Variation in Blood Transfusion and Coagulation Management in Traumatic Brain Injury at the Intensive Care Unit: A Survey in 66 Neurotrauma Centers Participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study

Abstract

Our aim was to describe current approaches and to quantify variability between European intensive care units (ICUs) in patients with traumatic brain injury (TBI). Therefore, we conducted a provider profiling survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The ICU Questionnaire was sent to 68 centers from 20 countries across Europe and Israel. For this study, we used ICU questions focused on 1) hemoglobin target level (Hb-TL), 2) coagulation management, and 3) deep venous thromboembolism (DVT) prophylaxis. Seventy-eight participants, mostly intensivists and neurosurgeons of 66 centers, completed the ICU questionnaire. For ICU-patients, half of the centers (N = 34; 52%) had a defined Hb-TL in their protocol. For patients with TBI, 26 centers (41%) indicated an Hb-TL between 70 and 90 g/L and 38 centers (59%) above 90 g/L. To treat trauma-related hemostatic abnormalities, the use of fresh frozen plasma (N = 48; 73%) or platelets (N = 34; 52%) was most often reported, followed by the supplementation of vitamin K (N = 26; 39%). Most centers reported using DVT prophylaxis with anticoagulants frequently or always (N = 62; 94%). In the absence of hemorrhagic brain lesions, 14 centers (21%) delayed DVT prophylaxis until 72 h after trauma. If hemorrhagic brain lesions were present, the number of centers delaying DVT prophylaxis for 72 h increased to 29 (46%). Overall, a lack of consensus exists between European ICUs on blood transfusion and coagulation management. The results provide a baseline for the CENTER-TBI study, and the large between-center variation indicates multiple opportunities for comparative effectiveness research.

Introduction

The management of hemorrhage and disordered coagulation is a common and critically important challenge in trauma patients. This is particularly the case for patients with severe traumatic brain injury (TBI), where physicians have to balance the risks of progressive hemorrhage in the brain against secondary thrombotic complications including deep venous thrombosis (DVT). Many controversies continue to exist regarding the appropriate management for optimizing blood and coagulation status.

Transfusion thresholds for anemia are a particularly controversial area in TBI. According to the guidelines,^1,2 transfusion in general critically ill patients is recommended at a restrictive hemoglobin target level (Hb-TL) of 70 g/L rather than a liberal Hb-TL of 90 or 100 g/L. Whether such target levels also apply to patients with TBI is unclear.^3,4 Inappropriate use of blood products exposes patients to a number of systemic risks and may even lead to progressive hemorrhagic injury post-TBI.³ However, cerebral oxygenation may be improved with higher hemoglobin concentrations,^5,6 whereas restrictive transfusion thresholds may predispose to brain tissue hypoxia and may increase the risk of early mortality.⁷ On the other hand, a recent large retrospective cohort study indicated that a restrictive blood transfusion policy was not associated with increased mortality and can be cost-effective in patients with TBI.⁸ An additional challenge for the management of both blood and coagulation status is the presence of coagulopathy.⁹ Both pro- and anticoagulatory abnormalities can be observed after TBI in around 1 of 3 patients.^10
–12 Coagulopathy at admission is associated with increased mortality and poor neurological outcome.^12
–14 Coagulopathy may result from defective clot initiation, poor clot formation, or hyperfibrinolysis. Acidosis, hypothermia, coagulation factor consumption or dilution, and the more recently described acute coagulopathy of trauma-shock, which results from widespread endothelial activation after hypoperfusion, may contribute to coagulopathy.¹⁵ Finally, patients with TBI are at increased risk of venous thromboembolism (VTE; around 20%)¹⁶ compared with general intensive care unit (ICU) patients (around 6–8%).¹⁷ Here, the balance between the prevention of VTE and the risk of (progressive) hemorrhage of the brain depends largely on the timing of thromboprophylaxis with anticoagulants. However, current Brain Trauma Foundation (BTF) guidelines do not make clear recommendations on coagulation management.¹⁸

In summary, no definitive evidence exists to guide physicians in determining the transfusion and coagulation management in patients with (severe) TBI. This will likely lead to variations in management. Our aim was to describe and quantify variability in European ICUs for blood transfusion and coagulation management in patients with TBI, using a survey among European neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in TBI (CENTER-TBI) study.^19,20

Methods

Participating centers

This study is part of the prospective, longitudinal CENTER-TBI study in 68 centers from 20 countries across Europe and Israel. The CENTER-TBI investigators and participants are listed in Supplementary Data 1 (see online supplementary material at http://www.liebertpub.com).. In 2014, before the start of inclusion of patients, the principle investigators of each center were asked to complete a set of questionnaires on structure and process of care: the Provider Profiling Questionnaires.^19,20 The questionnaires were about TBI management irrespective of systemic injuries. One of these questionnaires concerned ICU management.

