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Abstract 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.

Abstract 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-1β 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.

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.

Abstract 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

Abstract 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.

Abstract 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.

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.

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.

BackgroundChronic 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.MethodsA 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.ResultsA 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.ConclusionIt 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.

BackgroundSurvival 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.MethodsTwenty-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.ResultsThe 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.ConclusionOur data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome.

Prognostication is important in the management of critically ill traumatic brain injury (TBI) patients, as it may guide decisions on treatment intensity. Changes in functional connectivity that arise due to TBI have been observed in several brain networks using resting-state functional magnetic resonance imaging (rs-fMRI). Studies suggest that cognitive dysfunction following TBI can, in part, be explained by changes in functional connectivity. The overall aim of this study was to investigate whether easy-to-calculate graph theory-based summaries of brain network functional connectivity can discriminate between patients with favorable and unfavorable outcomes. To further substantiate these results, we used the Louvain algorithm to detect the community structure of each TBI patient, to assess whether it differs from that of healthy individuals.We performed fMRI on 44 TBI patients who were admitted to the neurocritical care unit. Long-term functional outcome was determined at 6–12 months using the Glasgow outcome scale (GOS), with GOS 1–3 being defined as an unfavorable outcome. Functional connectivity was measured using Pearson’s correlation coefficient. We derived topographical summaries of brain network connectivity using graph theory. We computed the participation coefficient (PC) and the module degree z-score (MDZ) for each parcel in the cortical template of Thomas Yeo et al. (2011). As topographical summaries of the network parameters we used the median, maximum and standard deviation (SD) of PC and MDZ in each of the seven functional networks that are included in the cortical parcellation of Yeo et al. Age and sedative medications were used as nuisance regressors.Using multivariate logistic regression, we observed no statistically significant association between the topographical summaries of brain connectivity and the dichotomized GOS. Thus, although graph theoretical measures applied to brain network connectivity patterns have previously been reported to be associated with cognitive dysfunction, they appear to be unable to predict long-term functional outcomes in critically ill TBI patients. Similarly, the extent to which TBI patient’s community structures differed from that of healthy individuals, measured using adjusted mutual information, was also not associated with the dichotomized GOS.In summary, our results suggest that Meso-scale graph theoretical analyses of rs-fMRI brain network connectivity patterns can be expected to perform poorly as a prognostic tool in critically ill TBI patients.

Abstract Background Mild traumatic brain injury (mTBI), i.e. a TBI with an admission Glasgow Coma Scale (GCS) of 13–15, is a common cause of emergency department visits. Only a small fraction of these patients will develop a traumatic intracranial hemorrhage (tICH) with an even smaller subgroup suffering from severe outcomes. Limitations in existing management guidelines lead to overuse of computed tomography (CT) for emergency department (ED) diagnosis of tICH which may result in patient harm and higher healthcare costs. Objective To perform a systematic review and meta-analysis to characterize known and potential novel risk factors that impact the risk of tICH in patients with mTBI to provide a foundation for improving existing ED guidelines. Methods The literature was searched using MEDLINE, EMBASE and Web of Science databases. Reference lists of major literature was cross-checked. The outcome variable was tICH on CT. Odds ratios (OR) were pooled for independent risk factors. Results After completion of screening, 17 papers were selected for inclusion, with a pooled patient population of 26,040 where 2,054 cases of tICH were verified through CT (7.9%). Signs of a skull base fracture (OR 11.71, 95% CI 5.51–24.86), GCS

Abstract Extracorporeal membrane oxygenation (ECMO) is a life-supportive treatment in neonatal patients with refractory lung and/or heart failure. Intracranial hemorrhage (ICH) is a severe complication and reliable predictors are warranted. The aims of this study were to explore the incidence and possible predictors of ICH in ECMO-treated neonatal patients. We performed a single-center retrospective observational cohort study. Patients aged ≤ 28 days treated with ECMO between 2010 and 2018 were included. Exclusion criteria were ICH, ischemic stroke, cerebrovascular malformation before ECMO initiation or detected within 12 h of admission, ECMO treatment 12 h. The primary outcome was a CT-verified ICH. Logistic regression models were employed to identify possible predictors of the primary outcome. Of the 223 patients included, 29 (13%) developed an ICH during ECMO treatment. Thirty-day mortality was 59% in the ICH group and 16% in the non-ICH group (p

