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Schematic diagram of the glycolysis. Lack of oxygen will block the production of ATP from the citric acid cycle. In order to generate energy from the anaerobic glycolysis NADH needs to be converted to NAD + , which favors the conversion of pyruvate to lactate. The result will be an increase in lactate. Ischemia eventually leads to a decrease in the available glucose, which decreases the production of pyruvate. The sum effect of these events will be an increase in the lactate/pyruvate ratio.
Source publication
Microdialysis is a technique for sampling the chemistry of the interstitial fluid of tissues and organs in animal and man. It is minimally invasive and simple to perform in a clinical setting. Although microdialysis samples essentially all small molecular substances present in the interstitial fluid the use of microdialysis in neurointensive care h...
Context in source publication
Context 1
... 2 molecules of ATP. It enters the citric acid cycle provided that oxygen is available. The citric acid cycle is the dominant producer of energy yielding 36 molecules of ATP. If the tissue is exposed to ischemia (a decrease in blood flow causing an inadequate supply of oxygen and glucose) the production of ATP from the citric acid cycle decreases (Fig. ...
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Background and purpose:
Delayed cerebral ischemia is a severe complication of aneurysmal SAH and is associated with a high case morbidity and fatality. The total blood volume and the presence of intraventricular blood on CT after aneurysmal SAH are associated with delayed cerebral ischemia. Whether quantified location-specific (cisternal, intraven...
Citations
... During anaerobic processes, pyruvate is converted to lactate, decreasing pyruvate and increasing lactate levels and the lactate/pyruvate (L/P) ratio. Hyperlactatemia in plasma is defined as lactate levels between 3 and 4 mmol/L, while an L/P ratio above 25 indicates significant tissue ischemia [21]. ...
Objectives
This explorative porcine study investigated the immediate postoperative response of inflammatory protein markers and ischemic metabolites in peritoneal abdominal wall tissue during and after hyperthermic intraperitoneal chemotherapy (HIPEC) assessed by microdialysis.
Methods
Eight cancer-free female pigs underwent imitation cytoreductive surgery (CRS) followed by HIPEC (90 min) using a carboplatin dosage of 800 mg/m ² . A subperitoneal microdialysis catheter was placed in the abdominal wall to sample inflammatory protein markers and ischemic metabolites. During and after HIPEC, dialysates and blood samples were collected over 8 h. Inflammatory protein expression levels were quantified using Proximity Extension Assay (Olink Target 96 Inflammation panel). In addition, concentrations of ischemic metabolites were quantified using a CMA600 microdialysis analyzer.
Results
An immediate response of 27 proteins, including proteins from the TNF family, early inflammatory chemokines, pro- and anti-inflammatory proteins, was found within the first 30 min after HIPEC initiation. This was followed by a modest and relatively constant inflammatory response. Glycerol concentrations tended to decrease during the sampling period, while glucose showed more stable levels. Constant hyperlactatemia exceeding the plasma levels was seen during and after HIPEC, with no significant tissue ischemia as indicated by the lactate/pyruvate ratios.
Conclusions
In a porcine model, CRS with HIPEC leads to an immediate and relatively constant increased inflammatory and ischemic peritoneal tissue short-time response. The explorative findings contribute to the debate on the value of HIPEC in combination with CRS and call for future studies to further investigate the inflammatory and metabolic tissue responses.
... MD sampling is unique in that it samples the brain extracellular fluid in a continuous fashion [151][152][153][154][155][156][157][158]. As such, it can sample a biological compartment in which several proteins act on cell membrane receptors. ...
There has been an explosion of research into biofluid (blood, cerebrospinal fluid, CSF)-based protein biomarkers in traumatic brain injury (TBI) over the past decade. The availability of very large datasets, such as CENTRE-TBI and TRACK-TBI, allows for correlation of blood- and CSF-based molecular (protein), radiological (structural) and clinical (physiological) marker data to adverse clinical outcomes. The quality of a given biomarker has often been framed in relation to the predictive power on the outcome quantified from the area under the Receiver Operating Characteristic (ROC) curve. However, this does not in itself provide clinical utility but reflects a statistical association in any given population between one or more variables and clinical outcome. It is not currently established how to incorporate and integrate biofluid-based biomarker data into patient management because there is no standardized role for such data in clinical decision making. We review the current status of biomarker research and discuss how we can integrate existing markers into current clinical practice and what additional biomarkers do we need to improve diagnoses and to guide therapy and to assess treatment efficacy. Furthermore, we argue for employing machine learning (ML) capabilities to integrate the protein biomarker data with other established, routinely used clinical diagnostic tools, to provide the clinician with actionable information to guide medical intervention.
... Microdialysis was developed to determine the biochemical composition of interstitial tissue [96]. It is now mainly used for the monitoring of critically ill patients with brain injury to identify ischemia-associated metabolic changes [97]. Due to the semi-permeable membrane, it is limited to the analysis of ions and small metabolites. ...
Background
While not traditionally included in the conceptual understanding of circulation, the interstitium plays a critical role in maintaining fluid homeostasis. Fluid balance regulation is a critical aspect of septic shock, with a well-known association between fluid balance and outcome. The regulation of transcapillary flow is the first key to understand fluid homeostasis during sepsis.
Main text
Capillary permeability is increased during sepsis, and was classically considered to be necessary and sufficient to explain the increase of capillary filtration during inflammation. However, on the other side of the endothelial wall, the interstitium may play an even greater role to drive capillary leak. Indeed, the interstitial extracellular matrix forms a complex gel-like structure embedded in a collagen skeleton, and has the ability to directly attract intravascular fluid by decreasing its hydrostatic pressure. Thus, interstitium is not a mere passive reservoir, as was long thought, but is probably major determinant of fluid balance regulation during sepsis. Up to this date though, the role of the interstitium during sepsis and septic shock has been largely overlooked. A comprehensive vision of the interstitium may enlight our understanding of septic shock pathophysiology. Overall, we have identified five potential intersections between septic shock pathophysiology and the interstitium: 1. increase of oedema formation, interacting with organ function and metabolites diffusion; 2. interstitial pressure regulation, increasing transcapillary flow; 3. alteration of the extracellular matrix; 4. interstitial secretion of inflammatory mediators; 5. decrease of lymphatic outflow.
Conclusions
We aimed at reviewing the literature and summarizing the current knowledge along these specific axes, as well as methodological aspects related to interstitium exploration.
... Cerebral glutamate is a very sensitive and early marker of energy depletion and thereby an indirect marker of cerebral ischemia. [32][33][34][35] We found no changes in cerebral glutamate levels after oral nimodipine administration, suggesting that there was no cerebral compromise. Cerebral glycerol is an indicator of cell membrane breakdown and therefore a marker of manifest ischemia. ...
Introduction:
Nimodipine is routinely administered to aneurysmal subarachnoid hemorrhage patients to improve functional outcomes. Nimodipine can induce marked systemic hypotension, which might impair cerebral perfusion and brain metabolism.
Methods:
Twenty-seven aneurysmal subarachnoid hemorrhage patients having multimodality neuromonitoring and oral nimodipine treatment as standard of care were included in this retrospective study. Alterations in mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), brain tissue oxygen tension (pbtO2), and brain metabolism (cerebral microdialysis), were investigated up to 120 minutes after oral administration of nimodipine (60 mg or 30 mg), using mixed linear models.
Results:
Three thousand four hundred twenty-five oral nimodipine administrations were investigated (126±59 administrations/patient). After 60 mg of oral nimodipine, there was an immediate statistically significant (but clinically irrelevant) drop in MAP (relative change, 0.97; P<0.001) and CPP (relative change: 0.97; P<0.001) compared with baseline, which lasted for the whole 120 minutes observation period (P<0.001). Subsequently, pbtO2 significantly decreased 50 minutes after administration (P=0.04) for the rest of the observation period; the maximum decrease was -0.6 mmHg after 100 minutes (P<0.001). None of the investigated cerebral metabolites (glucose, lactate, pyruvate, lactate/pyruvate ratio, glutamate, glycerol) changed after 60 mg nimodipine. Compared with 60 mg nimodipine, 30 mg induced a lower reduction in MAP (relative change, 1.01; P=0.02) and CPP (relative change, 1.01; P=0.03) but had similar effects on pbtO2 and cerebral metabolism (P>0.05).
Conclusions:
Oral nimodipine reduced MAP, which translated into a reduction in cerebral perfusion and oxygenation. However, these changes are unlikely to be clinically relevant, as the absolute changes were minimal and did not impact cerebral metabolism.
... [41][42][43][44][45][46][47][48][49][50] Since its invention, cMD has identified changes in brain metabolism post-TBI. 4,5,9,12,14,15,51,52 Studies have also reported injury-induced changes in the bECF proteome, 53-57 but there have not been any studies (to our knowledge) that directly compared matching bECF and CSF samples for injury-induced changes in protein biomarker levels. It should be noted that cMD technology has known issues that can affect the outcome of protein analysis of bECF samples, such as the non-specific binding of proteins to the catheter. ...
Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n = 7; GCS 3–8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.
... As such, MD enables sampling of the brain extracellular fluid (ECF) and provides complementary information on the drug distribution in the brain because repeated sampling can be performed (7). However, when used to obtain brain ECF samples, it is only semiquantitative because the extraction efficiency or relative recovery cannot be calculated (8). ...
Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.
... Initially, we selected a delay time of 20 min between measured cerebral hemodynamic parameters and microdialysis sample collection. A minimum delay time of 5 min is expected based on our microdialysis sampling characteristics [49]. However, this does not account for chemical reaction times leading to the production of measured metabolites or delays in their extracellular expression, via either active or passive transport, and diffusion to the sampling catheter (i.e., "washout" time) that enables detection by microdialysis. ...
Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical neuromonitoring of cerebral hemodynamics, which has recently shown promise for the prediction of postoperative white matter injury in this patient population, and invasive cerebral microdialysis biomarkers. We compared cerebral tissue oxygen saturation (StO2), relative total hemoglobin concentration (rTHC), and relative cerebral blood flow (rCBF) measured by optics against the microdialysis biomarkers of metabolic stress and injury (lactate–pyruvate ratio (LPR) and glycerol) in neonatal swine models of deep hypothermic cardiopulmonary bypass (DHCPB), selective antegrade cerebral perfusion (SACP), and deep hypothermic circulatory arrest (DHCA). All three optical parameters were negatively correlated with LPR and glycerol in DHCA animals. Elevation of LPR was found to precede the elevation of glycerol by 30–60 min. From these data, thresholds for the detection of hypoxic-ischemia-associated cerebral metabolic distress and neurological injury are suggested. In total, this work provides insight into the timing and mechanisms of neurological injury following hypoxic-ischemia and reports a quantitative relationship between hypoxic-ischemia severity and neurological injury that may inform DHCA management.
... Relative recovery [26,64] was not determined in the present study, however, it can be assumed to be similar between the paired catheters, thus differences between these should not be affected by changes in recovery. ...
Background
Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment of subsequent secondary brain injury. The study objective was to compare levels of inflammatory mediators in the interstitial fluid of the perihemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) in the acute phase after surgical evacuation of ICH, with the hypothesis being that a difference could be demonstrated between the PHZ and the SNX.
Methods
In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis catheters: one in the PHZ and one in the SNX that is remote from the ICH. The microdialysate was analyzed for energy metabolites (including lactate pyruvate ratio and glucose) and for inflammatory mediators by using a multiplex immunoassay of 27 cytokines and chemokines at 6–10 h, 20–26 h, and 44–50 h after surgery.
Results
A metabolic crisis, indicated by altered energy metabolic markers, that persisted throughout the observation period was observed in the PHZ when compared with the SNX. Proinflammatory cytokines interleukin (IL) 8, tumor necrosis factor α, IL-2, IL-1β, IL-6 and interferon γ, anti-inflammatory cytokine IL-13, IL-4, and vascular endothelial growth factor A were significantly higher in PHZ compared with SNX and were most prominent at 20–26 h following ICH evacuation.
Conclusions
Higher levels of both proinflammatory and anti-inflammatory cytokines in the perihemorrhagic brain tissue implies a complex role for inflammatory mediators in the secondary injury cascades following ICH surgery, suggesting a need for targeted pharmacological interventions.
... Plasma, CSF and microdialysis samples were analysed at median (range) 14 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) hours, 38 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), and 59 (52-68) hours after surgery. ...
... The median concentration of tau decreased between 14 (4-22) and 59 (52-68) hours after surgery (p = 0.023; Fig. 3c), whereas the median concentration of NF-L did not significantly change over time (p = 0.072; Fig. 3d). Plasma concentration of Aβ40 increased between 14 (4-22) and 59 (52-68) hours after surgery (p = 0.029, Fig. 3a), and Aβ42 increased between 14 (4-22) and 38 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) hours (p = 0.027, Fig. 3b). In contrast, plasma concentration of tau decreased between 14 (4-22) and 59 (52-68) hours after surgery (p = 0.045; Fig. 3c). ...
... In contrast, plasma concentration of tau decreased between 14 (4-22) and 59 (52-68) hours after surgery (p = 0.045; Fig. 3c). Plasma concentration of NF-L increased between 14 (4-22) hours and 38 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) hours (p = 0.029; Fig. 3d), but remained unchanged thereafter. Fig. 3a,b). ...
Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.
... While we cannot exclude an in ammatory response also in the SNX, our data argue for more marked changes occurring in the PHZ. Furthermore there are known challenges with interpretation of microdialysis data with regards to relative recovery, which is dependent on several factors, (47,71) and which was not determined in the present study. However, relative recovery can be assumed to be similar between the paired catheters, thus differences between these should not be affected by changes in recovery. ...
Background:
Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment.
Methods:
In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis (MD) catheters; one in the perihemorrhagic zone (PHZ), and one in non-eloquent cortex (SNX) remote from the ICH. The microdialysate was analysed for energy metabolites (including lactate/pyruvate ratio (LPR) and glucose) and for inflammatory mediators using a multiplex immunoassay of 27 cytokines and chemokines at 6-10 hours, 20-26 hours and 44-50 hours after surgery.
Results:
Deranged energy metabolic markers suggestive of a metabolic crisis were found in PHZ compared to SNX, persistent throughout the 50 hours. Pro-inflammatory cytokines IL-8, TNF-α, IL-2, IL-1β, IL-6 and IFN-γ, anti-inflammatory cytokine IL-13, IL-4, and VEGF-A were significantly higher in PHZ compared to SNX, most prominent at 20-26 hours following ICH evacuation.
Conclusions:
Higher levels of pro- and anti-inflammatory cytokines in the perihemorrhagic brain tissue suggests a role for inflammatory mediators involved in secondary injury cascades potentially exacerbating tissue injury, which may constitute a target for future medical interventions.
