Introduction
The injured brain is extremely sensitive and vulnerable to body temperature changes [
1,
2]. An increase in temperature leads to an increase in cerebral metabolism, with augmented cerebral blood flow, and a concurrent increase in cerebral blood volume. If the compensatory mechanisms are exhausted, this high cerebral blood volume [
3] may raise ICP [
4]. In an experimental model of brain contusion, hyperthermia (39 °C for 3 h) caused enlargement of the contusion volume and had a negative effect on outcome [
5].
High body temperature can also worsen the cerebral ischemia. In experimental models of brain ischemia, hyperthermia increased the release of glutamate [
6] and the extent of tissue damage [
7]. Even though TBI is a different pathology from acute ischemic stroke, there is evidence [
8] that abnormalities in flow metabolism coupling and areas of true ischemia are fairly common in patients with TBI.
Most patients with moderate and severe TBI experience hyperthermia during their intensive care unit (ICU) stay [
9‐
11] and are therefore exposed to the deleterious effects of increased temperature on ICP, brain metabolism, and risk of ischemia.
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 [
12‐
14], rectum [
12,
13,
15‐
17], esophagus [
12], pulmonary artery [
13,
18], and jugular vein [
15], which are collectively indicated as core temperature (CT), or placed externally (axillary [
13] and tympanic [
12] temperatures).
Unfortunately, temperatures measured outside the brain may markedly underestimate the BT, especially when it rises [
18]. The mean difference between BT and CT is 0.3–0.4 °C, but it may be significantly higher during the development of pyrexia (up to 2.6 °C) depending on several factors [
15,
18‐
21]. Nevertheless, direct BT monitoring in patients with brain injuries is rarely used [
22].
We consulted a centralized data collection covering several centers in Europe [
23] to obtain information on simultaneously monitored BT and ICP. The aims of this study were the following:
1.
To provide a general description of BT, ICP, and CPP in a limited sample of patients with TBI.
2.
To clarify the relationships between BT, ICP, and CPP during acute BT changes.
Discussion
Fever is frequent after traumatic, ischemic, and hemorrhagic injuries [
10,
29‐
32]. In experimental models induced hyperthermia increases the extent of the contusion volume and is associated with a worse outcome [
5]. However, spontaneous fever is different from the external heating of animal heads used in the experimental setting. Moreover, the direct effect of fever on the extent of neurological injury in clinical practice is particularly difficult to separate from the impact of infection (which very often is the cause of fever and originates complex inflammatory cascades).
However, there is some indirect evidence that spontaneous fever may precipitate neurologic injury in patients with ischemic stroke and multiple sclerosis [
33‐
35]. In subarachnoid hemorrhage, fever control is associated with reduced cerebral metabolic distress, irrespective of ICP [
30]. Meanwhile, in patients with TBI, there is an association between duration and intensity of fever with worse outcome [
10].
Finally, temperature elevations may lead to ICP perturbations [
18] and, conversely, fever treatments (both physical and pharmacological) may reduce ICP [
36,
37].
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 [
38]; thus, to understand brain physiology better, direct information on BT would be of great interest, even if it requires an invasive approach [
39].
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.
1a). All patients experienced BT higher than 38 °C, which is consistent with previous data [
9,
18,
21].
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 [
18].
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.
3). One possible explanation is that BT ≤ 37.4 °C depends on active manipulations, generally those used to control pathologically high ICP. Even though the physiological range of BT has not been established yet, current evidence suggests that it should be higher than 37 °C [
15‐
21], the normal body temperature [
40]. In fact, BT was generally higher than body temperature in all papers [
15‐
21] but two [
14,
29]. BT below this level is not physiological and may well depend on active treatment (i.e., intentional moderate cooling) or be a side effect of other therapies (deep sedation, myorelaxants, etc.) generally used to treat hICP. Bearing these considerations in mind, we separated Fig.
3 into two areas, showing in gray the part where we suspect the effect of treatment.
Focusing on the ICP increase with BT more than 37.5 °C, our data partially contrast with some previous reports. Four studies [
18,
19,
21,
41] found no consistent relationship between BT and ICP when monitoring data were pooled and analyzed. However, the pattern we describe was found in one report of 72 patients, and in another series in which ICP was studied as a function of body rather than BT [
11,
17].
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 (
p < 0.0001) but, more importantly, they were clinically relevant, with a median ICP increase of 4.5 mm Hg, that, in 40% of the episodes has crossed the threshold of 20 mm Hg by the end of BT elevation. During these episodes active treatment for intracranial hypertension was provided, including osmotherapy and sedative and vasoactive drugs, documented by the total of 128 interventions during 44 BT elevation episodes (Table
2). It is therefore plausible to consider that therapy mitigated the actual ICP and CPP deteriorations caused by the rise in BT. In the absence of treatment, more severe ICP and CPP alterations could well result from BT increases.
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 [
9,
18] suggested an association, but this was not confirmed by Hushak et al. [
21]. In clinical practice, it is a common observation at the bedside that ICP can worsen during the development of fever and a recent consensus statement on TBI management suggested the correction of hyperthermia as one of the first steps for ICP control [
42].
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.
2) have some inaccuracy, and measurements of BT and CT might not correspond perfectly.
Acknowledgements
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
Declarations
Conflicts of interest
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.
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