After traumatic brain injury (TBI), fever is frequent. Brain temperature (BT), which is directly linked to body temperature, may influence brain physiology. Increased body and/or BT may cause secondary brain damage, with deleterious effects on intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcome.
Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), a prospective multicenter longitudinal study on TBI in Europe and Israel, includes a high resolution cohort of patients with data sampled at a high frequency (from 100 to 500 Hz). In this study, simultaneous BT, ICP, and CPP recordings were investigated. A mixed-effects linear model was used to examine the association between different BT levels and ICP. We additionally focused on changes in ICP and CPP during the episodes of BT changes (Δ BT ≥ 0.5 °C lasting from 15 min to 3 h) up or downward. The significance of ICP and CPP variations was estimated with the paired samples Wilcoxon test (also known as Wilcoxon signed-rank test).
Twenty-one patients with 2,435 h of simultaneous BT and ICP monitoring were studied. All patients reached a BT of 38 °C and experienced at least one episode of ICP above 20 mm Hg. The linear mixed-effects model revealed an association between BT above 37.5 °C and higher ICP levels that was not confirmed for lower BT. We identified 149 episodes of BT changes. During BT elevations (
Patients after TBI usually develop BT > 38 °C soon after the injury. BT may influence brain physiology, as reflected by ICP and CPP. An association between BT exceeding 37.5 °C and a higher ICP was identified but not confirmed for lower BT ranges. The relationship between BT, ICP, and CPP become clearer during rapid temperature changes. During episodes of temperature elevation, BT seems to have a significant impact on ICP and CPP.
This article is related to the Invited Commentary available at
The injured brain is extremely sensitive and vulnerable to body temperature changes [
High body temperature can also worsen the cerebral ischemia. In experimental models of brain ischemia, hyperthermia increased the release of glutamate [
Most patients with moderate and severe TBI experience hyperthermia during their intensive care unit (ICU) stay [
A substantial proportion of experimental and clinical evidence on the interplay between hyperthermia and the brain is based on temperature measured outside the brain, either with sensors measuring temperature in the bladder [
Unfortunately, temperatures measured outside the brain may markedly underestimate the BT, especially when it rises [
We consulted a centralized data collection covering several centers in Europe [ To provide a general description of BT, ICP, and CPP in a limited sample of patients with TBI. To clarify the relationships between BT, ICP, and CPP during acute BT changes.
Of the 2,138 patients in the ICU in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) data collection, a subgroup of 277 patients had high frequency digital signals from ICU monitoring (full waveform resolution at sampling frequencies at least 100 Hz, provided by the patient monitors) and was named High Resolution (HR) CENTER-TBI substudy (HR CENTER-TBI). These patients were enrolled in 21 centers from January 2015 to December 2017 and treated in accordance with current evidence-based guidelines for TBI [
Data collection in the CENTER-TBI study adhered to ethical standards; medical ethical committees of all participating centers approved the study. Informed consent was obtained in accordance with local regulations [
Data were collected using ICM + software (Cambridge Enterprise Ltd, Cambridge, UK,
Parallel to the digital HR monitoring, information on specific therapeutic interventions (such as osmotherapy, changes in sedation, suctioning, etc.) was recorded and synchronized to the corresponding monitored variables using ICM + . Interventions and their timing were subsequently extracted using HDFView Software (The HDF5 Group,
CT was not recorded at high frequencies in the selected patient cohort, and thus the information on maximal daily CT (with the probe located in rectum, bladder, esophagus, tympanum, and nasopharynx) together with the epidemiological data were accessed using a bespoke data management tool, Neurobot (
Data are summarized as mean and standard deviation or as median and interquartile range (IQR). For the general description of BT, ICP, and CPP, colored maps were plotted (with per-minute data presented on a color scale) for the first 7 days of HR monitoring. Only simultaneous recordings of ICP and BT were analyzed, and missing values were excluded from the analysis.
