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COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Epidemiological studies project a significant rise in cases of chronic subdural haematoma over the next 20 years. Patients with this condition are frequently older and medically complex, with baseline characteristics that may increase peri-operative risk. The intra-operative period is only a small portion of a patient's total hospital stay, with a majority of patients in the United Kingdom transferred between institutions for their surgical and rehabilitative care. Definitive management remains surgical, but peri-operative challenges exist which resonate with other surgical cohorts where multidisciplinary working has become the gold standard. These include shared decision-making, medical optimisation, the management of peri-operative anticoagulation and the identification of key points of equipoise for examination in the future trials. In this narrative review, we use a stereotyped patient journey to provide context to the recent literature, highlighting where multidisciplinary expertise may be required to optimise patient care and maximise the benefits of surgical management. We discuss the triage, pre-operative optimisation, intra-operative management and immediate postoperative care of patients undergoing surgery for a chronic subdural haematoma. We also discuss where adjunctive medical management may be indicated. In so doing, we present the current and emerging evidence base for the role of an integrated peri-operative medicine team in the care of patients with a chronic subdural haematoma.

Background\ud \ud In patients with severe brain injury, withdrawal of life-sustaining measures (WLSM) is common in intensive care units (ICU). WLSM constitutes a dilemma: instituting WLSM too early could result in death despite the possibility of an acceptable functional outcome, whereas delaying WLSM could unnecessarily burden patients, families, clinicians, and hospital resources. We aimed to describe the occurrence and timing of WLSM, and factors associated with timing of WLSM in European ICUs in patients with traumatic brain injury (TBI).\ud \ud \ud \ud Methods\ud \ud The CENTER-TBI Study is a prospective multi-center cohort study. For the current study, patients with traumatic brain injury (TBI) admitted to the ICU and aged 16 or older were included. Occurrence and timing of WLSM were documented. For the analyses, we dichotomized timing of WLSM in early (

Introduction Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King’s College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. Conclusion These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.

Background Convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation for COVID-19 treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial that potentially influence treatment outcomes. Methods SARS-CoV-2 RNA in nasopharyngeal swabs collected pre-treatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Results Of 1274 subjects, 90% were PCR-positive with viral loads 118-1.7x10 11 IU/ml. Median viral loads were 40-fold higher in those seronegative for IgG antibodies (n=354; 28%) compared to seropositives (n=939; 72%). Frequencies of B.1.1.7 increased from

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly. We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray. During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens. Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

Background. Preliminary evidence has highlighted a likely association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods. 46 individuals who received critical care for COVID-19 at Addenbrooke’s hospital (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (+ 2.1) months following acute illness. Patient and matched control (N=460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using an N=66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings. COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) than expected given the matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p=0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia. A trend towards reduced deficits with time from illness (r~=0.15) did not reach statistical significance. Interpretation. Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

Background\ud \ud The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency.\ud \ud \ud \ud Methods\ud \ud We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe.\ud \ud \ud \ud Results\ud \ud From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N = 11, 61%) or locally (N = 7, 39%) and primary IRB approval was obtained after one (N = 8, 44%), two (N = 6, 33%) or three (N = 4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional IRB approval was required in 55% of countries and could increase duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75–224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p = 0.0074).\ud \ud \ud \ud Conclusion\ud \ud We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.

Background The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency. Methods We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe. Results From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N = 11, 61%) or locally (N = 7, 39%) and primary IRB approval was obtained after one (N = 8, 44%), two (N = 6, 33%) or three (N = 4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional IRB approval was required in 55% of countries and could increase duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75–224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p = 0.0074). Conclusion We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.

