Case-mix, care pathways, and outcomes in patients
with traumatic brain injury in CENTER-TBI
Citation for published version (APA):
Steyerberg, E. W., Wiegers, E., Sewalt, C., Buki, A., Citerio, G., De Keyser, V., Ercole, A., Kunzmann, K.,
Lanyon, L., Lecky, F., Lingsma, H., Manley, G., Nelson, D., Peul, W., Stocchetti, N., von Steinbuechel, N.,
Vande Vyvere, T., Verheyden, J., Wilson, L., ... van Heugten, C. M. (2019). Case-mix, care pathways, and
outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre,
longitudinal, cohort study. Lancet Neurology, 18(10), 923-934. https://doi.org/10.1016/S1474-
4422(19)30232-7
Document status and date:
Published: 01/10/2019
DOI:
10.1016/S1474-4422(19)30232-7
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923
Articles
Lancet Neurol 2019; 18: 923–34
See Comment page 904
*Authors contributed equally
†Collaborators listed in the
appendix
Department of Public Health,
Erasmus MC, University
Medical Center Rotterdam,
Rotterdam, Netherlands
(Prof E W Steyerberg PhD,
E Wiegers MSc, C Sewalt MSc,
H Lingsma PhD);
Department of
Biomedical Data Sciences,
Leiden University Medical
Center, Leiden, Netherlands
(Prof E W Steyerberg);
Department of Neurosurgery,
Medical School,
(Prof A Buki MD), and
Neurotrauma Research Group,
János Szentágothai Research
Centre (Prof A Buki), University
of Pécs, Pécs, Hungary;
NeuroIntensive Care, ASST di
Monza, Monza, Italy
(Prof G Citerio MD); School of
Medicine and Surgery,
Università Milano Bicocca,
Milan, Italy (Prof G Citerio);
Department of Neurosurgery
(V De Keyser MA,
Prof A I R Maas MD), and
Department of Radiology
(T Vande Vyvere MSc), Antwerp
University Hospital, Edegem,
Belgium; Division of
Anaesthesia, University of
Cambridge, Addenbrooke’s
Hospital, Cambridge, UK
(A Ercole MD, Prof D K Menon);
MRC Biostatistics Unit,
University of Cambridge,
Cambridge, UK
(K Kunzmann PhD);
International Neuroinformatics
Coordinating Facility
(L Lanyon PhD), and
Department of Physiology and
Pharmacology, Section of
Perioperative Medicine and
Intensive Care (D Nelson MD),
Karolinska Institute,
Stockholm, Sweden; Centre for
Urgent and Emergency Care
Research, Health Services
Research Section, School of
Case-mix, care pathways, and outcomes in patients with
traumatic brain injury in CENTER-TBI: a European
prospective, multicentre, longitudinal, cohort study
Ewout W Steyerberg, Eveline Wiegers*, Charlie Sewalt*, Andras Buki, Giuseppe Citerio, Véronique De Keyser, Ari Ercole, Kevin Kunzmann,
Linda Lanyon, Fiona Lecky, Hester Lingsma, Geoffrey Manley, David Nelson, Wilco Peul, Nino Stocchetti, Nicole von Steinbüchel,
Thijs Vande Vyvere, Jan Verheyden, Lindsay Wilson, Andrew I R Maas*, David K Menon,* and the CENTER-TBI Participants and Investigators†
Summary
Background The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the
characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient
case-mix, care pathways, and outcomes of TBI.
Methods CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry.
Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an
indication for CT. Patients were dierentiated by care pathway and assigned to the emergency room (ER) stratum
(patients who were discharged from an emergency room), admission stratum (patients who were admitted to a
hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and
biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT
core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale
Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The
core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal
(RRID: SCR_015582).
