The perfusate travels the length of the probe and is then collected by a centrally located outflow tube Figure 2. To begin the procedure, a microsyringe slowly pumps the perfusate into the inflow port of the probe, and the solution flows distally through the length of the probe. Solutes within the perfusate diffuse from the perfusion solution to the brain tissue interstitium, but, more importantly, molecules from the extracellular fluid diffuse into the probe.
If the perfusion rate is sufficiently slow, the analytes reach concentration equilibrium between the perfusate and the extracellular space of the brain. The equilibrated solution containing the analyte of interest is collected at 30 to 60 min intervals from the centrally located outflow tube and analyzed at the bedside or in the laboratory Figure 2. Analyte recovery is determined by perfusion rates, probe permeability, and tissue tortuosity.
As a result, the concentration of analyte in the dialysate was usually less than the concentration surrounding the probe membrane. The fractional recovery, the ratio between the concentration of analyte in the perfusate and in the extracellular space, provided an indirect measure of the concentration within the extracellular space.
With a perfusion rate of 3. In the last ten years, however, technical advances have resulted in the typical perfusion rate being 0. Portable, low-volume micropumps that can be worn by ambulatory patients are now commercially available, making microdialysis studies possible in ambulatory patients. In addition to perfusate flow rate, the analyte recovery is also determined by the permeability properties of the probe membrane. Most probes have a molecular weight cut-off of 20 to 30 ku although probes with a molecular weight cut-off of ku are now available.
Probes permeable to low-weight molecules are entirely satisfactory for the study of most drugs, small metabolites, and some small proteins. Analyte recovery is further influenced by the ease with which the analyte diffuses in the extracellular space. This geometric complexity is expressed quantitatively by a biophysical property called tortuosity Figure 3. The greater the tortuosity, the more diffusion is impeded and the lower the analyte recovery. The tortuosity in pathological states like tumors is different than in normal brain, so direct comparisons of analyte concentrations in normal and abnormal brains must be approached with some caution.
Several analytes are widely used in clinical microdialysis. These compounds are biochemical signatures of the structural and functional state of the neuropil adjacent to the probe. To be used for clinical monitoring, an analyte must be reasonably stable and the analytical method must be straightforward and applicable to the very small volumes of dialysate. Currently, bedside collection and analysis of glucose, lactate, glutamate, and glycerol is possible using commercially available instrumentation CMA Microdialysis AB, Solna, Sweden.
More exotic analytes, such as cytokines, free radicals, nitrate and nitrite, or drugs, can be collected and assayed off-line at the leisure of the analytical laboratory Figure 4. Glucose and lactate are commonly used to assess the bioenergetic state of the brain, whether physiological aerobic or anaerobic metabolism is occurring.
Physiological levels for glucose and lactate are established; thus, alterations in these levels provide useful biochemical information. An increase in lactate and decrease in glucose, for example, indicates a state of bioenergetic crisis wherein anaerobic metabolism is active. The increased reliance of tumors on anaerobic metabolism would likely result in a more anaerobic ratio, making this well-established neurochemical parameter of interest to neuro-oncologists  ,  , .
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Glutamate is the most abundant excitatory amino acid in the mammalian brain. In traumatic brain injury and ischemia, uncontrolled release of this neurotransmitter, which usually follows bioenergetic deterioration, results in excitotoxicity, unregulated activation of ligand-gated channels that induces cellular calcium uptake resulting in Caspase activation, mitochondrial quenching, and, ultimately, cell death.
Several publications suggest that glutamate is released by infiltrating glioma cells, potentially killing obstructing normal cells and thereby facilitating invasion. Thus, this analyte may also be of interest in neuro-oncological microdialysis studies  , . Glycerol, the small, three-carbon backbone of the triglycerides residing in the cell membrane, is released upon degradation of the membrane's constituents. Elevations in glycerol level generally follow bioenergetic failure and activation of excitotoxicity, and are, therefore, an indicator of late cellular distress.
Because glycerol is a biomarker of membrane dissolution and cell death, it could potentially be an ideal indicator of response to tumor cell-killing therapeutics  , . Microdialysis permits characterization of the neurochemical milieu within brain tumors. Few studies have been conducted. The results suggest that gliomas have a higher level of anaerobic metabolism than normal brain, may release glutamate into the surrounding neuropil potentially facilitating invasion, and new analytes may be discovered by microdialysis coupled to mass spectroscopy.
