Stroke is the second leading cause of mortality worldwide and the third leading cause of patient disability, affecting approximately 1 in 4 people during their lifetime [1]. Endovascular therapy (EVT) has proven to be an effective treatment for patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO), with improved outcomes and reduced mortality compared to medical management alone [2, 3]. Following the onset of stroke, about one-third of patients present with sub-febrile fever that can persist for up to 24 hours [4]. The findings in relation to the effects of body temperature on outcomes following AIS are contradictory. Prior studies showed that pyrexia was associated with poorer outcomes and increased short- and long-term mortality after AIS [5, 6, 7, 8, 9]. Increased body temperature within the first 24 hours of ischemic stroke is considered to be a risk factor for hemorrhagic transformation in patients with or without recombinant tissue plasminogen activator (rt-PA) thrombolysis [5, 10, 11]. However, other studies have shown a likely beneficial effect of higher body temperature on clot thrombolysis within the first three hours of hospital admission, and on neurological improvement within a few hours of hospital admission [12]. Moreover, a prospective study on 516 patients who presented with ischemia within 6 hours of stroke-onset found that low body temperature was independently associated with the development of severe ischemic stroke [13]. Only a few studies have examined the effects of post-EVT body temperature on the outcomes from ischemic stroke [14, 15], while the associations between body temperature, clinical outcome and symptomatic intracranial hemorrhage (sICH) following EVT are still unknown. The aim of this study was therefore to investigate for associations between elevated body temperature within 24 hours of EVT for large vessel occlusion stroke and sICH as well as clinical outcomes.

This was a retrospective study of consecutive patients who presented with acute large vessel occlusion stroke and were treated with EVT from August 2018 to June 2021 at a university hospital in China. The inclusion criteria were: patient age $\ge$18 years, presentation within 24 hours of the time last seen well (TLSW0), and occlusion of the terminal internal carotid, M1, or M2 segments of the middle cerebral artery or basilar artery. The exclusion criteria were: known or diagnosed infection on the day of stroke, pre-mRS $>$1, onset of TLSW $>$24 hours, patients who underwent intra-arterial thrombolysis only without mechanical thrombectomy, reperfusion of the suspected occlusion vessel before thrombectomy, a history of severe respiratory failure or malignant tumor, and lost to follow-up with no 3 month mRS data. Of 97 patients enrolled, 7 were excluded because they received only intra-arterial thrombolysis without thrombectomy, and one because of spontaneous reperfusion. Thus, a total of 89 patients were included in the study.

A total of 89 consecutive patients (mean age 66.35 $\pm$ 12.85 years, of which 74.16% were male) with large vessel occlusion ischemic stroke and who underwent EVT met the study inclusion criteria. Patients were divided into two groups according to their PBT reading within 24 hours of EVT. The clinical characteristics of these two groups are summarized in Table 1. The median NIHSS admission score (IQR) of the overall study group was 16.0 (12.0, 21.0), with a significant difference observed between the two groups (Table 1). No other differences in patient demographics or in baseline ASPECTS were bet between the two groups. Reperfusion (TICI $>$2b) occurred in 75 (84.3%) of the study patients.

The clinical outcomes of the study participants are shown in Table 2. Patients with elevated PBT had a higher mRS score upon discharge (4, IQR 1.5–5) compared to those with normal PBT (2, IQR 1–4; p = 0.002), with 17 (30.9%) requiring discharge to a hospice or palliative care compared to 3 (8.8%) for the normal PBT group (p = 0.015). Overall, 39 (43.8%) patients had a favorable outcome at 3 months post-discharge, with a lower incidence in the high PBT group (30.9%) than in the normal PBT group (64.7%; p = 0.002). The high PBT group showed increased mortality at 3 months post-discharge (45.5% vs 20.6%, respectively; p = 0.018) and a poorer outcome as defined by an mRS of $\ge$3 (69.1% vs 35.3%, respectively; p = 0.002). The PBT $\ge$37.3 °C group also had a higher sICH than the PBT 37.3 °C group, but this was not statistically significant (p = 0.11).

In the group of patients with a PBT between 37.3 °C and 38 °C, no significant associations were found with poor clinical outcome. However, PBT $\ge$38 °C was associated with an increased risk of poor clinical outcomes, with an adjusted OR of 25.6 (95% CI: 5.2–126.8; p 0.001), as shown in Table 3.

In patients with PBT between 37.3 °C and 38 °C, no association was seen with mortality at 3 months. However, the high PBT group had an increased risk of 3-month mortality, (OR = 6.56, 95% CI: 1.75–24.6; p = 0.01) (Table 4). After adjustment for sex, NIHSS admission scores and DPT, a PBT $\ge$38 °C within 24 hours of EVT was associated with an increased risk of sICH (OR = 8.84, 95% CI: 1.70–46.01; p = 0.01) (Table 5). PBT $\ge$38 °C within 24 hours of EVT was also associated with an increased risk of in-patient death or hospice discharge (OR = 10.48, 95% CI: 2.04–53.92; p = 0.005) (Table 6).

This study found that elevated PBT ($\ge$38 °C) within 24 hours of EVT in patients with large vessel occlusion stroke was associated with a higher incidence of discharge to hospice or death, poorer clinical outcome (mRS $\ge$3 at 3 months post-discharge), increased 3-month mortality, and less functional independence. In contrast to previous studies that reported no relationship between PBT and the risk of hemorrhagic transformation [14, 15], we found that PBT $\ge$38 °C within 24 hours of EVT was associated with an increased risk of sICH. In patients who present with high initial NIHSS, posterior circulation stroke or AF, this may be an indicator of increased severity of disease and thus explain the association with PBT.

The body temperature of patients with ischemic stroke increases in the first 72 hours, with the harmful effects of hyperthermia occurring in the first 48 hours. In contrast, the neuroprotection afforded by hypothermia occurs during the first 24 hours following stroke onset [18]. With cerebral ischemia, increased body temperature leads to subsequent neurotransmitter release, increased metabolic demand, free-radical production, and disruption of the blood-brain barrier [19]. These events increase the risk of brain cell death and lead to a potentially larger cerebral infarct volume and unfavorable clinical outcomes [19, 20]. Higher body temperature was independently associated with major neurological improvement in patients with severe ischemic stroke treated with thrombolysis via rtPA [21].

Inflammatory factors may also play an important role in the elevated temperatures observed following EVT. Following an acute ischemic stroke, inflammatory factors are regarded as an inevitable pathological consequence of post-cerebral ischemia, which can begin within a few minutes and last for days to weeks or even longer [22]. Elevated levels of acute inflammatory response markers, including interleukin-6 (IL-6) and C-reactive protein (CRP), are associated with poor outcomes after stroke [23]. The IL-6 level is independently associated with futile reperfusion in the setting of EVT and with poor outcome [24]. CRP is also independently associated with early complications and with patient outcome following recanalization by EVT [25]. A high neutrophil-lymphocyte ratio (NLR) at admission may predict poorer functional outcomes following EVT in patients with AIS [22]. A low lymphocyte-monocyte ratio (LMR) or high NLR within 24 hours of EVT was also independently associated with poorer functional outcome, whereas the LMR and NLR at admission were not significant predictors of outcome at 3 months [26].

A multicenter randomized controlled trial (The Cooling for Ischemic Stroke Trial, COOLIST) on the effects of hypothermia following ischemic stroke failed to demonstrate any benefit from surface cooling [27]. Mild hypothermia is a precipitating factor for the development of pneumonia, thus reducing its potential therapeutic efficacy [27].

Inadvertent hypothermia following EVT for anterior circulation stroke is not associated with improvement in functional outcome or a reduction in mortality, but with increased risk of bradyarrhythmia and pneumonia [28]. Although therapeutic hypothermia has a positive effect on the molecular pathways of ischemic injury, the benefits from systemic hypothermia remain limited due to the time taken to reach targeted temperatures and to the related complications. Endovascular delivery of hypothermia is a novel approach to cool the affected brain tissue using selective and rapid local control of the local temperature [29]. Maintaining normothermia might be preferable to therapeutic hypothermia in the early phase of post-ischemic stroke. Paracetamol may also have a favorable effect on functional outcomes in patients with higher temperature, but further research is warranted [29, 30, 31]. The maintenance of normal body temperature may therefore be more suitable and safer than hypothermia therapy.

This was a single-center retrospective study that included anterior and posterior circulation strokes. Data on inflammatory markers such as C-reactive protein was not collected. Prospective, multicenter, large-scale trials are warranted in the future.

This study found that elevated PBT ($\ge$38 °C) within 24 hours of EVT was significantly associated with a higher incidence of discharge to hospice or inpatient death, poorer clinical outcome, higher 3-month mortality, lower incidence of functional independence, and increased risk of symptomatic intracranial hemorrhage. Prospective, multicenter, large-scale trials are warranted to confirm these findings.

YC, BC, and SY conceived and designed the study. YC, SY, BC, TNN, MM, MA, and JWellington drafted the manuscript. ZY, WL, and GC performed the surgery. ZY, GC, WL, JWu, DL, and JL collected the data and followed up with patients. SY, YC, and BC analyzed and interpreted the data. All authors discussed, edited, and approved the final manuscript.

The study was approved by Foshan Sanshui District People’s Hospital review board (shengwei202105) and individual consent for this retrospective analysis was waived. Written informed consent was not required due to the retrospective nature of the study and the blinded data acquisition.

We appreciate patients’ contributions and colleagues at the study.

The projected is supported by Foshan Medical Technology Innovation Platform Construction Foundation, China (FS0AA-KJ218-1301-0012).

The authors declare no conflict of interest.