Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in 66 neurotrauma centers participating in the CENTER-TBI study
Critical Care volume 21, Article number: 233 (2017)
No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI.
A 29-item survey on ICP monitoring and treatment was developed on the basis of literature and expert opinion, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study.
The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately 90% of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomographic abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%).
Substantial variation was found regarding monitoring and treatment policies in patients with TBI and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research.
Secondary brain injury associated with elevated intracranial pressure (ICP) is an important cause of mortality and morbidity in patients with severe traumatic brain injury (TBI) . Therefore, identifying high ICP and optimizing its management is believed to be critically important. Yet, no definitive evidence exists on how ICP should be monitored and treated . Patient and treatment heterogeneity make conducting randomized controlled trials (RCTs) challenging. On one hand, the majority of RCTs done to date have produced nonsignificant findings . On the other hand, observational studies, which are easier to conduct, are at risk for confounding by indication, hampering causal inference [4, 5].
In the absence of conclusive evidence, treatment policy is usually based on local practices, individual preferences, and resource availability [6,7,8,9]. It is likely that centers and practitioners individually balance potential benefits and risks of different ICP management strategies, which may result in some centers being relatively aggressive and others being more conservative in their treatment policies.
A novel and promising approach in estimating treatment effectiveness is to exploit the existing variation by comparing standard practices between different centers or countries, which is referred to as comparative effectiveness research (CER) [10, 11]. The Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (grant 602150) is currently recruiting and will use CER methodology to study treatment effectiveness of ICP management . As a first step, we examined self-perceived practices of ICP monitoring and associated treatment policies by sending a survey to the centers participating in the CENTER-TBI study. Because previous European survey studies that addressed ICP management were published more than 10 years ago [12, 13], this study will provide an up-to-date overview of ICP management in Europe. Topics identified as showing substantial between-center variation that are plausibly associated with patient outcome will be selected for CER, and their treatment effectiveness can be studied once the CENTER-TBI patient-level data become available.
All centers participating in the prospective, longitudinal, observational CENTER-TBI study (https://www.center-tbi.eu/) were asked to complete a set of questionnaires on structures and processes of care for patients with TBI. Questionnaires were sent to 71 centers in 20 countries between 2014 and 2015 . Three centers dropped out of the CENTER-TBI study, resulting in 68 eligible centers from Austria (n = 2), Belgium (n = 4), Bosnia and Herzegovina (n = 2), Denmark (n = 2), Finland (n = 2), France (n = 7), Germany (n = 4), Hungary (n = 2), Israel (n = 2), Italy (n = 9), Lithuania (n = 2), Latvia (n = 3), The Netherlands (n = 7), Norway (n = 2), Romania (n = 1), Serbia (n = 1), Spain (n = 4), Sweden (n = 2), the United Kingdom (n = 9), and Switzerland (n = 1).
Questionnaire development and administration
A set of questionnaires designed to measure structure and process of TBI care was developed on the basis of available literature and expert opinion. These questionnaires were comprehensively described in a previous publication . Pilot testing was undertaken in 16 of the participating centers, and feedback was incorporated into the final questionnaire design.
One of the questionnaires contained 29 questions on ICP monitoring and treatment at the intensive care unit (ICU) (Additional file 1). In most questions, we explicitly asked for the “general policy,” which was defined as the treatment or monitoring modality estimated to be used in more than 75% of patients, recognizing that there might be exceptions. In some questions, we asked for quantitative estimations. The representatives of the centers could indicate how often they used a particular monitoring or treatment strategy (never = 0–10%, rarely = 10–30%, sometimes = 30–70%, frequently = 70–90%, always = 90–100%). The options “frequently” and “always” were interpreted as representing the general policy, in line with a previous report . All definitions used in the questionnaire are described in Additional file 2.
We calculated frequencies and percentages for all variables related to the number of responders for that variable. We examined factors associated with a relatively aggressive ICP monitoring and treatment strategy with the chi-square test or Fisher’s exact test as appropriate. Centers were classified as being relatively aggressive if they (a) place an ICP monitor in patients with a Glasgow Coma Scale (GCS) score ≤ 8 and an abnormal head computed tomographic (CT) scan, and (b) if they generally perform at least one of three second-tier treatments that represent a maximum therapy intensity (barbiturates, decompressive craniectomy, and hypothermia < 35 °C) .