Relatively few studies have been performed using microdialysis in patients with brain tumors. Bianchi et al. They examined 21 high-grade tumors, including 15 classified as grade IV glioblastoma and 6 as grade III anaplastic astrocytoma or anaplastic oligodendroglioma. The extracellular levels of choline, aspartate, taurine, gamma-aminobutyric acid GABA , and leucine in grade III tumors were not different from adjacent normal brain, whereas they were significantly increased in grade IV tumors than in normal brain.
There was no difference between grade III and grade IV tumors in the concentrations of phenylalanine, isoleucine, tyrosine, valine, and lysine, but the concentrations of choline, aspartate, taurine, GABA, leucine, and glutamate were significantly elevated in glioblastomas than in grade III tumors. The concentration of glutamate was decreased in the glioma tissue of both grades; however, the normal parenchyma adjacent to the tumor showed significant elevation in the extracellular concentration of glutamate.
It is possible that this glutamate elevation in adjacent tissue may represent the invasive penumbra of the tumor. The concentrations of choline and the amino acids glutamate, leucine, taurine, and tyrosine showed significant positive correlations with the degree of tumor cell proliferation. The authors reported that seizures, which are relatively common in subjects with gliomas, were a significant confounding variable when the extracellular concentrations of aspartate, glutamate, and GABA were considered. These findings are congruent with a small number of publications reporting neurochemical patterns in patients with epilepsy who underwent simultaneous electrode and microdialysis probe placement prior to seizure surgery  — .
Seizure foci are associated with increased glutamate and lactate and decreased glucose, which may indicate bioenergetic distress with impaired glutamate cycling. Melani et al. They evaluated adenosine levels in the extracellular fluid of 21 human high-grade gliomas using brain microdialysis techniques coupled to high-performance liquid chromatography.
The adenosine concentration was 2. They concluded that the adenosine concentrations reached in the tumor tissue were sufficient to stimulate all adenosine receptor subtypes, potentially suppressing local anti-tumor immune responses and affecting glial and endothelial cell proliferation. Roslin et al. Two catheters were implanted, one in the tumor and the other in the peritumoral tissue, during a stereotactic biopsy procedure.
The patients were mobilized on the same day as the operation. Microdialysis samples were collected the next day and subsequently analyzed for glucose, lactate, pyruvate, glutamate, and glycerol to establish baseline levels of these analytes. In addition, in vitro measurements were performed after the removal of the probes to estimate recovery for the flow rates and catheters used. Glucose levels were lower in the tumor than in the peritumoral tissue, indicating the tumor's high energy demand. Lactate level was significantly higher in tumor tissue, supporting previous reports that high grade astrocytomas, like many tumors, use glycolysis rather than respiration to meet energy demand.
The tumors were also classified as necrotic and non-necrotic, according to the radiological findings. The necrotic tumors showed significantly higher levels of glutamate and tended to exhibit higher levels of glycerol than the non-necrotic tumors.
Principles of Cerebral Microdialysis
These findings may be explained by the release of intracellular glutamate stores and cell-membrane glycerol by cell destruction. Flannery et al. Extracellular proteases like cathepsin S may facilitate astrocytoma invasion. Cathepsin S expression was detected by ELISA in 5 out of 10 tumor microdialysates, while protease activity was detected in 5 out of 11 tumor microdialysates. Cathepsin S expression was also detected in microdialysate from the normal brain tissue. These authors concluded that characterization of the extracellular environment of brain tumors in vivo using microdialysis may be a useful tool to identify the protease profile of brain tumors.
In a rather unique study, Lindvall et al. They examined 4 patients with glioblastoma who received either a biopsy or a craniotomy prior to transport. During these procedures, microdialysis catheters were placed in tumor tissue or brain tissue adjacent to the tumor, as well as in normal cerebral tissue. In tumor tissue, there was a small decrease in glucose and an increase in glutamate.
No other significant differences were observed in the cerebral metabolites following air transport. Since only minor differences in levels of cerebral metabolites after air transport were observed compared to a previous fasting sample, the authors concluded that post-operative air transport of patients with brain tumors did not result any major cellular damage or cerebral metabolic changes. Importantly also, they demonstrated the technical feasibility of cerebral microdialysis in a unique and demanding environment.
These studies illustrate the remarkable potential for microdialysis in basic investigation of brain tumor biochemistry. Study of the in vivo neurochemistry of brain tumors may facilitate development of new diagnostic and therapeutic possibilities in neuro-oncology. Therapy-related changes in brain tumor neurochemistry can also be analyzed by microdialysis.
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Only a few studies have been conducted to date and changes in conventional analytes have not been detected in the acute setting, but future studies at later time points might demonstrate neurochemical changes indicative of therapeutic effect. One study using mass spectroscopy to detect novel analytes has shown considerable promise to discover new biomarkers of brain tumor response to therapy. Tabatabaei et al. Two microdialysis catheters, one in the tumor and the other in the peritumoral tissue, were implanted during a stereotactic biopsy.
Fasting samples were analyzed daily, before and during 5 days of radiotherapy given in 2 Gy fractions. In general, the levels of lactate, glutamate, and glycerol were higher in tumor tissue, although these differences were not statistically significant. They could not detect any significant changes during the 5 days of radiotherapy in any of the metabolites analyzed.
Radiotherapy up to 10 Gy given in 5 fractions did not influence the glucose metabolism, nor did it induce any acute cytotoxic effect detected by elevated glutamate or glycerol levels. The study confirmed the glycolytic properties of glucose metabolism in malignant glioma, but did not demonstrate the neurochemical signatures of cell death. Furthermore, the study was limited only to 5 days of therapy.
Thus, it is possible that more prolonged studies might show more robust neurochemical signatures of cytolysis. Wibom et al. These investigators, however, used very sophisticated analytical techniques to discover new analytes that might be markers of therapy effects. The microdialysis catheters were implanted in tumor as well as the brain adjacent to tumor. Reference samples were also collected subcutaneously from patients' abdomens. The samples were analyzed by gas chromatography coupled with time-of-flight mass spectrometry, and the acquired data was processed by hierarchical multivariate curve resolution and analyzed with orthogonal partial least-squares.
To enable detection of treatment-induced alterations, the data was normalized by individual treatment over time. A total of metabolites were reliably detected, of which 67 were identified. The investigators found distinct metabolic differences between the tumor and the adjacent normal brain. There were also marked differences between the intracranial and subcutaneous samples, indicating that the metabolites detected in the brain did not reflect systemic metabolic events.
They also observed systematic metabolic changes induced by radiotherapy in both tumor and normal brain. The metabolite patterns affected by treatment were different between tumor and normal brain, both containing highly discriminating information. If validated, findings such as these may contribute to increased molecular knowledge of basic glioblastoma pathophysiology and raise the possibility of detecting metabolic marker patterns associated to early treatment response. Microdialysis has been used for many years to study pharmacokinetics in animals and humans.
A few studies of brain tumor chemotherapy pharmacokinetics in patients have demonstrated the technical feasibility and safety of in vivo measurement of temozolamide and methotrexate. Even more exciting is the prospect of direct intratumoral delivery of chemotherapeutic agents using microdialysis. All of the studies are preliminary, however, they illustrate the potential of microdialysis in neuro-oncology.
Boschi et al.
Advanced cerebral monitoring in neurocritical care Barazangi N, Hemphill III J C Neurol India
This review covers the technical aspects of microdialysis in mice and includes references to many of the published studies on pharmacokinetics and drug delivery. While microdialysis has been used in rats since the s, the advent of genetically engineered mice considerably extended the power of studies using this technique. Since , when microdialysis first entered the clinical arena, there have been a few studies using microdialysis to deliver drugs and to investigate penetration and kinetics of systemically delivered chemotherapeutic agents.
In , Ronquist et al. Up to 3 microdialysis probes were implanted in the tumor tissue through small dural incisions, and micropumps delivered buffered isotonic 0. The patients were treated for 14 to 21 days without side effects ascribable to DAB or the microdialysis probes. Massive tumor necrosis occurred as judged by comparison of computed tomography performed before and after DAB treatment. DAB administered in this way was well tolerated and showed promising anti-tumor activity in these patients with inoperable malignant glioma.
