Introduction

Traumatic Brain Injury (TBI) is an important threat to public health with a crude incidence rate of up to 849 per 100,000 people in European countries [1, 2]. TBI is emerging as one of the leading causes of death and disability worldwide resulting in huge personal suffering and far-reaching socioeconomic consequences [3, 4].

Different perspectives on various aspects of care exist, and the evidence underpinning guideline recommendations for treatment of patients with TBI is weak [3, 5]. There is growing realization that randomized clinical trials alone will not be able to provide the evidence base that is needed to address these knowledge gaps [6]. Comparative effectiveness research (CER) has been proposed as a good complementary approach to strengthen the evidence base. CER has been defined as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care” [7]. CER exploits between-center differences in patient management by comparing centers that perform a certain intervention routinely to others that do not. This approach is expected to be particularly suitable for TBI since large between-center differences in both patient management and outcomes have been previously reported [8, 9].

The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study is a large-scale observational multicenter study focusing on characterization and CER in TBI. The first step for CER is to provide an overview of variation in structures and processes of care in the participating centers (‘provider profiling’). Such an overview can be used to identify areas where large between-center variation exists, to guide future CER analyses. But it can also directly be used for CER. For example, treatment effectiveness of a certain intervention can be studied by comparing outcome in patients from centers that routinely perform the intervention to outcome in patients from centers that do not routinely perform the intervention. Therefore, the objective of the current study is to quantify variation in general structure and process characteristics among centers participating in the CENTER-TBI study and to identify topics for CER.

Material and Methods

Development process of the Provider Profiling Questionnaires

The PP questionnaires went through a comprehensive developing process to warrant completeness and relevance of topics and face validity of questions. The neurotrauma evidencemap (http://neurotrauma.evidencemap.org/) was searched for gaps and inconsistencies in knowledge of optimal treatment and organization of TBI care, and used to define topics of interest. We included topics relevant for CER as well as topics relevant for descriptive analyses. Initial questions were formulated based on literature and suggestions from experts in the field. Available surveys and questionnaires in the field of TBI or critical care [10, 11] were searched for and used for the (re)formulation of (additional) questions.

Questions related either to structures or processes of general or TBI-specific care. Structure refers to the conditions under which patient care is provided (e.g. the number of beds, trauma center designation, hospital facilities), and process refers to activities that constitute patient care (e.g. general hospital or department policies) [12]. Structural information could be extracted from hospital databases, annual reports and local registries. Process information refers to general policies rather than individual treatment preferences of responsible physicians. General policy was defined as ‘the way the large majority of patients (>75%) with a certain indication would be treated’, recognizing that there might be exceptions. We included open questions and multiple-choice questions. All questions were presented with text boxes that contained definitions and a short explanation about the interpretation and completion of the question. The definitions used in this paper are summarized in the Supplemental material (S2 File).

Experts in the field provided feedback on the initial formulated questions and proposed new questions and topics in three subsequent phases. Consulted experts included neurosurgeons, (neuro)intensivists, neurologists, emergency department (ED) physicians, rehabilitation physicians, medical ethicists, health care economists and epidemiologists. Some of the consulted experts had previous experience with the design and conduct of surveys in the field of TBI or critical care. In a first phase, a small group of involved experts discussed the questionnaires during an email conversation and a group discussion. In a second phase, an international expert panel, consisting of 25 experts from 9 countries, was consulted per email. These experts provided feedback on one or more of the questionnaires. Decisions on proposed content and formulation were then made during a group discussion with a small group of involved experts. These draft PP questionnaires were then pilot-tested in 16 of the participating CENTER-TBI centers. Each center completed two or three questionnaires, such that each questionnaire was pilot-tested at least three times. All answers were checked for unexpected or missing values and ambiguous questions were subsequently reformulated or deleted. Pilot-testers additionally completed a form in which they were asked to provide feedback, which was incorporated accordingly. All these processes resulted in a final set of eleven questionnaires related to different phases of TBI care (see Table 1). In total, there were 321 questions included in the PP.

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Table 1. Characteristics of the Provider Profiling questionnaires.

https://doi.org/10.1371/journal.pone.0161367.t001

Results

Completion process

All 71 eligible centers completed the provider profiling questionnaire about general structural and process information. Questionnaires were completed by multiple persons per center, including neurologists, neurosurgeons, trauma surgeons, intensivists, research nurses and administrative staff members. The 71 centers were from 20 European countries (see Fig 1). Each country had 1 to 9 participating centers (median = 2.5). The United Kingdom (UK) had most centers participating (n = 9), while Serbia and Switzerland both had one participating center. Thirteen of the included centers were from relatively lower-income countries and 25 centers were from countries in South and East Europe (including Israel).

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Fig 1. Centers and countries included in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study Note.

