Abstract
Practices for controlling intracranial pressure (ICP) in traumatic brain injury (TBI) patients admitted to the intensive care unit (ICU) vary considerably between centres. To help understand the rational basis for such variance in care, this study aims to identify the patient-level predictors of changes in ICP management. We extracted all heterogeneous data (2,008 pre-ICU and ICU variables) collected from a prospective cohort (<em>n</em>=844, 51 ICUs) of ICP-monitored TBI patients in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. We developed the TILTomorrow modelling strategy, which leverages recurrent neural networks to map a token-embedded time series representation of all variables (including missing values) to an ordinal, dynamic prediction of the following day's five-category therapy intensity level (TIL(Basic)) score. With 20 repeats of 5-fold cross-validation, we trained TILTomorrow on different variable sets and applied the TimeSHAP (temporal extension of SHapley Additive exPlanations) algorithm to estimate variable contributions towards predictions of next-day changes in TIL(Basic). Based on Somers' Dxy, the full range of variables explained 68% (95% CI: 65–72%) of the ordinal variation in next-day changes in TIL(Basic) on day one and up to 51% (95% CI: 45–56%) thereafter, when changes in TIL(Basic) became less frequent. Up to 81% (95% CI: 78–85%) of this explanation could be derived from non-treatment variables (i.e., markers of pathophysiology and injury severity), but the prior trajectory of ICU management significantly improved prediction of future de-escalations in ICP-targeted treatment. Whilst there was no significant difference in the predictive discriminability (i.e., area under receiver operating characteristic curve [AUC]) between next-day escalations (0.80 [95% CI: 0.77–0.84]) and de-escalations (0.79 [95% CI: 0.76–0.82]) in TIL(Basic) after day two, we found specific predictor effects to be more robust with de-escalations. The most important predictors of day-to-day changes in ICP management included preceding treatments, age, space-occupying lesions, ICP, metabolic derangements, and neurological function. Serial protein biomarkers were also important and may serve a useful role in the clinical armamentarium for assessing therapeutic needs. Approximately half of the ordinal variation in day-to-day changes in TIL(Basic) after day two remained unexplained, underscoring the significant contribution of unmeasured factors or clinicians' personal preferences in ICP treatment. At the same time, specific dynamic markers of pathophysiology associated strongly with changes in treatment intensity and, upon mechanistic investigation, may improve the timing and personalised targeting of future care.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Protocols
https://www.clinicaltrials.gov/study/NCT02210221
Funding Statement
This research was supported by the National Institute for Health Research (NIHR) Brain Injury MedTech Co-operative. CENTER-TBI was supported by the European Union 7th Framework programme (EC grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA), from Integra LifeSciences Corporation (USA), and from NeuroTrauma Sciences (USA). CENTER-TBI also acknowledges interactions and support from the International Initiative for TBI Research (InTBIR) investigators. S.B. is funded by a Gates Cambridge Scholarship. E.B. is funded by the Medical Research Council (MR N013433-1) and by a Gates Cambridge Scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:The list of sites, ethical committees, approval numbers, and approval dates can be found online: https://www.center-tbi.eu/project/ethical-approval. Ethikkommission der Medizinischen Universitat Wien of Medizinische Universitat Wien Universitatsklinik fur Unfallchirurgie gave ethical approval for this work; Ethikkommission der Medizinischen Universitat Innsbruck of Medizinische Universitat Innsbruck Universitatsklinik fur Neurologie gave ethical approval for this work; Centraal Ethisch Comite, Ethisch Comite Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen of Antwerp University Hospital gave ethical approval for this work; Centraal Ethisch Comite, Ethisch Comite Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen Comite d'Ethique 412 of CHR Citadelle gave ethical approval for this work; Centraal Ethisch Comite, Ethisch Comite Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen Comite d'Ethique hospitalo-facultaire niversitaire de Liege (707) of CHU gave ethical approval for this work; Centraal Ethisch Comite, Ethisch Comite Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen Comissie Medische Ethiek UZ KU Leuven / Onderzoek of UZ Leuven gave ethical approval for this work; De Videnskabsetiske Komiteer for Region Syddanmark of Odense Universiteitshospital, Neurokirurgisk afdeling gave ethical approval for this work; De Videnskabsetiske Komiteer for Region Syddanmark of Region Hovedstaden Rigshopitalet gave ethical approval for this work; Varsinais suomen sairaanhoitopiirin kuntayhtyma, Eettinen Toimikunta of Turku University Hospital gave ethical approval for this work; Varsinais suomen sairaanhoitopiirin kuntayhtyma, Eettinen Toimikunta of Helsinki University Central Hospital gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of APHP gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of CHRU de Besancon gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of Lille University Hospital gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of University Hospital of Grenoble gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of University Hospital Nancy gave ethical approval for this work; Agence Nationale de Securite du Medicament et des Produits de Sante ANSM of CHU Poitiers gave ethical approval for this work; Ethikkommission Medizinsche Fakultat Heidelberg of Universitatsklinikum Heidelberg Neurochirurgische Kliniki gave ethical approval for this work; Ethikkommission an der Medizinsche Fakultat Der rheinsch-Westfalischen Technischen Hocgschule Aachen of Charite | Campus Virchow Klinikum gave ethical approval for this work; Ethikkommission an der Medizinsche Fakultat Der rheinsch-Westfalischen Technischen Hocgschule Aachen of Uniklinik RWTH Aachen gave ethical approval for this work; Ethikkommission Medizinsche Fakultat Heidelberg of Klinikum Ludwigsburg gave ethical approval for this work; ETT TUKEB Egeszsegugyi Tudomanyos Tanacs Pecsi Tudomanyegyetem of Pecsi Tudomanyegyetem Klinikai Kozpont gave ethical approval for this work; ETT TUKEB Egeszsegugyi Tudomanyos Tanacs Szegedi Tudomanyegyetem of zegedi tudomanyegyetem orvostudomanyi kar Szent Gyorgyi Albert Klinikai Kozpont gave ethical approval for this work; Helsinki Committee, Rambam Health Care Campus of Rambam Medical Center gave ethical approval for this work; Hadassah Medical Organization IRB of Hadassah-hebrew University Medical Center gave ethical approval for this work; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Direzione Scientifica Comitato Etico of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico gave ethical approval for this work; Comitato Etico, Ospedale San Raffaele of Ospedale San Raffaele gave ethical approval for this work; Comitato Etico Interaziendale A.O.U. 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Data Availability
Individual participant data, including data dictionary, the study protocol, and analysis scripts are available online, conditional to approved study proposal, with no end date. Interested investigators must submit a study proposal to the management committee at https://www.center-tbi.eu/data. Signed confirmation of a data access agreement is required, and all access must comply with regulatory restrictions imposed on the original study.All code used in this project can be found at the following online repository: https://github.com/sbhattacharyay/TILTomorrow (DOI: 10.5281/zenodo.11060742).