Provider Profiling Questionnaire

The Provider Profiling Questionnaire was developed in a systematic manner. The literature (including guidelines and available surveys) was reviewed and experts of various disciplines (neurosurgeons, [neuro]intensivists, neurologists, emergency department physicians, rehabilitation physicians, medical ethicists, health care economists, and epidemiologists) were consulted throughout the different phases in the development process. Preliminary questionnaires were pilot-tested in 16 of the participating centers for unexpected or missing values and ambiguity, and received feedback was incorporated. For more information about the development, administration, and content of the total set of provider profiling questionnaires, see Cnossen and colleagues.¹⁹ In this study, we focus on 10 questions (with additional subquestions) on hemoglobin target levels, trauma-related coagulation management, and use and timing of thromboprophylaxis (see online supplementary material at http://www.liebertpub.com/neu).

Hemoglobin target level and coagulation management

Participants were explicitly asked for their general policy rather than for individual treatment preferences. General policy was defined as “the way the large majority of patients (>75%) with a certain indication would be treated.” The ICU questionnaire consisted mostly of multiple-choice questions and one open question; the Hb-TL in the protocol at the ICU for the general ICU population. For the hemoglobin unit conversion from mmol/L toward g/L, we multiplied with the factor 1.6 and then rounded up to tens.

Statistical analysis

Descriptive statistics (frequencies and percentages) were used to describe the treatment policies reported by the participating centers. For some questions, in which centers had to indicate how often a certain approach was taken by choosing never (in 0–10% of cases), rarely (in 10–30% of cases), sometimes (in 30–70% of cases), frequently (in 70–90% of cases), and always (90–100% of cases), categories were combined (e.g., combining always and frequently) because of low numbers in these categories.

To gain more insight into characteristics that determine treatment policies, we divided centers in relatively high- and middle-income countries versus lower-income countries, and in countries from different geographical locations (North and West Europe vs. South and East Europe and Israel). The designation into relatively lower-income countries was based on a 2007 report by the European Commission,²¹ and the designation into geographic location was based on the classification by the United Nations. Analyses were performed using the Statistical Package for Social Sciences (version 21; SPSS, Inc., Chicago, IL.²²

Results

Participating centers

Sixty-six centers of the 68 centers completed the ICU questionnaire (response rate = 97%). The questionnaire was completed by intensivists (N = 33; 50%), neurosurgeons (N = 23; 35%), administrative staff (N = 11; 17%), neurologists (N = 5; 8%), anesthetists (N = 5; 8%), and a trauma surgeon (N = 1; 2%). Almost all the centers had an academic affiliation (N = 60; 91%), and most centers were designated as a level I trauma center (N = 44; 67%). Centers had a median of 33 (interquartile range [IQR], 22–44) beds for general ICU patients and treated a median of 92 (IQR, 52–160) patients with TBI, of all severities, annually. An extensive overview of all the center characteristics is described in a previous publication.¹⁹

For the management of TBI at the ICU, most centers indicated to follow the 2007 BTF guidelines (N = 28; 42%) or institutional guidelines (N = 21; 32%), which were broadly based on BTF. Some centers indicated they did not have specific guidelines for management of TBI (N = 11; 17%) or that they developed a guideline independently from available guidelines (N = 2; 3%).

Hemoglobin target level

Half of the centers (N = 34; 52%) reported to have Hb-TLs described in their protocol for general/non-TBI ICU patients. The reported Hb-TL varied (open question): 110 (N = 1; 3%), 100 (N = 8; 28%), 90 (N = 4; 14%), 80 (N = 9; 31%), 70 (N = 5; 18%), 80–100 (N = 1; 3%), and 70–80 g/L (N = 1, 3%). In non-neurological critically ill patients, 35 of the centers (56%) reported an Hb-TL between 70 and 80 g/L. In patients with TBI, 10 of the centers (16%) indicated to use an Hb-TL between 70 and 80 g/L. The remainder of the centers used higher Hb-TL: between 80 and 90 g/L (N = 16; 25%), between 90 and 100 g/L (N = 20; 31%), and above 100 g/L (N = 18; 28%; Table 1).

Table 1.

Red Blood Cell Transfusion Policy ^a

Items questionnaire	No. completed	N	(%)
Protocol at the ICU
Protocol	65
- Presence of a protocol with an Hb-TL		34	(52)
- Absence of a protocol with an Hb-TL		31	(48)
Transfusion at Hb-TL in protocol (open question) (g/L)	29
- 110		1	(3)
- 100		8	(28)
- 90		4	(14)
- 80		9	(31)
- 70		5	(18)
- 80–100		1	(3)
- 70–80		1	(3)
In non-neurological critically ill patients
Transfusion at Hb-TL (g/L)	63
- > 100 g/L		1	(2)
- Between 90 and 100		6	(9)
- Between 80 and 90		21	(33)
- Between 70 and 80		35	(56)
In patients with TBI^b
Transfusion at Hb-TL (g/L)	64
- >100		18	(28)
- Between 90 and 100		20	(31)
- Between 80 and 90		16	(25)
- Between 70 and 80		10	(16)

Frequencies and percentage of centers with corresponding answers.

General policy: the way the large majority of patients (>75%) with a certain indication would be treated at the intensive care.

Policy in the acute phase.

ICU, Intensive Care Unit; Hb-TL, hemoglobin target levels; TBI, traumatic brain injury; g/L, grams per liter.

Coagulation management

Transfusion with fresh frozen plasma was most often reported for correction of trauma-related coagulopathy (N = 48; 73%), followed by the use of platelets (N = 34; 52%). Coagulopathy was most often managed with vitamin K (N = 26; 39%), fibrinogen (N = 19; 29%), prothrombin complex concentrate (PCC; N = 17; 26%), tranexamic acid (N = 7; 11%), or recombinant factor VIIa (N = 3; 5%). One center reported to use desmopressin, in addition to tranexamic acid (Fig. 1).

FIG. 1.

Trauma-related coagulopathy treatment. Bars represent the percentage of centers that indicated to use this treatment as general policy (the way the large majority of patients >75% with a certain indication would be treated). In order of always and frequently summed. Always: in 90–100% of cases; Frequently: in 70–90% of cases; Sometimes: in 30–70% of cases; Rarely: in 10–30% of cases; Never: in 0–10% of cases.

Most centers indicated that they use DVT prophylaxis with anticoagulants frequently (N = 18; 27%) or always (N = 44; 67%) in patients with TBI. Fourteen centers (21%) indicated they generally wait 72 h after trauma before commencing DVT prophylaxis in the absence of hemorrhagic brain lesions. However, twice that number of centers (N = 29; 46%) indicated to wait 72 h after trauma in the presence of hemorrhagic brain lesions. Low-molecular-weight heparin was most commonly indicated as the prophylactic drug of choice (N = 54; 82%), followed by subcutaneous unfractioned heparin (N = 7; 11%) and intravenous heparin (N = 1; 2%; Table 2).

Table 2.

Coagulation Policies, Deep Venous Thrombosis ^a

Items questionnaire	No. completed	N	(%)
DVT prophylaxis
Frequency of DVT prophylaxis (%)	66
- Never (0–10)		1	(2)
- Rarely (10–30)		0	(0)
- Sometimes (30–70)		3	(4)
- Frequently (70–90)		18	(27)
- Always (90–100)		44	(67)
Start in the absence of hemorrhagic lesions (h)	65
- <24		26	(40)
- 24–72		24	(37)
- >72		14	(21)
- Never		1	(2)
Start in the presence of hemorrhagic lesions (h)	63
- <24		5	(8)
- 24–72		25	(40)
- >72		29	(46)
- Never		4	(6)
Start after intracranial surgery (h)	64
- <24		10	(16)
- 24–72		31	(48)
- >72		21	(33)
- Never		2	(3)
Pharmacological DVT prophylaxis	66
- Subcutaneous unfractioned heparin		7	(11)
- Intravenous heparin		1	(2)
- Low-molecular-weight heparin		54	(82)

Frequencies and percentage of centers with corresponding answers.

General policy: the way the large majority of patients >75% with a certain indication would be treated at the intensive care.

DVT, deep venous thrombosis.

Most centers indicated that they would always test a coagulation panel before the insertion of a parenchymal sensor (N = 45; 69%) or a ventricular catheter (N = 46; 71%). The reported minimum platelet count for the insertion of a ventricular catheter was variable: >100 × 10⁹/L (N = 30; 46%), >80 × 10⁹/L (N = 9; 14%) or >50 × 10⁹/L (N = 9; 14%). In most of the remaining centers, the minimum platelet count depended on the surgeon (N = 13; 20%). Also, the reported minimum international normalized ratio (INR) considered safe for placement of a ventricular catheter was variable: <1.4 (N = 21; 33%), <1.3 (N = 17; 26%), or <1.2 (N = 8; 12%). Again, in most of the remaining centers the minimum INR was indicated to depend on surgeon's individual preferences (N = 15; 23%) (Table 3).

Table 3.

Coagulation Policies, ICP Monitoring ^a

Items questionnaire	No. completed	N	(%)
Checks before insertion of parenchymal sensor for ICP monitoring
Coagulation panel (%)	65
- Never (0–10)		4	(6)
- Rarely (10–30)		2	(3)
- Sometimes (30–70)		5	(8)
- Frequently (70–90)		5	(8)
- Always (90–100)		45	(69)
- Not available^b		4	(6)
Checks before insertion ventricular catheter for ICP monitoring
Coagulation panel (%)	65
- Never (0–10)		3	(4)
- Rarely (10–30)		2	(3)
- Sometimes (30–70)		5	(8)
- Frequently (70–90)		4	(6)
- Always (90–100)		46	(71)
- Not available^b		5	(8)
Minimum platelet count ( × 10⁹/L)	65
- >150		1	(2)
- >100		30	(46)
- >80		9	(14)
- >50		9	(14)
- Depending on the surgeon		13	(20)
- No minimum		0	(0)
- Other		3	(4)
Minimum INR	65
- <1.4		21	(33)
- <1.3		17	(26)
- <1.2		8	(12)
- Depending on the surgeon		15	(23)
- No minimum		0	(0)
- Other		4	(6)

Frequencies and percentage of centers with corresponding answers.

General policy: the way the large majority of patients >75% with a certain indication would be treated at the intensive care.

Centers that did not have this technique.

DVT, deep venous thrombosis; ICP, intracranial pressure; INR, international normalized ratio; L, liter.

Twenty-nine centers indicated identical policies for coagulation management (always using DVT prophylaxis, and always obtaining a coagulation panel before insertion of a parenchymal or ventricular catheter). The majority of these centers are located in South and East Europe and Israel (N = 13; 56%) versus (N = 16; 37%) in North and West Europe and the majority are located in high-income countries (N = 26; 47%) versus (N = 3; 27%) in lower-income countries.

Discussion

This study shows large between-center variation in blood transfusion and coagulation-directed policies in critically ill patients with TBI. More centers indicated a restrictive Hb-TL (between 70 and 80 g/L) in general ICU patients compared to patients with TBI. Reported coagulation management was variable regarding timing of DVT prophylaxis with anticoagulants, minimum platelet count and INR values before intracranial pressure (ICP) probe insertion, and correction of trauma-related coagulopathy.

The large between-center differences are likely, in part, explained by a lack of evidence on optimal management of patients with TBI. A majority of centers in our study reported to adhere to the 2007 BTF guidelines for the treatment of patients with TBI, but this guideline does not provide specific recommendations on red blood cell transfusion or coagulopathy management. Equally, some trauma guidelines have stated policies on blood transfusion and coagulation in trauma patients, of which some pertain to patients with TBI, but recommendations are still scarce.^1,2,23 A recent update of the Cochrane Review of all Red Cell Transfusion trials reported on 12,587 patients identified in 31 randomized trials and suggested that a restrictive, rather than liberal, transfusion practice improves outcomes, but noted the data were very limited for neurocritical care.²⁴ Regarding patients with TBI, several trials have been conducted on blood transfusion management,^25,26 and the reversal of coagulopathy,^27,28 but these all had a limited power. A recent large, retrospective, single-center study in TBI patients admitted to the intensive care⁸ found that transfusion guided by a restrictive Hb-TL was associated with significantly less time with fever, higher cost-effectiveness, and had the same risk of mortality compared with a liberal Hb-TL. Another explanation for the variation in management would be the between-center variation in the content of available protocols. For example, we found that even between centers that do have a protocol on red blood cell transfusion policy, the reported Hb-TL still varied substantially. Overall, in patients with TBI, there is no conclusive evidence or clear guidance in guidelines and protocols on blood transfusion and coagulopathy treatment. Still, with an aging TBI demographic with an increased prevalence of comorbidity, coagulation management might even become more complex. Concurrent use of anticoagulant and -platelet medication is a growing concern; previous warfarin treatment, for example, is associated with an increased risk of poor outcome.²⁹ In addition, coagulation management in TBI is further complicated by the recent introduction of newer anticoagulants, such as direct thrombin inhibitors (dabigatran, argatroban).³⁰

For DVT prophylaxis, the BTF guidelines do provide a recommendation, which was formulated quite broadly: DVT prophylaxis with anticoagulants can be started if the brain injury is stable and the benefit is considered to outweigh the risk of increased intracranial hemorrhage. Recommendations on the preferred agent, dose, or timing are lacking.¹⁸ In our study, only 65% of centers indicated that they always would implement DVT prophylaxis. A review including 15 studies and 4491 patients on DVT occurrence in TBI published in 2015 showed that DVT incidence is significantly increased (18% vs. approximately 2%) when pharmaceutical prophylaxis is not given in the first 8 days.³¹ For the timing issue in DVT prophylaxis, a novel theoretical prophylaxis protocol, “the Parkland Protocol,” has been recently described.³² The protocol takes into account the likelihood of natural progression of brain hemorrhage and in that way determines the timing of anticoagulation. The risk classification is based on the stability of the brain hemorrhage at a computed tomography (CT) scan, the modified Berne Norwood criteria (subdural hematoma >8 mm, epidural hematoma >8 mm, contusion or intraventricular hemorrhage >2 cm, multiple contusions per lobe, and subarachnoid hemorrhage with abnormal CT angiography), and the presence of an ICP monitor or craniectomy. A randomized, controlled trial including 62 low risk patients showed the safety of this protocol for this group: no progression of brain hemorrhage with the use of low-molecular-weight heparin at 24 h post-injury and one DVT with the use of placebo at 24 h post-injury.³³ However, more evidence is needed before this protocol can be widely accepted for the guidelines.

The large between-center variation we found is in line with previous studies. For critically ill trauma patients, several surveys have been conducted to study the management of trauma-related hemorrhage and coagulopathy.^34
–36 These studies also found large differences in clinical practices, even among level I trauma centers, for example, in the use of viscoelastic testing. In the survey of Hamada and colleagues, the reported Hb-TLs in critically ill trauma patients were compared with patients with TBI and were significantly higher in patients with TBI, like in our study.³⁷ In addition, two previous surveys were conducted that report the percentage of respondents that chose specific Hb-TLs and the rationale for blood transfusion in patients with TBI (coagulation management was not assessed). In the study of Sena and colleagues, a newly developed multiple-choice survey was completed by 312 physicians of the trauma surgery, neurosurgery, and ICU department of level I trauma centers in the United States.³⁸ In the study of Badenes and colleagues, a newly developed multiple-choice survey was used as well, but was completed by 868 respondents, mostly specialists in anesthesiology and intensive care, worldwide.³⁹ In the study of Sena and colleagues, 55% of respondents chose a restrictive policy of 70 g/L or less. Likewise, in the study of Badenes and colleagues, 50% of respondents chose a low Hb-TL of 70 or 80 g/L, whereas in our study 16% chose a Hb-TL between 70 and 80 g/L. The difference could either be explained by a difference in patient population (severely injured patients with TBI in the study of Sena and colleagues), by a difference in answer options (we did not have an answer option below 70 g/L), or by a difference in policy between Europe and other continents.

Strengths of our study include the comprehensive development process of the questionnaires and the high response rate of 97%. Limitations include the survey design, resulting in perceived practices rather than actual practices. Although we explicitly asked for general policy and data were anonymously collected, we cannot exclude differences between current findings and actual treatment in the participating centers. In addition, questions were aimed to assess general policy and contained no specific details on patient characteristics. This is not representative for clinical practice (possibly making the questions more difficult to answer). In addition, we could not make a distinction between pharmaceutical versus mechanical DVT prophylaxis. A further limitation comprises the representativeness of our sample. The majority of centers were academic level I trauma centers with a special interest in neurotrauma. Findings are therefore not generalizable to nonspecialized centers. In addition, differences between centers could represent differences in case mix instead of true practice.

The practice variability we report supports that evidence on optimal treatment approaches is needed. Such evidence can potentially be obtained in a nonrandomized design by comparing outcomes between centers with different treatment policies. Such a comparative effectiveness research approach exploits the existing between-center variation. Data on real-time patient management and clinically relevant outcomes in the CENTER-TBI study are now being collected.²⁰ Future research on blood transfusion and coagulation management in patients with TBI could lead to prevention of progressive brain hemorrhage and secondary problems like coagulopathy and VTE. For now, the optimal transfusion strategies to correct coagulopathy in terms of the ratio of packed blood cells, fresh frozen plasma (or similar products), and platelets are still being debated.⁴⁰ This debate pertains both to optimal strategies with regard to reversal of trauma-related coagulopathy and management of coagulopathy induced by conventional agents (such as vitamin K antagonists) and newer ones such as direct thrombin inhibitors.^9,30,41 Still, others warn for the use of transfusion considering the possibility of complications of transfusion and unknown effects on (functional) outcome.⁴² Also, for coagulation (enhancing) products, larger studies are needed to prove a positive balance between the beneficial effects in terms of patient outcome and adverse effects on (thromboembolic) complications.^{27,28,42

–45} New evidence is clearly needed on these topics, given that control of blood and coagulation status could have a large impact on patient outcome, especially in patients with TBI.

Conclusions

In conclusion, we showed substantial variation in blood and coagulation management of patients with TBI at the ICUs in 66 centers in Europe and Israel participating in the CENTER-TBI study. This variation may be largely attributable to the lack of guidelines and high-quality evidence on these topics. The large practice variation provides an opportunity to study the effectiveness of different policies in comparative effectiveness research.

Footnotes

Acknowledgments

The authors thank all clinical and research staff at the CENTER-TBI sites for completing the provider profiling questionnaires.

This work was supported by European Commission FP7 Framework Program 602150.

Data used in preparation of this manuscript were obtained in the context of CENTER-TBI, a large collaborative project with the support of the European Commission 7th Framework program (602150). The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Center-TBI Investigators and Participants

Adams Hadie¹ Alessandro Masala² Allanson Judith³ Amrein Krisztina⁴ Andaluz Norberto⁵ Andelic Nada⁶ Andrea Nanni² Andreassen Lasse⁷ Anke Audny⁸ Antoni Anna⁹ Ardon Hilko¹⁰ 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 Joukje⁸⁵

¹Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital & University of Cambridge, Cambridge, United Kingdom.

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

³Department of Clinical Neurosciences, Addenbrooke's Hospital & University of Cambridge, Cambridge, United Kingdom.

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

⁵University of Cincinnati, Cincinnati, Ohio.

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

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

⁸Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway, Tromso, Norway.

⁹Trauma Surgery, Medical University Vienna, Vienna, Austria.

¹⁰Department of Neurosurgery, Elisabeth-Tweesteden Ziekenhuis, Tilburg, The Netherlands.

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

¹²Riga Eastern Clinical University Hospital, Riga, Latvia.

¹³Raymond Poincare Hospital, Assistance Publique–Hopitaux de Paris, Paris, France.

¹⁴NeuroIntensive Care, Niguarda Hospital, Milano, Italy.

¹⁵Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

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

¹⁷Cambridge University Hospitals, Cambridge, United Kingdom.

¹⁸Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands.

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

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

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

²²Deparment of Neurosurgery & Anesthesia & Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden.

²³NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, United Kingdom.

²⁴Intensive care Unit, CHU Poitiers, Poitiers, France.

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

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

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

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

²⁹Department of Neurology, Odense University Hospital, Odense, Denmark.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

⁴⁷Department of Anesthesiology, University Hospital of Aachen, Aachen, Germany.

⁴⁸Department of Anesthesia & Neurointensive Care, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom.

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

⁵⁰Radiology/MRI department, MRC Cognition and Brain Sciences Unit, Cambridge, United Kingdom.

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

⁵²Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

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

⁵⁴Brain Physics Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

⁵⁵Intensive Care Unit, CHR Citadelle, Liège, Belgium.

⁵⁶Intensive Care Unit, CHU, Liège, Belgium.

⁵⁷Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom.

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

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

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

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

⁶²Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.

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

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

⁶⁵Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

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

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

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

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

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

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

⁷²Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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

⁷⁴Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/School of Medicine, Shanghai, China.

⁷⁵Emergency Department, CHU, Liège, Belgium.

⁷⁶Department of Computing, Imperial College London, London, United Kingdom.

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

⁷⁸Department of Neurosurgery, Neurosciences Centre & JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India.

⁷⁹Department of Neurosurgery, Erasmus MC, Rotterdam, The Netherlands.

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

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

⁸²Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden.

⁸³Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

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

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

⁸⁶International Neurotrauma Research Organization, Vienna, Austria.

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

⁸⁸Department of Neurosurgery, UZ Gent, Gent, Belgium.

⁸⁹Department of Neurosurgery, Clinical Center of Vojvodina, Novi Sad, Serbia.

⁹⁰Helsinki University Central Hospital, Helsinki, Finland.

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

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

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

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

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

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

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

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

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

¹⁰⁰Department of Anesthesiology & Intensive Care, University Hospitals Southhampton NHS Trust, Southhampton, United Kingdom.

¹⁰¹icoMetrix NV, Leuven, Belgium.

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

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

¹⁰⁴Intensive Care Unit, Southmead Hospital, Bristol, Bristol, United Kingdom.

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

¹⁰⁶Department of Neurosurgery, CHU, Liège, Belgium.

¹⁰⁷Department of Neurosurgery, The Walton Center NHS Foundation Trust, Liverpool, United Kingdom.

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

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

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

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

¹¹²Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

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

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

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

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

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

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

¹¹⁹International Projects Management, ARTTIC, Munchen, Germany.

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

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

¹²²Intensive Care Unit, CHU Dupuytren, Limoges, France.

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

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

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

¹²⁶Rezekne Hospital, Rēzekne, Latvia.

¹²⁷Department of Anesthesia, Critical Care & Pain Medicine, NHS Lothian & University of Edinburg, Edinburgh, United Kingdom.

¹²⁸Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom.

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

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

¹³¹Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, The Netherlands.

¹³²Broad Institute, Cambridge, Massachusetts; Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Boston, Massachusetts.

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

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

¹³⁵Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany.

¹³⁶University Hospital Heidelberg, Heidelberg, Germany.

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

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

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

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

¹⁴¹Department of Emergency Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

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

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

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

¹⁴⁵Universitätsmedizin Göttingen, Göttingen, Germany.

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

¹⁴⁷Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, United Kingdom.

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

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

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

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

¹⁵²Department of Neurosurgery, Kings College London, London, United Kingdom.

¹⁵³Radiology/MRI Department, CHU, Liège, Belgium.

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

¹⁵⁵Pauls Stradins Clinical University Hospital, Riga, Latvia.

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

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

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

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

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

¹⁶¹Division of Psychology, University of Stirling, Stirling, United Kingdom.

¹⁶²VTT Technical Research Center, Tampere, Finland.

¹⁶³University of Florida, Gainesville, Florida.

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

¹⁶⁵Department of Intensive Care, Erasmus MC, Rotterdam, The Netherlands.

Author Disclosure Statement

No competing financial interests exist

References

Carson

J.L.

, Guyatt

, Heddle

N.M.

, Grossman

B.J.

, Cohn

C.S.

, Fung

M.K.

, Gernsheimer

, Holcomb

J.B.

, Kaplan

L.J.

, Katz

L.M.

, Peterson

, Ramsey

, Rao

S.V.

, Roback

J.D.

, Shander

, and Tobian

A.A.

(2016). Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA, 316, 2025–2035.

Rossaint

, Bouillon

, Cerny

, Coats

T.J.

, Duranteau

, Fernandez-Mondejar

, Filipescu

, Hunt

B.J.

, Komadina

, Nardi

, Neugebauer

E.A.

, Ozier

, Riddez

, Schultz

, Vincent

J.L.

, and Spahn

D.R

. (2016). The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit. Care, 20, 100.

Vedantam

, Yamal

J.M.

, Rubin

M.L.

, Robertson

C.S.

, and Gopinath

S.P.

(2016). Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds. J. Neurosurg., 125, 1229–1234.

Lelubre

, and Taccone

F.S.

(2016). Transfusion strategies in patients with traumatic brain injury: which is the optimal hemoglobin target?. Minerva Anestesiol. 82, 112–116.

Smith

M.J.

, Stiefel

M.F.

, Magge

, Frangos

, Bloom

, Gracias

, and Le Roux

P.D.

(2005). Packed red blood cell transfusion increases local cerebral oxygenation. Crit. Care Med., 33, 1104–1108.

Zygun

D.A.

, Nortje

, Hutchinson

P.J.

, Timofeev

, Menon

D.K.

, and Gupta

A.K.

(2009). The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit. Care Med., 37, 1074–1078.

Yamal

J.M.

, Benoit

J.S.

, Doshi

, Rubin

M.L.

, Tilley

B.C.

, Hannay

H.J.

, and Robertson

C.S.

(2015). Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury. J. Trauma Acute Care Surg., 79, 843–849.

Ngwenya

L.B.

, Suen

C.G.

, Tarapore

P.E.

, Manley

G.T.

, and Huang

M.C.

(2017). Safety and cost efficiency of a restrictive transfusion protocol in patients with traumatic brain injury. J. Neurosurg. 1–8.

Maegele

, Schöchl

, Menovsky

, Maréchal

, Marklund

, Buki

, and Stanworth

S.J.

(2017). Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol. 16, 630–647.

10.

Laroche

, Kutcher

M.E.

, Huang

M.C.

, Cohen

M.J.

, and Manley

G.T.

(2012). Coagulopathy after traumatic brain injury. Neurosurgery, 70, 1334–1345.

11.

Maegele

(2013). Coagulopathy after traumatic brain injury: incidence, pathogenesis, and treatment options. Transfusion, 53, Suppl. 1, 28S–37S.

12.

Harhangi

B.S.

, Kompanje

E.J.

, Leebeek

F.W.

, and Maas

A.I.

(2008). Coagulation disorders after traumatic brain injury. Acta Neurochir. (Wien), 150, 165–175; discussion, 175.

13.

Wafaisade

, Lefering

, Tjardes

, Wutzler

, Simanski

, Paffrath

, Fischer

, Bouillon

, and Maegele

; Trauma Registry of DGU. (2010). Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit. Care, 12, 211–219.

14.

Greuters

, van den Berg

, Franschman

, Viersen

V.A.

, Beishuizen

, Peerdeman

S.M.

, and Boer

; ALARM-BLEEDING investigators. (2011). Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury. Crit. Care, 15, R2.

15.

Brohi

, Cohen

M.J.

, Ganter

M.T.

, Schultz

M.J.

, Levi

, Mackersie

R.C.

, and Pittet

J.F.

(2008). Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J. Trauma, 64, 1211–1217; discussion, 1217.

16.

Skrifvars

M.B.

, Bailey

, Presneill

, French

, Nichol

, Little

, Duranteau

, Huet

, Haddad

, Arabi

, McArthur

, Cooper

D.J.

, and Bellomo

; EPO-TBI investigators; the ANZICS Clinical Trials Group. (2016). Venous thromboembolic events in critically ill traumatic brain injury patients. Intensive Care Med. 43, 419–428.

17.

PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook

, Meade

, Guyatt

, Walter

, Heels-Ansdell

, Warkentin

T.E.

, Zytaruk

, Crowther

, Geerts

, Cooper

D.J.

, Vallance

, Qushmaq

, Rocha

, Berwanger

, and Vlahakis

N.E.

(2011). Dalteparin versus unfractionated heparin in critically ill patients. N. Engl. J. Med., 364, 1305–1314.

18.

Carney

, Totten

A.M.

, O'Reilly

, Ullman

J.S.

, Hawryluk

G.W.

, Bell

M.J.

, Bratton

S.L.

, Chesnut

, Harris

O.A.

, Kissoon

, Rubiano

A.M.

, Shutter

, Tasker

R.C.

, Vavilala

M.S.

, Wilberger

, Wright

D.W.

, and Ghajar

(2016). Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery, 80, 6–15

19.

Cnossen

M.C.

, Polinder

, Lingsma

H.F.

, Maas

A.I.

, Menon

, and Steyerberg

E.W.

; CENTER-TBI Investigators and Participants. (2016). 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 11, e0161367.

20.

Maas

A.I.

, Menon

D.K.

, Steyerberg

E.W.

, Citerio

, Lecky

, Manley

G.T.

, Hill

, Legrand

, and Sorgner

; CENTER-TBI Investigators and Participants. (2015). Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery, 76, 67–80.

21.

European Comission. (2007). Remuneration of researchers in the public and private sectors. European Communities: Brussels.

22.

IBM Corp. (2012). Released 2012. IBM SPSS Statistics for Windows [OR Macintosh], Version 21.0. IBM Corp.: Armonk, NY.

23.

Nyquist

, Jichici

, Bautista

, Burns

, Chhangani

, DeFilippis

, Goldenberg

F.D.

, Kim

, Liu-DeRyke

, Mack

, and Meyer

(2017). Prophylaxis of Venous Thrombosis in Neurocritical Care Patients: An Executive Summary of Evidence-Based Guidelines: A Statement for Healthcare Professionals From the Neurocritical Care Society and Society of Critical Care Medicine. Crit. Care Med., 45, 476–479.

24.

Carson

J.L.

, Stanworth

S.J.

, Roubinian

, Fergusson

D.A.

, Triulzi

, Doree

, and Hebert

P.C.

(2016). Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst. Rev., 10, CD002042.

25.

Robertson

C.S.

, Hannay

H.J.

, Yamal

J.M.

, Gopinath

, Goodman

J.C.

, Tilley

B.C.

, Epo Severe TBI Trial Investigators, Baldwin

, Rivera Lara

, Saucedo-Crespo

, Ahmed

, Sadasivan

, Ponce

, Cruz-Navarro

, Shahin

, Aisiku

I.P.

, Doshi

, Valadka

, Neipert

, Waguspack

J.M.

, Rubin

M.L.

, Benoit

J.S.

, and Swank

(2014). Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA, 312, 36–47.

26.

McIntyre

L.A.

, Fergusson

D.A.

, Hutchison

J.S.

, Pagliarello

, Marshall

J.C.

, Yetisir

, Hare

G.M.

, and Hebert

P.C.

(2006). Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit. Care, 5, 4–9.

27.

Yuan

, Wu

, Du

Z.Y.

, Sun

Y.R.

, Yu

, Li

Z.Q.

, Wu

X.H.

, Mao

, Zhou

L.F.

, and Hu

(2015). Low-dose recombinant factor VIIa for reversing coagulopathy in patients with isolated traumatic brain injury. J. Crit. Care, 30, 116–120.

28.

Etemadrezaie

, Baharvahdat

, Shariati

, Lari

S.M.

, Shakeri

M.T.

, and Ganjeifar

(2007). The effect of fresh frozen plasma in severe closed head injury. Clin. Neurol. Neurosurg., 109, 166–171.

29.

Batchelor

J.S.

, and Grayson

(2013). A meta-analysis to determine the effect of preinjury antiplatelet agents on mortality in patients with blunt head trauma. Br. J. Neurosurg., 27, 12–18.

30.

Pakraftar

, Atencio

, English

, Corcos

, Altschuler

E.M.

, and Stahlfeld

(2014). Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans. World. J. Clin. Cases, 2, 362–366.

31.

Abdel-Aziz

, Dunham

C.M.

, Malik

R.J.

, and Hileman

B.M.

(2015). Timing for deep vein thrombosis chemoprophylaxis in traumatic brain injury: an evidence-based review. Crit. Care, 19, 96.

32.

Phelan

H.A.

, Eastman

A.L.

, Madden

C.J.

, Aldy

, Berne

J.D.

, Norwood

S.H.

, Scott

W.W.

, Bernstein

I.H.

, Pruitt

, Butler

, Rogers

, and Minei

J.P.

(2012). TBI risk stratification at presentation: a prospective study of the incidence and timing of radiographic worsening in the Parkland Protocol. J. Trauma Acute Care Surg., 73, 2 Suppl. 1, S122–S127.

33.

Phelan

H.A.

, Wolf

S.E.

, Norwood

S.H.

, Aldy

, Brakenridge

S.C.

, Eastman

A.L.

, Madden

C.J.

, Nakonezny

P.A.

, Yang

, Chason

D.P.

, Arbique

G.M.

, Berne

, and Minei

J.P.

(2012). A randomized, double-blinded, placebo-controlled pilot trial of anticoagulation in low-risk traumatic brain injury: The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP I) study. J. Trauma Acute Care Surg., 73, 1434–1441.

34.

Schafer

, Driessen

, Frohlich

, Sturmer

E.K.

, and Maegele

; TACTIC partners (2015). Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres. Scand. J. Trauma Resusc. Emerg. Med., 23, 74.

35.

Albrecht

, Schafer

, Sturmer

E.K.

, Driessen

, Betsche

, Schenk

, and Maegele

(2017). Practice management of acute trauma haemorrhage and haemostatic disorders across German trauma centres. Eur. J. Trauma Emerg. Surg., 43, 201–214.

36.

Driessen

, Schafer

, Albrecht

, Schenk

, Frohlich

, Sturmer

E.K.

, and Maegele

; TACTIC partners. (2015). Infrastructure and clinical practice for the detection and management of trauma-associated haemorrhage and coagulopathy. Eur. J. Trauma Emerg. Surg., 41, 413–420.

37.

Hamada

S.R.

, Gauss

, Pann

, Dunser

, Leone

, and Duranteau

(2015). European trauma guideline compliance assessment: the ETRAUSS study. Crit. Care, 19, 423.

38.

Sena

M.J.

, Rivers

R.M.

, Muizelaar

J.P.

, Battistella

F.D.

, and Utter

G.H.

(2009). Transfusion practices for acute traumatic brain injury: a survey of physicians at US trauma centers. Intensive Care Med. 35, 480–488.

39.

Badenes

, Oddo

, Suarez

J.I.

, Antonelli

, Lipman

, Citerio

, and Taccone

F.S.

(2017). Hemoglobin concentrations and RBC transfusion thresholds in patients with acute brain injury: an international survey. Crit. Care, 21, 159.

40.

Hallet

, Lauzier

, Mailloux

, Trottier

, Archambault

, Zarychanski

, and Turgeon

A.F.

(2013). The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit. Care Med., 41, 2800–2811.

41.

Gaist

, Garcia Rodriguez

L.A.

, Hellfritzsch

, Poulsen

F.R.

, Halle

, Hallas

, and Pottegard

(2017). Association of antithrombotic drug use with subdural hematoma risk. JAMA, 317, 836–846.

42.

Reddy

G.D.

, Gopinath

and Robertson

C.S.

(2015). Transfusion in traumatic brain injury. Curr. Treat. Options Neurol., 17, 46.

43.

Joseph

, Hadjizacharia

, Aziz

, Kulvatunyou

, Tang

, Pandit

, Wynne

, O'Keeffe

, Friese

R.S.

, and Rhee

(2013). Prothrombin complex concentrate: an effective therapy in reversing the coagulopathy of traumatic brain injury. J. Trauma Acute Care Surg., 74, 248–253.

44.

Schochl

, Schlimp

C.J.

, and Maegele

(2014). Tranexamic acid, fibrinogen concentrate, and prothrombin complex concentrate: data to support prehospital use?. Shock, 41, Suppl. 1, 44–46.

45.

Schochl

, Voelckel

, Maegele

, Kirchmair

, and Schlimp

C.J.

(2014). Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit. Care, 18, R147.

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