Reprinted and updated from Maas et al. (2015). Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury: a prospective longitudinal observational study. Neurosurgery, 76:67–80, under a CC BY licence, with permission from professor A.I. Maas.

https://doi.org/10.1371/journal.pone.0161367.g001

General structural characteristics

The participating centers were predominately academic centers (n = 65, 92%), designated as a level I or II trauma center (n = 54, n = 74%) and situated in an urban location (n = 70, 99%, see Table 2). The majority of participants indicated that they had access to a helicopter platform (n = 57, 80%) and an acute trauma team (n = 63, 89%). Around half of the centers (n = 40, 57%) had a dedicated neuro ICU. Centers from relatively high- and middle-income countries more often indicated that they have a dedicated neuro ICU (n = 35, 61%) than centers from relatively lower-income countries (n = 5, 39%, p = .13, S1 Table). The large majority of centers had participated previously in research about acute cerebral disorders. Fifty-one (72%) centers were involved in more than five neurotrauma research applications over the past five years (see Table 2).

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Table 2. General structural characteristics of the participating centers (n = 71).

https://doi.org/10.1371/journal.pone.0161367.t002

The median number of beds in the participating centers was 1000 (IQR 682–1395) of which 31 (IQR 22–44) were ICU beds (see Table 3 and S1 Fig). Centers had a median of 3 (IQR 2–6) resuscitation rooms at the ED and 24 (IQR 16–39) operating rooms. Three (IQR 2–4) of these were potentially available for TBI patients. The median number of annual ED visits was 53,428 (IQR 30,002–90,268). The median number of annual ICU admission was 1240 (IRQ 560–2019), of which 91 (IQR 52–160) were TBI patients.

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Table 3. Volume characteristics of the participating centers (n = 71).

https://doi.org/10.1371/journal.pone.0161367.t003

Seventy-five per cent (n = 53) of the centers had separate 24/7 emergency operation rooms. The majority of centers indicated that they had an electronic patient system at the ward (n = 57, 80%) and the ICU (n = 56, 79%). There was variation in the organization of the ICU in the participating centers; i.e. 45 (64%) centers had a closed ICU organization, 3 (4%) an open ICU organization and the remainder (n = 22, 32%) a mixed ICU organization. Centers from relatively high- and middle-income countries more often reported that they had a closed ICU structure (n = 40, 70%) compared to centers from relatively lower-income countries (n = 5, 39%). Step down beds were available in 71% (n = 50) of the centers. Centers from North and West Europe more often reported that they had a step down bed facility than centers from South and East Europe and Israel (n = 36, 80% vs. n = 14, 56%, p = .03, S1 Table). Maximum laboratorium turnaround times, the possibility for in-hospital coma stimulation and the location of TBI relevant facilities also varied widely among the included centers (see Table 4).

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Table 4. Hospital facilities of the participating centers (n = 71).

https://doi.org/10.1371/journal.pone.0161367.t004

On average 14 neurologists, 10 neurosurgeons, 17 intensivists, 4 trauma surgeons and 10 ED physicians were working in the centers (see Table 5). Nearly all centers (n = 69, 97%) had at least one residency program for trainees towards becoming a specialist. The specialist most often in charge of TBI patients at respectively the ED, ward and ICU were predominately ED physicians, neurosurgeons and intensivists. Most centers had 24/7 in-house availability of OR personnel (n = 62, 87%) and CT technicians (n = 66, 93%). Median intensivist-to-patient ratio, and ICU nurse-to-patient ratio were 1: 5 (IQR 1:3 to 1:8) and 1:2 (IQR 1:1 to 1:3). Night coverage at the ICU was performed by a certified intensivist in two-third of the centers (n = 44, 65%) and by a trainee or fellow in the remainder of centers. Almost all centers from the relatively lower-income countries (n = 12, 92%) reported that night coverage was performed by a certified intensivist, in comparison to 58% of the centers from the relatively high- and middle-income countries. Also, more centers from South and East Europe (n = 22, 88%) had night coverage by a certified intensivist, compared to centers from North and West Europe (n = 22, 51%, S1 Table).

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Table 5. Staffing characteristics of the participating centers (n = 71).

https://doi.org/10.1371/journal.pone.0161367.t005

General process characteristics

With regard to computed tomography (CT) scanning in patients with mild TBI at the ED, 79% of the centers (n = 54) indicated to use CT guidelines (see Table 6). In addition, seven centers (10%) from Austria, Denmark, France, Spain and Sweden routinely determine S100B as a prognostic biomarker for neurological deterioration at the ED. There was variation among centers in their ICU admission policy; i.e. 44 (64%) centers generally admit patients with moderate TBI (Glasgow Coma Scale (GCS) 9–12) and CT abnormalities to the ICU, while 25 (36%) centers only admit these patients to the ICU in the presence of other risk factors. This variation was also shown for moderate TBI patients without CT abnormalities and patients with mild TBI on anti-coagulant therapy. There was a trend towards a higher ICU admission rate in centers from relatively high- and middle-income countries than in centers from relatively lower-income countries (S2 Table).

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Table 6. General process information of the participating centers (n = 71).

https://doi.org/10.1371/journal.pone.0161367.t006

The large majority of participants (n = 61, 91%) indicated that their general policy is to insert intracranial pressure (ICP) monitors in patients with GCS <9 and CT abnormalities. However, centers vary in whether they would place an ICP monitor in patients with GCS <9 without CT abnormalities and patients with intraventricular haemorrhages. Variation in ICP monitoring is also reported within the centers, since half of the centers indicated that there is structural variation between (neuro)surgeons in their center with regard to the decision to place an ICP monitor. The threshold for medical management of elevated ICP was 20 mmHg in the large majority of centers (n = 57, 87%). However, centers varied widely in their threshold for decompressive craniotomy; i.e. in 12% (n = 7) the threshold was 20 mmHg, in 57% (n = 35) the threshold was 25 mmHg and in 31% (n = 19) the threshold was 30 mmHg.