CT was recorded daily by the investigators as the maximum and lowest temperature measured during a 24-h interval. To provide a comparison between BT and CT, maximum daily CT was compared with the highest BT recorded during the corresponding monitoring day.
To examine the relations between absolute values of six BT ranges (< 36.4, 36.5–36.9, 37–37.4, 37.5–37.9, 38–38.4, and > 38.5 °C) and ICP, we used a generalized mixed-effects linear model, with a random intercept per patient (that accounts for the repeated measurements in single patients). For the model, the per-minute values of BT and ICP were used. To correct for potential confounders, the mixed model was adjusted for TBI severity using poststabilization motor Glasgow Coma Scale ratings and pupil response [
To assess the effects on ICP and CPP of BT changes over time, episodes of BT elevation and reduction were manually selected according to the following criteria: elevations or reductions of at least 0.5 °C lasting from 15 min to 3 h. A maximum of five episodes was identified in each patient. BT elevation and reduction episodes were analyzed separately.
To assess the significance of ICP and CPP changes in response to BT, the baseline and end episode ICP and CPP within an episode were compared using the paired samples Wilcoxon test (also known as Wilcoxon signed-rank test). A
All statistical analysis was done using R (“R: A language and environment for statistical computing.” R Foundation for Statistical Computing, Vienna, Austria.
The study comprised 21 patients from four centers with simultaneous BT and ICP HR monitoring. Details of their baseline characteristics are given in Table Patients’ general characteristics Age Sex GCS (after stabilization in the ED) Pupils Marshall classification Decompression Duration of simultaneous BT and ICP monitoring (h) Duration of whole HR monitoring (h) GOSE at 6 months 23 M 8 Both reactive III Yes 159 169 6 70 M 10 Both reactive VI Yes 28 162 1 31 M 9 – VI No 110 115 – 25 M 4 Both reactive II No 104 123 – 53 M 8 – – Yes 19 39 1 17 M 7 Both reactive II No 112 120 7 55 M 15 Both reactive VI No 81 84 5 48 F 14 Both reactive II No 77 98 5 50 M 12 Both reactive I No 263 307 1 32 M 4 Both reactive III No 36 62 – 71 M 11 Both reactive III No 138 144 1 46 M 7 One reactive – No 352 583 5 37 M 6 – VI No 168 214 1 51 M 3 Both reactive VI Yes 92 105 5 44 M 8 Both reactive – Yes 51 69 3 69 M 10 – VI No 58 419 1 66 F 8 Both unreactive – No 88 133 1 55 F 8 Both reactive II No 218 245 – 36 M 7 Both reactive VI No 35 36 5 50 M 3 Both reactive VI No 211 219 1 69 M 8 Both reactive II No 35 37 5 This table shows patients’ main baseline characteristics. An en dash indicates missing data BT, brain temperature, ED, emergency department, GCS, Glasgow Coma Scale, GOSE, Glasgow Outcome Scale Extended, HR, high resolution, ICP, intracranial pressure
Twenty of 21 patients had daily maximum CTs recorded, for a total of 93 ICU days during which both BT and CT were measured.
The median BT for all the patients was 37.6 °C (IQR 37.3–37.9), with the lowest value of 36.0 °C reached in five patients and the highest, 39.7 °C, reached in one. All patients reached a BT of 38 °C or higher during the monitoring. BT varied widely among the patients. Figure BT ( Comparison between maximal daily BT with the corresponding maximal CT. The image represents 93 available comparisons of maximal daily BT (from HR data) with the corresponding daily maximal CT (recorded manually) in 20 patients. BT and CT dots are connected by the line but, in fact, represent single measurements. In the majority of cases, BT (blue dots/line) are higher than CT (red dots/line) (
Median ICP was 13 mm Hg (IQR 11–20). During approximately a third of monitoring time (31%), ICP reached > 20 mm Hg. All patients experienced at least one episode of hICP (Fig.