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. Plain language summary 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. Scientific summary Background Chronic subdural haematoma (CSDH) is a common neurological disorder predominantly affecting older people, affecting approximately 5000 people aged over 65 years in the UK each year. Its incidence is increasing owing to an ageing population, alongside the growing use of antithrombotic agents. The majority of CSDHs do not cause symptoms and are managed conservatively. In those that do cause symptoms, surgical evacuation remains the mainstay of management, which achieves a good recovery in approximately 80% of patients. The remaining 10–20% of patients may suffer a recurrence, requiring further surgery. Additional and alternative measures to surgery are sought to improve outcomes in this patient group. Inflammation has been implicated in the pathogenesis of CSDHs, which suggests a role for anti-inflammatory medications, such as steroids. Therefore, steroids may serve as a useful adjunct or even alternative to surgery. However, to date, there is a lack of high-quality evidence in the form of a randomised clinical trial or meta-analysis. This trial investigates the clinical effectiveness of a steroid, dexamethasone, in patients with symptomatic CSDH. Objectives Primary objective The primary objective of the trial was to determine the clinical effectiveness of a 2-week course of dexamethasone for adult patients with a symptomatic CSDH, assessed by comparing the rate of favourable outcomes [defined as a Modified Rankin Scale (mRS) score of 0–3] at 6 months after randomisation between the treatment and the control arm. This outcome was reviewed centrally by a clinically trained investigator blinded to treatment allocation. Secondary objectives The secondary objectives were to compare the following outcomes between the treatment and the control arm of the trial: number of CSDH-related surgical interventions undertaken during the index admission number of CSDH-related surgical interventions undertaken during subsequent admissions in the follow-up period Glasgow Coma Scale (GCS) score at discharge from the neurosurgical unit (NSU) and at 6 months Modified Rankin Scale score at discharge from the NSU and at 3 months Barthel Index score at discharge from the NSU and at 3 and 6 months mortality (30 days and 6 months) EuroQol-5 Dimensions, five-level version (EQ-5D-5L), utility index at discharge from the NSU and at 3 and 6 months length of stay in the NSU discharge destination from the NSU length of stay in secondary care rates of adverse events (AEs). An economic evaluation was also undertaken to estimate the cost-effectiveness of dexamethasone compared with placebo. Tertiary objectives Postoperative recurrence is a tertiary outcome measure and is defined as a symptomatic recurrence requiring reoperation of a previously evacuated ipsilateral CSDH. Methods Trial design The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) trial is a multicentre, pragmatic, clinical phase III, randomised, double-blind, placebo-controlled trial of a tapering 2-week course of dexamethasone in patients with a symptomatic CSDH. The pragmatic design meant that the trial ran in parallel with standard clinical care, with the only difference being the addition of the trial drug (dexamethasone) or placebo. Intervention Two-week tapering course of dexamethasone (with matching placebo as the control). Participants Participants were screened for eligibility from 23 NSUs across the UK, with the admitting neurosurgical team determining eligibility for participation. Participants were adult patients aged ≥ 18 years with a symptomatic CSDH confirmed on cranial imaging (computerised tomography or magnetic resonance imaging of the brain). The patient or their legal representative had to provide informed consent. In the absence of a legal representative, an independent healthcare professional provided authorisation for enrolment. Patients were excluded in the presence of any of the following criteria: presence of a condition for which steroids are clearly contraindicated patients who are (or within 1 month of) receiving regular oral or intravenous glucocorticoid steroids (this did not include inhaled or topical steroids, nor did it include those receiving a single intraoperative dose of dexamethasone for anti-emesis) previous enrolment in this trial for a prior episode time interval from time of admission to the NSU to first dose of trial medication exceeded 72 hours chronic subdural haematoma in the presence of a cerebrospinal fluid shunt severe lactose intolerance or a known hypersensitivity to dexamethasone or other excipients a history of psychotic disorders unwillingness to take products containing gelatine. Patients who were screened but not included in the study were recorded on a screening log and reported centrally, with both the number of failures and the reasons for failure to recruit to the trial documented. Trial procedures Patients were managed in NSUs in accordance with standard practice. In the UK, this typically includes burr hole evacuation with the use of a subdural drain for most symptomatic patients. The decision for surgery or active monitoring was made on an individual patient basis by the blinded admitting clinical team in conjunction with the patient, in keeping with the pragmatic nature of the trial. Enrolment in the trial took place irrespective of the decision to operate and the timing of surgical intervention. Patients were randomised in 1 : 1 allocation using a computer-generated randomisation schedule, stratified by site using permuted blocks of random sizes (two or four). An interactive web-based response system was used to allocate treatment packs of 62 overencapsulated 2-mg dexamethasone tablets or 62 identical placebo capsules. The enrolled participants, clinical and research team and outcome assessors were blinded to the treatment allocation. The assigned treatment was administered as part of the routine drug round by the ward nurses. Oral administration was the preferred option, but administration via a nasogastric tube was offered to those unable to swallow. The latter method required opening of the capsules for crushing of the contents, allowing potential unblinding of the ward nurse. Therefore, the content of any opened capsules was not documented in the patient notes to maintain the blinding of the neurosurgeons and research staff. Trial drug compliance was recorded through inpatient drug charts during admission or by completion of a medication diary. Data were collected at baseline (on admission to the neurosurgical department) as part of routine standard of care, on discharge from the acute NSU, at 30 days, at 3 months and at 6 months. Patients were monitored in line with routine clinical