Clinical Use of Cerebral Microdialysis in Patients with Aneurysmal Subarachnoid Hemorrhage—State of the Art

Objective To review the published literature on the clinical application of cerebral microdialysis (CMD) in aneurysmal subarachnoid hemorrhage (SAH) patients and to summarize the evidence relating cerebral metabolism to pathophysiology, secondary brain injury, and outcome. Methods Study selection: Two reviewers identified all manuscripts reporting on the clinical use of CMD in aneurysmal SAH patients from MEDLINE. All identified studies were grouped according to their focus on brain metabolic changes during the early and subacute phase after SAH, their association with mechanisms of secondary brain injury and outcome. Results The review demonstrated: (1) limited literature is available in the very early phase before the aneurysm is secured. (2) Brain metabolic changes related to early and delayed secondary injury mechanisms may be used in addition to other neuromonitoring parameters in the critical care management of SAH patients. (3) CMD markers of ischemia may detect delayed cerebral ischemia early (up to 16 h before onset), underlining the importance of trend analysis. (4) Various CMD-derived parameters may be associated with patient outcome at 3–12 months, including CMD-lactate-to-pyruvate-ratio, CMD-glucose, and CMD-glutamate. Conclusion The clinical use of CMD is an emerging area in the literature of aneurysmal SAH patients. Larger prospective multi-center studies on interventions based on CMD findings are needed.

iNTRODUCTiON First reports on monitoring of brain metabolism using cerebral microdialysis (CMD) in patients with subarachnoid hemorrhage (SAH) date back to the year 1992 (1). Despite the long-standing availability of this technique, recommendations for treatment decisions based on CMD monitoring have just been recently published as a consensus statement by clinical experts (2).
Cerebral microdialysis has improved our understanding of pathophysiological mechanisms of early and delayed brain injury in SAH patients by providing metabolic information derived from brain tissue on a cellular level, in addition to intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF), brain tissue oxygen tension (PbtO2), and electrographic monitoring (electroencephalography and electrocorticography). So far, changes in brain metabolism have been associated with known complications after SAH and may also help to detect impending secondary brain injury early or before they have evolved into irreversibility. Moreover, abnormalities in CMD-derived parameters have been linked to poor brain tissue and functional outcome and may therefore be integrated in the multimodal approach of neuroprognostication. In addition, the effect of commonly applied pharmacological and non-pharmacological treatments on brain metabolism can be studied on an individual level, thereby enhancing the concept of personalized medicine in neurocritical care patients.

Microdialysis Methodology
The principle of CMD is to mimic a capillary blood vessel in the brain for the assessment of local cerebral metabolism (3). A tubular semi-permeable membrane on the tip of the CMD catheter is perfused with an isotonic or colloid-enriched fluid that equilibrates with the extracellular space by simple diffusion. All molecules small enough to pass the membrane follow their electro-chemical gradient into the tube. Established catheters have a membrane length of 1 cm and pore sizes of either 20 or 100 kDa, which do not show differences in the recovery of small molecules (4). A perfusion speed of 0.3 µl/min is recommended in clinical use, which leads to a relative recovery rate (dialyzate concentration divided by true concentration) of about 70% for the most commonly assessed molecules (5).
Criteria for CMD monitoring are not well defined. It can be used as part of the "multimodal neuromonitoring bundle" (Figure 1A) in ventilated ("poor-grade") patients or in patients with a secondary neurological deterioration. As a primary monitoring device, the probe should be placed in the frontal lobe (anterior/middle cerebral artery watershed), ipsilateral to the ruptured aneurysm, or the maximal blood clot load. When used in patients with secondary deterioration, location can also be guided by local practice to identify tissue at risk (for example, by CT perfusion or transcranial ultrasound) (2,6). The catheter can be inserted into the brain tissue either by using a cranial access device (bolt) or by tunneling (Figure 1A), penetrating the skull via a craniotomy ( Figure 1B) or a twist drill hole. The dialyzate of the first hours should be discarded due to the insertion trauma and dilution effect of the flush sequence filling the system.