We examined whether there were differences between and within geographic regions in the use of first- and second-tier treatments. Countries were divided into seven geographic regions (Northern Europe, Western Europe, United Kingdom, Southern Europe, Eastern Europe, Baltic states, and Israel). Within each region, we examined the percentage of centers which indicated that the particular treatment was their general policy. In addition, we assessed the influence of geographic region on treatment decision by performing logistic regression analysis with treatment as the dependent variable (general policy yes/no) and geographic region (categorical variable) as an independent variable. The Nagelkerke R 2 was reported, representing the proportion of variation in treatment that can be explained by geographic region. Analyses were performed using IBM SPSS Statistics version 21 software .
Sixty-six centers (97% response rate) completed the questionnaire on ICP monitoring and treatment in patients with severe TBI. Questionnaires were completed mainly by intensive care physicians (n = 33, 50%) and neurosurgeons (n = 23, 35%). Most centers (n = 60, 91%) had an academic affiliation, and 44 (67%) were designated level I trauma centers (see Additional file 2 for definitions). Centers had a median of 33 (IQR 22–44) ICU beds in total and treated a median of 92 (IQR 52–160) patients with severe TBI annually. Forty-three (65%) centers had adopted a “closed” ICU model, which is defined as an ICU model where a critical care physician (intensivist) is primarily responsible for the delivery of care for patients at the ICU . An “open” model, defined as an ICU model where the admitting physician (e.g., neurosurgeon) is primarily responsible for the care of ICU patients, was adopted in three (5%) centers . A “mixed” model, which is an ICU model where the admitting physician is primarily responsible but the care is provided by a critical care physician, was adopted in 20 (30%) centers. Approximately half (n = 39) of the centers had a dedicated neurosciences ICU. Approximately three-fourths of sites (n = 49, 74%) indicated that they used the 2007 Brain Trauma Foundation (BTF) guidelines or institutional guidelines that were based on the BTF guidelines.
Indications for ICP monitoring
The majority of participants (n = 58, 91%) indicated that they would generally place an ICP monitor in patients with GCS ≤ 8 and CT abnormalities (Fig. 1). ICP monitors were less often considered for other indications, such as GCS ≤ 8 without CT abnormalities (n = 15, 23%), inability to assess a patient with CT abnormalities clinically (e.g., due to sedatives; n = 11, 17%), and intraventricular hemorrhage (n = 21, 33%). Around one-third of the participants would place an ICP monitor in patients with polytrauma (GCS > 8) who require extracranial surgery or mechanical ventilation but would not otherwise have an indication for ICP monitoring. Patient-specific reasons for not monitoring ICP included when the risk of raised ICP was considered low (n = 40, 62%), patients were considered unsalvageable (n = 37, 57%), or GCS was > 8 (n = 37, 57%) (Additional file 2).
Variability in monitoring and treatment of intracranial hypertension
There is large variation in monitoring and treatment characteristics among European centers treating patients with TBI (Fig. 2a and b).
Parenchymal and ventricular ICP devices
Both parenchymal and ventricular ICP devices were available in more than half of centers (n = 38, 59%). One-third (n = 21) of the participants indicated that they used only parenchymal monitors, whereas five (8%) participants indicated that they used only ventricular catheters. In centers that used both types of monitors, parenchymal monitors were typically used routinely, with ventricular catheters placed either when the ventricles were enlarged or when cerebrospinal fluid (CSF) drainage was indicated. When a ventricular drain was used, half of the participants indicated that their local practice was generally to leave the drain open (n = 19, 50%), and the other half indicated a policy of intermittent drainage (n = 19, 50%) (Fig. 2a).
Precautions with ICP monitor placement
Half of the participants (55% ventricular catheter and 43% parenchymal sensor) indicated that they generally administered prophylactic antibiotics prior to the insertion of an ICP monitor, which was continued in around 10% of the centers. The majority of participants (n = 50, 77%) generally assessed the patient’s coagulation status prior to ICP monitor insertion. There was wide variability regarding the minimum international normalized ratio and minimum platelet count considered safe for device insertion (Fig. 2a).
Half of the participants (n = 33) indicated that they generally used at least one additional neuromonitoring device (Additional file 2). Transcranial Doppler was generally applied in 24 (38%) centers, and brain tissue oxygenation was used in 12 (19%) centers.
First-tier treatment of elevated ICP
The majority of participants indicated an ICP threshold for medical treatment > 20 mmHg (n = 54, 83%) (Fig. 2b). There was less consensus on cerebral perfusion pressure (CPP) treatment thresholds; 39 participants (59%) indicated a threshold of 60 mmHg in their center, whereas 25 (38%) indicated individualized CPP targets.
Propofol (n = 54, 83%), midazolam (n = 48, 75%), fentanyl (n = 37, 58%), and morphine (n = 32, 51%) were generally used as part of first-tier treatment in patients with elevated ICP, whereas the use of α2-agonists (n = 10, 16%) and barbiturates (n = 12, 19%) was less frequent (Fig. 2b and Additional file 2). Neuromuscular blocking agents were generally used in 16 (25%) centers. Participants typically preferred a specific combination of sedatives and analgesics as part of first-tier treatments: 50 participants (76%) indicated they used two to four of eight sedatives and analgesics as general policy and the other interventions only infrequently (Additional file 2).
Regarding the use of osmotic therapy, two-thirds of the participants indicated generally using mannitol (n = 43, 65%) and/or hypertonic saline (n = 44, 67%). Seventeen participants indicated the use of mannitol, but not hypertonic saline, as their general policy, whereas 18 participants indicated the opposite. Fourteen (22%) participants indicated generally using hypertonic saline in conjunction with mannitol (Fig. 2b). Crystalloids were the most commonly used intravenous fluids to augment CPP (n = 60, 91%), whereas other fluids (starches, albumin, and other combinations) were less often used (12–23%). Vasopressors were generally used in almost all centers to support CPP (n = 63, 96%). Among the parameters used to titrate vasoactive drugs, mean arterial pressure targets (n = 51, 77%) and transpulmonary thermodilution monitoring by means of pulse contour cardiac output (n = 35, 53%) were most often used (Additional file 2).
Second-tier treatments for refractory intracranial hypertension
Among the second-tier treatments, decompressive craniectomy (n = 26, 39%), barbiturates (n = 21, 32%), and CSF drainage (n = 22, 33%) were the most often employed (Fig. 2b). Hypothermia and hyperventilation (partial pressure of carbon dioxide < 30 mmHg) were the general policy in 24.6% and 15.4% of the centers, respectively, whereas approximately one-third of the participants indicated never using hypothermia and hyperventilation (Additional file 2). Participants typically preferred one (n = 27, 42%) or two (n = 20, 31%) second-tier treatments and indicated use of the other options infrequently (Additional file 2). Details on indication, administration, and targets of second-tier treatments are presented in Additional file 2 and show a high degree of variability.
Factors associated with aggressive monitoring and treatment policies
Around half of the centers were classified as using an aggressive ICP monitoring and treatment policy (n = 32, 48%). Centers with an open or mixed ICU model more often applied an aggressive ICP management style in comparison to centers with a closed ICU model (p = 0.05). We did not find significant associations between aggressiveness and any of the other factors studied (Table 1).
Influence of geographic region on treatment decisions
The use of first- and second-tier treatments varied substantially within and between geographic regions (Table 2). Morphine and CSF drainage showed the largest within-region variation, with approximately half of the participants within each region stating they generally use these treatments. Between-region differences were especially pronounced for barbiturates as first-tier treatment. Barbiturates were used mainly in the Baltic states and Eastern Europe, and geographic region explained 63% of the variance in barbiturate use. In addition, the use of mannitol varied substantially across regions, with all participants in the Baltic states, Eastern Europe, and Israel indicating they generally use mannitol, whereas only 11% of the participants in Northern Europe stated they generally use mannitol. In Northern Europe, Western Europe, and the United Kingdom, propofol, midazolam, morphine, and hypertonic saline are generally applied as first-tier treatment, whereas participants in Southern Europe, the Baltic states, and Eastern Europe also indicated they generally use fentanyl, barbiturates, CSF drainage, and mannitol.
We found substantial variation in the general approaches to ICP monitoring and treatment among 66 European neurotrauma centers. The majority of centers indicated that they would insert an ICP monitor in patients with severe TBI and head CT abnormalities. There was no consensus on other indications, however, nor was there consensus on peri-insertion precautions. The use of both first- and second-tier treatments for elevated ICP varied widely between centers and regions. We found that half of the centers employed a relatively aggressive ICP management approach, and the other half reported using a more conservative approach.