In , Bergenheim et al. One or two catheters were implanted in tumor tissue, and 2 reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue. Treatment was given for a mean of 9. The treatment was well tolerated by the patients except for 2 patients in whom transient brain edema appeared near the probe. No other complications related to the technique were encountered.
During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found, potentially indicating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident.
The metabolism in normal brain was unaffected during treatment. These authors concluded that microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in fully mobilized patients with glioblastoma while simultaneously allowing assessment of the neurochemical effects resulting from the treatment. The elevation of glutamate and taurine may indicate that DAB induced cellular toxicity while the unchanged level of glycerol probably indicates that no direct increase in phospholipase activity or degradation of membrane phospholipids occurred.
In case of fever, accuracy of the temperature- dependent readings is questioned. In addition, surgery- associated complications must also be considered additional tissue damage, bleeding, infection. Basic treatment aims in patients suffering from severe TBI are to optimise cerebral perfusion, improve oxygenation and stabilise metabolism in order to prevent secondary progression of underlying brain damage.
For this, integration of extended neuromonitoring in our daily clinical routine appears helpful. Extended neuromonitoring may provide more detailed insight into otherwise occult changes. For this, SjvO 2 , ptiO 2 , microdialysis, TCD and electroencephalographic studies provide important data enabling characterisation of functional influences defining threshold values and the adaption of therapeutic interventions in type, extent and duration fig.
These monitoring modalities aid in preventing excessive therapeutic corrections which by themselves can induce additional damage. In this context, aggressive volume administration to increase CPP has been associated with a sustained risk of ARDS  and abdominal compartment syndrome , excessive ventilatory support to increase paO 2 is feared to induce additional pulmonary damage , aggressive lowering of arterial blood glucose to prevent hyperglycaemia- induced cell damage increases frequency and extent of hypoglycaemic episodes , and a categorical transfusion regimen to improve cerebral oxygenation is offset by transfusion- related complications .
Basic neuromonitoring limited to ICP and CPP cannot assess changes in cerebral perfusion, oxygenation, metabolism and electrophysiological function. Consequently, we are bound to not only miss important signs of deterioration but we will also fail to adapt and reduce therapeutic interventions once previous impairment has been corrected. There is increasing evidence that extended neuromonitoring can be used to:.
As already shown by Rosner and colleagues, the optimal CPP defined by the lowest ICP must be identified within each patient  and is subject to a strong intra- and interpatient variability even within a single day. According to the original description, optimal CPP was 90 mm Hg. Whether this also resulted in a CPP- dependent improvement of cerebral perfusion, oxygenation and metabolism cannot be determined as extended neuromonitoring had not been integrated in this study. This was also corroborated by Marin-Caballos and colleagues nicely demonstrating that ptiO 2 values can be used to determine the lower most acceptable CPP threshold .
The authors convincingly concluded that the generally recommended CPP threshold of 60 mm Hg is insufficient. This underscores the necessity of continuously assessing ptiO 2 and cerebral metabolism. In this context, a normal CPP of approximately 70 mm Hg has been shown to be insufficient for the perifocal tissue compared to normal appearing tissue in which ptiO 2 was significantly higher .
CPP exceeding 75 mm Hg is required to induce highest ptiO 2 values . Similar findings were also reported by Spiotta and colleagues . Bearing this in mind reduction for example, of the CPP to 50 mm Hg is possible but cannot and should not be extended to all patients, especially if the appropriate neuromonitoring, e.
In this context, lactate and the calculated lactate to pyruvate ratio reliably reflect insufficient cerebral perfusion and oxygen delivery responsible for energetic and metabolic impairment [27, 56]. Improvement in cerebral perfusion and correction of anaemia successfully normalised brain lactate to pyruvate ratio, glycero, and glutamate concentrations . As in all critically ill patients lung protective ventilation is recommended to avoid lung injury and haemodynamic instability. Ventilatory settings are adjusted according to pre-defined paO 2 and paCO 2 targets. Even during deep sedation and hypothermia, the metabolically active brain requires sufficient amounts of oxygen to fuel energy-consuming processes.
For this, we require sufficient cardiac output, optimal local perfusion, adequate haemoglobin concentration and sufficient pulmonary function to enable ideal oxygen transport and cerebral oxygen supply. Under conditions of controlled hypothermia and pharmacological coma cerebral oxygen consumption is decreased.
Thus, a categorical paO 2 level dictating the ventilatory support might be inadequate as it promotes aggressive ventilatory settings. Cerebral oxygenation using ptiO 2 and SjvO 2 are very helpful in guiding ventilatory support. As shown under clinical conditions, an increase in FiO 2 significantly increased ptiO 2 [26, 57] and reduced cerebral lactate .
Interestingly, a too aggressive increase in ptiO 2 using normobaric hyperoxia FiO 2 1. As shown under experimental conditions, increasing oxygen supply alone is insufficient to improve cerebral oxygenation if impaired cerebral perfusion is not corrected .
Positive end expiratory pressure PEEP. Elevated PEEP can induce pulmonary and circulatory impairment, especially during hypovolaemia by impairing venous backflow to the heart, thereby resulting in secondary reduced pulmonary perfusion with worse blood oxygenation. In addition, increased PEEP can contribute to elevated ICP due to impaired cerebral venous outflow and can also reduce mean arterial and cerebral perfusion pressure, thereby impairing cerebral perfusion and oxygenation [52, 59]. Uncontrolled and prophylactic hyperventilation during the first days following TBI induces additional secondary ischaemic brain damage  and must be avoided meticulously.
Hypocapnia-induced vasoconstriction mediates impaired perfusion, metabolic and neurochemical alterations as reflected by reduced ptiO 2 and SjvO 2 and elevated extracellular glutamate and lactate . Interestingly, even small changes in paCO 2 from 38 to 34 mm Hg within normal limits are detrimental . Consequently, extended neuromonitoring should also be performed in patients during anticipated normoventilation. Hyperventilation is an easy and helpful therapeutic intervention to decrease elevated ICP . However, we should control hyperventilation by using appropriate neuromonitoring techniques to unmask signs of cerebral ischaemia due to hyperventilation-induced vasoconstriction because normal ICP levels achieved by hyperventilation will cause us to miss relevant pathological processes within the brain.
This can only be prevented by integrating appropriate neuromonitoring. Reduced SjvO 2 , ptiO 2 and signs of metabolic impairment lactate, glutamate, lactate-to-pyruvate ratio [64, 65] aid in assessing the lowest possible paCO 2 level [66—69] and avoid active induction of secondary brain damage.
To prevent insufficient cerebral oxygenation adequate oxygen supply must be maintained. For this, an appropriate number of oxygen carriers, i. At present, it still remains unclear which haemoglobin count is optimal in patients with severe TBI. From a physiological point of view the haematocrit is optimal whenever the tissue is sufficiently supplied with oxygen without reducing perfusion due to increased viscosity.
Thus, any form of severe haemodilution should be avoided. Whether a gradual and slow decrease in haematocrit developing over days as observed under clinical conditions following severe TBI will also impair cerebral oxygenation and metabolism remains unclear. Concomitant therapy due to hypothermia and deep sedation could increase the hypoxic threshold, thereby allowing a lower haematocrit level and thus decreasing transfusion requirement. Under controlled critical care conditions with stable CPP and stable oxygenation and ventilation, ptiO 2 can be used to define the transfusion threshold [72, 73].
Concomitantly, CPP must be maintained above 60 mm Hg to prevent cerebral hypoxia determined by ptiO 2 due to low haemoglobin levels . These data show that ptiO 2 and brain metabolic parameters can be used to continuously assess critical transfusion threshold. Adapting the transfusion threshold based on a neuromonitoring-guided approach is expected to enable us to determine the correct time point and amount of transfusion of red blood cells, thereby avoiding categorical and even inadequate transfusion practice.
The impact of neuromonitoring-guided transfusion practice on morbidity and mortality is currently being investigated in more detail. Hyperglycaemia induces mitochondrial damage, aggravates oxidative stress, impairs neutrophil function, reduces phagocytosis, and diminishes intracellular destruction of ingested bacteria.
These destructive cascades can be prevented by fast normalisation of elevated blood glucose levels. Maintaining blood glucose levels within tight limits between 4. The increased frequency of hypoglycaemia during the first days following injury was associated with sustained mortality [79—81]. As shown by Vespa and co-workers reducing blood glucose levels to 4.
Thus, any correction to low normal blood glucose values should be tightly controlled by extended neuromonitoring. With the help of cerebral microdialysis the influence of insulin administration on brain metabolism can be characterised. Cerebral microdialysis also helps in assessing optimal brain glucose levels. Persistently low brain glucose levels were associated with electrographic seizures, non-ischaemic reductions in cerebral perfusion pressure, decreased jugular venous oxygen saturation, increased glutamate levels, and poor outcome .
Integrating brain glucose measurements in clinical routine has allowed us to optimise nutritional support to correct cerebral hypoglycaemia by increasing arterial blood glucose levels. This can be achieved by optimising enteral or parenteral nutrition fig.
Intracranial hypertension impairs cerebral perfusion, oxygenation and metabolism. Decompressive craniectomy, in turn, will improve cerebral perfusion, oxygenation and metabolism which is most effective with dura enlargement [89—94]. The presence of pathological neuromonitoring before clinical deterioration  underscores the importance of integrating extended neuromonitoring in clinical routine. Consequently, extended neuromonitoring can aid in deciding when to perform a decompressive craniectomy . The best of knowledge expressed in the maxim of evidence-based medicine requires clinically convincing and statistically sound data.
In this context double blind, placebo-controlled, multicentre, international clinical trials are far superior to meta-analyses, systematic reviews, retrospective analyses, and expert opinions or individual experience. None of the techniques, including the non-invasive and continuous measurement of peripheral oxygen saturation SpO 2 as commonly used in daily clinical routine, have ever been investigated in a double blind, placebo-controlled, multicentre, international clinical trial with the aim of proving their importance in reducing mortality and improving outcome.
Given ethical considerations it will not be possible to conduct a double blind, placebo-controlled clinical trial in which patients will be deprived of a certain neuromonitoring technique, as positive findings have been observed in individual patients and retrospective analyses. For a reliable interpretation and conduction of clinical trials evaluating the level of evidence for any technique requires an adequate level of experience.
To gain this adequate level of experience, in turn, sufficient time and number of patients are required. Objectively seen, we are still midst in a learning phase and cannot assume that the current knowledge is set in stone as reflected by the steadily growing number of publications investigating the usefulness of extended neuromonitoring in clinical diagnostics and therapy. We must realize that the underlying pathophysiological interactions and circuits are multi- dimensional and that focusing on only one parameter is wrong.
In this context, brain glucose, for example, is strongly influenced by blood glucose and perfusion indirectly reflected by ptiO 2 fig. Blood glucose as well as perfusion are influenced by other interventions which must also be considered. At the same time, oversimplification of very complex problems for facilitated integration in clinical routine must be avoided.
This can only be provided by specialists. To make interpretation of the obtained data even more complicated we pretend to already have found the optimal treatment form when only focusing on one parameter. In reality, however, the conflicting impact, i. Although we are lacking a scientifically sound basis, we are convinced that we treat our patients to their benefit based on our current knowledge and experience. From a scientific point of view and in face of our duty to improve current intensive care medicine, it is unfair and not justified to downgrade the different techniques of extended neuromonitoring.
Ongoing as well as future investigations will improve our understanding and subsequently the fine-tuning of our treatment options. At present, the level of evidence is convincing for the experienced specialists and doubtful for the sceptics and those who are not familiar with these techniques. With the integration of extended neuromonitoring we were able to significantly reduce the amount of transfused red blood cells and diminish the rate of acute lung injury due to excessive volume administration.
Correspondence: Professor John F. Incidence and outcome of traumatic brain injury in an urban area in Western Europe over 10 years. Eur Surg Res. Severe traumatic brain injury in Switzerland — feasibility and first results of a cohort study. Swiss Med Wkly. Monitoring intracranial pressure in traumatic brain injury. Anesth Analg. Metabolic failure precedes intracranial pressure rises in traumatic brain injury: a microdialysis study.
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