interpretation of Data
Concentrations of CMD parameters represent the local metabolic environment surrounding the membrane and cannot be extrapolated to other regions of the brain. Knowledge of catheter location is therefore mandatory for data interpretation. The gold tip of the CMD probe is visible on head CT (Figure 2B), thus its exact location in the brain can be determined and classified by the monitored tissue (gray vs. white matter), lobe, or by the spatial relation to focal pathologies (intralesional/perilesional vs. radiologically normal-appearing brain tissue). The dependency of molecular concentrations on probe location argues for the interpretation of temporal dynamics (trend analysis) in addition to absolute values. Calculating ratios of different CMD parameters (e.g., CMD-lactate-to-CMD-pyruvate-ratio, CMD-LPR) creates variables independent of absolute concentrations and recovery.
The dialyzate is sampled into microvials and analyzed for point of care parameters including CMD-glucose, CMD-lactate, CMD-pyruvate, CMD-glutamate, and CMD-glycerol at the patient's bedside. A measurement interval of 1 h is commonly used in clinical practice.
Glucose is an important energy substrate for neuronal tissue. Its concentration in the brain depends on systemic supply, diffusivity in the brain tissue, and local consumption. In the process of aerobic glycolysis, it is metabolized to pyruvate and further converted into acetyl-coenzyme A, which is used for mitochondrial energy production. Under conditions of brain tissue hypoxia or mitochondrial dysfunction, pyruvate is fermented into lactate. The LPR reflects the cytoplasmatic redox state and is a marker of anaerobic metabolism and/or mitochondrial dysfunction. The concept of mitochondrial dysfunction arose from observations of impaired cerebral energy metabolism despite normal perfusion and substrate availability. The underlying pathophysiological mechanisms are not sufficiently elucidated. CMD-glutamate has fewer clinical implications, however, elevated concentrations of this excitatory neurotransmitter are considered to be a marker of ischemia and excitotoxicity. Glycerol is a component of neuronal cell membranes, thus CMD-glycerol concentrations are a surrogate marker of cell membrane damage, e.g., under conditions of hypoxia or ischemia.

MATeRiALS AND MeTHODS
The aim of this review is to summarize the current knowledge of this technique in the critical care management of SAH patients and to discuss its limitations. A MEDLINE search was performed to identify all studies reporting on the clinical use of CMD in aneurysmal SAH patients. The selection process is summarized in Figure 2. All identified studies were grouped according to their focus on the brain metabolic changes during the early and subacute phase after SAH, their association with mechanisms of secondary brain injury and outcome.  is pathophysiologically related to, but temporally separated from the subsequent occurrence of delayed cerebral ischemia (DCI). EBI is the result of the initial hemorrhage leading to a cascade of ischemic injury, global brain swelling and early mitochondrial dysfunction, as well as pressure-related side effects due to parenchymal hematoma or early hydrocephalus. available during coiling, several studies have investigated changes in cerebral metabolism during aneurysm surgery ( Table 2) (9)(10)(11)(12)(13). Commonly used CMD sampling intervals between 10 and 60 min seem to be too imprecise to depict periprocedural changes in brain metabolism (9)(10)(11), although increases in CMD-LPR and CMD-glutamate levels following prolonged artery clipping and ischemic complications were reported (9,10). The largest study, including 38 aneurysmal SAH patients, found no significant differences in metabolic markers of brain tissue ischemia during transient artery occlusion (median occlusion time was 14 min) (11). In two patients with a prolonged occlusion time of more than 30 min, a pronounced increase of CMD-glutamate was observed (11). The feasibility of rapid-sampling microdialysis (obtaining values up to every 30 s) was investigated during temporal lobe retraction and transient artery occlusion (13). While metabolic changes reached a maximum after 3-10 min during temporal lobe retraction, increasing CMD-lactate and decreasing CMDglucose levels were observed until clip removal during artery occlusion (13). A higher sampling frequency in CMD monitoring may help to define a threshold for ischemia to prevent irreversible tissue damage during aneurysm obliteration.