Discussion

We found considerable variation in general structure and process characteristics among 71 specialized neurotrauma centers participating in the CENTER-TBI study. Most of these centers were high-volume academic level I trauma centers situated in an urban location. Centers varied widely in their ICU organization, hospital facilities and admission- and treatment policies. The effectiveness of these structures and interventions can therefore adequately be studied with CER.

Our provider profiling questionnaires have strengths and limitations. One of the strengths is the comprehensive development process, which consisted of several stages and involved many experts. As a consequence, the questionnaires address all aspects relevant to TBI care. Secondly, local investigators were extensively informed about the aim, procedures and practical issues during presentations, workshops and emails. This might explain the 100% response rate. The length of our questionnaires can be regarded as a limitation. Long questionnaires have been associated with lower data quality [14, 15], an effect that is often due to fatigue and boredom [15]. Since the questionnaires could be spread over time and over different persons, the negative effect of length was however confined.

Another limitation of our study concerns the generalizability of our findings. The included centers comprise a group of neurotrauma centers participating in a European multicenter study. Our findings therefore cannot be generalized to all centers caring for neurotrauma patients in Europe. Furthermore, our study provides information on what centers reported rather than characteristics that were directly observed. Therefore, we cannot exclude that some of our findings provide a too optimistic picture. For example, almost all centers indicated that they would insert an ICP monitor in patients with severe TBI and CT abnormalities, which is recommended by Brain Trauma Foundation guidelines. However, a systematic review about guideline adherence reported that ICP monitoring guidelines were only followed in one-third of the patients [5]. Later, results from the ongoing CENTER-TBI study will provide insight into discrepancies between reported and actual policies in the participating centers.

The concordance rate between duplicate questions (median: 0.85), indicates a certain degree of subjectivity in the responses. The concordance rate was especially low for process questions, which indicates that there might be differences in policy among wards and doctors, no clear policy at all or difficulties in understanding and interpreting the questions. It might also indicate that some of the doctors that completed the questionnaire might not be representative of their department or center. Although our concordance rate was very similar to a 2001 survey study among European countries [11], results on process characteristics should be interpreted with caution. The reported concordance rate does not account for chance concordance since no statistical measures are available that do account for chance and can also provide one figure for different outcomes (dichotomous, categorical and continuous) that we had in our questionnaire. When interpreting the concordance rate, it should however be acknowledged that some answers might be similar by chance.

Finally, there were only 13 centers from a relatively lower-income country and 25 centers from South and East Europe (including Israel). We therefore had limited power to detect differences between centers from relatively high-and middle-income countries versus centers from relatively lower-income countries and centers from different geographic locations.

Although we studied a sample of highly specialized centers, we found substantial differences in important structural and process characteristics. Largest differences were seen in the specialization and organization of the ICU, i.e. half of the centers indicated to have a dedicated neuro ICU and 64% indicated to have a closed ICU organization. Additionally, rehabilitation facilities varied widely, with half of the centers having an in-hospital rehabilitation unit and the possibility for coma stimulation. We also found large differences in the reported policies regarding ICU admission and ICP monitoring across centers. The variation in structure and process among specialized neurotrauma centers was in line with previous survey studies [11, 12]. Enblad and associates [11] included European centers with a particular interest in neuro ICU and brain monitoring in their survey study. They also found large between-center differences in structures of care (e.g. 76% had a separate NICU, 50% had a neurosurgeon as ICU director). Checkley and associates [12] reported similar findings. They conducted a survey in 69 centers participating in the United States critical illness and injury outcome study. The majority of their centers were teaching hospitals with critical care training. However, 58% of their centers had a closed ICU organization and their annual hospital admission rate ranged from 1,170 to 56,330, indicating large between-center differences in volume. Also there were large differences in the protocols available at their surveyed ICUs.

Although in this study we only reported on general structure and process characteristics, it is clear that the between-center variation is substantial and provides an opportunity for CER. Variation among centers and countries comprises an important prerequisite for CER and enables between-center and between-country comparisons of effective structures and processes of care. We can for example study the influence of a dedicated neuro ICU on outcome in severe TBI patients by studying patients’ outcome in the 40 centers with a dedicated neuro ICU and in the 30 centers without a dedicated neuro ICU. This requires outcome data on patient level, which are currently collected in the CENTER-TBI study. In such a comparison it is important to correct for differences in other structural and process characteristics between these centers, which can potentially be accomplished with advanced statistical modelling. Other potential interesting topics for CER based on the current study include the effectiveness of an in-hospital rehabilitation unit, the effectiveness of high-volume vs. low-volume hospitals, the effectiveness of closed vs. mixed ICU organization, and the effectiveness of admission- and ICP monitoring policies.

Conclusion

Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches.

