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A substantial minority of patients who survive an acquired brain injury develop a state of sympathetic hyperactivity that can persist for weeks or months, consisting of periodic episodes of increased heart rate and blood pressure, sweating, hyperthermia, and motor posturing, often in response to external stimuli. The unifying term for the syndrome—paroxysmal sympathetic hyperactivity (PSH)—and clear diagnostic criteria defined by expert consensus were only recently established. PSH has predominantly been described after traumatic brain injury (TBI), in which it is associated with worse outcomes. The pathophysiology of the condition is not completely understood, although most researchers consider it to be a disconnection syndrome with paroxysms driven by a loss of inhibitory control over excitatory autonomic centres. Although therapeutic strategies to alleviate sympathetic outbursts have been proposed, their effects on PSH are inconsistent between patients and their influence on outcome is unknown. Combinations of drugs are frequently used and are chosen on the basis of local custom, rather than on objective evidence. New rigorous tools for diagnosis could allow better characterisation of PSH to enable stratification of patients for future therapeutic trials. ; GM is funded by the Research Foundation, Flanders as senior clinical investigator. DKM is supported by the National Institute for Healthcare Research (NIHR), UK, through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre and a NIHR Senior Investigator Award, and is supported by a European Union Framework Program 7 grant (CENTER-TBI; grant agreement no. 602150).

Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets. ; CSH is supported by a Wellcome Trust PhD for Clinicians. MPC is funded by the John and Lucille van Geest Foundation. DKM is supported by a Senior Investigator Award from the National Institute for Health Research, UK (NIHR), by the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, and a Framework Program 7 grant from the European Union (CENTER-TBI; Grant No: 602150) ; This is the final version of the article. It first appeared from Elsevier via https://doi.org/ 10.1016/j.tins.2016.03.002

There is an increasing incidence of military traumatic brain injury (TBI), and similar injuries are seen in civilians in war zones or terrorist incidents. Indeed, blast-induced mild TBI has been referred to as the signature injury of the conflicts in Iraq and Afghanistan. Assessment involves schemes that are common in civilcian practice but, in common with civilian TBI, takes little account of information available from modern imaging (particularly diffusion tensor magnetic resonance imaging) and emerging biomarkers. The efficient logistics of clinical care delivery in the field may have a role in optimizing outcome. Clinical care has much in common with civilian TBI, but intracranial pressure monitoring is not always available, and protocols need to be modified to take account of this. In addition, severe early oedema has led to increasing use of decompressive craniectomy, and blast TBI may be associated with a higher incidence of vasospasm and pseudoaneurysm formation. Visual and/or auditory deficits are common, and there is a significant risk of post-traumatic epilepsy. TBI is rarely an isolated finding in this setting, and persistent post-concussive symptoms are commonly associated with post-traumatic stress disorder and chronic pain, a constellation of findings that has been called the polytrauma clinical triad.

Objective: To explore the relationship between various autoregulatory indices in order to determine which approximate small-vessel/microvascular autoregulatory capacity most accurately. Methods: Utilizing a retrospective cohort of traumatic brain injury (TBI) patients (N=41) with: transcranial Doppler (TCD), intracranial pressure (ICP) and cortical laser Doppler flowmetry (LDF), we calculated various continuous indices of autoregulation and cerebrovascular responsiveness: A. ICP derived (pressure reactivity index (PRx) – correlation between ICP and mean arterial pressure (MAP), PAx – correlation between pulse amplitude of ICP (AMP) and MAP, RAC – correlation between AMP and cerebral perfusion pressure (CPP)), B. TCD derived (Mx – correlation between mean flow velocity (FVm) and CPP, Mx_a – correlation betrween FVm and MAP, Sx – correlation between systolic flow velocity (FVs) and CPP, Sx_a – correlation between FVs and MAP, Dx – correlation between diastolic flow index (FVd) and CPP, Dx_a – correlation between FVd and MAP), and LDF derived (Lx – correlation between LDF cerebral blood flow (CBF) and CPP, Lx_a – correlation between LDF-CBF and MAP). We assessed the relationship between these indices via Pearson correlation, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC) and k-means cluster analysis (KMCA). Results: LDF based autoregulatory index (Lx) was most associated with TCD based Mx/Mx_a and Dx/Dx_a across Pearson correlation, PCA, AHC and KMCA. Lx was only remotely associated with ICP based indices (PRx, PAx, RAC). TCD based Sx/Sx_a were more closely associated with ICP derived PRx, PAx and RAC. This indicates that vascular derived indices of autoregulatory capacity (ie. TCD and LDF based) co-vary, with Sx/Sx_a being the exception. Whereas, indices of cerebrovascular reactivity derived from pulsatile CBV (ie. ICP indices) appear to not be closely related to those of vascular origin. Conclusions: Transcranial Doppler Mx is the most closely associated with LDF based Lx/Lx_a. Both Sx/Sx-a and the ICP derived indices appear to be dissociated with LDF based cerebrovascular reactivity, leaving Mx/Mx-a as a better surrogate for the assessment of cortical small vessel/microvascular cerebrovascular reactivity. Sx/Sx_a co-cluster/co-vary with ICP derived indices, as seen in our previous work. ; This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada – Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150) MC is supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1790). JD is supported by a Woolf Fisher Scholarship (NZ).