CMD and Acute Focal Neurological Deficits after SAH
Most patients underwent aneurysm clipping. In a study including 26 poor-grade SAH patients (68% Hunt and Hess grade IV-V), CMD-LPR and CMD-glutamate were highest at the start of neuromonitoring, indicating metabolic distress (mean CMD-LPR > 40) and excitotoxicity, and significantly decreased thereafter (14). A higher CMD-LPR was associated with poor 3-month outcome (modified Rankin scale 4-6). CMD-glucose significantly decreased, however, did not reach critically low levels in this cohort with systemic glucose levels of 135-150 mg/ dl (7.5-8.3 mmol/l) (14). A study including 149 SAH patients, of whom 89 (60%) were admitted with good clinical grades (WFNS grades ≤ 3), reported higher CMD-LPR and CMD-lactate levels in poor-grade patients, already at the start of neuromonitoring, compared to good-grade patients (18). Moreover, higher CMDglycerol levels were reported in poor-grade patients, significantly decreasing over the first days (18). In another study including 97 SAH patients, the authors compared patients with and without acute focal neurological deficits immediately after SAH due to SAH-related parenchymal hematoma and/or perioperative/periinterventional ischemia. In patients with focal deficits, CMD-lactate, CMD-LPR, CMDglutamate, and CMD-glycerol were pathologically increased throughout the first week, whereas these parameters remained within normal range in patients without acute neurological deficits (16,17). CMD-glucose levels were significantly lower in patients with acute focal deficits (16,17), despite higher blood glucose concentrations (overall mean blood glucose levels were approximately 7.2-8.3 mmol/l = 130-150 mg/dl) (29). Regarding temporal dynamics, a trend toward normalization of CMD values was associated with clinical improvement, whereas further deterioration was associated with permanent neurological deficits in patients with acute focal deficits (16).

CMD and Admission global Cerebral edema
Two studies compared cerebral metabolic changes in patients with and without global cerebral edema (GCE) diagnosed by CT-imaging of the brain. Helbok et al. found an association between a higher frequency of metabolic crisis (significantly higher LPR, lower brain glucose levels) and GCE (15). Zetterling    (21). Despite this discrepancy, these findings indicate altered brain energy metabolism in SAH patients with GCE. Intracranial hypertension (ICP > 20 mmHg), often a result of brain edema or focal lesions, was associated with a pathologically elevated LPR (>40) and significantly lower CMD-glucose levels (19).