practice until discharge, and at 3 and 6 months, to score clinical outcomes. Sample size This sample size was calculated with the following assumptions: a favourable outcome rate of 80–85% in the control arm and allowing for up to 15% loss to follow-up. A target sample size of 750 patients was needed to detect an increase in favourable outcome rate from 80–85% to 88–93%, with a power of 81–92% at the 5% significance level (two sided). An 8% increase in the rate of favourable outcome (mRS score of 0–3) at 6 months represents a clinically important treatment effect. Statistical analysis Data were analysed in accordance with the prespecified statistical analysis plan that was agreed prior to unblinding of data. Outcome data were analysed using a modified intention-to-treat analysis (all patients were included as randomised, except for those who withdrew consent for participation in the trial and those lost to follow-up). The primary outcome (mRS score at 6 months) was dichotomised into favourable (0–3) or unfavourable (4–6) outcomes. Primary analysis estimated the absolute difference between the intervention arm and the control arm in the proportions achieving a favourable outcome. A normal approximation was used to produce 95% confidence intervals (CIs) and a two-sided p-value testing the null hypothesis of no difference. Secondary analysis included a logistic regression and proportional odds logistic regression of the original mRS score adjusting for baseline covariates of age and Glasgow Coma Scale (GCS) score. Economic evaluation In the base-case analysis, costs were estimated over the 6-month trial period from an NHS and a Personal Social Services perspective. Outcomes were quality-adjusted life-years (QALYs) derived from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), at NSU discharge and at the 3- and 6-month follow-ups. Analyses were undertaken to estimate the mean incremental cost and effect, and enable the net monetary benefit (NMB) (a negative score indicates that the intervention is not estimated to be cost-effective) to be calculated, along with the cost-effectiveness acceptability curve (CEAC) (probability that dexamethasone was cost-effective). NMB and CEAC values at a willingness-to-pay threshold of £20,000 per QALY are reported. Results Primary outcome An outcome of mRS score of 0–3 occurred in 286 out of 341 patients (83.9%) in the dexamethasone arm and 306 out of 339 patients (90.3%) in the placebo arm at 6 months (difference −6.4%, 95% CI −11.4% to −1.4%; p = 0.01). After adjustment for prespecified covariates (age > 70 years and GCS score on admission), the odds ratio (OR) of a favourable outcome with dexamethasone was 0.55 (95% CI 0.33 to 0.91; p = 0.022), favouring placebo. Secondary outcomes Modified Rankin Scale at discharge and 3 months At 3 months, 268 out of 322 patients (83.2%) in the dexamethasone arm and 298 out of 326 patients (91.4%) in the placebo arm had a favourable outcome, for a between-group difference of −8.2% (95% CI −13.3% to −3.1%) in favour of the placebo arm. There was no significant difference in mRS score between the two arms at discharge [255/318 (80.2%) in the dexamethasone arm and 263/316 (83.2%) in the placebo arm for a difference of −3.0% (95% CI −9.1% to 3.0%)]. Mortality At discharge, 8 out of 375 patients (2.1%) in the dexamethasone arm and 2 out of 373 patients (0.5%) in the placebo arm had died (OR 4.08, 95% CI 1.01 to 27.2). At 6 months, 30 out of 341 patients (8.8%) in the dexamethasone arm and 17 out of 339 patients (5.0%) in the placebo arm had died (OR 1.83, 95% CI 0.99 to 3.45). Number of chronic subdural haematoma-related surgical interventions undertaken The number of surgical interventions undertaken during the index admission or during subsequent admissions during the follow-up period was similar in both arms. However, in the subset of patients who received surgery, repeat surgery for recurrence of the CSDH was performed in 6 out of 349 patients (1.7%) in the dexamethasone arm and in 25 out of 350 patients (7.1%) in the placebo arm. EuroQol-5 Dimensions, five-level version, utility index (at discharge and at 3 and 6 months) The mean EQ-5D-5L, utility index scores were compared. At discharge, the difference was −0.03 (95% CI −0.07 to 0.01), favouring placebo. At 3 months, the difference was −0.07 (95% CI −0.12 to −0.02), favouring placebo. At 6 months, the difference was −0.03 (95% CI −0.09 to 0.02), favouring placebo. Glasgow Coma Scale (at discharge and at 6 months) Glasgow Coma Scale was grouped into scores of 9–12 and 13–15. The percentage of patients with a score of 13–15 was similar at discharge (99.7% in the placebo arm vs. 99.2% in the dexamethasone arm). Insufficient data at 6 months prevented analysis. Barthel Index (at discharge and at 3 and 6 months) No significant difference was seen between the placebo arm and the dexamethasone arm at discharge, 3 months or 6 months. Length of stay in the neurosurgical unit The mean length of stay was 9.03 days in the placebo arm and 9.32 days in the dexamethasone arm. Length of stay in secondary care The mean length of stay was 13.0 days in the dexamethasone arm and 13.7 days in the placebo arm, with no significant difference between the two arms (0.95, 95% CI 0.835 to 1.09; p = 0.467). Discharge destination from the neurosurgical unit No significant difference was observed between the placebo arm and the dexamethasone arm when comparing discharge destinations. Rates of adverse events The odds of an adverse event of special interest were greater in the dexamethasone arm than in the placebo arm (OR 3.40, 95% CI 1.81 to 6.85). Similarly, the odds of a serious adverse event occurring were greater in the dexamethasone arm than in the placebo arm (OR 2.49, 95% CI 1.54 to 4.15). Economic evaluation The mean incremental cost for dexamethasone was estimated to be −£143.73 (95% CI −£1793 to £1505), with a QALY of −0.012 (95% CI −0.027 to 0.003), compared with placebo. The associated NMB of dexamethasone compared with placebo was −£97.19, with an estimated 46% probability of being cost-effective. Conclusions Implications for healthcare Dexamethasone for the treatment of symptomatic CSDH resulted in a lower proportion of favourable outcomes, as measured with the mRS, and a larger number of AEs than placebo. This treatment regime was also not estimated to be cost-effective (based on the NMB). Therefore, dexamethasone is not recommended in the treatment of CSDH. Implications for research The results of our literature review indicate that this study is the first multicentre randomised controlled trial to investigate the clinical effectiveness and cost-effectiveness of dexamethasone in the management of symptomatic CSDH. It provides evidence to inform the role of dexamethasone in this condition. 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.