OBJECTIVE: To perform two scoping systematic reviews of the literature on cytokine measurement in cerebral microdialysis (CMD) and cerebrospinal fluid (CSF) in aneurysmal subarachnoid hemorrhage (SAH) patients, aiming to summarize the evidence relating cytokine levels to pathophysiology, disease progression, and outcome. METHODS: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. DATA SOURCES: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. STUDY SELECTION: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. DATA EXTRACTION: Patient demographic and study data were extracted to tables. RESULTS: There were 9 studies identified describing the analysis of cytokines via CMD in 246 aneurysmal SAH patients. Similarly, 20 studies were identified describing the analysis of CSF cytokines in 630 patients. The two scoping systematic reviews demonstrated the following: (1) limited literature available on CMD cytokine measurement in aneurysmal SAH with some preliminary data supporting feasibility of measurement and potential association between interleukin (IL)-6 and patient outcome. (2) Various CSF measured cytokines may be associated with patient outcome at 3–6 months, including IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. (3) There is a small literature body supporting an association between acute/subacute CSF transforming growth factor levels and the development of chronic hydrocephalus at 2–3 months. CONCLUSION: The evaluation of CMD and CSF cytokines is an emerging area of the literature in aneurysmal SAH. Further large prospective multicenter studies on cytokines in CMD and CSF need to be conducted. ; This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada – Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund EPT has received funding support from Swedish Society of Medicine (Grant no. SLS-587221). AH receives support from the Medical Research Council (MRC), Cambridge Biomedical Research Centre, Royal College of Surgeons of England (G0802251) These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM, and an NIHR Research Professorship to PJAH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150) PJH receives support from the National Institute of Health Research, Cambridge Biomedical Research Centre.

Objective: To perform two scoping systematic reviews of the literature on cytokine measurement in cerebral microdialysis (CMD) and cerebrospinal fluid (CSF) in aneurysmal subarachnoid hemorrhage (SAH) patients, aiming to summarize the evidence relating cytokine levels to pathophysiology, disease progression, and outcome. Methods: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Data sources: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. Study selection: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. Data extraction: Patient demographic and study data were extracted to tables. Results: There were 9 studies identified describing the analysis of cytokines via CMD in 246 aneurysmal SAH patients. Similarly, 20 studies were identified describing the analysis of CSF cytokines in 630 patients. The two scoping systematic reviews demonstrated the following: (1) limited literature available on CMD cytokine measurement in aneurysmal SAH with some preliminary data supporting feasibility of measurement and potential association between interleukin (IL)-6 and patient outcome. (2) Various CSF measured cytokines may be associated with patient outcome at 3-6 months, including IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. (3) There is a small literature body supporting an association between acute/subacute CSF transforming growth factor levels and the development of chronic hydrocephalus at 2-3 months. Conclusion: The evaluation of CMD and CSF cytokines is an emerging area of the literature in aneurysmal SAH. Further large prospective multicenter studies on cytokines in CMD and CSF need to be conducted. ; This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund. ET has received funding support from Swedish Society of Medicine (grant no. SLS-587221). AH receives support from the Medical Research Council (MRC) (Studentship for Neuro-inflammation following Human Traumatic Brain Injury - G0802251), Cambridge Biomedical Research Centre, and Royal College of Surgeons of England. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; grant agreement no. 602150). PH receives support from the National Institute of Health Research, Cambridge Biomedical Research Centre.