The linear mixed-effects model examined the interplay between six ranges of BT and ICP (Fig. Generalized linear mixed model effects on ICP of six BT ranges. Generalized linear mixed model, including ICP (mm Hg) as dependent variable (predicted values with 95% confidence interval) in six ranges of BT (°C) as independent variable. BT < 36.4 °C was taken as the reference group. The gray area indicates the values below the physiological BT range, which are likely to depend on active treatment. The asterisks indicate the following
We identified 149 episodes of BT changes (at least 0.5 °C): 79 elevations and 70 reductions (Fig. BT elevation/reduction episodes. BT, brain temperature, ΔBT, change in brain temperature, ICP, intracranial pressure
Figure ICP response to BT changes. ICP at the beginning and end of BT episodes. Interventions recorded during HR monitoring Intervention HR monitoring, BT elevation episodes, BT reduction episodes, Fluids 35 8 3 Osmotherapy 122 4 5 Suctioning 450 33 20 Physiotherapy 571 24 31 Sedatives 609 27 22 Vasopressors 678 32 25 Total 2465 128 106 BT, brain temperature, HR, high resolution
Starting from a median baseline BT of 38 °C (IQR 37.7–38.4) in the 70 episodes of BT reduction, there was a median decrease of 0.67 °C (IQR 0.58–0.81). ICP decreased as well, with a median reduction of 1.7 mm Hg (IQR − 1.22 to 6.03) (
Fever is frequent after traumatic, ischemic, and hemorrhagic injuries [
However, there is some indirect evidence that spontaneous fever may precipitate neurologic injury in patients with ischemic stroke and multiple sclerosis [
Finally, temperature elevations may lead to ICP perturbations [
Most studies have monitored body temperature by either external or internal probes. However, existing evidence demonstrates, that BT can not necessarily be predicted from systemic temperature [
To our knowledge, this is the first study to use continuous, high frequency, simultaneous monitoring of BT and ICP in patients with TBI.
The first aim was to describe the behavior of BT, ICP, and CPP and their interactions in a selected sample of patients during the first week after injury. BT showed a range of changes (Fig.
Intermittent daily CT recording provided, as expected, less information on the occurrence of elevated temperatures than the more granular documentation offered by HR. According to CT maximal daily values, temperatures above 38 °C were disclosed for 46 days and a pathological BT was measured for 65 days. This finding indicate that CT may underestimate the severity of hyperthermia, as reported previously [
Concomitantly, ICP was generally well controlled, as reflected by a median of 13 mm Hg (IQR 11–20). However, ICP fluctuated, so each patient suffered some hICP episodes and low CPP (< 60 mm Hg).
The generalized linear mixed model gave a biphasic pattern, tending toward higher ICP with BT above 37.5 °C and the opposite below BT of 37.4 °C (Fig.
Focusing on the ICP increase with BT more than 37.5 °C, our data partially contrast with some previous reports. Four studies [
The second aim of this study was to elucidate the impact of rapid BT changes (from 15 min to 3 h) on ICP and CPP. We explored 149 episodes of significant BT changes (more than 0.5 °C) and found that both ICP and CPP deteriorated when BT rose. ICP and CPP changes were significant (
Reductions of BT were studied in 70 episodes. These events too affected ICP and CPP, reducing them both slightly but significantly.
Three previous studies looked into the relationship between ICP and rapid BT changes. Two studies from our group [
Our analysis has limitations: first, it involved a limited number of patients in few centers. Generalization of our results, therefore, would call for a larger cohort. Second, the physiopathological hypothesis linking BT to ICP and CPP is based on changes in cerebral metabolism, blood flow and content, as suggested in the Introduction. Since we did not measure these variables, our interpretation of the findings has to be considered speculative. Moreover, our study lacks the data on temperature treatments; this makes the conclusion about the natural physiological behavior of BT and ICP more complicated. Finally, our data set did not include simultaneous and continuous high frequency recording of CT and BT, which could be extremely informative; consequently, our comparison of CT and BT was restricted to a limited data set. The graphical comparison of BT and CT (Fig.
BT can be monitored in patients with TBI during their time in the ICU, and temperature tends to vary widely, with frequent significant BT elevations (BT > 38 °C). A general analysis indicates that BT exceeding 37.5 °C seems to involve a concomitant rise in ICP. The relationships between BT, ICP, and CPP become clearer during rapid temperature changes. During episodes of temperature increase, BT seems to have a significant impact on ICP and CPP despite active treatment to prevent intracranial hypertension. A similar but less severe impact is seen when temperature decreases.
We are grateful to our patients with TBI for helping us in our efforts to improve care and outcome for TBI.
Collaboration group: CENTER-TBI High Resolution (HR ICU) Sub-Study Participants and Investigators: Audny Anke8, Ronny Beer9, Bo-Michael Bellander10, Erta Beqiri11, Andras Buki12,13, Manuel Cabeleira14, Arturo Chieregato11, Giuseppe Citerio15,16, Hans Clusmann17, Endre Czeiter18,19, Marek Czosnyka14, Bart Depreitere20, Ari Ercole21, Shirin Frisvold22, Stefan Jankowski23, Danile Kondziella24, Lars-Owe Koskinen25, Ana Kowark26, David K. Menon21, Geert Meyfroidt27, Kirsten Moeller28, David Nelson10, Anna Piippo-Karjalainen29, Andreea Radoi30, Arminas Ragauskas31, Rahul Raj29, Jonathan Rhodes32, Saulius Rocka31, Rolf Rossaint28, Juan Sahuquillo30, Oliver Sakowitz33,34, Nina Sundström35, Riikka Takala36, Tomas Tamosuitis37, Olli Tenovuo38, Peter Vajkoczy39, Alessia Vargiolu16, Rimantas Vilcinis40, Stefan Wolf41, Alexander Younsi34, Frederick A. Zeiler21,42
FO, PS, MC, and TZ collected the patients’ data. TB, FO, and EW analyzed the data and drafted the tables and figures. TB and NS interpreted the data and drafted the article. TB, FO, and NS designed the study protocol, NS supervised the study. RH, SR, YS, MC, TZ, and BI were involved in regular meetings on the manuscript and reviewed the manuscript multiple times. All authors were involved in the design of the CENTER-TBI study and reviewed and approved the final version of the manuscript.
Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement. This research is funded by the European Commission 7th Framework program (602,150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA), from Integra LifeSciences Corporation (USA), and from Neurotrauma Sciences (USA). The funders had no role in the design of the study and collection, analysis, interpretation of data and in writing the article. The datasets used and/or analyzed during the current study are available via
Dr. Birg reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), and grants from Neurotrauma Sciences (USA) during the conduct of the study. Dr. Ortolano reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), and grants from Neurotrauma Sciences (USA) during the conduct of the study. Dr. Wiegers reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), and grants from Neurotrauma Sciences (USA) during the conduct of the study. Dr. Smielewski reports grants from the European Commission 7th Framework program (602150) during the conduct of the study; personal fees from Cambridge Enterprise Ltd, Cambridge, UK, outside the submitted work. Dr. Savchenko reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), and grants from Neurotrauma Sciences (USA) during the conduct of the study. Dr. Ianosi reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study. Dr. Helbok reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study. Dr. Rossi reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study. Dr. Carbonara reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study. Dr. Zoerle reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study. Dr. Stochetti reports grants from the European Commission 7th Framework program (602150), grants from the Hannelore Kohl Stiftung (Germany), grants from OneMind (USA), grants from Integra LifeSciences Corporation (USA), grants from Neurotrauma Sciences (USA), during the conduct of the study.
In each recruiting site ethical approval was given; an overview is available online [
ClinicalTrials.gov: NCT02210221.
Intensive care unit
High resolution
Traumatic brain injury
Arterial blood pressure
Mean arterial blood pressure
Intracranial pressure
Cerebral perfusion pressure
Brain temperature
Standard deviation
Interquartile range
High ICP
Glasgow coma scale
Glasgow outcome scale extended
Emergency room
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.