The Clinical Use of CMD as a Marker of Cerebral Hypoperfuison and DCi in SAH Patients
Delayed cerebral ischemia occurs in up to 30% of SAH patients, mostly between 4 and 10 days after the hemorrhage, and was defined by an international group of experts as either clinical deterioration or cerebral infarction not attributable to other causes (83). In the literature published before 2010, we found a considerable heterogeneity in the definition of delayed ischemia after SAH. Detailed information on the definition used in individual trials is given in Table 4.
Several studies investigated metabolic changes associated with parameters of cerebral perfusion, including CBF, CPP, and imaging surrogates. In summary, a negative correlation between CBF and CMD-lactate, CMD-LPR, CMD-glutamate, and CMDglycerol has been described, while CMD-pyruvate and CMDglucose are commonly positively correlated with CBF (25,31,32,35,(38)(39)(40). Other studies focused on DCI and found increases in CMD-lactate and CMD-glutamate as early sensitive markers (17). Metabolic derangement with increasing CMD-LPR (> 40) and decreasing CMD-glucose (< 0.7 mmol/l) may occur up to 16 h before DCI onset (26,32). In the following, we give detailed information on some studies, all studies are listed in Table 4.
Schmidt et al. found an association of CPP < 70 mmHg with a higher incidence of metabolic crisis (CMD-LPR > 40 and CMD-glucose levels < 0.7 mmol/l) and further worsening of brain metabolism at lower CPP values (41). Similarly, a higher CMD-LPR and increased episodes of metabolic distress (CMD-LPR > 40) were observed at a CPP < 60 mmHg in another study including 19 SAH patients (23). However, it is important to elaborate that a high CMD-LPR may also indicate metabolic distress in the absence of ischemia. In this regard, Jacobsen et al. defined an elevated LPR (>30), together with pyruvate levels within normal range (>70 μmol/l) as mitochondrial dysfunction and found this pattern to be 7.5-fold more common than metabolic changes indicative for cerebral ischemia (LPR > 30 and CMD-pyruvate < 70 μmol/l) (28). Mitochondrial dysfunction was moreover associated with higher levels of CMD-glucose and lower levels of CMD-glutamate and CMD-glycerol compared to ischemic episodes.
In poor-grade SAH patients requiring sedation and mechanical ventilation, neurological deterioration may not be detected. In these patients, CMD provides useful information on the metabolic state of the injured brain and may even indicate metabolic changes before DCI occurs. Sarrafzadeh et al. reported higher levels of CMD-lactate and CMD-glutamate in patients with DCI compared to those who did not develop DCI already on day 1      In patients without evidence of cerebral ischemia CMD-glucose and CMD-pyruvate levels were significantly higher and CMD-glutamate, CMDglycerol, and CMD-lactate levels and the CMD-LPR were lower compared to patients becoming brain dead. During the time between brain death (complete ischemia) and cessation of treatment, CMD-glucose, and CMD-pyruvate were not detectable and there was a further increase of CMD-glutamate and CMD-glycerol levels   and throughout the first week after the bleeding (17). A higher CMD-LPR was observed from day 3 on (17). This is in line with findings by Nilsson et al., who concluded that CMD-lactate and CMD-glutamate may be the earliest and most sensitive markers of ischemia, followed by the CMD-LPR and CMD-glycerol (30). Furthermore, lower brain glucose levels during the first 3 days after SAH were reported in DCI patients, despite higher blood glucose concentrations when compared to patients who did not develop DCI (29). Changes in CMD parameters were observed even 12-16 h before the occurrence of DCI and included a significant increase in CMD-LPR to values >40 and decreases in CMD-glucose to levels <0.7 mmol/l (26,32,37). At a comparable time point, also elevations of CMD-lactate, CMD-glutamate, and CMDglycerol were reported (43,44). The sensitivity of the method is limited due to the local measurement. Therefore, ischemia occurring in brain tissue distant to the monitoring catheter may not be detected (26,37). Lack of specificity results from metabolic distress secondary to non-ischemic CMD-LPR elevations and hyperglycolytic (non-ischemic) lactate increase (28,72). Nevertheless, CMD had a higher specificity for predicting DCI than transcranial ultrasound and conventional angiography (44). Unfortunately, most studies do not report on the effect of current treatment strategies for DCI (induced hypertension, intraarterial spasmolysis). Sarrafzadeh et al. reported a decrease in CMD-glutamate levels, but no change in other parameters, associated with "triple-H therapy" (17). Further research focusing on metabolic changes following such interventions is surely warranted.
In summary, studies assessing CBF directly in the region around the CMD probe revealed a highly consistent metabolic pattern of increased CMD-lactate, CMD-glutamate, CMDglycerol levels, and CMD-LPR during episodes of hypoperfusion, whereas CMD-glucose and CMD-pyruvate levels were positively correlated with CBF. CMD-lactate and CMD-glutamate are early and sensitive markers of impending DCI, but lack of specificity. However, CMD parameters showed a higher specificity for predicting DCI than transcranial ultrasound and conventional angiography (37,43,44). Regarding trend analyses, a CMD-LPR increase above 40 and decreasing CMD-glucose concentrations preceded the occurrence of delayed ischemia by several hours (26,32); however, ischemia that occurred remote from the CMD probe or in the contralateral hemisphere was not detected (26).

CMD in Monitoring Treatment effects
Several studies have investigated the effect of pharmacological and non-pharmacological interventions on cerebral metabolism as summarized in Table 5. Studied interventions included the treatment of intracranial hypertension, either with osmotherapy (45,46), by cerebrospinal fluid drainage via external ventriculostomy (53), or by decompressive craniectomy (49,50), fever treatment with diclofenac or targeted temperature management (51,52,54), the management of anemia and administration of packed red blood cells (47,48,52), and the administration of erythropoietin or verapamil (55,56). The impact of enteral nutrition and insulin on brain metabolism will be discussed in the next chapter.