Strengths of this study include the high response rate (97%), the extensive development process of the questionnaire, and the comprehensive examination of both monitoring and treatment. In addition, because our survey was completed by centers that are currently collecting patient-level data for the CENTER-TBI study, the results of this study can be used directly as input for the CER analyses once the patient-level data become available. A limitation of our study is that the included centers represent a select group of European neurotrauma centers that are prominent in the field of neurotrauma care and research. Consequently, the picture obtained might be skewed. In addition, this study is dependent on perceived practices rather than on clinical data. Although we repeatedly emphasized confidentiality of results, we cannot exclude that some physicians presented (even subconsciously) a more favorable image or presented individual treatment preferences rather than the general policy in a center. This can be explored when individual patient-level data are available. A further limitation is that we asked for isolated general treatments but did not assess specific combinations. In clinical practice, however, different treatments are used simultaneously, and outcome might be determined by the combination of treatments provided rather than by one particular intervention.
The substantial variation in strategies for ICP management in our study was in line with previous survey studies in Europe [12, 13] and the United States . For example, Hesdorffer et al.  found that mannitol, hypertonic saline, and hyperventilation were generally used in half of their centers. Guidelines have been proposed to reduce treatment variation in medicine . Although there has been an increase in protocolization of medicine and awareness of guidelines during the last decade, variation in ICP management may not have been reduced [12, 13]. Moreover, some participants claimed using treatments that are discouraged in the BTF guidelines. For example, one-fifth of the participants specified using barbiturates as first-tier treatment, whereas this is a second-tier treatment in the BTF guidelines . The discrepancy between BTF guidelines and reported policies indicates that there is little consensus among neurotrauma centers with respect to ICP management. This might be due to the relatively small evidence base underpinning the guidelines .
Our study has several implications for the planned CER analyses. We found wide variation for most of the topics studied, which enables analyzing effectiveness of ICP management at the hospital level. Analyzing effectiveness at the hospital level might be especially useful for treatments that were indicated to be used “rarely,” “sometimes,” or “frequently” by the large majority of participants. For these treatments, patient characteristics play an important role, and these can dramatically confound conventional patient-level analyses [4, 5]. Caution should be applied, however, in the interpretation of the effects of treatments that are performed solely in some regions and not in others. For example, barbiturates are often used as first-tier treatment in the Baltic states and Eastern Europe but not in other regions. A harmful or beneficial effect could therefore also be attributed to other aspects of care in the particular regions rather than to barbiturate use itself. In principle, it is possible to adjust statistically for between-center differences other than the treatment variable of interest with a random-effects model with a random intercept for center. However, when correlations between the treatment variable of interest and other factors that differ between centers are strong, such as for the first-line use of barbiturates and region, this might not be sufficiently captured by the random-effects model. In such a case, differences in outcome cannot be attributed with certainty to the treatment under study.
On the basis of our findings, we recommend prioritizing the following topics for CER because of the feasibility of the center-level approach:
ICP monitoring in patients with indications other than GCS ≤ 8 and CT abnormalities
Parenchymal vs. ventricular monitoring (with and without CSF drainage)
Use of first-tier treatments for elevated ICP (including use of neuromuscular blocking agents, mannitol vs. hypertonic saline vs. mannitol + hypertonic saline, fentanyl vs. no fentanyl, fluid management)
Use of second-tier treatments (including decompressive craniectomy vs. barbiturates vs. hypothermia)
The effect of an aggressive ICP management policy vs. a more conservative approach
Substantial variation was found in the monitoring and treatment of patients with severe TBI and intracranial hypertension. These results indicate a lack of consensus among European neurotrauma centers and provide an important opportunity and necessity for CER to support the development of optimal treatment protocols for these severely affected patients.
Brain Trauma Foundation
Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury
Comparative effectiveness research
Cerebral perfusion pressure
Glasgow Coma Scale
Intensive care unit
International normalized ratio
- PaCO2 :
Partial pressure of carbon dioxide
Randomized controlled trial
Traumatic brain injury
Balestreri M, Czosnyka M, Hutchinson P, Steiner LA, Hiler M, Smielewski P, Pickard JD. Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury. Neurocrit Care. 2006;4(1):8–13.
Maas AI, Menon DK, Lingsma HF, Pineda JA, Sandel ME, Manley GT. Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. J Neurotrauma. 2012;29(1):32–46.
Bragge P, Synnot A, Maas AI, Menon DK, Cooper DJ, Rosenfeld JV, Gruen RL. A state-of-the-science overview of randomized controlled trials evaluating acute management of moderate-to-severe traumatic brain injury. J Neurotrauma. 2016;33(16):1461–78.
Signorello LB, McLaughlin JK, Lipworth L, Friis S, Sorensen HT, Blot WJ. Confounding by indication in epidemiologic studies of commonly used analgesics. Am J Ther. 2002;9(3):199–205.
