Prognostic value of near-infrared spectroscopy regional oxygen saturation and cerebrovascular reactivity index in acute traumatic neural injury: a CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Cohort Study.

BACKGROUND: Near-infrared spectroscopy regional cerebral oxygen saturation (rSO2) has gained interest as a raw parameter and as a basis for measuring cerebrovascular reactivity (CVR) due to its noninvasive nature and high spatial resolution. However, the prognostic utility of these parameters has not yet been determined. This study aimed to identify threshold values of rSO2 and rSO2-based CVR at which outcomes worsened following traumatic brain injury (TBI). METHODS: A retrospective multi-institutional cohort study was performed. The cohort included TBI patients treated in four adult intensive care units (ICU). The cerebral oxygen indices, COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and arterial blood pressure) were calculated for each patient. Grand mean thresholds along with exposure-based thresholds were determined utilizing sequential chi-squared analysis and univariate logistic regression, respectively. RESULTS: In the cohort of 129 patients, there was no identifiable threshold for raw rSO2 at which outcomes were found to worsen. For both COx and COx_a, an optimal grand mean threshold value of 0.2 was identified for both survival and favorable outcomes, while percent time above - 0.05 was uniformly found to have the best discriminative value. CONCLUSIONS: In this multi-institutional cohort study, raw rSO2was found to contain no significant prognostic information. However, rSO2-based indices of CVR, COx and COx_a, were found to have a uniform grand mean threshold of 0.2 and exposure-based threshold of - 0.05, above which clinical outcomes markedly worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

A randomised, double blind, placebo-controlled trial of a two-week course of dexamethasone for adult patients with a symptomatic Chronic Subdural Haematoma (Dex-CSDH trial).

Background: Chronic subdural haematoma is a collection of 'old blood' and its breakdown products in the subdural space and predominantly affects older people. Surgical evacuation remains the mainstay in the management of symptomatic cases. Objective: The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) randomised trial investigated the clinical effectiveness and cost-effectiveness of dexamethasone in patients with a symptomatic chronic subdural haematoma. Design: This was a parallel, superiority, multicentre, pragmatic, randomised controlled trial. Assigned treatment was administered in a double-blind fashion. Outcome assessors were also blinded to treatment allocation. Setting: Neurosurgical units in the UK. Participants: Eligible participants included adults (aged ≥ 18 years) admitted to a neurosurgical unit with a symptomatic chronic subdural haematoma confirmed on cranial imaging. Interventions: Participants were randomly assigned in a 1 : 1 allocation to a 2-week tapering course of dexamethasone or placebo alongside standard care. Main outcome measures: The primary outcome was the Modified Rankin Scale score at 6 months dichotomised to a favourable (score of 0-3) or an unfavourable (score of 4-6) outcome. Secondary outcomes included the Modified Rankin Scale score at discharge and 3 months; number of chronic subdural haematoma-related surgical interventions undertaken during the index and subsequent admissions; Barthel Index and EuroQol 5-Dimension 5-Level utility index score reported at discharge, 3 months and 6 months; Glasgow Coma Scale score reported at discharge and 6 months; mortality at 30 days and 6 months; length of stay; discharge destination; and adverse events. An economic evaluation was also undertaken, during which the net monetary benefit was estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Results: A total of 748 patients were included after randomisation: 375 were assigned to dexamethasone and 373 were assigned to placebo. The mean age of the patients was 74 years and 94% underwent evacuation of their chronic subdural haematoma during the trial period. A total of 680 patients (91%) had 6-month primary outcome data available for analysis: 339 in the placebo arm and 341 in the dexamethasone arm. On a modified intention-to-treat analysis of the full study population, there was an absolute reduction in the proportion of favourable outcomes of 6.4% (95% confidence interval 11.4% to 1.4%; p = 0.01) in the dexamethasone arm compared with the control arm at 6 months. At 3 months, the between-group difference was also in favour of placebo (-8.2%, 95% confidence interval -13.3% to -3.1%). Serious adverse events occurred in 60 out of 375 (16.0%) in the dexamethasone arm and 24 out of 373 (6.4%) in the placebo arm. The net monetary benefit of dexamethasone compared with placebo was estimated to be -£97.19. Conclusions: This trial reports a higher rate of unfavourable outcomes at 6 months, and a higher rate of serious adverse events, in the dexamethasone arm than in the placebo arm. Dexamethasone was also not estimated to be cost-effective. Therefore, dexamethasone cannot be recommended for the treatment of chronic subdural haematoma in this population group. Future work and limitations: A total of 94% of individuals underwent surgery, meaning that this trial does not fully define the role of dexamethasone in conservatively managed haematomas, which is a potential area for future study. Trial registration: This trial is registered as ISRCTN80782810. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/15/02) and is published in full in Health Technology Assessment; Vol. 28, No. 12. See the NIHR Funding and Awards website for further award information.