CMD and Systemic glucose Management
There is still an ongoing debate on the optimal systemic glucose target in critically ill patients (84,85). CMD-glucose levels represent the net effect of delivered glucose and glucose consumption. Little is known about the impact of glucose transport and diffusion in acutely brain injured patients.
Severe hyperglycemia (>200 mg/dl = 11.1 mmol/l) is associated with poor outcome in SAH patients (86). Some studies investigated the association between systemic and brain interstitial glucose levels ( Table 6). Oddo et al. described the brain metabolic profile during episodes of "low" (<4.4 mmol/), "tight" (4.4-6.7 mmol/l), "intermediate" (6.8-10 mmol/l), and high blood glucose levels in a mixed population of neurocritical care patients, including 10 patients with SAH. Compared to intermediate systemic glucose levels, tight glycemic control was associated with lower CMD-glucose levels and more episodes of CMD-glucose < 0.7 mmol/l, as well as a higher CMD-LPR and more episodes of metabolic crisis (CMD-LPR > 40 and CMD-glucose concentrations < 0.7mmol/l). Metabolic crisis and CMD-glucose < 0.7 mmol/l were associated with higher hospital mortality (61). The significant association of systemicand CMD-glucose is supported by the results of other groups (59,66); however, some studies indicate a poor correlation (63,67), especially in the injured brain. Decreased CMD-glucose is moreover observed when delivery is reduced (i.e., reduction in CBF) or under conditions of increased consumption (i.e., higher body temperature, seizures and the occurrence of cortical spreading depolarizations) (66,78,82).
Pathologically low CMD-glucose levels (<0.7 or <0.6 mmol/l) were associated with poor outcome in SAH patients (41,61,63). In the recent consensus statement on the use of CMD, clinical experts suggest to intervene when pathologically low CMDglucose levels are detected (2). This attempt should only be made with respect to probe location (in healthy-appearing brain tissue on head computed tomography), baseline blood glucose levels, and in the absence of brain ischemia. Proposed interventions targeting higher systemic glucose levels include intravenous or enteral glucose administration and the reevaluation of insulin treatment (2).
While no data on intravenous glucose administration are available, three studies sought to investigate the impact of enteral feeding on cerebral metabolism. Schmidt et al. did not observe a direct relation between CMD-glucose levels and the energy content of the administered enteral nutrition (66). Other groups investigating the temporal association of enteral feeding and the metabolic profile revealed time-related increases in CMD-glucose levels not affecting other CMD parameters (58,59). CMD-glucose levels even increased from critically low (<0.7 mmol/l) levels at baseline independent of probe location (59).
Insulin treatment was associated with a decrease of CMDglucose independent of serum glucose levels, resulting in a higher incidence of critically low CMD-glucose levels (<0.6 mmol/l) (64,67), especially under conditions of cerebral metabolic distress (LPR > 40) (66). Moreover, rapid reductions in serum glucose concentrations were associated with a decrease in CMD-glucose (57). In line with this, a higher serum glucose variability was associated with a higher rate of cerebral metabolic distress (60). In Compared to hemoglobin concentrations between 10 and 11 g/dl, episodes of CMD-LPR > 40 occurred 1.9 times more often when hemoglobin was between 9 and 10 g/dl, and 3.8 times more often when hemoglobin was below 9 g/dl (45% of measurements showed CMD-LPR > 40, respectively)   Hunt and Hess grade II n = 2 (12%), III n = 6 (35%), IV n = 2 (12%), V n = 7 (41%)

