Diurnal brain temperature rhythms and mortality after brain injury: a prospective and retrospective cohort study

ObjectiveTo determine the clinical relevance of brain temperature (TBr) variation in patients after traumatic brain injury (TBI). DesignCohort study with prospective (healthy participant) and retrospective (TBI patient) arms. SettingSingle neuroimaging site in the UK (prospective arm); intensive care sites contributing to the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) High Resolution ICU (HR ICU) Sub-Study (retrospective arm). Participants40 healthy adults aged 20-40 years recruited for non-invasive brain thermometry and all patients up to May 2020 that had TBr measured directly and were not subjected to Targeted Temperature Management (TTM). Main outcome measuresA diurnal change in TBr (healthy participants); death in intensive care (patients). ResultsIn healthy participants, mean TBr (38.5 SD 0.4{degrees}C) was higher than oral temperature (36.0 SD 0.5{degrees}C), and 0.36{degrees}C higher in luteal females relative to follicular females and males (95% confidence interval 0.17 to 0.55, P=0.0006 and 0.23 to 0.49, P<0.0001, respectively). TBr increased with age, most notably in deep brain regions (0.6{degrees}C over 20 years; 0.11 to 1.07, P=0.0002). The mean maximal spatial TBr range was 2.41 (SD 0.46){degrees}C, with highest temperatures in the thalamus. TBr varied significantly by time of day, especially in deep brain regions (0.86{degrees}C; 0.37 to 1.26, P=0.0001), and was lowest in the late evening. Diurnal TBr in cortical white matter across participants ranged from 37.0 to 40.3{degrees}C. In TBI patients (n=114), mean TBr (38.5 SD 0.8{degrees}C) was significantly higher than body temperature (TBo 37.5 SD 0.5{degrees}C; P<0.0001) and ranged from 32.6 to 42.3{degrees}C. Only 25/110 patients displayed a diurnal temperature rhythm; TBr amplitude was reduced in older patients (P=0.018), and 25/113 patients died in intensive care. Lack of a daily TBr rhythm, or an age increase of 10 years, increased the odds of death 12-fold and 11-fold, respectively (OR for death with rhythm 0.09; 0.01 to 0.84, P=0.035 and for death with ageing by 1 year 1.10; 1.05 to 1.16, P=0.0002). Mean TBr was positively associated with survival (OR for death 0.45 for 1{degrees}C increase; 0.21 to 0.96, P=0.040). ConclusionsHealthy TBr exceeds TBo and varies by sex, age, menstrual cycle, brain region, and time of day. Our 4-dimensional reference resource for healthy TBr can guide interpretation of TBr data in multiple clinical settings. Daily temperature variation is frequently disrupted or absent in TBI patients, in which TBr variation is of greater prognostic use than absolute TBr. Older TBI patients lacking a daily TBr rhythm are at greatest risk of death in intensive care. Appropriately controlled trials are needed to confirm the predictive power of TBr rhythmicity in relation to patient outcome, as well as the clinical utility of TTM protocols in brain-injured patients. RegistrationUK CRN NIHR CPMS 42644; ClinicalTrials.gov number, NCT02210221. SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIBrain temperature (TBr) can be measured directly in brain-injured patients via intracranial probe, but this method cannot be used in healthy individuals. C_LIO_LITBr can be measured non-invasively using magnetic resonance spectroscopy (MRS), but this method is not appropriate for most brain-injured patients. C_LIO_LISince physiological reference ranges for TBr in health have not been established, the clinical relevance of TBr variation in patients is unknown, and the use of TTM in neurocritical care remains controversial. C_LI What this study addsO_LIA reference map for healthy adult TBr at three clinically-relevant time points that can guide interpretation of TBr measured directly, or by MRS, in multiple clinical settings. C_LIO_LIOur results suggest that loss of diurnal TBr rhythmicity after TBI increases the odds of intensive care death 12-fold; some TTM strategies may be clinically inappropriate. C_LI