Chronic subdural haematoma is one of the most common conditions managed in adult neurosurgery and mainly affects older people. It is an 'old' collection of blood and blood breakdown products found on the surface of the brain. Surgery to drain the liquid collection is effective, with most patients improving. Given that inflammation is involved in the disease process, a commonly used steroid, dexamethasone, has been used alongside surgery or instead of surgery since the 1970s. However, there is no consensus or high-quality studies confirming the effectiveness of dexamethasone for the treatment of chronic subdural haematoma. This study was designed to determine the effectiveness of adding dexamethasone to the normal treatment for patients with a symptomatic chronic subdural haematoma. The benefit of adding dexamethasone was measured using a disability score called the Modified Rankin Scale, which can be divided into favourable and unfavourable outcomes. This was assessed at 6 months after entry into the study. In total, 748 adults with a symptomatic chronic subdural haematoma treated in neurosurgical units in the UK participated. Each participant had an equal chance of receiving either dexamethasone or a placebo because they were assigned randomly. Neither the patients nor the investigators knew who received dexamethasone and who received placebo. Most patients in both groups had an operation to drain the haematoma and experienced significant functional improvement at 6 months compared with their initial admission to hospital. However, patients who received dexamethasone had a lower chance than patients who received placebo of favourable recovery at 6 months. Specifically, 84% of patients who received dexamethasone had recovered well at 6 months, compared with 90% of patients who received placebo. There were more complications in the group that received dexamethasone. This trial demonstrates that adding dexamethasone to standard treatment reduced the chance of a favourable outcome compared with standard treatment alone. Therefore, this study does not support the use of dexamethasone in treating patients with a symptomatic chronic subdural haematoma.

Temporal Statistical Relationship between Regional Cerebral Oxygen Saturation (rSO2) and Brain Tissue Oxygen Tension (PbtO2) in Moderate-to-Severe Traumatic Brain Injury: A Canadian High Resolution-TBI (CAHR-TBI) Cohort Study.

Brain tissue oxygen tension (PbtO2) has emerged as a cerebral monitoring modality following traumatic brain injury (TBI). Near-infrared spectroscopy (NIRS)-based regional cerebral oxygen saturation (rSO2) can non-invasively examine cerebral oxygen content and has the potential for high spatial resolution. Past studies examining the relationship between PbtO2 and NIRS-based parameters have had conflicting results with varying degrees of correlation. Understanding this relationship will help guide multimodal monitoring practices and impact patient care. The aim of this study is to examine the relationship between PbtO2 and rSO2 in a cohort of TBI patients by leveraging contemporary statistical methods. A multi-institutional retrospective cohort study of prospectively collected data was performed. Moderate-to-severe adult TBI patients were included with concurrent rSO2 and PbtO2 monitoring during their stay in the intensive care unit (ICU). The high-resolution data were analyzed utilizing time series techniques to examine signal stationarity as well as the cross-correlation relationship between the change in PbtO2 and the change in rSO2 signals. Finally, modeling of the change in PbtO2 by the change in rSO2 was attempted utilizing linear methods that account for the autocorrelative nature of the data signals. A total of 20 subjects were included in the study. Cross-correlative analysis found that changes in PbtO2 were most significantly correlated with changes in rSO2 one minute earlier. Through mixed-effects and time series modeling of parameters, changes in rSO2 were found to often have a statistically significant linear relationship with changes in PbtO2 that occurred a minute later. However, changes in rSO2 were inadequate to predict changes in PbtO2. In this study, changes in PbtO2 were found to correlate most with changes in rSO2 approximately one minute earlier. While changes in rSO2 were found to contain information about future changes in PbtO2, they were not found to adequately model them. This strengthens the body of literature indicating that NIRS-based rSO2 is not an adequate substitute for PbtO2 in the management of TBI.

Intracranial Pressure-Derived Cerebrovascular Reactivity Indices and Their Critical Thresholds: A Canadian High Resolution-Traumatic Brain Injury Validation Study.

Current neurointensive care guidelines recommend intracranial pressure (ICP) and cerebral perfusion pressure (CPP) centered management for moderate-severe traumatic brain injury (TBI) because of their demonstrated associations with patient outcome. Cerebrovascular reactivity metrics, such as the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC index, have also demonstrated significant prognostic capabilities with regard to outcome. However, critical thresholds for cerebrovascular reactivity indices have only been identified in two studies conducted at the same center. In this study, we aim to determine the critical thresholds of these metrics by leveraging a unique multi-center database. The study included a total of 354 patients from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative. Based on 6-month Glasgow Outcome Scores, patients were dichotomized into alive versus dead and favorable versus unfavorable. Chi-square values were then computed for incrementally increasing values of each physiological parameter of interest against outcome. The values that generated the greatest chi-squares for each parameter were considered to be the thresholds with the greatest outcome discriminatory capacity. To confirm that the identified thresholds provide prognostic utility, univariate and multivariable logistical regression analyses were performed adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. Through the chi-square analysis, a lower limit CPP threshold of 60 mm Hg and ICP thresholds of 18 mm Hg and 22 mm Hg were identified for both survival and favorable outcome predictions. For the cerebrovascular reactivity metrics, different thresholds were identified for the two outcome dichotomizations. For survival prediction, thresholds of 0.35, 0.25, and 0 were identified for PRx, PAx, and RAC, respectively. For favorable outcome prediction, thresholds of 0.325, 0.20, and 0.05 were found. Univariate logistical regression analysis demonstrated that the time spent above/below thresholds were associated with outcome. Further, multivariable logistical regression analysis found that percent time above/below the identified thresholds added additional variance to the IMPACT core model for predicting both survival and favorable outcome. In this study, we were able to validate the results of the previous two works as well as to reaffirm the ICP and CPP guidelines from the Brain Trauma Foundation (BTF) and the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

Molecular anatomy of adult mouse leptomeninges.

Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.

The impact of sedative and vasopressor agents on cerebrovascular reactivity in severe traumatic brain injury.

BACKGROUND: The aim of this study is to evaluate the impact of commonly administered sedatives (Propofol, Alfentanil, Fentanyl, and Midazolam) and vasopressor (Dobutamine, Ephedrine, Noradrenaline and Vasopressin) agents on cerebrovascular reactivity in moderate/severe TBI patients. Cerebrovascular reactivity, as a surrogate for cerebral autoregulation was assessed using the long pressure reactivity index (LPRx). We evaluated the data in two phases, first we assessed the minute-by-minute data relationships between different dosing amounts of continuous infusion agents and physiological variables using boxplots, multiple linear regression and ANOVA. Next, we assessed the relationship between continuous/bolus infusion agents and physiological variables, assessing pre-/post- dose of medication change in physiology using a Wilcoxon signed-ranked test. Finally, we evaluated sub-groups of data for each individual dose change per medication, focusing on key physiological thresholds and demographics. RESULTS: Of the 475 patients with an average stay of 10 days resulting in over 3000 days of recorded information 367 (77.3%) were male with a median Glasgow coma score of 7 (4-9). The results of this retrospective observational study confirmed that the infusion of most administered agents do not impact cerebrovascular reactivity, which is confirmed by the multiple linear regression components having p value > 0.05. Incremental dose changes or bolus doses in these medications in general do not lead to significant changes in cerebrovascular reactivity (confirm by Wilcoxon signed-ranked p value > 0.05 for nearly all assessed relationships). Within the sub-group analysis that separated the data based on LPRx pre-dose, a significance between pre-/post-drug change in LPRx was seen, however this may be more of a result from patient state than drug impact. CONCLUSIONS: Overall, this study indicates that commonly administered agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity in TBI (nor do they impair cerebrovascular reactivity). Though further investigation in a larger and more diverse TBI patient population is required.

Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia.

The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1ß (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation.

BACKGROUND: Astrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. METHODS: We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. RESULTS: We confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1ß and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC. CONCLUSIONS: Ventral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Cerebrovascular Reactivity Is Not Associated With Therapeutic Intensity in Adult Traumatic Brain Injury: A Validation Study.

Within traumatic brain injury (TBI) care, there is growing interest in pathophysiological markers as surrogates of disease severity, which may be used to improve and individualize care. Of these, assessment of cerebrovascular reactivity (CVR) has been extensively studied given that it is a consistent, independent factor associated with mortality and functional outcome. However, to date, the literature supports little-to-no impact of current guideline-supported therapeutic interventions on continuously measured CVR. Previous work in this area has suffered from a lack of validation studies, given the rarity of time-matched high-frequency cerebral physiology with serially recorded therapeutic interventions; thus, we undertook a validation study. Utilizing the Winnipeg Acute TBI database, we evaluated the association between daily treatment intensity levels, as measured through the therapeutic intensity level (TIL) scoring system, and continuous multi-modal-derived CVR measures. CVR measures included the intracranial pressure (ICP)-derived pressure reactivity index, pulse amplitude index, and RAC index (a correlation between the pulse amplitude of ICP and cerebral perfusion pressure), as well as the cerebral autoregulation measure of near-infrared spectroscopy-based cerebral oximetry index. These measures were also derived over a key threshold for each day and were compared to the daily total TIL measure. In summary, we could not observe any overall relationship between TIL and these CVR measures. This validates previous findings and represents only the second such analysis to date. This helps to confirm that CVR appears to remain independent of current therapeutic interventions and is a potential unique physiological target for critical care. Further work into the high-frequency relationship between critical care and CVR is required.

An overview of clinical cerebral microdialysis in acute brain injury.

Cerebral microdialysis may be used in patients with severe brain injury to monitor their cerebral physiology. In this article we provide a concise synopsis with illustrations and original images of catheter types, their structure, and how they function. Where and how catheters are inserted, their identification on imaging modalities (CT and MRI), together with the roles of glucose, lactate/pyruvate ratio, glutamate, glycerol and urea are summarized in acute brain injury. The research applications of microdialysis including pharmacokinetic studies, retromicrodialysis, and its use as a biomarker for efficacy of potential therapies are outlined. Finally, we explore limitations and pitfalls of the technique, as well as potential improvements and future work that is needed to progress and expand the use of this technology.

Long-term health-related quality of life after trauma with and without traumatic brain injury: a prospective cohort study.

To purpose was to assess and compare the health-related quality of life (HRQoL) and risk of depression two years after trauma, between patients with and without traumatic brain injury (TBI) in a mixed Swedish trauma cohort. In this prospective cohort study, TBI and non-TBI trauma patients included in the Swedish Trauma registry 2019 at a level II trauma center in Stockholm, Sweden, were contacted two years after admission. HRQoL was assessed with RAND-36 and EQ-5D-3L, and depression with Montgomery Åsberg depression Rating Scale self-report (MADRS-S). Abbreviated Injury Score (AIS) head was used to grade TBI severity, and American Society of Anesthesiologists (ASA) score was used to assess comorbidities. Data were compared using Chi-squared test, Mann Whitney U test and ordered logistic regression, and Bonferroni correction was applied. A total of 170 of 737 eligible patients were included. TBI was associated with higher scores in 5/8 domains of RAND-36 and 3/5 domains of EQ-5D (p < 0.05). No significant difference in MADRS-S. An AIS (head) of three or higher was associated with lower scores in five domains of RAND-36 and two domains of EQ-5D but not for MADRS-S. An ASA-score of three was associated with lower scores in all domains of both RAND-36 (p < 0.05, except mental health) and EQ-5D (p < 0.001, except anxiety/depression), but not for MADRS-S. In conclusion, patients without TBI reported a lower HRQoL than TBI patients two years after trauma. TBI severity assessed according to AIS (head) was associated with HRQoL, and ASA-score was found to be a predictor of HRQoL, emphasizing the importance of considering pre-injury health status when assessing outcomes in TBI patients.