Measurements took place between 3 and 22 days after SAH
White matter, hemisphere deemed at greatest risk for secondary injury, classified as normal-appearing or perilesional brain tissue To investigate the impact of enteral nutrition on cerebral glucose levels Enteral nutrition significantly increased CMD-glucose levels (1.59-2.03 mmol/l) with a delay of 3 h. This increase was independent of insulin administration, absolute levels of serum glucose, evidence of cerebral metabolic distress, and microdialysis probe location. Also critically low CMD-glucose concentrations were increased. There was a significant association between serum and CMD-glucose levels Blood glucose levels were defined as "tight" (4.4-6.7 mmol/l) or "intermediate" (6.8-10 mmol/l). Tight blood glucose was associated with lower levels of CMD-glucose, more episodes of CMD-glucose < 0.7 mmol/l, higher CMD-LPR and a more frequent occurrence of metabolic crisis (CMD-LPR > 40 and CMD-glucose levels < 0.7 mmol/l). Low CMD-glucose levels and metabolic crisis were associated with higher hospital mortality To investigate the impact of intravenous insulin on cerebral metabolism CMD-glucose levels, but not serum glucose levels, decreased significantly 3 h after the start of the insulin infusion. Episodes of low CMD-glucose (<0.6 mmol/l) were (non-significantly) more common in patients who received insulin. CMD-lactate and CMD-pyruvate levels did not change, CMD-glycerol concentrations slightly increased, and CMD-glutamate levels decreased after the start of insulin treatment (65) Single-center, prospective, observational 24 WFNS grade I n = 5 (21%), II n = 4 (17%), III n = 2 (8%), IV n = 6 (25%), V n = 7 (29%) Data were collected on days 1-10 after SAH Vascular territory of the aneurysm; insertion into lesioned tissue was avoided To investigate the longterm effect of insulin on cerebral metabolism Median daily CMD-glucose levels decreased after the initiation of insulin treatment and were significantly lower, compared to baseline, 4 days after insulin start. A significant increase in CMD-glycerol levels was observed 1 day after insulin start, which was not significant thereafter. CMDglutamate levels significantly decreased over time (66) Single ceter, retrospective, observational 50 Hunt and Hess grade II n = 3 (6%), III n = 7 (14%), IV n = 15 (30%), V n = 25 (50%) Monitoring was started 2 days (median) after SAH and maintained for 108 h (mean)

Normal-appearing white matter
To elucidate the relations between enteral nutrition, insulin treatment and cerebral metabolism There was no direct association between CMD-glucose levels and the energy content of the administered enteral nutrition. There was a significant association between CMD and serum glucose levels. When the CMD-LPR was <40, higher CMD and serum glucose levels were associated with a higher insulin dose. When the CMD-LPR was >40, a higher insulin dose was associated with lower CMD-glucose levels, despite higher serum glucose concentrations (67) Single ceter, prospective, observational 19 WFNS grade I n = 1 (5.3%), II n = 1 (5.3%), III n = 1 (5.3%), IV n = 11 (58%), V n = 5 (26%) The mean monitoring time was 147 h. Data are reported for days 1-7 after SAH Cortical, frontal, classified as radiologically normalappearing or adjacent to ischemic lesions To elucidate the relation between brain and serum glucose levels CMD-glucose levels decreased over days 1-7. There was a significant correlation between CMD and serum glucose levels (r = 0.27). CMD-lactate and CMD-pyruvate levels increased over time, beginning on day 3. CMD-glutamate levels peaked on day 1 and decreased thereafter.  summary, tight glycemic control may be associated with pathologically low CMD-glucose levels (neuroglucopenia) in critically ill patients with acute neurologic injury. If brain metabolic monitoring indicates critically low glucose levels (i.e., <0.2 mmol/l) targeting a more liberal glucose regimen (110-150 mg/dl or up to 180 mg/dl) may be indicated.

CMD and Outcome
Studies reporting an association of CMD parameters with patient outcome are summarized in Table 7. The largest study includes 182 SAH patients and found higher CMD-LPR and CMD-glutamate values during the first week after SAH being significantly and independently associated with poor functional outcome after 12 months (50). Patients with poor functional 3-6 months outcome had significantly more episodes of CMD-LPR > 40 and CMD-glutamate levels > 10 μmol/l compared to those with favorable outcome (71). An elevated CMD-LPR was also associated with hospital mortality (57). Pathologically low CMD-glucose levels < 0.7 mmol/l were observed more often in patients with poor outcome and in those who died (41,61,63). Elevated CMD-lactate is a less specific marker for neuroprognostication, as both, associations with good (in a hyperglycolytic context) and poor (due to hypoxia) outcome were reported (72). Trend analysis is important as a shift to hypermetabolism, indicated by an increase in both, CMD-lactate and CMDpyruvate levels, was observed in patients with favorable outcome. Persistent low CMD-pyruvate levels without increase to normal values were associated with poor outcome (69). Persistent low CMD-glutamate levels were associated with good functional outcome, whereas increases at day 1 and day 7 were associated with poor outcome (74).

DiSCUSSiON
This review demonstrates that CMD is a powerful tool providing almost continuous brain metabolic information at bedside. Based on the published literature, pathological changes in brain metabolism are associated with disease severity, mechanisms of primary and secondary brain injury, and poor long-term outcome after SAH.
As summarized in this review, the major limitation of the published literature is that CMD monitoring was reported mostly in small single-center trials of neurological and neurosurgical ICUs with extensive experience in the use of CMD as adjunct to other multimodal neuromonitoring techniques. In many centers, implementation of CMD as a clinical tool is still limited due to financial constraints and the lack of evidence to improve patient's outcome. Future trials may address this gap in the literature by targeting brain metabolic parameters as endpoints to improve brain homeostasis as no monitoring tool can improve patient's outcome unless coupled with a therapeutic intervention. On the other hand, there is a need to re-define commonly used outcome parameters and to move from a simplistic functional outcome score to a more sophisticated approach including neuropsychological testing, quality of life measures, and brain tissue outcome.
The invasiveness of CMD limits its application to poor-grade SAH patients. This implicates that this review merely summarizes brain metabolic changes of unconscious patients and results are not generalizable to all clinical grades. Based on the recently published consensus statement, the use of CMD is recommended in poor-grade SAH patients with prolonged ventilation and patients with secondary neurologic deterioration requiring mechanical ventilation.
Despite these limitations metabolic monitoring in the early and subacute phase after SAH provides insight into pathophysiological mechanisms of primary and secondary brain injury on the brain tissue level. As shown in our review, the detection of impeding ischemia is the most extensively studied application of CMD in SAH patients. CMD has been shown to have the potential to be used as early warning tool of brain tissue ischemia hours before the insult (17,43,44), even if clinically silent (26). In this regard, it is important to mention that we recognized a large variability in the definition of DCI throughout the published literature. Although more homogeneity was detected after the year 2010 when Vergouwen et al. defined DCI based on clinical and/or radiographic criteria (83), earlier studies are difficult to compare as information on radiographic evidence of new infarctions related to vasospasm were commonly not reported.
Another limitation is that microdialysis probe location differed in individual studies by means of targeting either brain tissue ipsilateral to the bleeding aneurysm or the contralateral hemisphere and monitoring the cortical gray matter vs. subcortical white matter. Furthermore, probe location was rarely adequately addressed as covariate in multivariate models, which limits the interpretation of results and conclusions. It is important to mention that brain chemistry can only be interpreted correctly based on the relation to focal injury on brain imaging ("normal appearing brain tissue" vs. "perilesional" vs. "intralesional") (2). As recommended by clinical experts, future trials reporting microdialysis data should at least include information on catheter location, the catheter type used, perfusion fluid composition, the perfusion fluid flow rate, and time from ictus to monitoring (2).
The interpretation of CMD-derived information requires profound knowledge of the complex underlying pathophysiology. As shown in Table 1, metabolic changes may be ambiguous, as similar patterns may indicate different underlying pathophysiological processes. However, taking into account, the occurrence of specific patterns in relation to the bleeding onset may help to discriminate between early and late onset ischemic patterns or patterns of mitochondrial dysfunction. A clinical guidance is given in Table 1 and may be combined with other neuromonitoring parameters such as brain tissue oxygenation, ICP, and CBF.
Clinical implication of microdialysis monitoring besides the detection of secondary ischemic insults include guidance of systemic glucose management, CPP optimization, defining individual transfusion thresholds and monitoring of brain chemistry during pharmacological and non-pharmacological interventions (41,49,51,52,57,61,63,67).
