Quantifying the relationship between time to command-following and outcomes after TBI: the 1% rule

Importance Recovery of command-following after traumatic brain injury (TBI) is an important prognostic indicator, however, the relationship between time to command-following and long-term functional outcome is not clear. Objective Evaluate the association between command-following and outcome 1-year after TBI. Design Cohort study of participants with moderate-severe TBI in the TBI Model Systems (TBIMS) who were followed 1-year post injury, and validation in an independent dataset from the Brain Trauma Research Center (BTRC) database. Setting TBIMS is a multi-center study of participants with moderate-severe TBI treated in an inpatient rehabilitation hospital. The BTRC database is derived from a single US level 1 trauma center and includes patients with severe TBI. Participants TBIMS: N=9,052 (mean+/-SD age 38+/-18 years, 76% male, 67% white); BTRC: N=228 (mean age 37+/-17 years, 76% male, 91% white). Participants did not follow commands on acute hospital admission and survived to discharge. Exposure Days to command-following during hospitalization. Main Outcome Glasgow Outcome Scale Extended (GOSE) score <4 (i.e., death or dependency) 1-year post TBI. Results: Participants in TBIMS were more likely than those in BTRC to follow commands during acute hospitalization (90% vs 63%; p<0.001) and had a shorter median time to command-following (5 vs 9.5 days; p< 0.001). For each additional week without command-following, the odds ratio for death or dependency at 1 year was 1.30 (95% CI: [1.26,1.35]; p<0.001) in TBIMS and 1.49 ([1.15, 1.97]; p=0.003) in BTRC. Time to command-following had an AUC of 0.61 [0.59, 0.63] in TBIMS and 0.65 [0.53, 0.76]) in BTRC. Each additional day without command-following was associated with a 1.18% (1.16%, 1.20%) increase in the proportion of participants with death or dependency at 1-year in TBIMS and 1.05% (0.99%, 1.11%) in BTRC. Conclusion: Time to command-following after moderate-severe TBI is associated with 1-year outcomes, but the predictive accuracy of absence of command-following on any single post-injury day is limited. In two independent cohorts, the likelihood of death or dependency increased by ~1% for each additional day without command-following. Clinicians should be cautious when prognosticating based on the absence of command-following in the first five weeks after TBI. ### Competing Interest Statement Dr. Hammond receives royalties from Springer/Demos and Lash Publishing, and she has served on Advisory Boards for Avanir and Otsuka Pharmaceuticals. Dr. Zafonte reported receiving royalties from Springer/Demos for the text Brain Injury Medicine as well as serving on the scientific advisory boards of Myomo, and One Care.ai. Dr. Giacino occasionally receives honoraria from academic and medical institutions for conducting training seminars on the Coma Recovery Scale- Revised. ### Funding Statement Dr. Snider receives funding from the National Institute of Neurologic Disorders and Stroke (1K23NS136767-01), American Heart Association, and National Institute of Biomedical Imaging and Bioengineering (1U01EB034228-01). Dr. Giacino receives funding from National Institutes of Health, National Institute of Neurologic Disorders and Stroke (U01 NS1365885; UG3NS117844-02; 5U01NS114140; 5UH3NS112826-04; 5R01NS102574-04; 5UH3NS095554-04), National Institute on Disability, Independent Living, and Rehabilitation Research (90DPCP0008; 90DPTB0011; 90DPHF0006; 90DPTB0027), and U.S. Department of Defense (W81XWH2210925; W81XWH-15-9-0001; W81XWH1910861). Dr. Hammond receives funding from National Institute on Disability, Independent Living, and Rehabilitation Research (grants 90DPTB0035, 90DPTB0022, 90DPTB0002, 90DPHF0006, 90DPTB0017, and 90RTEM0008); National Institutes of Health (UG3NS117844 and 1R01NS118009), PCORI UWSC9923/PCS-1604-35115; Department of Defense (W81XWH-18-1-0796); University of California- San Francisco; University of Michigan (SUBK10416CSPR-002). Dr. Kowalski receives funding from: NIH National Institute of Neurological Disorders and Stroke (LRP). Dr. Zafonte receives funding from National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR), Administration for Community Living (90DPCP0008-01-00, 90DP0039) Dr. Bodien receives funding from: NIH National Institute of Neurological Disorders and Stroke (U01 NS1365885, U01-NS086090), and the National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR), Administration for Community Living (90DPCP0008-01-00, 90DP0039). Dr. Walker receives funding from National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR), Administration for Community Living (90DBTB0021). ### 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: Institutional Review Boards at each TBIMS site and the BTRC approved the study, and participants surrogates provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors