Traumatic brain injury (TBI) contributes to the global burden of disease in a sizeable manner (1). The incidence of TBI has risen in the past years (2) and is estimated to become even more relevant with increasing events of traffic accidents and falls of the elderly (3, 4).

Traumatic brain injury can be complicated by additional injuries, such as traumatic spinal injuries (TSIs). When studying patients with spinal cord injury, the rate of concomitant TBI was estimated between 40 and 74% (5, 6). TBI in most of these patients was classified as mild (7). It is postulated that in the context of spine trauma, simultaneous TBI events are underdiagnosed (8). Unsurprisingly, TBI pertaining to spinal cord injury was found to be most frequent when the cervical and thoracic spine are affected (9).

Although various reports on TBI from a spinal injury perspective exist, little is known about the converse case of concomitant isolated spine trauma in patients suffering primarily from TBI. A recent meta-analysis found the rate of concomitant TSI in patients with TBI to be at around 13%, with cervical spinal injury amounting to almost half of the injuries diagnosed (10). This consolidates previous reports on cervical spine injury in larger patient cohorts with TBI (11). Indeed, patients with severe TBI were found to be at a particularly higher risk for sustaining injuries to the cervical spine (12).

Previous literature, while epidemiologically describing the prevalence of and risk factors for concomitant TBI and TSI, rarely elucidates the neurological outcomes of affected patients. In a retrospective analysis, patients with simultaneous TBI and TSI were reported to show increased motor deficits and limited functional gains in rehabilitation (13). Nevertheless, the question whether patients with concomitant TBI and TSI bear an inherent risk for a worse neurological outcome or a higher rate of mortality has yet to be tackled by prospectively collected observational data.

This study hence aimed at assessing the prevalence and characteristics of patients with TBI and concurrent, isolated TSI and comparing outcomes of such patients with TBI only in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) cohort.

While there is a wealth of epidemiological data on TBI studied from an SCI perspective, the potential role of a simultaneous TSI in exacerbating neurological deficits in patients with TBI remains largely unexplored. This study reported on concomitant TSI using data from a large prospectively followed up cohort of patients presenting with TBI as their main diagnosis and provided propensity-matching analyses to determine the influence of such injury on their global functional outcomes.

In this cohort, the rate of patients with TBI sustaining further isolated injury of at least serious intensity to the spine was found to be 4%. The rift between our current findings and previous analyses indicating higher rates of TSI in patients with TBI of up to 13% (10) could well be attributed to differences in the applied methodology, especially as to what is defined as an “injury.” One key difference could be the AIS used in this study. The AIS is a standardized tool to reliably classify injuries and assess their severity (18, 19). Patients with TBI were regarded to have suffered a concomitant TSI when the AIS score of the cervical, thoracic, or lumbar spine satisfied at least serious severity. In this functional outcome-oriented analysis, thresholds for defining TSI were set as a trade-off between including patients with very minor and clinically negligible injuries that would otherwise skew the analysis and over-estimate TSI in patients with TBI vs. solely including patients undergoing surgical spinal stabilization and hence overlooking patients sustaining TSI with a “relevant” burden of disease that was managed non-surgically.

In a similar vein, an analysis excluding patients showing further injuries beyond TSI was envisaged to help eliminate possible confounders through further injuries (for example, to the skeletal system), and, therefore, yield a less-biased analysis that could compare characteristics and outcomes of isolated TSI+TBI vs. TBI-only patients. Indeed, further propensity-matching and logistic regression analyses compared patients with TBI, and systemic injuries (that included TSI) did show systemic injuries to be associated with unfavorable outcomes and to prevent full recovery.

Confirming data in previous studies, more than 60% of the spinal injuries diagnosed in our cohort were cervical (10). This was previously linked to the physiological bio-mechanical proximity of the cervical spine to the head (20), rendering concomitant injury to the cervical spine in TBI cases more likely than to other regions of the spine (10). Regarding injury causes, incidental falls and road traffic accidents accounted for the majority of TBIs (47 and 40%, respectively). On the one hand, the rate of road traffic accidents seems to be higher in this cohort than what has been previously reported in (isolated) TBI in high-income countries (21), which lends grounds for speculation that road accidents (which are usually poly-traumas in nature), might contribute to an increased risk of concomitant injury, especially with previous studies showing a high proportion of SCI patients with TBI to be victims of road traffic accidents (9). In addition, motor traffic accidents and herein old age, in particular, have been associated with higher odds of cervical spine injury (22). On the other hand, the larger proportion of incidental falls confirms a worldwide trend of increasing TBI rates secondary to falls of the elderly (4). In this cohort, patients with suspected or confirmed alcohol use amounted to 26%. Indeed, alcohol has been previously shown to be the strongest risk factor for clinical TBI in patients with SCI (7), hinting at the possibility that this could be another factor that fosters concomitant injury.

Missed diagnosis of simultaneous spinal injury in patients with TBI was deemed detrimental in the past and accounted for further neurological deterioration (11), especially because patients suffering severe TBI are difficult to assess clinically and possess a higher risk of sustaining injuries to the cervical spine (12). In terms of prognosis, this observation is, however, not reflected by the data we present, in which outcomes were comparable between TBI+TSI and TBI-only patients. Rather, it is conceivable that the probability of missing relevant spine trauma in the wake of comprehensive CT and MRI imaging [that was less available 20 years earlier (11)] in the participating study centers should be low. This is further supported by the fact that in this cohort, 86% of the patients were primarily transported to a more specialized trauma center (part of the CENTER-TBI study group) where the availability of the necessary infrastructure for diagnosis and treatment of spine trauma (especially spine stabilization surgery) is expected to be higher. It is therefore advisable that given the relevant rate of TSI in patients with TBI and the complex spine surgery these patients might potentially require, patients with TBI are primarily presented to specialized trauma centers of maximum care, especially when concomitant TSI is suspected. This effect could indeed be of even more relevance in the context of patients with mTBI since our analysis demonstrated how in the case of the subgroup of patients with mTBI, isolated TSI (or TSI in conjunction with systemic injuries) does indeed hinder full recovery and negatively influence outcomes.

Although most of the patients in the TBI+TSI cohort were admitted to the ICU, there was no significant difference in mortality when comparing them to patients with isolated TBI in our study. This hints at the possibility that in TBI patients with concomitant TSI, the intracranial injury still represents the main prognosis-limiting factor, especially in severe and moderate TBI. The disparity between the findings on patients with mTBI and all patients of the cohort emphasizes on how the prognosis of patients with moderate and severe TBI is limited by their cranial injury and how TSI becomes more relevant in patients sustaining mTBI, that are otherwise less limited in terms of their neurological outcomes. The question is to whether the necessity of intubation and mechanical ventilation is a result of loss of consciousness owing to TBI or of respiratory failure secondary to injury of the cervical spine remains and cannot be explored using the data provided, although previous reports have indicated the presence of the latter patient group (12).

Similarly, two-thirds of the patients in the TBI+TSI cohort showed a favorable outcome (divided in half between complete recovery and incomplete recovery with a GOSe > 5), leaving a third with unfavorable outcomes in our current analysis. Interestingly, an older study estimated patients with the recovery of neurological function after severe and moderate TBI and concomitant cervical TSI (no mTBIs included) to be at about a third (11), which is very comparable to the data we present. Apart from that, little data have been provided in previous epidemiological studies on the specific functional outcomes of TBI patients with concomitant TSI. This once again emphasizes the importance of the data presented in this study, in which the rates of mortality and unfavorable outcomes in TBI patients with concomitant TSI were comparable to the respective rates observed in a matched group of TBI patients without TSI.

In summary, this analysis of prospective observational data sheds light on the current prognosis of patients suffering from TBI with a concomitant isolated or non-isolated TSI in the CENTER-TBI participating centers, showing an outcome that is comparable with what is known in the literature (15). The data presented underscore the role of specialized trauma care centers in preventing further neurological deterioration owing to concomitant TSI especially in patients with mTBI through early detection and adequate therapy of spine trauma.

Several important limitations must be noted. As an observational study focused on TBI, in general, no additional information on the exact nature of the spine injury or its treatment (that included surgical details) was recorded in the CENTER-TBI database. Thus, injuries to the spinal cord could have been present in some patients but not in others, potentially leading to a considerable heterogeneity for the variable “spine trauma.” This should be considered when interpreting our current results. Additional studies are needed to assess how different types of spine and spinal cord injuries relate to outcomes in patients with TBI. To the same end, detailed parameters assessing specifically the spine function, such as motor and sensory function of the extremities, as well as the function of the autonomic nerve system, were not available but would be desirable both for the description of the baseline clinical status and for the evaluation of recovery at follow-up. In terms of outcome analysis, the matching process is dependent on the chosen covariables and unmeasured covariables that might play an important role are not accounted for. Finally, as only TBI patients with concomitant spine trauma were included, the sample sizes of the different subgroups of patients in our analyses were limited. Larger cohorts are needed for a more robust generalizability and to possibly detect more subtle effects of a concomitant spine injury on outcomes in patients with TBI.

The data analyzed in this study was obtained from the CENTER-TBI database; the following licenses/restrictions apply: Upon a reasonable request, access to the dataset must first be reviewed and approved by the CENTER-TBI Management Committee and should be directed to https://www.center-tbi.eu/data.

Ethical approval was obtained for each recruiting site. A complete list is given on https://www.center-tbi.eu/project/ethical-approval or available as a Supplementary file. All patients had to give their written informed consent before enrollment in CENTER-TBI.

Study concept and design and data collection and analysis: LR and AY. Data interpretation and reviewing and editing: LR, OA, AU, and AY. Writing the manuscript: LR and OA. Supervision: AY. All authors approved the final version of the submitted manuscript.

CENTER-TBI was supported by the European Union 7th Framework program (EC Grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA), and Integra LifeSciences Corporation (USA). Those funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Cecilia Åkerlund¹, Krisztina Amrein², Nada Andelic³, Lasse Andreassen⁴, Audny Anke⁵, Anna Antoni⁶, Gérard Audibert⁷, Philippe Azouvi⁸, Maria Luisa Azzolini⁹, Ronald Bartels¹⁰, Pál Barzó¹¹, Romuald Beauvais¹², Ronny Beer¹³, Bo-Michael Bellander¹⁴, Antonio Belli¹⁵, Habib Benali¹⁶, Maurizio Berardino¹⁷, Luigi Beretta⁹, Morten Blaabjerg¹⁸, Peter Bragge¹⁹, Alexandra Brazinova²⁰, Vibeke Brinck²¹, Joanne Brooker²², Camilla Brorsson²³, Andras Buki²⁴, Monika Bullinger²⁵, Manuel Cabeleira²⁶, Alessio Caccioppola²⁷, Emiliana Calappi ²⁷, Maria Rosa Calvi⁹, Peter Cameron²⁸, Guillermo Carbayo Lozano²⁹, Marco Carbonara²⁷, Simona Cavallo¹⁷, Giorgio Chevallard³⁰, Arturo Chieregato³⁰, Giuseppe Citerio^{31, 32}, Hans Clusmann³³, Mark Coburn³⁴, Jonathan Coles³⁵, Jamie D. Cooper³⁶, Marta Correia³⁷, Amra Cović ³⁸, Nicola Curry³⁹, Endre Czeiter²⁴, Marek Czosnyka²⁶, Claire Dahyot-Fizelier⁴⁰, Paul Dark⁴¹, Helen Dawes⁴², Véronique De Keyser⁴³, Vincent Degos¹⁶, Francesco Della Corte⁴⁴, Hugo den Boogert¹⁰, Bart Depreitere⁴⁵, Ðula Ðilvesi⁴⁶, Abhishek Dixit⁴⁷, Emma Donoghue²², Jens Dreier⁴⁸, Guy-Loup Dulière⁴⁹, Ari Ercole⁴⁷, Patrick Esser⁴², Erzsébet Ezer⁵⁰, Martin Fabricius⁵¹, Valery L. Feigin⁵², Kelly Foks⁵³, Shirin Frisvold⁵⁴, Alex Furmanov⁵⁵, Pablo Gagliardo⁵⁶, Damien Galanaud¹⁶, Dashiell Gantner²⁸, Guoyi Gao⁵⁷, Pradeep George⁵⁸, Alexandre Ghuysen⁵⁹, Lelde Giga⁶⁰, Ben Glocker⁶¹, Jagoš Golubovic⁴⁶, Pedro A. Gomez ⁶², Johannes Gratz⁶³, Benjamin Gravesteijn⁶⁴, Francesca Grossi⁴⁴, Russell L. Gruen⁶⁵, Deepak Gupta⁶⁶, Juanita A. Haagsma⁶⁴, Iain Haitsma⁶⁷, Raimund Helbok¹³, Eirik Helseth⁶⁸, Lindsay Horton ⁶⁹, Jilske Huijben⁶⁴, Peter J. Hutchinson⁷⁰, Bram Jacobs⁷¹, Stefan Jankowski⁷², Mike Jarrett²¹, Ji-yao Jiang⁵⁸, Faye Johnson⁷³, Kelly Jones⁵², Mladen Karan⁴⁶, Angelos G. Kolias⁷⁰, Erwin Kompanje⁷⁴, Daniel Kondziella⁵¹, Evgenios Kornaropoulos⁴⁷, Lars-Owe Koskinen⁷⁵, Noémi Kovács⁷⁶, Ana Kowark⁷⁷, Alfonso Lagares⁶², Linda Lanyon⁵⁸, Steven Laureys⁷⁸, Fiona Lecky^{79, 80}, Didier Ledoux⁷⁸, Rolf Lefering⁸¹, Valerie Legrand⁸², Aurelie Lejeune⁸³, Leon Levi⁸⁴, Roger Lightfoot⁸⁵, Hester Lingsma⁶⁴, Andrew I.R. Maas⁴³, Ana M. Castaño-León⁶², Marc Maegele⁸⁶, Marek Majdan²⁰, Alex Manara⁸⁷, Geoffrey Manley⁸⁸, Costanza Martino⁸⁹, Hugues Maréchal⁴⁹, Julia Mattern⁹⁰, Catherine McMahon⁹¹, Béla Melegh⁹², David Menon⁴⁷, Tomas Menovsky⁴³, Ana Mikolic⁶⁴, Benoit Misset⁷⁸, Visakh Muraleedharan⁵⁸, Lynnette Murray²⁸, Ancuta Negru⁹³, David Nelson¹, Virginia Newcombe⁴⁷, Daan Nieboer⁶⁴, József Nyirádi², Otesile Olubukola⁷⁹, Matej Oresic⁹⁴, Fabrizio Ortolano²⁷, Aarno Palotie^{95, 96, 97}, Paul M. Parizel⁹⁸, Jean-François Payen⁹⁹, Natascha Perera¹², Vincent Perlbarg¹⁶, Paolo Persona¹⁰⁰, Wilco Peul¹⁰¹, Anna Piippo-Karjalainen¹⁰², Matti Pirinen⁹⁵, Dana Pisica⁶⁴, Horia Ples⁹³, Suzanne Polinder⁶⁴, Inigo Pomposo²⁹, Jussi P. Posti ¹⁰³, Louis Puybasset¹⁰⁴, Andreea Radoi ¹⁰⁵, Arminas Ragauskas¹⁰⁶, Rahul Raj¹⁰², Malinka Rambadagalla¹⁰⁷, Isabel Retel Helmrich⁶⁴, Jonathan Rhodes¹⁰⁸, Sylvia Richardson¹⁰⁹, Sophie Richter⁴⁷, Samuli Ripatti⁹⁵, Saulius Rocka¹⁰⁶, Cecilie Roe¹¹⁰, Olav Roise^{111, 112}, Jonathan Rosand¹¹³, Jeffrey V. Rosenfeld¹¹⁴, Christina Rosenlund¹¹⁵, Guy Rosenthal⁵⁵, Rolf Rossaint⁷⁷, Sandra Rossi¹⁰⁰, Daniel Rueckert⁶¹, Martin Rusnák¹¹⁶, Juan Sahuquillo¹⁰⁵, Oliver Sakowitz^{90, 117}, Renan Sanchez-Porras¹¹⁷, Janos Sandor¹¹⁸, Nadine Schäfer⁸¹, Silke Schmidt¹¹⁹, Herbert Schoechl¹²⁰, Guus Schoonman¹²¹, Rico Frederik Schou¹²², Elisabeth Schwendenwein⁶, Charlie Sewalt⁶⁴, Ranjit D. Singh¹⁰¹, Toril Skandsen^{123, 124}, Peter Smielewski²⁶, Abayomi Sorinola¹²⁵, Emmanuel Stamatakis⁴⁷, Simon Stanworth³⁹, Robert Stevens¹²⁶, William Stewart¹²⁷, Ewout W. Steyerberg⁶⁴, ¹²⁸, Nino Stocchetti¹²⁹, Nina Sundström¹³⁰, Riikka Takala¹³¹, Viktória Tamás¹²⁵, Tomas Tamosuitis¹³², Mark Steven Taylor²⁰, Braden Te Ao⁵², Olli Tenovuo¹⁰³, Alice Theadom⁵², Matt Thomas⁸⁷, Dick Tibboel¹³³, Marjolein Timmers⁷⁴, Christos Tolias¹³⁴, Tony Trapani²⁸, Cristina Maria Tudora⁹³, Andreas Unterberg⁹⁰, Peter Vajkoczy ¹³⁵, Shirley Vallance²⁸, Egils Valeinis⁶⁰, Zoltán Vámos⁵⁰, Mathieu van der Jagt¹³⁶, Gregory Van der Steen⁴³, Joukje van der Naalt⁷¹, Jeroen T.J.M. van Dijck ¹⁰¹, Inge A. van Erp¹⁰¹, Thomas A. van Essen¹⁰¹, Wim Van Hecke¹³⁷, Caroline van Heugten⁴², Dominique Van Praag¹³⁸, Ernest van Veen⁶⁴, Thijs Vande Vyvere¹³⁷, Roel P. J. van Wijk¹⁰¹, Alessia Vargiolu³², Emmanuel Vega⁸³, Kimberley Velt⁶⁴, Jan Verheyden¹³⁷, Paul M. Vespa¹³⁹, Anne Vik^{123, 140}, Rimantas Vilcinis¹³², Victor Volovici⁶⁷, Nicole von Steinbüchel³⁸, Daphne Voormolen⁶⁴, Petar Vulekovic⁴⁶, Kevin K.W. Wang¹⁴¹, Daniel Whitehouse⁴⁷, Eveline Wiegers⁶⁴, Guy Williams⁴⁷, Lindsay Wilson⁶⁹, Stefan Winzeck⁴⁷, Stefan Wolf¹⁴², Zhihui Yang¹¹³, Peter Ylén¹⁴³, Alexander Younsi⁹⁰, Frederick A. Zeiler^{47, 144}, Veronika Zelinkova²⁰, Agate Ziverte⁶⁰, Tommaso Zoerle²⁷

¹Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden

²János Szentágothai Research Centre, University of Pécs, Pécs, Hungary

³Division of Surgery and Clinical Neuroscience, Department of Physical Medicine and Rehabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway

⁴Department of Neurosurgery, University Hospital Northern Norway, Tromso, Norway

⁵Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway, Tromso, Norway

⁶Trauma Surgery, Medical University Vienna, Vienna, Austria

⁷Department of Anesthesiology & Intensive Care, University Hospital Nancy, Nancy, France

⁸Raymond Poincare hospital, Assistance Publique – Hopitaux de Paris, Paris, France

⁹Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy

¹⁰Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands

¹¹Department of Neurosurgery, University of Szeged, Szeged, Hungary

¹²International Projects Management, ARTTIC, Munchen, Germany

¹³Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria

¹⁴Department of Neurosurgery & Anesthesia & intensive care medicine, Karolinska University Hospital, Stockholm, Sweden

¹⁵NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK

¹⁶Anesthesie-Réanimation, Assistance Publique – Hopitaux de Paris, Paris, France

¹⁷Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino - Orthopedic and Trauma Center, Torino, Italy

¹⁸Department of Neurology, Odense University Hospital, Odense, Denmark

¹⁹BehaviourWorks Australia, Monash Sustainability Institute, Monash University, Victoria, Australia

²⁰Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia

²¹Quesgen Systems Inc., Burlingame, CA, United States

²²Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

²³Department of Surgery and Perioperative Science, Umeå University, Umeå, Sweden

²⁴Department of Neurosurgery, Medical School, University of Pécs, Hungary and Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Hungary

²⁵Department of Medical Psychology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

²⁶Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

²⁷Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

²⁸ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia

²⁹Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain

³⁰NeuroIntensive Care, Niguarda Hospital, Milan, Italy

³¹School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy

³²NeuroIntensive Care, ASST di Monza, Monza, Italy

³³Department of Neurosurgery, Medical Faculty RWTH Aachen University, Aachen, Germany

³⁴Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany

³⁵Department of Anesthesia & Neurointensive Care, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom

³⁶School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, VIC, Australia

³⁷Radiology/MRI department, MRC Cognition and Brain Sciences Unit, Cambridge, United Kingdom

³⁸Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany

³⁹Oxford University Hospitals NHS Trust, Oxford, United Kingdom

⁴⁰Intensive Care Unit, CHU Poitiers, Potiers, France

⁴¹University of Manchester NIHR Biomedical Research Centre, Critical Care Directorate, Salford Royal Hospital NHS Foundation Trust, Salford, United Kingdom

⁴²Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom

⁴³Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium

⁴⁴Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy

⁴⁵Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium

⁴⁶Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

⁴⁷Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

⁴⁸Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

⁴⁹Intensive Care Unit, CHR Citadelle, Liège, Belgium

⁵⁰Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary

⁵¹Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark

⁵²National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand

⁵³Department of Neurology, Erasmus MC, Rotterdam, the Netherlands

⁵⁴Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway

⁵⁵Department of Neurosurgery, Hadassah-hebrew University Medical center, Jerusalem, Israel

⁵⁶Fundación Instituto Valenciano de Neurorrehabilitación (FIVAN), Valencia, Spain

⁵⁷Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/school of medicine, Shanghai, China

⁵⁸Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden

⁵⁹Emergency Department, CHU, Liège, Belgium

⁶⁰Neurosurgery clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia

⁶¹Department of Computing, Imperial College London, London, United Kingdom

⁶²Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain

⁶³Department of Anesthesia, Critical Care and Pain Medicine, Medical University of Vienna, Austria

⁶⁴Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands

⁶⁵College of Health and Medicine, Australian National University, Canberra, ACT, Australia

⁶⁶Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical Sciences, New Delhi, India

⁶⁷Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands

⁶⁸Department of Neurosurgery, Oslo University Hospital, Oslo, Norway

⁶⁹Division of Psychology, University of Stirling, Stirling, United Kingdom

⁷⁰Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital & University of Cambridge, Cambridge, United Kingdom

⁷¹Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

⁷²Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom

⁷³Salford Royal Hospital NHS Foundation Trust Acute Research Delivery Team, Salford, United Kingdom

⁷⁴Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

⁷⁵Department of Clinical Neuroscience, Neurosurgery, Umeå University, Umeå, Sweden

⁷⁶Hungarian Brain Research Program - Grant No. KTIA_13_NAP-A-II/8, University of Pécs, Pécs, Hungary

⁷⁷Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany

⁷⁸Cyclotron Research Center, University of Liège, Liège, Belgium

⁷⁹Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK

⁸⁰Emergency Department, Salford Royal Hospital, Salford, United Kingdom

⁸¹Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany

⁸²VP Global Project Management CNS, ICON, Paris, France

⁸³Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France

⁸⁴Department of Neurosurgery, Rambam Medical Center, Haifa, Israel

⁸⁵Department of Anesthesiology & Intensive Care, University Hospitals Southhampton NHS Trust, Southhampton, United Kingdom

⁸⁶Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and Sportmedicine, Witten/Herdecke University, Cologne, Germany

⁸⁷Intensive Care Unit, Southmead Hospital, Bristol, Bristol, Uinted Kingdom

⁸⁸Department of Neurological Surgery, University of California, San Francisco, CA, United States

⁸⁹Department of Anesthesia & Intensive Care, M. Bufalini Hospital, Cesena, Italy

⁹⁰Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

⁹¹Department of Neurosurgery, The Walton centre NHS Foundation Trust, Liverpool, United Kingdom

⁹²Department of Medical Genetics, University of Pécs, Pécs, Hungary

⁹³Department of Neurosurgery, Emergency County Hospital Timisoara, Timisoara, Romania

⁹⁴School of Medical Sciences, Örebro University, Örebro, Sweden

⁹⁵Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

⁹⁶Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston, MA, United States

⁹⁷Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, United States

⁹⁸Department of Radiology, University of Antwerp, Edegem, Belgium

⁹⁹Department of Anesthesiology & Intensive Care, University Hospital of Grenoble, Grenoble, France

¹⁰⁰Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy

¹⁰¹Dept. of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Dept. of Neurosurgery, Medical Center Haaglanden, The Hague, Netherlands

¹⁰²Department of Neurosurgery, Helsinki University Central Hospital

¹⁰³Division of Clinical Neurosciences, Department of Neurosurgery and Turku Brain Injury Centre, Turku University Hospital and University of Turku, Turku, Finland

¹⁰⁴Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique, Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France

¹⁰⁵Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Barcelona, Spain

¹⁰⁶Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania

¹⁰⁷Department of Neurosurgery, Rezekne Hospital, Latvia

¹⁰⁸Department of Anaesthesia, Critical Care & Pain Medicine NHS Lothian & University of Edinburg, Edinburgh, United Kingdom

¹⁰⁹Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom

¹¹⁰Department of Physical Medicine and Rehabilitation, Oslo University Hospital/University of Oslo, Oslo, Norway

¹¹¹Division of Orthopedics, Oslo University Hospital, Oslo, Norway

¹¹²Institue of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

¹¹³Broad Institute, Cambridge MA Harvard Medical School, Boston MA, Massachusetts General Hospital, Boston MA, United States

¹¹⁴National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, VIC, Australia

¹¹⁵Department of Neurosurgery, Odense University Hospital, Odense, Denmark

¹¹⁶International Neurotrauma Research Organisation, Vienna, Austria

¹¹⁷Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany

¹¹⁸Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary

¹¹⁹Department Health and Prevention, University Greifswald, Greifswald, Germany

¹²⁰Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg, Austria

¹²¹Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands

¹²²Department of Neuroanesthesia and Neurointensive Care, Odense University Hospital, Odense, Denmark

¹²³Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway

¹²⁴Department of Physical Medicine and Rehabilitation, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

¹²⁵Department of Neurosurgery, University of Pécs, Pécs, Hungary

¹²⁶Division of Neuroscience Critical Care, John Hopkins University School of Medicine, Baltimore, USA

¹²⁷Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, United Kingdom

¹²⁸Dept. of Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands

¹²⁹Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy

¹³⁰Department of Radiation Sciences, Biomedical Engineering, Umeå University, Umeå, Sweden

¹³¹Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland

¹³²Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania

¹³³Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands

¹³⁴Department of Neurosurgery, Kings college London, London, United Kingdom

¹³⁵Neurologie, Neurochirurgie und Psychiatrie, Charité – Universitätsmedizin Berlin, Berlin, Germany

¹³⁶Department of Intensive Care Adults, Erasmus MC– University Medical Center Rotterdam, Rotterdam, the Netherlands

¹³⁷icoMetrix NV, Leuven, Belgium

¹³⁸Psychology Department, Antwerp University Hospital, Edegem, Belgium

¹³⁹Director of Neurocritical Care, University of California, Los Angeles, United States

¹⁴⁰Department of Neurosurgery, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

¹⁴¹Department of Emergency Medicine, University of Florida, Gainesville, Florida, United States

¹⁴²Department of Neurosurgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

¹⁴³VTT Technical Research Centre, Tampere, Finland

¹⁴⁴Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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