The only treatment decision based on changes in brain metabolism currently recommended by clinical experts is the treatment of low cerebral glucose taking into account baseline Hunt and Hess grade II n = 3 (11%), III n = 6 (21%), IV n = 3 (11%), V n = 16 (57%) Monitoring was initiated 1 day (median) after SAH. Data are reported up to 12 days after SAH White matter at greatest risk for secondary brain injury; classified as normal or perilesional tissue Investigating associations between CMD-K + levels, brain metabolism and functional outcome Elevated cerebral CMD-K + levels (above the median of 3 mmol/l) were associated with CMD-LPR > 40, CMD-lactate > 4 mmol/l and poor outcome. CMD-K + concentrations positively correlated with CMD-lactate and CMD-glutamate levels and the CMD-LPR. CMD-LPR > 40 was independently associated with poor functional outcome Blood glucose levels were defined as "tight" (4.4-6.7 mmol/l) or "intermediate" (6.8-10 mmol/l). Tight blood glucose was associated with lower levels of CMD-glucose, more episodes of CMD-glucose < 0.7 mmol/l, higher CMD-LPR and a more frequent occurrence of metabolic crisis (CMD-LPR > 40 and CMD-glucose levels < 0.7 mmol/l). Low CMD-glucose levels and metabolic crisis were associated with higher hospital mortality    n/a n/a n/a Data are reported between 2 and 12 days after SAH n/a Investigating the effect of remote ischemic preconditioning on brain metabolism Over the duration of remote ischemic preconditioning, the CMD-LPR and CMDglycerol levels decreased. To investigate an association between CSD and CMDglucose level CSD were not associated with changes in CMD-glucose levels Data are reported for days 1-10 after SAH. CMD was performed for 7-10 days Vascular territory of the aneurysm; patients were excluded if the tip of the CMD probe was close to a parenchymal hemorrhage To relate changes in cerebral metabolism to the emergence of bacterial meningitis On the day when bacterial meningitis was diagnosed, CMD-glucose levels and the CMDlactate-to-glucose-ratio were significantly lower than 3 days before. Compared to controls, only the decrease in CMD-glucose levels was more pronounced in patients with bacterial meningitis. A decrease in CMD-glucose levels of 1 mmol/l showed the highest combined sensitivity and specificity (81) (Abstract only) Single-center, prospective, observational 4 n/a n/a n/a Investigating the impact of temperature changes on CMD-glutamate levels In all patients, mild head cooling resulted in a significant decrease in CMD-glutamate levels. In 2 patients, CMD-glutamate concentrations increased sharply with fever (82) Single-center, prospective, observational 6/18 GCS motor score 3 n = 3, 5 n = 1, 6 n = 2 n/a Cortical, normal-appearing tissue To assess the impact of fever on cerebral metabolism Neither the onset of fever (≥38.7°C) nor its resolution was associated with significant changes in cerebral metabolism systemic glucose concentration, catheter location, and the etiology of neuroglucopenia. In the knowledge of its potential, there is a need to integrate brain metabolic changes and to define CMDbased endpoints in future clinical trials.

CONCLUSiON
Cerebral microdialysis is used in the clinical management of severe SAH together with ICP, PbtO2, and other neuromonitoring parameters. In the knowledge of its limitations, this method provides a novel insight into pathophysiological processes of primary and secondary brain injury. Recent consensus on microdialysis monitoring paves the way for improved protocols and targeted interventions. The major task for future research integrates the prospective evaluation of predefined interventions to improve brain tissue physiology aiming toward a personalized management of SAH patients in the future.

AUTHOR CONTRiBUTiONS
RH was involved in the idea, design, data acquisition, article selection, writing, interpretation of data, and final revision of the manuscript. MK was involved in article selection, writing, interpretation of data, and final revision of the manuscript. AS, MG, and VR were involved in the data acquisition, interpretation of data, and final revision of the manuscript. BP, RB, and ES were involved in article selection, writing, interpretation of data, and final revision of the manuscript. All authors read and approved the final version of the manuscript and are accountable for the content, data interpretation, and data accuracy.