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.

Abstract To determine the incidence and identify predictors of brain infarctions (BI) in neonatal patients treated with extracorporeal membrane oxygenation (ECMO). We performed a retrospective cohort study at ECMO Centre Karolinska, Stockholm, Sweden. Logistic regression models were used to identify BI predictors. Neonates (age 0–28 days) treated with veno-arterial (VA) or veno-venous (VV) ECMO between 2010 and 2018. The primary outcome was a computed tomography (CT) verified BI diagnosed during ECMO treatment. In total, 223 patients were included, 102 patients (46%) underwent at least one brain CT and 27 patients (12%) were diagnosed with a BI. BI diagnosis was associated with increased 30-day mortality (48% vs. 18%). High pre-ECMO Pediatric Index of Mortality score, sepsis as the indication for ECMO treatment, VA ECMO, conversion between ECMO modes, use of continuous renal replacement therapy, and extracranial thrombosis were identified as independent predictors of BI development. The incidence of BI in neonatal ECMO patients may be higher than previously understood. Risk factor identification may help initiate steps to lower the risk or facilitate earlier diagnosis of BI in neonates undergoing ECMO treatment.

Introduction Mild traumatic brain injury (mTBI) is one of the most common reasons for emergency department (ED) visits. A portion of patients with mTBI will develop an intracranial lesion that might require medical or surgical intervention. In these patients, swift diagnosis and management is paramount. Several guidelines have been developed to help direct patients with mTBI for head CT scanning, but they lack specificity, do not consider the interactions between risk factors and do not provide an individualised estimate of intracranial lesion risk. The aim of this study is to create a model that estimates individualised intracranial lesion risks in patients with mTBI who present to the ED.Methods and analysis This will be a retrospective cohort study conducted at ED hospitals in Stockholm, Sweden. Eligible patients are adults (≥15 years) with mTBI who presented to the ED within 24 hours of injury and performed a CT scan. The primary outcome will be a traumatic lesion on head CT. The secondary outcomes will be any clinically significant lesion, defined as an intracranial finding that led to neurosurgical intervention, hospital admission ≥48 hours due to TBI or death due to TBI. Machine-learning models will be applied to create scores predicting the primary and secondary outcomes. An estimated 20 000 patients will be included.Ethics and dissemination The study has been approved by the Swedish Ethical Review Authority (Dnr: 2020-05728). The research findings will be disseminated through peer-reviewed scientific publications and presentations at international conferences.Trial registration number NCT04995068.