Out-of-hospital cardiac arrest (OHCA) is a major contributor to global morbidity and mortality, and many survivors experience significant neurological deficits despite intensive resuscitation care following the return of spontaneous circulation (ROSC) [1, 2, 3]. Thus, accurate prediction of neurological outcomes in OHCA patients helps guide treatment and supports effective resource allocation [4, 5].

Among studies related to neurological outcomes after ROSC, studies conducted on core body temperature (CT) have shown that hypothermia on admission is associated with poor neurological outcomes [6, 7]. Post-rewarming fever after targeted temperature management (TTM) may also contribute to poor prognosis in OHCA patients after ROSC [8, 9]. However, CT primarily reflects systemic physiological states and may not accurately represent cerebral thermal dynamics or the extent of hypoxic-ischemic brain injury [10]. In contrast, brain temperature (BT) is directly influenced by cerebral metabolic activity and regional blood flow, making it a more direct indicator of brain status [11, 12]. Yablonskiy et al. [13] demonstrated a strong correlation between BT changes and oxidative metabolism using functional magnetic resonance imaging. Similarly, Wang et al. [10] reported that BT is fundamentally dependent on the balance between metabolic heat production and heat dissipation. In patients with subarachnoid hemorrhage, a BT higher than CT has been associated with preserved mitochondrial function and improved neurological outcomes [14]. However, previous studies on temperature in OHCA have mostly focused on CT as a predictor of neurological outcomes [6, 7, 8, 9]. There have been no clinical studies specifically investigating the relationship between BT and neurological outcomes in patients with OHCA.

Therefore, the purpose of this study was to evaluate the association between BT and neurological outcomes in adult OHCA survivors. We hypothesized that lower BT during TTM would be correlated with poorer neurological outcomes, potentially reflecting the severity of hypoxic-ischemic brain injury.

In this study, we examined the relationship between BT and neurological outcomes in OHCA survivors who underwent TTM. We found that both BT_INI and BT_MAIN were significantly lower in patients with poor outcomes. Multivariable logistic regression analysis demonstrated that both BT_INI and BT_MAIN were independently associated with poor outcomes, whereas CT_INI and CT_MAIN were not. The prognostic performance of BT_INI and BT_MAIN was considered fair.

There have been several attempts to identify the association between body temperature and outcomes in cardiac arrest patients [6, 7, 8, 9, 20]. den Hartog et al. [20] reported that spontaneous hypothermia (35 °C) on intensive care unit admission independently predicts poor neurological outcomes after cardiac arrest, suggesting it may indicate impaired thermoregulation and severe hypoxic-brain injury. Similarly, Benz-Woerner et al. [6] found that lower spontaneous body temperature on admission is related with increased in-hospital mortality in comatose cardiac arrest survivors who received TTM. Additionally, prolonged passive rewarming correlated with poor outcomes, possibly indicating impaired thermoregulation [6]. Palka et al. [7] demonstrated that spontaneous hypothermia ($\le$34 °C) on admission is independently associated with early diffuse anoxic brain injury on initial computed tomography scans in post-cardiac arrest patients, suggesting its potential utility as a clinical marker of severe hypoxic brain injury.

Previous studies have demonstrated associations between low CT after ROSC and poor neurological outcomes [6, 7, 20]. However, CT may be influenced more by systemic physiological responses rather than directly reflecting hypoxic-ischemic brain injury. Coppler et al. [21] reported that in comatose cardiac arrest survivors, BT is on average 0.34 °C higher than CT and exceeds it by $\ge$1 °C in 7% of observations, with changes in BT also lagging behind CT by approximately 27 min. Therefore, BT is generally higher than CT, which seems to reflect active brain metabolism. Interestingly, in contrast to previous studies focusing primarily on CT, our findings highlight that a lower BT relative to CT is independently associated with poor outcomes. This relatively low BT may therefore reflect severe metabolic suppression and impaired cerebral perfusion after cardiac arrest.

BT is primarily regulated by the balance between metabolic heat production and heat removal via cerebral blood flow [22]. Cerebral blood flow not only delivers oxygen and nutrients but also dissipates heat generated by neuronal activity, thereby maintaining thermal homeostasis [11]. During cardiac arrest, cerebral perfusion is abruptly interrupted, resulting in a rapid decline in brain metabolic activity [23]. Because the brain has intrinsically high metabolic demands, it depends heavily on a continuous oxygen supply to sustain adenosine triphosphate (ATP) production through oxidative phosphorylation [12, 24]. When oxygen delivery ceases, ATP synthesis is severely impaired. Since cerebral heat production largely depends on oxygen-driven ATP synthesis, decreased metabolic activity after cardiac arrest results in a lower BT [12]. Severe brain injury can disrupt cerebral blood flow, which in turn affects BT regulation. Reduced perfusion may metabolically limit heat production, potentially leading to decreased BT. Zhu et al. [25] demonstrated that reduced cerebral blood flow results in lower BT relative to CT, highlighting the dominant role of perfusion in cerebral thermal regulation. In their rat model, different anesthetics were used to modulate cerebral perfusion, and BT was consistently lower than CT when blood flow was reduced [25]. The largest brain–core temperature gradient has been reported under $\alpha$-chloralose anesthesia, which produces the most profound cerebral hypoperfusion [25]. When hypercapnia was induced to enhance blood flow, BT increased in all groups, and the rate of temperature rise correlated with baseline perfusion levels [25]. These findings suggest that cerebral blood flow stabilizes BT by facilitating heat exchange with the systemic circulation [25].