Findings Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in
the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum,
1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had
mild TBI (GCS score 13–15). Compared with the core cohort, the registry had a higher proportion of patients in the ER
(9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients
in the core study were older than those in previous studies (median age 50 years [IQR 30–66], 1254 [28%] aged
>65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and
alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of
injury severity and type. Substantial inter-country dierences existed in care pathways and practice. Incomplete
recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission
stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum,
623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the
IMPACT prognostic model (observed to expected ratio 1·06 [95% CI 0·97–1·14]), but mortality was lower than expected
(0·70 [0·62–0·76]).
Interpretation Patients with TBI who presented to European centres in the core study were older than were those in
previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The
incomplete recovery of many patients should motivate precision medicine research and the identification of best
practices to improve these outcomes.
Funding European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences
Corporation.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction
The burden of traumatic brain injury (TBI) is widely
recognised as a large public health and societal problem.
TBI results in 1·5 million hospital admissions and
57 000 deaths in the EU each year,
1
but the landscape of
TBI in European hospitals is poorly character ised. In
November, 2017, a Commission in The Lancet Neurology
2
on
TBI high lighted the burden posed by TBI to patients,
relatives, and society, and pro vided recommendations to
improve patient outcomes through improved preven-
tion, clinical care, and research. One recommendation
was for large collab orative observa tional studies to collect
Articles
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Health and Related Research,
University of Sheffield,
Sheffield, UK (Prof F Lecky MD);
Department of Neurological
Surgery, University of
California, San Francisco, CA,
USA (Prof G Manley MD); Leiden
University Medical Centre and
Haaglanden Medical Centre,
University Neurosurgical
Centre Holland,
The Hague and Leiden,
Netherlands (Prof W Peul MD);
Department of
Pathophysiology and
Transplantation, Milan
University, Milan, Italy
(Prof N Stocchetti MD);
Neuroscience Intensive Care
Unit, Fondazione IRCCS Cà
Granda Ospedale Maggiore
Policlinico, Milan, Italy
(Prof N Stocchetti); Institute of
Medical Psychology and
Medical Sociology,
Universitätsmedizin
Göttingen, Göttingen,
Germany
(Prof N von Steinbüchel PhD);
Icometrix, Leuven, Belgium
(J Verheyden MSc, T V Vyvere);
Division of Psychology,
University of Stirling, Stirling,
UK (Prof L Wilson PhD); and
University of Antwerp,
Edegem, Belgium
(Prof A I R Maas)
Correspondence to:
Prof A I R Maas, Department of
Neurosurgery, Antwerp
Univ
ersity Hospital, Edegem
2650, Belgium
andrew.maas@uza.be
See
Online
for appendix
For more on CENTER-TBI see
www.center-tbi.eu
For more on InTBIR see
https://intbir.nih.gov/
longitudinal data, which could improve patient character-
isa tion to allow better targeting of therapies and ident ify
best practices through comparative eectiveness research.
The Collaborative European NeuroTrauma Eectiveness
Research (CENTER-TBI) project is a European study, done
within the InTBIR initiative,
3
that was designed to address
these needs.
4
The project in cludes a multi centre, longitudi-
nal, observational co hort study (core study) with highly
granular data collection, which included detailed longitudi-
nal clinical and outcome data, neuro imag ing repositories,
a DNA repository, and a blood and serum biobank; and a
registry, which collected basic administrative data.
The main aims are to: (1) better characterise TBI as a
disease and describe it in the European context, and (2)
identify the most eective clinical inter ventions for man-
aging TBI. Provider profiles of partici pating centres
were established to characterise structures and processes
of care in preparation for com parative eective ness
research.
5–10
We aim to describe the contem porary land-
scape of TBI in Europe, with a focus on the patient case-
mix, care path ways, and outcomes in the core study, and to
explore generalisability by comparison with data from
the registry.
Methods
Study design and participants
CENTER-TBI includes a core study and a registry.
4
65 centres initiated patient enrolment (figure 1). The core
study was an observational, longitudinal, cohort study of
patients with all severities of TBI, present ing between
Dec 19, 2014, and Dec 17, 2017, to centres across Europe
and Israel. Inclusion criteria were a clinical diag nosis of
TBI, indication for CT scanning, presentation to study
centre within 24 h of injury, and informed consent
obtained according to local and national require ments.
4
Participants were excluded if they had any severe pre-
existing neurological disorder that could confound
outcome assessments.
Patients were dierentiated by care pathway into
three strata: (1) emergency room (ER) stratum (patients
assessed in the ER and discharged), (2) admission stratum
(admitted to hospital ward), and (3) intensive care unit
(ICU) stratum (primary admission to the intensive care
unit). The assignment to a stratum was done prospectively
in the core study, and retrospectively in the registry.
Generalis ability of the core study was assessed through
comparison with the registry, which collected adminis-
trative data not requiring consent and covered a site-
specific, convenience-based period during the recruitment
period of the core study.
The CENTER-TBI study was done in accordance with all
relevant laws of the European Union, if directly applicable
or of direct eect, and all laws of the country where the
recruiting sites were located, includ ing, but not limited to,
the privacy and data protection laws and regulations, the
laws and regulations on the use of human materials, and
all relevant guidance relating to clinical studies from
time to time in force including, but not limited to, the
Research in context
Evidence before this study
In November, 2017, the Commission onTraumatic brain injury:
integrated approaches to improve prevention, clinical care, and
research in The Lancet Neurology highlighted existing
deficiencies in epidemiology and patient characterisation. An
extensive literature search was undertaken as a basis for
writing the Commission, which went beyond the academic
literature and included national and international policy
documents and statistical resources. These data were updated
through more focused literature reviews for this manuscript.
The Commission concluded that concerted efforts are urgently
needed to address deficiencies in prevention, care, and
research, and recommended that large collaborative studies be
done, which could provide the framework for precision
medicine and comparative effectiveness research.
Added value of this study
The CENTER-TBI registry and core study provide detailed
insights into the contemporary landscape of traumatic brain
injury (TBI) in Europe and constitute a unique resource for
improving the characterisation of TBI, developing precision
medicine approaches, and identification of best practices. The
epidemiology of TBI as observed in the CENTER-TBI core study
and registry differs from previous observational studies:
patients were older, were most commonly injured by a fall, and
many had comorbidities. Advanced neuroimaging and blood
biomarkers can improve characterisation of injury type and
severity. Differentiation of patients by care pathways provided
novel insights. Around 95% of patients discharged from the
emergency room or admitted to the ward, and a third of those
primarily admitted to the ICU, had a so-called mild TBI.
However, nearly a third of patients discharged from the
emergency room and over half of those admitted to the
hospital ward did not attain full recovery. There are substantial
national and regional variations in care pathways and clinical
management in Europe.
Implications of all the available evidence
The results from CENTER-TBI suggest that TBI should no longer
be considered predominantly a disease of otherwise healthy
young men. Falls were the most common cause of TBI and
should motivate an increased focus for prevention. Mild TBI
not only poses the greatest societal burden to health care, but
also affects functional recovery and quality of life more than
was commonly thought. Improved disease characterisation
can contribute to precision medicine approaches through the
development of multidimensional classifications of initial
injury severity and outcome. Variations in care offer an
opportunity for comparative effectiveness research to identify
best practice.
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925
International Council on Harmonisation guideline on
Good Clinical Practice (CPMP/ICH/135/95) and the
World Medical Association Declaration of Helsinki.
Informed consent by the patients or the legal represent-
ative or next of kin was obtained according to the local
legislations for all patients recruited in the core dataset of
CENTER-TBI and documented in the electronic case
report form.
Ethics approval was obtained for each recruiting site.
The list of sites, ethics committees, approval numbers,
and approval dates is available online.
11
Outcomes
Outcome assess ments were done at 6 months after
injury. The primary outcome measures were global func-
tion and health-related quality of life using the eight-
point Glasgow Outcome Scale (GOSE; overall eect of
injury, including extracranial injuries)
12
, the quality of life
after brain injury overall scale (Qolibri-OS),
13
and the
12-item short form health survey (SF-12v2).
14
Details of
data, imaging, biosamples collection and bank ing, data
handling, and analysis are provided in the appendix.
Data collection, handling, and storage
Clinical data were collected using a web-based elec-
tro nic case report form, with stratum-specific work flows
(QuesGen Systems Incorporated, Burlingame, CA,
USA). Variables were coded in accordance with the
Common Data Elements scheme established by the US
National Institutes of Health’s National Institute of
Neurological Disorders. Blood was banked for DNA
extraction and assayed for protein biomarkers (neuron
specific enolase [NSE], S100B, neurofilament light, total
tau, glial fibrillary acidic protein [GFAP], and ubiquitin
carboxyl-terminal hydrolase L1 [UCHL1]). Patients under-
went X-ray CT at admission (repeated if clinically indi-
cated), and MRI was obtained in a subset of patients.
We provide data on all admission CT examinations, bio-
marker data on the first 961 patients, and MRI data on
the 504 patients who underwent an initial MRI within
3 weeks of injury.
Data handling and storage
Data were de-identified and stored on a secure database,
hosted by the International Neuroinformatics Coordinating
Figure 1: Trial profile
The accrual to the emergency room, admission, and intensive care unit strata was defined prospectively in the core study, and retrospectively in the registry.
GOSE=Glasgow Outcome Scale Extended.
Number of centres
Registry
and core
study
58
Registry
only
2
Core
only
5
Registry
Core study
Number of patients
in core study
4559
Number of patients in
core study excluding those
after complete withdrawal
4516
Number of patients
in core study
available for analysis
4509
Number of patients
in registry available
for analysis
22782
Number of patients
enrolled in registry
study
22849
ER
9839 patients
(43%)
Admission
8571 patients
(38%)
ICU
4372 patients
(19%)
Complete withdrawal
of consent
43 patients
Exclusion of centres with
enrolment <5
7
Exclusion of patients with
incomplete data
67 patients
Withdrawn before
180 days without
any follow-up
6-month
follow-up with
GOSE available
ER
848 patients
Admission
1523 patients
ICU
2138 patients
694/814
(85%)
1264/1474
(86%)
1846/2082
(89%)
34 patients
49 patients
56 patients
For more on the Common
Data Elements scheme see
https://commondataelements.
ninds.nih.gov/
For more on the International
Neuroinformatics Coordinating
Facility see https://www.incf.org/
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Facility in Stockholm, Sweden. Source data verification of
major characteristics was undertaken on a quasi-random
sample of 1298 (28%) patients by a designated contract
research organisation (ICON, Paris, France). Detailed
cura tion was done by a multidisciplinary data curation
task force.
Overall ER stratum Admission stratum ICU stratum p value*
Demographic characteristics
Age (years) 50 (30–66) 48 (29–64) 53 (32–69) 49 (29–65) 0·001
>65 years 1254/4509 (27·8%) 209/848 (24·6%) 493/1523 (32·4%) 552/2138 (25·8%)
Sex ·· ·· ·· ·· <0·0001
Male 3023/4509 (67·0%) 473/848 (55·8%) 988/1523 (64·9%) 1562/2138 (73·1%) ··
Female ·· ·· ·· ·· ··
White 4158/4300 (96·7%) 810/831 (97·5%) 1452/1508 (96·3%) 1896/1961 (96·7%) 0·33
Socioeconomic characteristics
Years of education (n=3212) 13 (10–16) 13 (11–16) 13 (11–16) 12 (10–15) <0·0010
Highest level of education ·· ·· ·· ·· <0·0001
College or university 850/3566 (23·8%) 236/787 (30·0%) 334/1304 (25·6%) 280/1475 (19·0%) ··
Married or living with partner 2070/4075 (50·8%) 385/797 (48·3%) 717/1426 (50·3%) 968/1852 (52·3%) 0·15
Employment status before injury ·· ·· ·· ·· 0·05
Working 1946/3980 (48·9%) 427/816 (52·3%) 638/1414 (45·1%) 881/1750 (50·3%) ··
Pre-injury health status and medical history
Pre-injury ASA-PS classification ·· ·· ·· ·· 0·56
Patient with mild systemic disease 1410/4373 (32·2%) 268/843 (31·8%) 507/1502 (33·8%) 635/2028 (31·3%) ··
Patient with severe systemic disease 462/4373 (10·6%) 93/843 (11·0%) 159/1502 (10·6%) 210/2028 (10·4%) ··
Previous TBI 402/4158 (9·7%) 120/812 (14·8%) 149/1459 (10·2%) 133/1887 (7·0%) <0·0001
Anticoagulants 298/4345 (6·9%) 46/837 (5·5%) 133/1510 (8·8%) 119/1998 (6·0%) <0·0009
Platelet aggregation inhibitors 474/4345 (10·9%) 85/837 (10·2%) 178/1510 (11·8%) 211/1998 (10·6%) 0·38
Cause of injury and influence of alcohol
Cause of injury ·· ·· ·· ·· <0·0001
Road traffic incident 1682/4388 (38·3%) 266/836 (31·8%) 490/1499 (32·7%) 926/2053 (45·1%) ··
Incidental fall 2024/4388 (46·1%) 424/836 (50·7%) 761/1499 (50·8%) 839/2053 (40·9%) ··
Alcohol involved in the injury (yes or
suspected)
·· ·· ·· ·· ··
All causes 1054/4163 (25·3%) 137/828 (16·5%) 384/1452 (26·4%) 533/1883 (28·3%) <0·0001
Road traffic incident 262/1528 (17·1%) 25/260 (9·6%) 76/471 (16·1%) 161/797 (20·2%) <0·0001
Incidental Fall 533/1918 (27·8%) 72/414 (17·4%) 209/730 (28·6%) 252/774 (32·6%) <0·0001
Clinical presentation
GCS 15 (10–15) 15 (15–15) 15 (14–15) 9 (4–14) <0·0001
Mild (13–15) 2955/4330 (68·2%) 826/832 (99·3%) 1409/1489 (94·6%) 720/2009 (35·8%) ··
Moderate (9–12) 389/4330 (9·0%) 2/832 (0·2%) 59/1489 (4·0%) 328/2009 (16·3%) ··
Severe (3–8) 986/4330 (22·8%) 4/832 (0·5%) 21/1489 (1·4%) 961/2009 (47·8%) ··
Pupillary reactivity ·· ·· ·· ·· <0·0001
One pupil unreactive 164/4247 (3·9%) 3/795 (0·4%) 27/1436 (1·9%) 134/2016 (6·6%) ··
Two pupils unreactive 281/4247 (6·6%) 16/795 (2·0%) 19/1436 (1·3%) 246/2016 (12·2%) ··
Hypoxia (prehospital or ER phase) 299/4256 (7·0%) 3/818 (0·4%) 30/1457 (2·1%) 266/1981 (13·4%) <0·0001
Hypotension (prehospital or ER phase) 297/4296 (6·9%) 4/820 (0·5%) 26/1484 (1·8%) 267/1992 (13·4%) <0·0001
Any major extracranial injury (AIS ≥3) 1642/4509 (36·4%) 46/848 (5·4%) 422/1523 (27·7%) 1174/2138 (54·9%) <0·0001
CT characteristics
Any intracranial abnormality at local
reading
2268/3924 (57·8%) 53/768 (6·9%) 632/1317 (48·0%) 1583/1820 (87·0%) <0·0001
Any intracranial abnormality at central
reading
2434/4037 (60·3%) 103/804 (12·8%) 681/1379 (49·4%) 1650/1854 (89·0%) <0·0001
MRI characteristics
Any intracranial abnormality at central
reading
312/504 (61·9%) 32/123 (26·0%) 101/180 (56·1%) 179/197 (90·9%) <0·0001
(Table 1 continues on next page)