Bosco JL, Silliman RA, Thwin SS, Geiger AM, Buist DS, Prout MN, Yood MU, Haque R, Wei F, Lash TL. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol. 2010;63(1):64–74.
Sharma S, Gomez D, de Mestral C, Hsiao M, Rutka J, Nathens AB. Emergency access to neurosurgical care for patients with traumatic brain injury. J Am Coll Surg. 2014;218(1):51–7.
Skoglund K, Enblad P, Marklund N. Monitoring and sedation differences in the management of severe head injury and subarachnoid hemorrhage among neurocritical care centers. J Neurosci Nurs. 2013;45(6):360–8.
Cnossen MC, Polinder S, Andriessen TM, van der Naalt J, Haitsma I, Horn J, Franschman G, Vos PE, Steyerberg EW, Lingsma H. Causes and consequences of treatment variation in moderate and severe traumatic brain injury: a multicenter study. Crit Care Med. 2017;45(4):660–9.
van Essen TA, de Ruiter GC, Kho KH, Peul WC. Neurosurgical treatment variation of traumatic brain injury: evaluation of acute subdural hematoma management in Belgium and The Netherlands. J Neurotrauma. 2017;34(4):881–9.
Maas AI, Menon DK, Steyerberg EW, Citerio G, Lecky F, Manley GT, Hill S, Legrand V, Sorgner A, Participants CT, et al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery. 2015;76(1):67–80.
Timmons SD, Toms SA. Comparative effectiveness research in neurotrauma. Neurosurg Focus. 2012;33(1):E3.
Stocchetti N, Penny KI, Dearden M, Braakman R, Cohadon F, Iannotti F, Lapierre F, Karimi A, Maas Jr A, Murray GD, et al. Intensive care management of head-injured patients in Europe: a survey from the European brain injury consortium. Intensive Care Med. 2001;27(2):400–6.
Enblad P, Nilsson P, Chambers I, Citerio G, Fiddes H, Howells T, Kiening K, Ragauskas A, Sahuquillo J, Yau YH, et al. R3-Survey of traumatic brain injury management in European brain IT centres year 2001. Intensive Care Med. 2004;30(6):1058–65.
Cnossen MC, Polinder S, Lingsma HF, Maas AI, Menon D, Steyerberg EW, Investigators C-T, Participants. Variation in structure and process of care in traumatic brain injury: provider profiles of European neurotrauma centers participating in the CENTER-TBI study. PLoS One. 2016;11(8):e0161367.
Hesdorffer DC, Ghajar J. Marked improvement in adherence to traumatic brain injury guidelines in United States trauma centers. J Trauma. 2007;63(4):841–8.
Zuercher P, Groen JL, Aries MJ, Steyerberg EW, Maas AI, Ercole A, Menon DK. Reliability and Validity of the Therapy Intensity Level Scale: analysis of clinimetric properties of a novel approach to assess management of intracranial pressure in traumatic brain injury. J Neurotrauma. 2016;33(19):1768–74.
IBM Corporation. IBM SPSS Statistics for Windows version 21.0 software. Armonk, NY: IBM; 2012.
Nathens AB, Rivara FP, MacKenzie EJ, Maier RV, Wang J, Egleston B, Scharfstein DO, Jurkovich GJ. The impact of an intensivist-model ICU on trauma-related mortality. Ann Surg. 2006;244(4):545–54.
Thomas L, Cullum N, McColl E, Rousseau N, Soutter J, Steen N. Guidelines in professions allied to medicine. Cochrane Database Syst Rev. 2000;2:CD000349.
Brain Trauma Foundation, American Association of Neurological Surgeon, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24 Suppl 1:S1–106.
European Commission. The social situation in the European Union 2007. Luxembourg: Office for Official Publications of the European Union; 2007. p. 1–220.
The authors thank all clinical staff and researchers at the CENTER-TBI sites for completing the provider profiling questionnaires.
CENTER-TBI investigators and participants
Hadie Adams1, Masala Alessandro2, Judith Allanson3, Krisztina Amrein4, Norberto Andaluz5, Nada Andelic6, Nanni Andrea2, Lasse Andreassen7, Audny Anke8,Anna Antoni9, Hilko Ardon10, Gérard Audibert11, Kaspars Auslands12, Philippe Azouvi13, Camelia Baciu14, Andrew Bacon15, Rafael Badenes16, Trevor Baglin17, Ronald Bartels18, Pál Barzó19, Ursula Bauerfeind20, Ronny Beer21, Francisco Javier Belda16, Bo-Michael Bellander22, Antonio Belli23, Rémy Bellier24, Habib Benali25, Thierry Benard24, Maurizio Berardino26, Luigi Beretta27, Christopher Beynon 28, Federico Bilotta16, Harald Binder9, Erta Biqiri14, Morten Blaabjerg29, Stine Borgen Lund30, Pierre Bouzat31, Peter Bragge32, Alexandra Brazinova33, Felix Brehar34, Camilla Brorsson35, Andras Buki36, Monika Bullinger37, Veronika Bučková33, Emiliana Calappi38, Peter Cameron39, Lozano Guillermo Carbayo40, Elsa Carise24, Keri Carpenter41, Ana M. Castaño-León42, Francesco Causin43, Giorgio Chevallard14, Arturo Chieregato14, Giuseppe Citerio44, 45, Maryse Cnossen46, Mark Coburn47, Jonathan Coles48, Jamie D. Cooper49, Marta Correia50, Amra Covic51, Nicola Curry52, Endre Czeiter53, Marek Czosnyka54, Claire Dahyot-Fizelier24, François Damas55, Pierre Damas56, Helen Dawes57, Véronique De Keyser58, Francesco Della Corte59, Bart Depreitere60, Shenghao Ding61, Diederik Dippel62, Kemal Dizdarevic63, Guy-Loup Dulière55, Adelaida Dzeko64, George Eapen15, Heiko Engemann51, Ari Ercole65, Patrick Esser57, Erzsébet Ezer66, Martin Fabricius67, Valery L. Feigin68, Junfeng Feng61, Kelly Foks 62, Francesca Fossi14, Gilles Francony31, Janek Frantzén69, Ulderico Freo70, Shirin Frisvold71, Alex Furmanov72, Pablo Gagliardo73, Damien Galanaud25, Guoyi Gao74, Karin Geleijns41, Alexandre Ghuysen75, Benoit Giraud24, Ben Glocker76, Pedro A. Gomez 42, Francesca Grossi59, Russell L. Gruen 77, Deepak Gupta78, Juanita A. Haagsma46, Ermin Hadzic64, Iain Haitsma79, Jed A. Hartings80, Raimund Helbok21, Eirik Helseth81, Daniel Hertle28, Sean Hill82, Astrid Hoedemaekers83, Stefan Hoefer51, Peter J. Hutchinson1, Kristine Asta Håberg84, Bram Jacobs85, Ivan Janciak86, Koen Janssens58, Ji-yao Jiang74, Kelly Jones87, Jean-Pierre Kalala88, Konstantinos Kamnitsas76, Mladen Karan89, Jana Karau20, Ari Katila69, Maija Kaukonen90, David Keeling52, Thomas Kerforne24, Naomi Ketharanathan41, Johannes Kettunen91, Riku Kivisaari90, Angelos G. Kolias1, Bálint Kolumbán92, Erwin Kompanje93, Daniel Kondziella 67, Lars-Owe Koskinen35, Noémi Kovács92, Ferenc Kálovits94, Alfonso Lagares42, Linda Lanyon82, Steven Laureys95, Martin Lauritzen67, Fiona Lecky96, Christian Ledig76, Rolf Lefering97, Valerie Legrand98, Jin Lei61, Leon Levi99, Roger Lightfoot100, Hester Lingsma46, Dirk Loeckx101, Angels Lozano16, Roger Luddington17, Chantal Luijten-Arts83, Andrew I.R. Maas58, Stephen MacDonald17, Charles MacFayden65, Marc Maegele102, Marek Majdan33, Sebastian Major103, Alex Manara104, Pauline Manhes31, Geoffrey Manley105, Didier Martin106, Costanza Martino2, Armando Maruenda16, Hugues Maréchal55, Dagmara Mastelova86, Julia Mattern28, Catherine McMahon107, Béla Melegh108, David Menon65, Tomas Menovsky58, Cristina Morganti-Kossmann109, Davide Mulazzi38, Manuel Mutschler102, Holger Mühlan110, Ancuta Negru111, David Nelson82, Eddy Neugebauer102, Virginia Newcombe65, Quentin Noirhomme 95, József Nyirádi4, Mauro Oddo112, Annemarie Oldenbeuving113, Matej Oresic114, Fabrizio Ortolano38, Aarno Palotie91, 115, 116, Paul M. Parizel117, Adriana Patruno118, Jean-François Payen31, Natascha Perera119, Vincent Perlbarg25, Paolo Persona120, Wilco Peul121, Nicolas Pichon122, Henning Piilgaard67, Anna Piippo 90, Sébastien Pili Floury123, Matti Pirinen91, Horia Ples111, Suzanne Polinder46, Inigo Pomposo40, Marek Psota33, Pim Pullens117, Louis Puybasset124, Arminas Ragauskas125, Rahul Raj90, Malinka Rambadagalla126, Veronika Rehorčíková33, Jonathan Rhodes127, Sylvia Richardson128, Samuli Ripatti91, Saulius Rocka125, Nicolas Rodier122, Cecilie Roe129, Olav Roise130, Gerwin Roks131, Pauline Romegoux31, Jonathan Rosand132, Jeffrey Rosenfeld109, Christina Rosenlund133, Guy Rosenthal72, Rolf Rossaint47, Sandra Rossi120, Tim Rostalski110, Daniel Rueckert76,Arcaute Felix de Ruiz101, Martin Rusnák86, Marco Sacchi14, Barbara Sahakian65, Juan Sahuquillo134, Oliver Sakowitz135, 136, Francesca Sala118, Paola Sanchez-Pena25, Renan