Supporting Information

Acknowledgments

The authors would like to thank all CENTER-TBI investigators and their staff, who are listed below, for completing the provider profiling questionnaires. Authors would further like to thank Nada Andelic, Sasha Brazinova, Ruben van der Brande, Peter Cameron, Guiseppe Citerio, Ari Ercole, Thomas van Essen, Mathieu van der Jagt, Erwin Kompanje, Fiona Lecky, Joukje van der Naalt, David Nelson, Wilco Peul, Jukka Ranta, Cecilia Roe, Gerard Ribbers, Nino Stochetti, Olli Tenovuo and Lindsay Wilson for their help with the development of the provider profiling questionnaires.

CENTER-TBI investigators and participants

Principal Investigators and contact information:

Professor A.I. Maas: Andrew.Maas@uza.be

Professor D. Menon: dkm13@wbic.cam.ac.uk

Adams Hadie ¹, Alessandro Masala ², Allanson Judith ³, Amrein Krisztina ⁴, Andaluz Norberto ⁵, Andelic Nada ⁶, Andrea Nanni ², Andreassen Lasse ⁷, Anke Audny ⁸, Antoni Anna ⁹, Ardon Hilko ¹⁰, Audibert Gérard ¹¹, Auslands Kaspars ¹², Azouvi Philippe ¹³, Baciu Camelia ¹⁴, Bacon Andrew ¹⁵, Badenes Rafael ¹⁶, Baglin Trevor ¹⁷, Bartels Ronald ¹⁸, Barzó Pál ¹⁹, Bauerfeind Ursula ²⁰, Beer Ronny ²¹, Belda Francisco Javier ¹⁶, Bellander Bo-Michael ²², Belli Antonio ²³, Bellier Rémy ²⁴, Benali Habib ²⁵, Benard Thierry ²⁴, Berardino Maurizio ²⁶, Beretta Luigi ²⁷, Beynon Christopher ²⁸, Bilotta Federico ¹⁶, Binder Harald ⁹, Biqiri Erta ¹⁴, Blaabjerg Morten ²⁹, Borgen Lund Stine ³⁰, Bouzat Pierre ³¹, Bragge Peter ³², Brazinova Alexandra ³³, Brehar Felix ³⁴, Brorsson Camilla ³⁵, Buki Andras ³⁶, Bullinger Monika ³⁷, Bučková Veronika ³³, Calappi Emiliana ³⁸, Cameron Peter ³⁹, Carbayo Lozano Guillermo ⁴⁰, Carise Elsa ²⁴, Carpenter K. ⁴¹, Castaño-León Ana M. ⁴², Causin Francesco ⁴³, Chevallard Giorgio ¹⁴, Chieregato Arturo ¹⁴, Citerio Giuseppe ^{44, 45}, Cnossen Maryse ⁴⁶, Coburn Mark Coburn ⁴⁷, Coles Jonathan ⁴⁸, Cooper Jamie D. ⁴⁹, Correia Marta ⁵⁰, Covic Amra ⁵¹, Curry Nicola ⁵², Czeiter Endre ⁵³, Czosnyka Marek ⁵⁴, Dahyot-Fizelier Claire ²⁴, Damas François ⁵⁵, Damas Pierre ⁵⁶, Dawes Helen ⁵⁷, De Keyser Véronique ⁵⁸, Della Corte Francesco ⁵⁹, Depreitere Bart ⁶⁰, Ding Shenghao ⁶¹, Dippel Diederik ⁶², Dizdarevic Kemal ⁶³, Dulière Guy-Loup ⁵⁵, Dzeko Adelaida ⁶⁴, Eapen George ¹⁵, Engemann Heiko ⁵¹, Ercole Ari ⁶⁵, Esser Patrick ⁵⁷, Ezer Erzsébet ⁶⁶, Fabricius Martin ⁶⁷, Feigin Valery L. ⁶⁸, Feng Junfeng ⁶¹, Foks Kelly ⁶², Fossi Francesca ¹⁴, Francony Gilles ³¹, Frantzén Janek ⁶⁹, Freo Ulderico ⁷⁰, Frisvold Shirin ⁷¹, Furmanov Alex ⁷², Gagliardo Pablo ⁷³, Galanaud Damien ²⁵, Gao Guoyi ⁷⁴, Geleijns Karin ⁴¹, Ghuysen Alexandre ⁷⁵, Giraud Benoit ²⁴, Glocker Ben ⁷⁶, Gomez Pedro A. ⁴², Grossi Francesca ⁵⁹, Gruen Russell L. ⁷⁷, Gupta Deepak ⁷⁸, Haagsma Juanita A. ⁴⁶, Hadzic Ermin ⁶⁴, Haitsma Iain ⁷⁹, Hartings Jed A. ⁸⁰, Helbok Raimund ²¹, Helseth Eirik ⁸¹, Hertle Daniel ²⁸, Hill Sean ⁸², Hoedemaekers Astrid ⁸³, Hoefer Stefan ⁵¹, Hutchinson Peter J. ¹, Håberg Asta Kristine ⁸⁴, Jacobs Bram ⁸⁵, Janciak Ivan ⁸⁶, Janssens Koen ⁵⁸, Jiang Ji-yao ⁷⁴, Jones Kelly ⁸⁷, Kalala Jean-Pierre ⁸⁸, Kamnitsas Konstantinos ⁷⁶, Karan Mladen ⁸⁹, Karau Jana ²⁰, Katila Ari ⁶⁹, Kaukonen Maija ⁹⁰, Keeling David ⁵², Kerforne Thomas ²⁴, Ketharanathan Naomi ⁴¹, Kettunen Johannes ⁹¹, Kivisaari Riku ⁹⁰, Kolias Angelos G. ¹, Kolumbán Bálint ⁹², Kompanje Erwin ⁹³, Kondziella Daniel ⁶⁷, Koskinen Lars-Owe ³⁵, Kovács Noémi ⁹², Kálovits Ferenc ⁹⁴, Lagares Alfonso ⁴², Lanyon Linda ⁸², Laureys Steven ⁹⁵, Lauritzen Martin ⁶⁷, Lecky Fiona ⁹⁶, Ledig Christian ⁷⁶, Lefering Rolf ⁹⁷, Legrand Valerie ⁹⁸, Lei Jin ⁶¹, Levi Leon ⁹⁹, Lightfoot Roger ¹⁰⁰, Lingsma Hester ⁴⁶, Loeckx Dirk ¹⁰¹, Lozano Angels ¹⁶, Luddington Roger ¹⁷, Luijten-Arts Chantal ⁸³, Maas Andrew I.R. ⁵⁸, MacDonald Stephen ¹⁷, MacFayden Charles ⁶⁵, Maegele Marc ¹⁰², Majdan Marek ³³, Major Sebastian ¹⁰³, Manara Alex ¹⁰⁴, Manhes Pauline ³¹, Manley Geoffrey ¹⁰⁵, Martin Didier ¹⁰⁶, Martino Costanza ², Maruenda Armando ¹⁶, Maréchal Hugues ⁵⁵, Mastelova Dagmara ⁸⁶, Mattern Julia ²⁸, McMahon Catherine ¹⁰⁷, Melegh Béla ¹⁰⁸, Menon David ⁶⁵, Menovsky Tomas ⁵⁸, Morganti-Kossmann Cristina ¹⁰⁹, Mulazzi Davide ³⁸, Mutschler Manuel ¹⁰², Mühlan Holger ¹¹⁰, Negru Ancuta ¹¹¹, Nelson David ⁸², Neugebauer Eddy ¹⁰², Newcombe Virginia ⁶⁵, Noirhomme Quentin ⁹⁵, Nyirádi József ⁴, Oddo Mauro ¹¹², Oldenbeuving Annemarie ¹¹³, Oresic Matej ¹¹⁴, Ortolano Fabrizio ³⁸, Palotie Aarno ^{91, 115, 116}, Parizel Paul M. ¹¹⁷, Patruno Adriana ¹¹⁸, Payen Jean-François ³¹, Perera Natascha ¹¹⁹, Perlbarg Vincent ²⁵, Persona Paolo ¹²⁰, Peul Wilco ¹²¹, Pichon Nicolas ¹²², Piilgaard Henning ⁶⁷, Piippo Anna ⁹⁰, Pili Floury Sébastien ¹²³, Pirinen Matti ⁹¹, Ples Horia ¹¹¹, Polinder Suzanne ⁴⁶, Pomposo Inigo ⁴⁰, Psota Marek ³³, Pullens Pim ¹¹⁷, Puybasset Louis ¹²⁴, Ragauskas Arminas ¹²⁵, Raj Rahul ⁹⁰, Rambadagalla Malinka ¹²⁶, Rehorčíková Veronika ³³, Rhodes Jonathan ¹²⁷, Richardson Sylvia ¹²⁸, Ripatti Samuli ⁹¹, Rocka Saulius ¹²⁵, Rodier Nicolas ¹²², Roe Cecilie ¹²⁹, Roise Olav ¹³⁰, Roks Gerwin ¹³¹, Romegoux Pauline ³¹, Rosand Jonathan ¹³², Rosenfeld Jeffrey ¹⁰⁹, Rosenlund Christina ¹³³, Rosenthal Guy ⁷², Rossaint Rolf ⁴⁷, Rossi Sandra ¹²⁰, Rostalski Tim ¹¹⁰, Rueckert Daniel ⁷⁶, Ruiz de Arcaute Felix ¹⁰¹, Rusnák Martin ⁸⁶, Sacchi Marco ¹⁴, Sahakian Barbara ⁶⁵, Sahuquillo Juan ¹³⁴, Sakowitz Oliver ^{135, 136}, Sala Francesca ¹¹⁸, Sanchez-Pena Paola ²⁵, Sanchez-Porras Renan ^{28, 135}, Sandor Janos ¹³⁷, Santos Edgar ²⁸, Sasse Nadine ⁵¹, Sasu Luminita ⁵⁹, Savo Davide ¹¹⁸, Schipper Inger ¹³⁸, Schlößer Barbara ²⁰, Schmidt Silke ¹¹⁰, Schneider Annette ⁹⁷, Schoechl Herbert ¹³⁹, Schoonman Guus ¹³¹, Schou Rico Frederik ¹⁴⁰, Schwendenwein Elisabeth ⁹, Schöll Michael ²⁸, Sir Özcan ¹⁴¹, Skandsen Toril ¹⁴², Smakman Lidwien ¹⁴³, Smeets Dirk ¹⁰¹, Smielewski Peter ⁵⁴, Sorinola Abayomi ¹⁴⁴, Stamatakis Emmanuel ⁶⁵, Stanworth Simon ⁵², Stegemann Katrin ¹¹⁰, Steinbüchel Nicole ¹⁴⁵, Stevens Robert ¹⁴⁶, Stewart William ¹⁴⁷, Steyerberg Ewout W. ⁴⁶, Stocchetti Nino ¹⁴⁸, Sundström Nina ³⁵, Synnot Anneliese ^{149, 150}, Szabó József ⁹⁴, Söderberg Jeannette ⁸², Taccone Fabio Silvio ¹⁶, Tamás Viktória ¹⁴⁴, Tanskanen Päivi ⁹⁰, Tascu Alexandru ³⁴, Taylor Mark Steven ³³, Te Ao Braden ⁶⁸, Tenovuo Olli ⁶⁹, Teodorani Guido ¹⁵¹, Theadom Alice ⁶⁸, Thomas Matt ¹⁰⁴, Tibboel Dick ⁴¹, Tolias Christos ¹⁵², Tshibanda Jean-Flory Luaba ¹⁵³, Tudora Cristina Maria ¹¹¹, Vajkoczy Peter ¹⁵⁴, Valeinis Egils ¹⁵⁵, Van Hecke Wim ¹⁰¹, Van Praag Dominique ⁵⁸, Van Roost Dirk ⁸⁸, Van Vlierberghe Eline ¹⁰¹, Vande Vyvere Thijs ¹⁰¹, Vanhaudenhuyse Audrey ^{25, 95}, Vargiolu Alessia ¹¹⁸, Vega Emmanuel ¹⁵⁶, Verheyden Jan ¹⁰¹, Vespa Paul M. ¹⁵⁷, Vik Anne ¹⁵⁸, Vilcinis Rimantas ¹⁵⁹, Vizzino Giacinta ¹⁴, Vleggeert-Lankamp Carmen ¹⁴³, Volovici Victor ⁷⁹, Vulekovic Peter ⁸⁹, Vámos Zoltán ⁶⁶, Wade Derick ⁵⁷, Wang Kevin K.W. ¹⁶⁰, Wang Lei ⁶¹, Wildschut Eno ⁴¹, Williams Guy ⁶⁵, Willumsen Lisette ⁶⁷, Wilson Adam ⁵, Wilson Lindsay ¹⁶¹, Winkler Maren K.L. ¹⁰³, Ylén Peter ¹⁶², Younsi Alexander ²⁸, Zaaroor Menashe ⁹⁹, Zhang Zhiqun ¹⁶³, Zheng Zelong ²⁸, Zumbo Fabrizio ², de Lange Stefanie ⁹⁷, de Ruiter Godard C.W. ¹⁴³, den Boogert Hugo ¹⁸, van Dijck Jeroen ¹⁶⁴, van Essen Thomas A. ¹²¹, van Heugten Caroline ⁵⁷, van der Jagt Mathieu ¹⁶⁵, van der Naalt Joukje ⁸⁵