Objective: To perform two scoping systematic reviews of the literature on cytokine measurement in: 1. Cerebral Microdialysis (CMD) and 2. Cerebrospinal Fluid (CSF) in severe traumatic brain injury (TBI) patients. Methods: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Both were conducted in severe TBI patients only. Data Sources: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to Oct 2016), reference lists of relevant articles, and gray literature were searched Study Selection: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. Data Extraction: Patient demographic and study data was extracted to tables. Results: There were 19 studies identified describing the analysis of cytokines via CMD in 267 severe TBI patients. Similarly, there were 32 studies identified describing the analysis of CSF cytokines in 1363 severe TBI patients. The two systematic reviews demonstrated: 1. Limited literature available on CMD cytokine measurement in severe TBI, with some preliminary data supporting feasibility of measurement and associations between cytokines and patient outcome. 2. Various CSF measured cytokines may be associated with patient outcome at 6 to 12 months, including: IL-1b, IL-1ra, IL-6, IL-8, IL-10 and TNF. 3. There is little to no literature in support of an association between CSF cytokines and neuro-physiologic or tissue outcomes. Conclusions: The evaluation of CMD and CSF cytokines is an emerging area of the literature in severe TBI. Further large prospective multi-center studies on cytokines in CMD and CSF need to be conducted. ; This work was made possible through salary support through: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada – Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM, and an NIHR Research Professorship to PJAH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150) EPT has received funding support from Swedish Society of Medicine (Grant no. SLS-587221).

OBJECTIVE: To perform two scoping systematic reviews of the literature on cytokine measurement in: 1. cerebral microdialysis (CMD) and 2. cerebrospinal fluid (CSF) in severe traumatic brain injury (TBI) patients. METHODS: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Both were conducted in severe TBI (sTBI) patients only. DATA SOURCES: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. STUDY SELECTION: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. DATA EXTRACTION: Patient demographic and study data were extracted to tables. RESULTS: There were 19 studies identified describing the analysis of cytokines via CMD in 267 sTBI patients. Similarly, there were 32 studies identified describing the analysis of CSF cytokines in 1,363 sTBI patients. The two systematic reviews demonstrated: 1. limited literature available on CMD cytokine measurement in sTBI, with some preliminary data supporting feasibility of measurement and associations between cytokines and patient outcome. 2. Various CSF measured cytokines may be associated with patient outcome at 6-12 months, including interleukin (IL)-1b, IL-1ra, IL-6, IL-8, IL-10, and tumor necrosis factor 3. There is little to no literature in support of an association between CSF cytokines and neurophysiologic or tissue outcomes. CONCLUSION: The evaluation of CMD and CSF cytokines is an emerging area of the literature in sTBI. Further, large prospective multicenter studies on cytokines in CMD and CSF need to be conducted. ; This work was made possible through salary support through: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Traveling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Center, an NIHR Senior Investigator Award to DM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150). ET has received funding support from Swedish Society of Medicine (Grant no. SLS-587221). AH is supported by an MRC Studentship for Neuro-inflammation following Human Traumatic Brain injury (G0802251).

BACKGROUND: Both intracranial pressure (ICP) and the cerebrovascular pressure reactivity represent the dysregulation of pathways directly involved in traumatic brain injury (TBI) pathogenesis and have been used to inform clinical management. However, how these parameters evolve over time following injury and whether this evolution has any prognostic importance have not been studied. METHODS AND FINDINGS: We analysed the temporal profile of ICP and pressure reactivity index (PRx), examined their relation to TBI-specific mortality, and determined if the prognostic relevance of these parameters was affected by their temporal profile using mixed models for repeated measures of ICP and PRx for the first 240 hours from the time of injury. A total of 601 adults with TBI, admitted between September 2002 to January 2016, and with high-resolution continuous monitoring from a single centre, were studied. At 6 months postinjury, 133 (19%) patients had a fatal outcome; of those, 88 (78%) died from nonsurvivable TBI or brain death. The difference in mean ICP between those with a fatal outcome and functional survivors was only significant for the first 168 hours after injury (all p < 0.05). For PRx, those patients with a fatal outcome also had a higher (more impaired) PRx throughout the first 120 hours after injury (all p < 0.05). The separation of ICP and PRx was greatest in the first 72 hours after injury. Mixed models demonstrated that the explanatory power of the PRx decreases over time; therefore, the prognostic weight assigned to PRx should similarly decrease. However, the ability of ICP to predict a fatal outcome remained relatively stable over time. As control of ICP is the central purpose of TBI management, it is likely that some of the information that is reflected in the natural history of ICP changes is no longer apparent because of therapeutic intervention. CONCLUSIONS: We demonstrated the temporal evolution of ICP and PRx and their relationship with fatal outcome, indicating a potential early prognostic and therapeutic window. The combination of dynamic monitoring variables and their time profile improved prediction of outcome. Therefore, time-driven dynamic modelling of outcome in patients with severe TBI may allow for more accurate and clinically useful prediction models. Further research is needed to confirm and expand on these findings. ; DKM is supported by a Senior Investigator award from the NIHR and a European Union Seventh Framework Program grant (CENTER-TBI; grant no. 602150). PJH is supported by a Research Professorship from the NIHR, the NIHR Cambridge Biomedical Research Centre.

Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t₁⁄₂) in order to describe the "fall" rate in serum. Materials and methods: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. Results: Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t₁⁄₂ of about 24 h, even if very early sampling in these patients reveals rapid decreases (1–2 h) though possibly of non-cerebral origin. In contrast, the t₁⁄₂ for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t₁⁄₂ of about 24–48 h in severe TBI. The protein UCH-L1 (n = 9) presents a ₁⁄₂ around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. Conclusion: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI. ; ET: Swedish Society of Medicine (Grant no. SLS-587221). FZ: Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund. AB: Hungarian Brain Research Program—Grant No. KTIA_13_NAP-A- II/8. DM: National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DM. The authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150). AH: Medical Research Council, Cambridge Biomedical Research Centre, Royal College of Surgeons of England. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: Computed tomography (CT) is the most common imaging modality in traumatic brain injury (TBI). However, its conventional use requires expert clinical interpretation and does not provide detailed quantitative outputs, which may have prognostic importance. Deep learning could reliably and efficiently detect, distinguish, and quantify different lesion types, providing opportunities for personalised treatment strategies and clinical research. Methods: An initial convolutional neural network (CNN) was trained and validated on expert manual segmentations (97 scans). This CNN was then used to automatically segment a new set of 839 scans, which were then manually corrected by experts. From these, a subset of 184 scans was used to train a final CNN for multi-class, voxel-wise segmentation of lesion types. The performance of this CNN was evaluated on a held-out test set with 655 scans. External validation was performed on a large, independent set of 500 patients from a different continent. Findings: When compared to manual reference, CNN-derived lesion volumes showed a mean error of 0·86mL (95% CI -5·23 to 6·94) for intraparenchymal haemorrhage (IPH), 1·83mL (-12·01 to 15·66) for extra-axial haemorrhage (EAH), 2·09mL (-9·38 to 13·56) for perilesional oedema and 0·07mL (-1·00 to 1·13) for intraventricular haemorrhage (IVH). Further, the CNN detected lesions with AUCs of 0·90 (0·86-0·94) for IPH, 0·80 (0·75-0·85) for EAH, 0·95 (0·89-1·00) for IVH on the external, independent patient dataset. Interpretation: We demonstrate the ability of a CNN to separately segment, detect and quantify multi-class haemorrhagic lesions and importantly, perilesional oedema. These volumetric lesion estimates allow clinically relevant quantification of lesion burden and progression, with potential applications in clinical care and research in TBI. Funding: European Union 7th Framework Programme, Hannelore Kohl Stiftung; OneMind; Integra Neurosciences; European Research Council Horizon 2020; Engineering and Physical Sciences Research Council (UK); Academy of Medical Sciences/Health Foundation (UK); National Institute for Health Research (UK). ; CENTER-TBI study was supported by the European Union 7th Framework program (EC grant 602150). Additional funding sources: Hannelore Kohl Stiftung; NeuroTrauma Sciences; Integra Neurosciences; European Research Council (ERC) Horizon 2020 (EC grant 757173); Engineering and Physical Sciences Research Council (EPSRC) (EP/R511547/1); Academy of Medical Sciences/The Health Foundation (UK); National Institute for Health Research (UK).

Background: Traumatic brain injury is a major cause of death and severe disability worldwide with 1,000,000 hospital admissions per annum throughout the European Union.Therapeutic hypothermia to reduce intracranial hypertension may improve patient outcome but key issues are length of hypothermia treatment and speed of re-warming. A recent meta-analysis showed improved outcome when hypothermia was continued for between 48 hours and 5 days and patients were re-warmed slowly (1°C/4 hours). Previous experience with cooling also appears to be important if complications, which may outweigh the benefits of hypothermia, are to be avoided.Methods/design: This is a pragmatic, multi-centre randomised controlled trial examining the effects of hypothermia 32-35°C, titrated to reduce intracranial pressure 20 mmHg in accordance with the Brain Trauma Foundation Guidelines, 2007.Discussion: The Eurotherm3235Trial is the most important clinical trial in critical care ever conceived by European intensive care medicine, because it was launched and funded by the European Society of Intensive Care Medicine and will be the largest non-commercial randomised controlled trial due to the substantial number of centres required to deliver the target number of patients. It represents a new and fundamental step for ...

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.

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.