We acknowledge that the use of a zero-heat-flux sensor (3M™ Bair Hugger™) on the forehead, though clinically practical and noninvasive, presents inherent limitations when compared with invasive intracranial temperature monitoring methods. Prior validation studies comparing invasive intracranial and noninvasive forehead temperature sensors reported generally good agreement under stable physiological conditions, with a mean difference of approximately 0.4 °C [15]. However, during periods of rapid temperature changes, such as induction (–1.1 °C difference) and rewarming (0.7 °C difference), discrepancies were observed to be more pronounced due to thermal inertia and delayed heat conduction through the skin and skull [15]. Therefore, clinicians should interpret readings from a zero-heat-flux sensor with caution, especially during unstable physiological states.

Several limitations should be acknowledged. First, it was a single-center observational study with a relatively small sample size (n = 149), which may limit the generalizability of the findings due to potential institution-specific practices in TTM, patient selection criteria, or regional demographic factors. Second, BT was measured noninvasively using a zero-heat-flux thermometer placed on the forehead, which might not precisely reflect deep intracranial temperatures. Third, although we proposed plausible physiological mechanisms linking lower BT to impaired cerebral metabolism and perfusion, our study did not include comparisons with established prognostic tools, such as neuroimaging, neurophysiological assessments, and serum biomarker measurements, which could have provided more comprehensive insights. Despite the fair prognostic performance of BT (AUC, 0.728–0.773), direct comparisons with these prognostic tools would better clarify its role within a multimodal prognostic framework for cardiac arrest survivors. Fourth, our analysis was limited to patients who received TTM with a target temperature of 33 °C. As a result, we could not determine whether BT serves as a reliable predictor of neurological outcomes across various target temperatures. This limitation is particularly relevant given recent guideline recommendations favoring more individualized TTM strategies (e.g., 33–36 °C). Although a subset of patients (n = 25) in our cohort were treated at temperatures other than 33 °C, the sample size was insufficient for analysis. Future studies involving larger and more heterogeneous patient populations treated with various TTM strategies are warranted to enhance the external validity of our findings. Fifth, we examined neurological outcomes at 6 months after ROSC via structured phone interviews using the CPC scale. Although this method is practical for long-term follow-up, it may be less precise than in-person assessments and susceptible to observer bias, particularly when differentiating between adjacent categories such as CPC 3 (severe disability) and CPC 4 (vegetative state). Finally, this study focused on representative BT values at the initiation of TTM and during the maintenance phase. However, we did not examine temporal trends or fluctuations in BT throughout the entire cooling period. Future studies incorporating continuous BT monitoring may provide additional prognostic insights beyond those offered by static temperature measurements.

In this study, comatose OHCA patients who received TTM at 33 °C had a lower BT measured at both the initiation and maintenance phases of TTM. These BTs were independently associated with poor neurological outcomes at 6 months after ROSC. BT measurements demonstrated better prognostic value than CT. Our findings suggest that BT could serve as a more precise marker of hypoxic brain injury following cardiac arrest. Further larger-scale, multicenter studies would help confirm these findings and determine the clinical implications of direct BT monitoring during TTM.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.

SJR: Conceptualization, Data curation, Investigation, Writing-original draft, Writing-review & editing; BKL: Conceptualization, Data curation, Investigation, Writing-original draft, Writing-review & editing; DHL: Conceptualization, Formal analysis, Methodology, Project administration, Software, Writing-original draft, Writing-review & editing; YHJ: Conceptualization, Data curation, Investigation, Writing-review & editing; KWJ: Conceptualization, Data curation, Investigation, Writing-review & editing, Supervision; WYH: Data curation, Resources, Validation, Writing-review & editing. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was carried out in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Chonnam National University Hospital Institutional Review Board (Protocol No. CNUH-2021-017). Written informed consent was secured from all patients or their legal guardians before inclusion.

This study was supported by a grant (HCRI23024) of Chonnam National University Hwasun Hospital Institute for Biomedical Science.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM43855.