Serum biomarkers identify critically ill traumatic brain injury patients for MRI
Authors: Richter Sophie , Winzeck Stefan , Czeiter Endre , Amrein Krisztina , Kornaropoulos Evgenios N. , Verheyden Jan , Sugar Gabriela , Yang Zhihui , Wang Kevin , Maas Andrew I. R. , Steyerberg Ewout , Büki András , Newcombe Virginia F. J. , Menon David K. ,   the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Sub-study Participants and Investigators, Amrein Krisztina , Andelic Nada , Andreassen Lasse , Anke Audny , Azouvi Philippe , Bellander Bo‑Michael , Benali Habib , Buki Andras , Caccioppola Alessio , Calappi Emiliana , Carbonara Marco , Citerio Giuseppe , Clusmann Hans , Coburn Mark , Coles Jonathan , Correia Marta , Czeiter Endre , De Keyser Véronique , Degos Vincent , Depreitere Bart , Eikenes Live , Ezer Erzsébet , Foks Kelly , Frisvold Shirin , Galanaud Damien , Ghuysen Alexandre , Glocker Ben , Haberg Asta , Haitsma Iain , Helseth Eirik , Hutchinson Peter J. , Kornaropoulos Evgenios , Kovács Noémi , Kowark Ana , Laureys Steven , Ledoux Didier , Lingsma Hester , Maas Andrew I. R. , Manley Geoffrey , Menon David K. , Menovsky Tomas , Misset Benoit , Muraleedharan Visakh , Nakken Ingeborg , Newcombe Virginia , Nordhøy Wibeke , Nyirádi József , Ortolano Fabrizio , Parizel Paul M. , Perlbarg Vincent , Persona Paolo , Peul Wilco , Posti Jussi P. , Puybasset Louis , Richter Sophie , Roe Cecilie , Roise Olav , Rossaint Rolf , Rossi Sandra , Rueckert Daniel , Skandsen Toril , Sorinola Abayomi , Stamatakis Emmanuel , Steyerberg Ewout W. , Stocchetti Nino , Takala Riikka , Tamás Viktória , Tenovuo Olli , Vámos Zoltán , Van der Steen Gregory , Van Hecke Wim , Vyvere Thijs Vande , Verheyden Jan , Vik Anne , Volovici Victor , Westlye Lars T. , Williams Guy , Winzeck Stefan , Ylén Peter , Zoerle Tommaso 
Published: November 2022

Abstract
Background
Magnetic resonance imaging (MRI) carries prognostic importance after traumatic brain injury (TBI), especially when computed tomography (CT) fails to fully explain the level of unconsciousness. However, in critically ill patients, the risk of deterioration during transfer needs to be balanced against the benefit of detecting prognostically relevant information on MRI. We therefore aimed to assess if day of injury serum protein biomarkers could identify critically ill TBI patients in whom the risks of transfer are compensated by the likelihood of detecting management-altering neuroimaging findings.

Methods
Data were obtained from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Eligibility criteria included: TBI patients aged ≥ 16 years, Glasgow Coma Score (GCS) < 13 or patient intubated with unrecorded pre-intubation GCS, CT with Marshall score < 3, serum biomarkers (GFAP, NFL, NSE, S100B, Tau, UCH-L1) sampled ≤ 24 h of injury, MRI < 30 days of injury. The degree of axonal injury on MRI was graded using the Adams-Gentry classification. The association between serum concentrations of biomarkers and Adams-Gentry stage was assessed and the optimum threshold concentration identified, assuming different minimum sensitivities for the detection of brainstem injury (Adams-Gentry stage 3). A cost–benefit analysis for the USA and UK health care settings was also performed.

Results
Among 65 included patients (30 moderate-severe, 35 unrecorded) axonal injury was detected in 54 (83%) and brainstem involvement in 33 (51%). In patients with moderate-severe TBI, brainstem injury was associated with higher concentrations of NSE, Tau, UCH-L1 and GFAP. If the clinician did not want to miss any brainstem injury, NSE could have avoided MRI transfers in up to 20% of patients. If a 94% sensitivity was accepted considering potential transfer-related complications, GFAP could have avoided 30% of transfers. There was no added net cost, with savings up to £99 (UK) or $612 (US). No associations between proteins and axonal injury were found in intubated patients without a recorded pre-intubation GCS.

Conclusions
Serum protein biomarkers show potential to safely reduce the number of transfers to MRI in critically ill patients with moderate-severe TBI at no added cost.