¹ Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK

² Department of Anesthesia & Intensive Care,M. Bufalini Hospital, Cesena, Italy

³ Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK

⁴ János Szentágothai Research Centre, University of Pécs, Pécs, Hungary

⁵ University of Cincinnati, Cincinnati, Ohio, United States

⁶ Division of Surgery and Clinical Neuroscience, Department of Physical Medicine and Rehabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway

⁷ Department of Neurosurgery, University Hospital Northern Norway, Tromso, Norway

⁸ Department of Physical Medicine and Rehabilitation, University hospital Northern Norway

⁹ Trauma Surgery, Medical University Vienna, Vienna, Austria

¹⁰ Department of Neurosurgery, Elisabeth-Tweesteden Ziekenhuis, Tilburg, the Netherlands

¹¹ Department of Anesthesiology & Intensive Care, University Hospital Nancy, Nancy, France

¹² Riga Eastern Clinical University Hospital, Riga, Latvia

¹³ Raymond Poincare hospital, Assistance Publique–Hopitaux de Paris, Paris, France

¹⁴ NeuroIntensive Care, Niguarda Hospital

¹⁵ Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

¹⁶ Department Anesthesiology and Surgical-Trauma Intensive Care, Hospital Clinic Universitari de Valencia, Spain

¹⁷ Cambridge University Hospitals, Cambridge, UK

¹⁸ Department of Neurosurgery, Radboud University Medical Center

¹⁹ Department of Neurosurgery, University of Szeged, Szeged, Hungary

²⁰ Institute for Transfusion Medicine (ITM), Witten/Herdecke University, Cologne, Germany

²¹ Department of Neurocritical care, Innsbruck Medical University, Innsbruck, Austria

²² Deparment of Neurosurgery & Anesthesia & intensive care medicine, Karolinska University Hospital, Stockholm, Sweden

²³ NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK

²⁴ Intensive care Unit, CHU Poitiers, Poitiers, France

²⁵ Anesthesie-Réanimation, Assistance Publique–Hopitaux de Paris, Paris, France

²⁶ Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino—Orthopedic and Trauma Center, Torino, Italy

²⁷ Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy

²⁸ Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

²⁹ Department of Neurology, Odense University Hospital, Odense, denmark

³⁰ Departments of Neuroscience and Nursing Science, Norwegian University of Science and Technology, Trondheim, Norway

³¹ Department of Anesthesiology & Intensive Care, University Hospital of Grenoble, Grenoble, France

³² BehaviourWorks Australia, Monash Sustainability Institute, Monash University, Victoria, Australia

³³ Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia

³⁴ Department of Neurosurgery, Bagdasar-Arseni Emergency Clinical Hospital, Bucharest, Romania

³⁵ Department of Neurosurgery, Umea University Hospital, Umea, Sweden

³⁶ Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and Janos Szentagothai Research Centre, University of Pecs, Hungarian Brain Research Program, Pecs, Hungary

³⁷ Department of Medical Psychology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

³⁸ Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

³⁹ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

⁴⁰ Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain

⁴¹ Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands

⁴² Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain

⁴³ Department of Neuroscience, Azienda Ospedaliera Università di Padova, Padova, Italy

⁴⁴ NeuroIntensive Care, Azienda Ospedaliera San Gerardo di Monza, Monza, Italy

⁴⁵ School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy

⁴⁶ Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands

⁴⁷ Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany

⁴⁸ Department of Anesthesia & Neurointensive Care, Cambridge Universiyt Hospital NHS Foundation Trust, Cambridge, UK

⁴⁹ School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia

⁵⁰ Radiology/MRI department, MRC Cognition and Brain Sciences Unit, Cambridge, UK

⁵¹ Institute of Medical Psycholology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany

⁵² Oxford University Hospitals NHS Trust, Oxford, UK

⁵³ Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and Janos Szentagothai Research Centre, University of Pecs, Hungarian Brain Research Program (Grant No. KTIA 13 NAP-A-II/8), Pecs, Hungary

⁵⁴ Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

⁵⁵ Intensive Care Unit, CHR Citadelle, Liège, Belgium

⁵⁶ Intensive Care Unit, CHU, Liège, Belgium

⁵⁷ Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK

⁵⁸ Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium

⁵⁹ Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy

⁶⁰ Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium

⁶¹ Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

⁶² Department of Neurology, Erasmus MC, Rotterdam, the Netherlands

⁶³ Department of Neurosurgery, Medical Faculty and clinical center University of Sarajevo, Sarajevo, Bosnia Herzegovina

⁶⁴ Department of Neurosurgery, Regional Medical Center dr Safet Mujić, Mostar, Bosnia Herzegovina

⁶⁵ Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

⁶⁶ Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary

⁶⁷ Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark

⁶⁸ National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand

⁶⁹ Rehabilitation and Brain Trauma, Turku University Central Hospital and University of Turku, Turku, Finland

⁷⁰ Department of Medicine, Azienda Ospedaliera Università di Padova, Padova, Italy

⁷¹ Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway

⁷² Department of Neurosurgery, Hadassah-hebrew University Medical center, Jerusalem, Israel

⁷³ Fundación Instituto Valenciano de Neurorrehabilitación (FIVAN), Valencia, Spain

⁷⁴ Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/school of medicine, Shanghai, China

⁷⁵ Emergency Department, CHU, Liège, Belgium

⁷⁶ Department of Computing, Imperial College London, London, UK

⁷⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; and Monash University, Australia

⁷⁸ Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical Sciences, New Delhi-110029, India

⁷⁹ Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands

⁸⁰ Department of Neurosurgery, University of Cincinnati, Cincinnati, Ohio, USA

⁸¹ Department of Neurosurgery, Oslo University Hospital, Oslo, Norway

⁸² Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden

⁸³ Department of Intensive Care Medicine, Radboud University Medical Center

⁸⁴ Department of Medical Imaging, St. Olavs Hospital and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway

⁸⁵ Department of Neurology, University Medical Center Groningen, Groningen, Netherlands

⁸⁶ International Neurotrauma Research Organisation, Vienna, Austria

⁸⁷ National Institute for Stroke & Applied Neurosciences of the AUT University, Auckland, New Zealand

⁸⁸ Department of Neurosurgery, UZ Gent, Gent, Belgium

⁸⁹ Department of Neurosurgery, Clinical centre of Vojvodina, Novi Sad, Serbia

⁹⁰ Helsinki University Central Hospital

⁹¹ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

⁹² Hungarian Brain Research Program—Grant No. KTIA 13 NAP-A-II/8, University of Pécs, Pécs, Hungary

⁹³ Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

⁹⁴ Department of Neurological & Spinal Surgery, Markusovszky University Teaching Hospital, Szombathely, Hungary

⁹⁵ Cyclotron Research Center, University of Liège, Liège, Belgium

⁹⁶ Emergency Medicine Research in Sheffield, Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK

⁹⁷ Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany

⁹⁸ VP Global Project Management CNS, ICON, Paris, France

⁹⁹ Department of Neurosurgery, Rambam Medical Center, Haifa, Israel

¹⁰⁰ Department of Anesthesiology & Intensive Care, University Hospitals Southhampton NHS Trust, Southhampton, UK

¹⁰¹ icoMetrix NV, Leuven, Belgium

¹⁰² Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and Sportmedicine, Witten/Herdecke University, Cologne, Germany