Impact of Chronological Age and Biological Sex on Cerebrovascular Reactivity in Moderate/Severe Traumatic Brain Injury: A CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Study.

Impaired cerebrovascular reactivity has emerged as an important associate with poor long-term outcome after moderate/severe traumatic brain injury (TBI). However, our understanding of what drives or modulates the degree of impaired cerebrovascular function remains poor. Age and biological sex remain important modifiers of cerebrovascular function in health and disease, yet their impact on cerebrovascular reactivity after TBI remains unclear. The aim of this study was to explore subgroup responses based on age and biological sex on cerebral physiology. Data from 283 TBI patients from the CAnadian High Resolution TBI (CAHR-TBI) Research Collaborative were evaluated. Cerebrovascular reactivity was determined using high-frequency cerebral physiology for the derivation of three intracranial pressure (ICP)-based indices: 1) pressure reactivity index (PRx)-correlation between ICP and mean arterial pressure (MAP); 2) pulse amplitude index (PAx)-correlation between pulse amplitude of ICP (AMP) and MAP; and 3) RAC-correlation between AMP and cerebral perfusion pressure (CPP). Insult burden (% time above clinically defined thresholds) were calculated for these indices. These cerebral physiology indices were studied for their relationship with age via linear regression, age trichotomization (< 40, 40 - 60, > 60), and decades of age (< 30, 30-39, 40-49, 50-59, 60-69, > 69) schemes. Similarly, differences based on biological sex were assessed. A statistically significant positive linear correlation was found between PAx, RAC, and age. In corollary, a statistically significant relationship was found between increasing age on trichotomized and decades of age analysis with PAx and RAC measures. PRx failed to demonstrate such relationships to advancing age. There was no clear difference in cerebrovascular reactivity profiles between biological sex categories. These findings suggest that AMP-based cerebrovascular reactivity indices may be better positioned to detect impairment in TBI patients with advancing age. Further investigation into the utility of PAx and RAC is required, as they may prove useful for certain subgroups of patients.

Cerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury: a CAnadian High Resolution-TBI (CAHR-TBI) cohort study.

BACKGROUND: Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity. METHODS: A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx). RESULTS: A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact. CONCLUSIONS: In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.

Current state of high-fidelity multimodal monitoring in traumatic brain injury.

INTRODUCTION: Multimodality monitoring of patients with severe traumatic brain injury (TBI) is primarily performed in neuro-critical care units to prevent secondary harmful brain insults and facilitate patient recovery. Several metrics are commonly monitored using both invasive and non-invasive techniques. The latest Brain Trauma Foundation guidelines from 2016 provide recommendations and thresholds for some of these. Still, high-level evidence for several metrics and thresholds is lacking. METHODS: Regarding invasive brain monitoring, intracranial pressure (ICP) forms the cornerstone, and pressures above 22 mmHg should be avoided. From ICP, cerebral perfusion pressure (CPP) (mean arterial pressure (MAP)-ICP) and pressure reactivity index (PRx) (a correlation between slow waves MAP and ICP as a surrogate for cerebrovascular reactivity) may be derived. In terms of regional monitoring, partial brain tissue oxygen pressure (PbtO2) is commonly used, and phase 3 studies are currently ongoing to determine its added effect to outcome together with ICP monitoring. Cerebral microdialysis (CMD) is another regional invasive modality to measure substances in the brain extracellular fluid. International consortiums have suggested thresholds and management strategies, in spite of lacking high-level evidence. Although invasive monitoring is generally safe, iatrogenic hemorrhages are reported in about 10% of cases, but these probably do not significantly affect long-term outcome. Non-invasive monitoring is relatively recent in the field of TBI care, and research is usually from single-center retrospective experiences. Near-infrared spectrometry (NIRS) measuring regional tissue saturation has been shown to be associated with outcome. Transcranial doppler (TCD) has several tentative utilities in TBI like measuring ICP and detecting vasospasm. Furthermore, serial sampling of biomarkers of brain injury in the blood can be used to detect secondary brain injury development. CONCLUSIONS: In multimodal monitoring, the most important aspect is data interpretation, which requires knowledge of each metric's strengths and limitations. Combinations of several modalities might make it possible to discern specific pathologic states suitable for treatment. However, the cost-benefit should be considered as the incremental benefit of adding several metrics has a low level of evidence, thus warranting additional research.

Dexamethasone reduces vascular endothelial growth factor in comparison to placebo in post-operative chronic subdural hematoma samples: A target for future drug therapy?

Background: Chronic subdural hematoma (CSDH) is a collection of blood and fluid that arises on the brain surface due to a combination of trauma and/or inflammation. The mainstay of treatment is surgical drainage, but CSDH can recur. Dexamethasone has been shown to reduce CSDH recurrence, but its mechanism of action has not been fully elucidated. Understanding the inflammatory mediators driving CSDH formation and recurrence and how dexamethasone alters this can help develop new therapeutic strategies. Methods: A subgroup of adult patients recruited to the Dex-CSDH trial, randomized to dexamethasone or placebo, who had surgery for their CSDH, were included. CSDH fluid and peripheral blood were collected intraoperatively, from post-operative drains and operated recurrences. Samples were analyzed using a 12-plex panel of inflammatory mediators. Clinical patient data were also reviewed. Results: A total of 52 patients, with a mean age of 76 years, were included. Five recurrent CSDHs occurred. Vascular endothelial growth factor (VEGF) had the highest concentration across all CSDHs, and only matrix metalloproteinase (MMP)-9 had lower concentrations in CSDH compared to plasma but was increased in recurrent CSDHs. The interleukin (IL)-10 concentration was significantly lower in primary CSDHs that recurred. Most inflammatory mediators increased post-operatively, and dexamethasone significantly reduced the post-operative peak in VEGF on day 2, compared to placebo. Conclusion: It is evident that VEGF plays a critical role in the inflammatory response in CSDH. The post-operative reduction with dexamethasone could signal the mechanism by which it reduces recurrence. Novel therapies with a better side-effect profile than dexamethasone should be targeted at VEGF or potential alternatives such as IL-10 supplementation.

The cerebrospinal fluid proteome of preterm infants predicts neurodevelopmental outcome.

Background: Survival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants. Methods: Twenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured. Results: The CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18-24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development. Conclusion: Our data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome.

Dynamic prediction of mortality after traumatic brain injury using a machine learning algorithm.

Intensive care for patients with traumatic brain injury (TBI) aims to optimize intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The transformation of ICP and CPP time-series data into a dynamic prediction model could aid clinicians to make more data-driven treatment decisions. We retrained and externally validated a machine learning model to dynamically predict the risk of mortality in patients with TBI. Retraining was done in 686 patients with 62,000 h of data and validation was done in two international cohorts including 638 patients with 60,000 h of data. The area under the receiver operating characteristic curve increased with time to 0.79 and 0.73 and the precision recall curve increased with time to 0.57 and 0.64 in the Swedish and American validation cohorts, respectively. The rate of false positives decreased to ≤2.5%. The algorithm provides dynamic mortality predictions during intensive care that improved with increasing data and may have a role as a clinical decision support tool.

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study.

AIM: Perinatal asphyxia, resulting in hypoxic-ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long-term outcomes. METHODS: We prospectively enrolled 18-term born infants with HIE and 10-term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain-derived and inflammation associated proteins in their CSF. RESULTS: Increased CSF concentrations of several brain-specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha-II spectrin. The functional proteins included energy-related proteins like neuron-specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE. CONCLUSION: Brain-specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia.

Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.