does dextran is added to the perfusion fluid to maintain di- not necessarily equate to the true extracellular concen- alysate volume. Microdialysis in traumatic brain injury – methodology and pathophysiology 443

Critical appraisal sion of the extracellular space in vasogenic oedema will potentially lead to a lower tortuosity There are a number of points which require critical factor (i.e. ease of passage of molecules through evaluation in terms of the application of clinical cere- the extracellular fluid) and hence a higher di¤u- bral microdialysis. sion coe‰cient than in normal brain. (i) Microdialysis-induced tissue trauma. Animal (iii) The origin of neurotransmitters needs to be estab- studies have raised concerns regarding tissue trau- lished. It is important to determine whether neu- ma induced by catheter insertion. There is evi- rotransmitters detected in the dialysate reflect true dence of uncoupling of regional cerebral blood synaptic release or non-specific overflow from flow from local brain glucose metabolism for the synaptic and non-synaptic sources [27]. Currently first 24 hours after probe insertion which is [2, 4] the smallest catheters available are about 200 mm probably a consequence of relative size of the mi- external diameter. The synaptic cleft is approxi- crodialysis catheter. Other animal studies have mately 0.02 mm across. Consequently, it is not shown reticular fibre deposition and gliosis after possible to monitor neurotransmitter release in several days which is likely to be a consequence this region. However, evidence suggests that of lack of sterility of the catheter [3]. These factors many systems function via overflow mechanisms must be considered in the design of studies and in- as well as classic vesicular release from the pre- terpretation of the results. However, the recovery synaptic membrane, di¤usion across the synaptic rates of substances stabilise after 30 minutes, his- cleft and binding to post-synaptic membrane tological studies show only occasional microhae- receptors. morrhages [3] and the blood brain barrier remains intact [18]. Post-mortem studies in sheep and hu- Pathophysiology of traumatic brain injury man brains have revealed minimal or no distur- bance to the cerebral parenchyma as a result of There is now increasing experience of microdialysis microdialysis catheter implantation [13, 31]. in patients with severe traumatic brain injury. This has (ii) The e¤ect of vasogenic oedema on recovery also enabled biochemical signatures of adverse events to be needs to be considered. The expansion of the ex- defined, characterised by a reduction in cerebral glu- tracellular space in vasogenic oedema will poten- cose, increase in lactate, increase in lactate/pyruvate tially lead to a greater volume of distribution of ratio, increase in glutamate and increase in glycerol substances in this environment, resulting in a (Fig. 2). change in substance concentration. The expan- One of the initial studies performed in Sweden dem-

Fig. 2. Characteristic metabolic signature of physiological insult in a TBI patient showing reduction in glucose, increase in lactate and amino acid release in association with intracranial hypertension 444 P. J. Hutchinson onstrated the feasibility of the technique and identified the lactate/pyruvate ratio as a marker of energy distur- bance within the brain [22]. Subsequent studies have examined the impact of adverse events including ischemia and hypoxia [8, 9, 23] with a brain tissue oxygen threshold of approximately 10 mmHg resulting in significant derangements in microdialysis parameters. Cross-validation with Positron Emission Tomography (PET) has shown a good correlation between oxygen metabolism and microdialysis markers of the brain redox state (PET oxygen extraction fraction versus microdialysis lactate/pyruvate ratio) [11]. Seizures have been shown to be associated with increased extracellu- Fig. 3. CT scan showing peri-contusional placement of microdialy- lar glutamate [30]. Metabolic derangements in relation sis catheter, visible due to gold-tip to focal injury have been addressed in patients with acute subdural haematoma and contusions [6, 10, 24]. Other studies have sought to determine the impact an intention to treat basis, a consensus statement has of therapeutic interventions on cerebral chemistry. been produced to assist with the implementation of These interventions include hyperventilation, barbitu- the technique [1]. This statement addresses: (a) cathe- rate coma, hyperoxia and manipulation of cerebral ter placement recommending that for di¤use injury perfusion pressure (CPP). In terms of hyperventilation, one catheter may be placed in the right frontal region even brief periods have been shown to cause an in- and for focal lesions catheter placement in the peri- crease in the lactate/pyruvate ratio and release of glu- contusional tissue (Fig. 3) with option for a second tamate in penumbral areas [19]. Barbiturate coma has catheter in ‘‘normal’’ tissue (b) insertion artefact with been shown to associated with a reduction in extracel- the first hour of monitoring regarded as unreliable lular glutamate and lactate [7]. There is conflicting data (c) the lactate/pyruvate ratio as a sensitive marker of on the e¤ect of hyperoxia on cerebral metabolism with the brain redox state and secondary ischaemic injury one study demonstrating improvement in biochemical (with glucose, glycerol and glutamate as additional markers [26] and another showing slight reduction in markers of evolving ischemia) and (d) in terms of clin- lactate but with no change in the redox status [17]. ical use in traumatic brain injury, microdialysis in as- The e¤ect of manipulation of CPP is also unclear with sociation with other brain monitoring techniques may augmentation from 70 mmHg to 90 mmHg increasing assist in delivery of targeted therapy for prevention of the level of brain tissue oxygen and reducing oxygen secondary ischaemic injury. extraction fraction but not producing any significant changes in microdialysis variables [14]. Reduction in CPP from 73 mmHg to 62 mmHg, however, appeared Conclusion to be associated with normalisation of cerebral metab- There is increasing experience of the application of olism [25]. What is clear, however, is that considerable microdialysis to patients with TBI. There is no doubt biochemical heterogeneity exists between patients [21]. that this technique has increased our understanding of the pathophysiology of this condition. In terms of Clinical application the clinical application, microdialysis is now employed routinely in several centres. Current research is being In terms of the continuing clinical evaluation of mi- directed to determine the role of microdialysis as a crodialysis in TBI, there are two fundamental require- monitor of secondary injury on an individual intention ments. Firstly, that the changes in the biochemistry re- to treat basis. late to both tissue outcome (detected by late imaging) and patient outcome. Secondly, that therapeutic manoeuvres can be applied to ‘‘manipulate’’ the chemis- Acknowledgments try in a favourable direction. In order to address the P. J. Hutchinson is supported by an Academy of Medical application of microdialysis to patients with TBI on Sciences/Health Foundation Senior Surgical Scientist Fellowship. Microdialysis in traumatic brain injury – methodology and pathophysiology 445

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Hutchinson, Academic Department of F, Iannotti F, Karimi A, Lapierre F, Murray G, Ohman J, Neurosurgery, University of Cambridge, Box 167, Addenbrooke’s Persson L, Servadei F, Stocchetti N, Unterberg A (1997) EBIC- Hospital, Cambridge, UK, CB2 2QQ. e-mail: [email protected]