¹⁰³ Centrum für Schlaganfallforschung, Charité–Universitätsmedizin Berlin, Berlin, Germany

¹⁰⁴ Intensive Care Unit, Southmead Hospital, Bristol, Bristol, UK

¹⁰⁵ Department of Neurological Surgery, University of California, San Francisco, California, USA

¹⁰⁶ Department of Neurosurgery, CHU, Liège, Belgium

¹⁰⁷ Department of Neurosurgery, The Walton centre NHS Foundation Trust, Liverpool, UK

¹⁰⁸ Department of Medical Genetics, University of Pécs, Pécs, Hungary

¹⁰⁹ National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia

¹¹⁰ Department Health and Prevention, University Greifswald, Greifswald, Germany

¹¹¹ Department of Neurosurgery, Emergency County Hospital Timisoara, Timisoara, Romania

¹¹² Centre Hospitalier Universitaire Vaudois

¹¹³ Department of Intensive Care, Elisabeth-Tweesteden Ziekenhuis, Tilburg, the Netherlands

¹¹⁴ Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark

¹¹⁵ Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

¹¹⁶ Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

¹¹⁷ Department of Radiology, Antwerp University Hospital and University of Antwerp, Edegem, Belgium

¹¹⁸ NeuroIntenisve Care Unit, Department of Anesthesia & Intensive Care Azienda Ospedaliera San Gerardo di Monza, Monza, Italy

¹¹⁹ International Projects Management, ARTTIC, Munchen, Germany

¹²⁰ Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy

¹²¹ Dept. of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Dept. of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands

¹²² Intensive Care Unit, CHU Dupuytren, Limoges, France

¹²³ Intensive Care Unit, CHRU de Besançon, Besançon, France

¹²⁴ Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique, Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France

¹²⁵ Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania

¹²⁶ Rezekne Hospital, Latvia

¹²⁷ Department of Anaesthesia, Critical Care & Pain MedicineNHS Lothian & University of Edinburg, Edinburgh, UK

¹²⁸ Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK

¹²⁹ Department of Physical Medicine and Rehabilitation, Oslo University Hospital/University of Oslo, Oslo, Norway

¹³⁰ Division of Surgery and Clinical Neuroscience, Oslo University Hospital, Oslo, Norway

¹³¹ Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, the Netherlands

¹³² Broad Institute, Cambridge MA Harvard Medical School, Boston MA, Massachusetts General Hospital, Boston MA, USA

¹³³ Department of Neurosurgery, Odense University Hospital, Odense, Denmark

¹³⁴ Department of Neurosurgery, Vall d'Hebron University Hospital, Barcelona, Spain

¹³⁵ Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany

¹³⁶ University Hospital Heidelberg, Heidelberg, Germany

¹³⁷ Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary

¹³⁸ Department of Traumasurgery, Leiden University Medical Center, Leiden, The Netherlands

¹³⁹ Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg, Austria

¹⁴⁰ Department of Neuroanesthesia and Neurointensive Care, Odense University Hospital, Odense, Denmark

¹⁴¹ Department of Emergency Care Medicine, Radboud University Medical Center

¹⁴² Department of Physical Medicine and Rehabilitation, St.Olavs Hospital and and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway

¹⁴³ Neurosurgical Cooperative Holland, Department of Neurosurgery, Leiden University Medical Center and Medical Center Haaglanden, Leiden and The Hague, The Netherlands

¹⁴⁴ Department of Neurosurgery, University of Pécs, Pécs, Hungary

¹⁴⁵ Universitätsmedizin Göttingen, Göttingen, Germany

¹⁴⁶ Division of Neuroscience Critical Care, John Hopkins University School of Medicine, Baltimore, USA

¹⁴⁷ Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK

¹⁴⁸ Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy

¹⁴⁹ Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

¹⁵⁰ Cochrane Consumers and Communication Review Group, Centre for Health Communication and Participation, School of Psychology and Public Health, La Trobe University, Melbourne, Australia

¹⁵¹ Department of Reahabilitation, M. Bufalini Hospital, Cesena, Italy

¹⁵² Department of Neurosurgery, Kings college London, London, UK

¹⁵³ Radiology/MRI Department, CHU, Liège, Belgium

¹⁵⁴ Neurologie, Neurochirurgie und Psychiatrie, Charité–Universitätsmedizin Berlin, Berlin, Germany

¹⁵⁵ Pauls Stradins Clinical University Hospital, Riga, Latvia

¹⁵⁶ Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France

¹⁵⁷ Director of Neurocritical Care, University of California, Los Angeles, USA

¹⁵⁸ Department of Neurosurgery, St.Olavs Hospital and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway

¹⁵⁹ Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania

¹⁶⁰ Department of Psychiatry, University of Florida, Gainesville, Florida, USA

¹⁶¹ Division of Psychology, University of Stirling, Stirling, UK

¹⁶² VTT Technical Research Centre, Tampere, Finland

¹⁶³ University of Florida, Gainesville, Florida, USA

¹⁶⁴ Department of Neurosurgery, The HAGA Hospital, The Hague, The Netherlands

¹⁶⁵ Department of Intensive Care, Erasmus MC, Rotterdam, the Netherlands