Sanchez-Porras28, 135, Janos Sandor 137, Edgar Santos 28, Nadine Sasse 51, Luminita Sasu59, Davide Savo118, Inger Schipper138, Barbara Schlößer20, Silke Schmidt110, Annette Schneider97, Herbert Schoechl139, Guus Schoonman131, Frederik Schou Rico140, Elisabeth Schwendenwein9, Michael Schöll 28, Özcan Sir141, Toril Skandsen142, Lidwien Smakman143, Dirk Smeets101, Peter Smielewski54, Abayomi Sorinola144, Emmanuel Stamatakis65, Simon Stanworth52, Katrin Stegemann110, Nicole Steinbüchel145, Robert Stevens146, William Stewart147, Ewout W. Steyerberg46, Nino Stocchetti148, Nina Sundström35, Anneliese Synnot149, 150, József Szabó94, Jeannette Söderberg82, Fabio Silvio Taccone16, Viktória Tamás144, Päivi Tanskanen90, Alexandru Tascu34, Mark Steven Taylor 33, Ao Braden Te68, Olli Tenovuo 69, Guido Teodorani151, Alice Theadom68, Matt Thomas104, Dick Tibboel41, Christos Tolias152, Jean-Flory Luaba Tshibanda153, Cristina Maria Tudora111, Peter Vajkoczy154, Egils Valeinis155, Wim Van Hecke101, Dominique Van Praag58, Van Roost Dirk 88, Eline Van Vlierberghe101, Thijs vande Vyvere 101, Audrey Vanhaudenhuyse25, 95, Alessia Vargiolu118, Emmanuel Vega156, Jan Verheyden101, Paul M. Vespa 157, Anne Vik 158, Rimantas Vilcinis 159, Giacinta Vizzino 14, Carmen Vleggeert-Lankamp 143, Victor Volovici 79, Peter Vulekovic 89, Zoltán Vámos 66, Derick Wade 57, Kevin K.W. Wang 160, Lei Wang 61, Eno Wildschut 41, Guy Williams 65, Lisette Willumsen 67, Adam Wilson 5, Lindsay Wilson 161, Maren K.L. Winkler 103, Peter Ylén 162, Alexander Younsi 28, Menashe Zaaroor 99, Zhiqun Zhang 163, Zelong Zheng 28, Fabrizio Zumbo 2, Stefanie de Lange 97, Godard C.W. de Ruiter 143, Hugo den Boogert 18, Jeroen van Dijck 164, Thomas A. van Essen 121, Caroline van Heugten 57, Mathieu van der Jagt 165, Joukje van der Naalt 851
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, OH, 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 of Northern Norway, Tromsø, Norway
8 Department of Physical Medicine and Rehabilitation, University Hospital of Northern Norway, Tromsø, 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, Milan, Italy
15 Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
16 Department of Anesthesiology and Surgical-Trauma Intensive Care, Hospital Clinic Universitari de Valencia, Valencia, Spain
17 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
18 Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands
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 Department 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 Sustainable Development Institute, Monash University, Clayton, 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, Umeå University Hospital, Umeå, Sweden
36 Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and Janos Szentagothai Research Centre, University of Pecs, and 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, 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, Padua, Italy
44 Neurointensive Care, Azienda Ospedaliera San Gerardo di Monza, Monza, Italy
45 School of Medicine and Surgery, Università Milano Bicocca, Milan, 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 University Hospital NHS Foundation Trust, Cambridge, UK
49 School of Public Health and Preventive Medicine, Monash University and The Alfred Hospital, Melbourne, Australia
50 Radiology/MRI Department, MRC Cognition and Brain Sciences Unit, Cambridge, UK
51 Institute of Medical Psychology 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, and Hungarian Brain Research Program (grant KTIA 13 NAP-A-II/8), Pecs, Hungary
54 Brain Physics Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
55 Intensive Care Unit, CHR Citadelle, Liège, Belgium
56 Intensive Care Unit, CHU de Liège, 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 Medical Center, Rotterdam, the Netherlands
63 Department of Neurosurgery, Medical Faculty and Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
64 Department of Neurosurgery, Regional Medical Center dr Safet Mujić, Mostar, Bosnia and 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, NZ
69 Rehabilitation and Brain Trauma, Turku University Central Hospital and University of Turku, Turku, Finland
70 Department of Medicine, Azienda Ospedaliera Università di Padova, Padua, Italy
71 Department of Anesthesiology and Intensive Care, University Hospital of Northern Norway, Tromsø, 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 de Liège, 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, Clayton, Australia
78 Department of Neurosurgery, Neurosciences Centre & JPN Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
79 Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands
80 Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA
81 Department of Neurosurgery, Oslo University Hospital, Oslo, Norway
82 Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden
83 Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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, The Netherlands
86 International Neurotrauma Research Organisation, Vienna, Austria
87 National Institute for Stroke & Applied Neurosciences, Auckland University of Technology, Auckland, NZ
88 Department of Neurosurgery, University Hospital Ghent, Ghent, Belgium
89 Department of Neurosurgery, Clinical Centre of Vojvodina, Novi Sad, Serbia
90 Helsinki University Central Hospital, Helsinki, Finland
91 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
92 Hungarian Brain Research Program (grant 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, Central Nervous System, ICON plc, 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 Sports Medicine, 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, San Francisco, CA, USA
106 Department of Neurosurgery, CHU de Liège, 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, 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, Lausanne, Switzerland
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, Munich, Germany
120 Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padua, Italy
121 Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Department 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 Rēzekne Hospital, Rēzekne, Latvia
127 Department of Anaesthesia, Critical Care & Pain Medicine, NHS Lothian & University of Edinburgh, 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 The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; 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 Trauma Surgery, 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, Nijmegen, The Netherlands
142 Department of Physical Medicine and Rehabilitation, St. Olavs Hospital 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 Neurosciences Critical Care, John Hopkins University School of Medicine, Baltimore, MD, 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, Milan, 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 Rehabilitation, M. Bufalini Hospital, Cesena, Italy
152 Department of Neurosurgery, King’s College London, London, UK
153 Radiology/MRI Department, CHU de Liège, Liège, Belgium
154 Neurologie, Neurochirurgie und Psychiatrie, Charité – Universitätsmedizin Berlin, Berlin, Germany
155 Pauls Stradiņš 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, Los Angeles, CA, 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, FL, USA
161 Division of Psychology, University of Stirling, Stirling, UK
162 VTT Technical Research Centre, Tampere, Finland
163 University of Florida, Gainesville, FL, USA
164 Department of Neurosurgery, The HAGA Hospital, The Hague, The Netherlands
165 Department of Intensive Care, Erasmus Medical Center, Rotterdam, The Netherlands
Data used in the preparation of this article were obtained in the context of CENTER-TBI, a large collaborative project with the support of the European Commission Seventh Framework program (602150). In addition, TvE and WCP were supported by a grant from the Dutch Brain Foundation (Hersenstichting Nederland) for the Neurotraumatology Quality Registry (Net-QuRe) study.
Availability of data and materials
The datasets analyzed during the present study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. There are no patients included in present study, and participating centers have given consent by completing the questionnaires.
Consent for publication
The authors declare that they have no competing interests.
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Cnossen, M.C., Huijben, J.A., van der Jagt, M. et al. Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in 66 neurotrauma centers participating in the CENTER-TBI study. Crit Care 21, 233 (2017). https://doi.org/10.1186/s13054-017-1816-9
- Traumatic brain injury
- Intracranial hypertension
- Comparative effectiveness research