The precise mechanism of anaesthetic action on a neural level remains unclear. Recent approaches suggest that anaesthetics attenuate the complexity of interactions (connectivity) however evidence remains insufficient. We used tools from network and information theory to show that, during propofol-induced sedation, a collection of brain regions displayed decreased complexity in their connectivity patterns, especially so if they were sparsely connected. Strikingly, we found that, despite their low connectivity strengths, these regions exhibited an inordinate role in network integration. Their location and connectivity complexity delineated a specific pattern of sparse interactions mainly involving default mode regions while their connectivity complexity during the awake state also correlated with reaction times during sedation signifying its importance as a reliable indicator of the effects of sedation on individuals. Contrary to established views suggesting sedation affects only richly connected brain regions, we propose that suppressed complexity of sparsely connected regions should be considered a critical feature of any candidate mechanistic description for loss of consciousness.

Objective: Monitoring cerebral autoregulation (CA) is important for TBI patients, 1 as impaired CA correlates with poor outcome. 2 3 Today, automated algorithms allow to assess CPP for which autoregulation is best preserved (CPPopt) continuously and present it at the bedside 5 6 . Individualising CPP treatment using CPPopt is attractive and this has been recognised in published guidelines. However there are no specifications for its use clinically and it has therefore never been prospectively evaluated 1 . Numerous logistic, technical, feasibility and safety questions remain before the idea of selecting individual CPP treatment targets based on the state of CA 4 can be incorporated into clinical practice. How far are we from strict guidelines on the incorporation of this methodology into TBI protocols? Design: Literature review Subjects: Methods: Systematic review Results: The feasibility of CPPot-guided therapy has only been evaluated retrospectively and in non-clinical ways, whereas no studies exist on its safety. A prospective investigation of CPPopt-guided therapy has been initiated with ‘CppOpt Guided Therapy: Assessment of Target Effectiveness’ (COGiTATE), a multicenter randomized trial assessing feasibility and safety of a continuous CA monitoring-based therapy in adult TBI patients. Conclusions: COGiTATE seems to be the first step to define the physiological effect of targeting CPPopt and should pave the way toward establishing the exact protocol of CPPopt-oriented therapy and the phase III study. References: 1. Carney N, Totten AM, OʼReilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2016;80(1):1. doi:10.1227/NEU.0000000000001432. 2. Hlatky R, Furuya Y, Valadka AB, et al. Dynamic autoregulatory response after severe head injury. J Neurosurg. 2002;97(5):1054-1061. doi:10.3171/jns.2002.97.5.1054. 3. Czosnyka M, Czosnyka Z, Smielewski P. Pressure reactivity index: journey through the past 20 years. doi:10.1007/s00701-017-3310-1. 4. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med. 2002;30(4):733-738. http://www.ncbi.nlm.nih.gov/pubmed/11940737. Accessed December 28, 2017. 5. Aries MJH, Czosnyka M, Budohoski KP, et al. Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury*. Crit Care Med. 2012. doi:10.1097/CCM.0b013e3182514eb6. 6. Liu X, Maurits NM, Aries MJH, et al. Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm. J Neurotrauma. 2017;34(22):3081-3088. doi:10.1089/neu.2017.5003. 7. Depreitere B, Güiza F, Berghe G Van Den, et al. Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data. J Neurosurg. 2014;120(120):1451-1457. doi:10.3171/2014.3.JNS131500. 8. Güiza F, Meyfroidt G, Piper I, et al. Cerebral Perfusion Pressure Insults and Associations with Outcome in Adult Traumatic Brain Injury. doi:10.1089/neu.2016.4807. 9. Oshorov A V, Savin IA, Goriachev AS, Popugaev KA, Potapov AA, Gavrilov AG. [The first experience in monitoring the cerebral vascular autoregulation in the acute period of severe brain injury]. Anesteziol Reanimatol. (2):61-64. http://www.ncbi.nlm.nih.gov/pubmed/18540464. Accessed January 1, 2018. 10. Donnelly J, Czosnyka M, Adams H, et al. Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation. Crit Care Med. 2017;45(9):1464-1471. doi:10.1097/CCM.0000000000002575. 11. Dias C, Silva MJ, Pereira E, et al. Optimal Cerebral Perfusion Pressure Management at Bedside: A Single-Center Pilot Study. Neurocrit Care. 2015;23(1):92-102. doi:10.1007/s12028-014-0103-8. 12. Jaeger M, Dengl M, Jü, Schuhmann MU. Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury*. Crit Care Med. 2010;38(5):1343-1347. doi:10.1097/ccm.0b013e3181d45530.

Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.

To perform systematically a scoping review of the literature on commonly described continuous autoregulation measurement techniques in adult TBI. The goal was to provide an overview of methodology and comprehensive reference library of the available literature for each technique. Five separate small systematic reviews were conducted for each of the continuous techniques: pressure reactivity index (PRx), laser Doppler flowmetry (LDF), near infrared spectroscopy (NIRS) techniques, brain tissue oxygen tension (PbtO2), and thermal diffusion (TD) techniques. Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016) and reference lists of relevant articles were searched. A two-tier filter of references was conducted. The literature base identified from the individual searches was limited, except for PRx. The total number of articles utilizing each of the 5 searched techniques for continuous autoregulation in adult TBI were: PRx (28), LDF (4), NIRS (9), PbtO2 (10), and TD (8). All continuous techniques described in adult TBI are based on moving correlation coefficients. The premise behind the calculation of these moving correlation coefficients focuses on the impact of slow fluctuations in either MAP or CPP on some indirect measure of CBF, such as: intracranial pressure (ICP), LDF, NIRS signals, PbtO2 or TD CBF. The thought is the correlation between a hemodynamic driving factor, such as MAP or CPP, and a surrogate for CBF or cerebral perfusion sheds insight on the state of cerebral autoregulation. Both PRx and NIRS indices were validated experimentally against ‘golden standard’ static autoregulatory curve (Lassen curve) at least around lower threshold of autoregulation. PRx has the largest literature base supporting the association with patient outcome. Various methods of continuous autoregulation assessment are described within the adult TBI literature. Many studies exist on these various indices, suggesting an association between their values and patient morbidity/mortality.

Recent advances in functional neuroimaging have demonstrated novel potential for informing diagnosis and prognosis in the unresponsive wakeful syndrome and minimally conscious states. However, these technologies come with considerable expense and difficulty, limiting the possibility of wider clinical application in patients. Here, we show that high density electroencephalography, collected from 104 patients measured at rest, can provide valuable information about brain connectivity that correlates with behaviour and functional neuroimaging. Using graph theory, we visualize and quantify spectral connectivity estimated from electroencephalography as a dense brain network. Our findings demonstrate that key quantitative metrics of these networks correlate with the continuum of behavioural recovery in patients, ranging from those diagnosed as unresponsive, through those who have emerged from minimally conscious, to the fully conscious locked-in syndrome. In particular, a network metric indexing the presence of densely interconnected central hubs of connectivity discriminated behavioural consciousness with accuracy comparable to that achieved by expert assessment with positron emission tomography. We also show that this metric correlates strongly with brain metabolism. Further, with classification analysis, we predict the behavioural diagnosis, brain metabolism and 1-year clinical outcome of individual patients. Finally, we demonstrate that assessments of brain networks show robust connectivity in patients diagnosed as unresponsive by clinical consensus, but later rediagnosed as minimally conscious with the Coma Recovery Scale-Revised. Classification analysis of their brain network identified each of these misdiagnosed patients as minimally conscious, corroborating their behavioural diagnoses. If deployed at the bedside in the clinical context, such network measurements could complement systematic behavioural assessment and help reduce the high misdiagnosis rate reported in these patients. These metrics could also identify patients in whom further assessment is warranted using neuroimaging or conventional clinical evaluation. Finally, by providing objective characterization of states of consciousness, repeated assessments of network metrics could help track individual patients longitudinally, and also assess their neural responses to therapeutic and pharmacological interventions., The authors received funding from the UK Engineering and Physical Sciences Research Council (EP/P033199/1), Evelyn Trust (Cambridge, UK), the UK National Institute for Health Research (NIHR) as part of the Acute Brain Injury and Repair Theme of the Cambridge Biomedical Research Centre, the NIHR Brain Injury Healthcare Technology Cooperative, the NIHR Senior Investigator award, the James S. McDonnell Foundation, the Belgian National Fund for Scientific Research (FNRS), the European Commission, the Human Brain Project (EUH2020-fetflagship-hbp-sga1-ga720270), the Luminous project (EU-H2020-fetopen-ga686764), the French Speaking Community Concerted Research Action, the Belgian American Educational Foundation, the WallonieBruxelles Federation, the European Space Agency, the University and University Hospital of Liege (Belgium).

Individuals with Down Syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological ageing. This includes brain atrophy, β-amyloid deposition, cognitive decline and Alzheimer’s Disease; factors indicative of brain ageing. Here we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [11C]-PiB positron emission tomography (PET) scans to index levels of cerebral β-amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants’ was +2.49 years, significantly greater than controls (p

BACKGROUND: For critically ill adult patients with acute traumatic brain injury (TBI), we assessed the clinical and cost-effectiveness of: (a) Management in dedicated neurocritical care units versus combined neuro/general critical care units within neuroscience centres. (b) 'Early' transfer to a neuroscience centre versus 'no or late' transfer for those who present at a non-neuroscience centre. METHODS: The Risk Adjustment In Neurocritical care (RAIN) Study included prospective admissions following acute TBI to 67 UK adult critical care units during 2009-11. Data were collected on baseline case-mix, mortality, resource use, and at six months, Glasgow Outcome Scale Extended (GOSE), and quality of life (QOL) (EuroQol 5D-3L). We report incremental effectiveness, costs and cost per Quality-Adjusted Life Year (QALY) of the alternative care locations, adjusting for baseline differences with validated risk prediction models. We tested the robustness of results in sensitivity analyses. FINDINGS: Dedicated neurocritical care unit patients (N = 1324) had similar six-month mortality, higher QOL (mean gain 0.048, 95% CI -0.002 to 0.099) and increased average costs compared with those managed in combined neuro/general units (N = 1341), with a lifetime cost per QALY gained of £14,000. 'Early' transfer to a neuroscience centre (N = 584) was associated with lower mortality (odds ratio 0.52, 0.34-0.80), higher QOL for survivors (mean gain 0.13, 0.032-0.225), but positive incremental costs (£15,001, £11,123 to £18,880) compared with 'late or no transfer' (N = 263). The lifetime cost per QALY gained for 'early' transfer was £11,000. CONCLUSIONS: For critically ill adult patients with acute TBI, within neuroscience centres management in dedicated neurocritical care units versus combined neuro/general units led to improved QoL and higher costs, on average, but these differences were not statistically significant. This study finds that 'early' transfer to a neuroscience centre is associated with reduced mortality, improvement in QOL and is cost-effective.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications., We gratefully acknowledge financial support for participants as follows: P.J.H.-National Institute for Health Research (NIHR) Professorship and the NIHR Biomedical Research Centre, Cambridge; I.J. Medical Research Council (G1002277 ID 98489); A. H.-Medical Research Council, Royal College of Surgeons of England; K.L.H.C.-NIHR Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); M.G.B.-Wellcome Trust Dept Health Healthcare Innovation Challenge Fund (HICF-0510-080); L. H.-The Swedish Research Council, VINNOVA and Uppsala Berzelii Technology Centre for Neurodiagnostics; S. M.-Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico; D.K.M.-NIHR Senior Investigator Award to D.K.M., NIHR Cambridge Biomedical Research Centre (Neuroscience Theme), FP7 Program of the European Union; M. O.-Swiss National Science Foundation and the Novartis Foundation for Biomedical Research; J.S.-Fondo de Investigacion Sanitaria (Instituto de Salud Carlos III) (PI11/00700) co-financed by the European Regional Development; M.S.-NIHR University College London Hospitals Biomedical Research Centre; N. S.-Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico.