Academic Editor: Giovanni Grasso
Introduction: The aim of this study was to
investigate for possible associations between an early increase in body
temperature within 24 hours of endovascular therapy (EVT) for large vessel
occlusion stroke and the presence of symptomatic intracranial hemorrhage (sICH)
and other clinical outcomes. Methods: This was a retrospective study of
consecutive patients with large vessel occlusion stroke who were treated with EVT
from August 2018 to June 2021. Patients were divided into two groups based on the
presence of fever, as defined by a Peak Body Temperature (PBT) of
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
The patient’s body temperature was measured using a forehead
thermometer. Temperature readings were obtained upon admission and then routinely
every 4 hours post-EVT. The peak body temperature (PBT) was recorded as the
highest value within 24 hours of EVT. Fever was defined as a body temperature of
Patients with ischemic stroke post-EVT were divided into two groups according to
the presence or absence of fever (PBT
Functional clinical outcomes were evaluated using the pre-stroke mRS score upon
admission and at 3-months after EVT. Patients were assessed either remotely over
the telephone, or in-person during outpatient follow-up. Favorable outcome
(functional independence) was defined as an mRS score of 0–2, and poor outcome
as an mRS score of
Statistical analysis was performed using the SPSS Statistics Package (Version
26.0; IBM Corporation, Armonk, NY, USA). Continuous variables were presented as
the mean
A total of 89 consecutive patients (mean age 66.35
Total | PBT |
PBT |
χ |
p | |
Patients | 89 | 34 | 55 | ||
AT, Mean |
36.62 |
36.55 |
36.66 |
–0.977 | 0.332 |
Age, Mean |
66.35 |
65.82 |
66.673 |
–0.301 | 0.764 |
Male, n, % | 66 (74.16) | 21 (61.76) | 45 (81.82) | 4.409 | 0.036 |
Female, n, % | 23 (25.84) | 13 (38.24) | 10 (18.18) | 4.409 | 0.036 |
Hypertension, n, % | 55 (61.80) | 22 (64.71) | 33 (60.00) | 0.197 | 0.657 |
AF, n, % | 35 (39.33) | 9 (26.47) | 26 (47.27) | 3.811 | 0.051 |
DM, n, % | 17 (19.10) | 9 (26.47) | 8 (14.55) | 1.934 | 0.164 |
CAD, n, % | 22 (24.72) | 7 (20.59) | 15 (27.27) | 0.505 | 0.478 |
Previous Stroke, n, % | 21 (23.60) | 9 (26.47) | 11 (20.00) | 0.505 | 0.477 |
Dyslipidemia, n, % | 13 (14.61) | 5 (15.15) | 8 (14.82) | 0.002 | 0.966 |
CKD, n, % | 10 (11.24) | 3 (8.82) | 7 (12.73) | 0.321 | 0.571 |
Current smoker, n, % | 27 (30.34) | 13 (38.24) | 14 (25.46) | 1.624 | 0.203 |
NIHSS admission (IQR) | 16.0 (12.0, 21.0) | 14.0 (10.0, 17.0) | 18.0 (13.0, 22.0) | –3.032 | 0.002 |
ASPECTS pre-treatment (IQR) | 8.00 (8.00, 9.00) | 8.0 (7.75, 9.00) | 8.00 (8.00, 9.00) | –0.773 | 0.44 |
mRS pre-treatment (IQR) | 0.00 (0.00, 0.00) | 0.00 (0.00, 0.00) | 0.00 (0.00, 0.00) | –1.009 | 0.312 |
PC-stroke, n, % | 10 (11.24) | 1 (2.9) | 9 (16.4) | 2.569 | 0.109 |
AC-stroke, n, % | 79 (88.76) | 33 (97.1) | 46 (83.6) | 2.569 | 0.109 |
TOAST | |||||
LAA, n, % | 39 (43.82) | 19 (55.88) | 20 (36.36) | 4.522 | 0.340 |
CE, n, % | 40 (44.94) | 12 (35.29) | 28 (50.91) | ||
SVO, n, % | 1 (1.12) | 0 (0.00) | 1 (1.89) | ||
SOE, n, % | 5 (5.62) | 1 (2.94) | 4 (7.27) | ||
SUE, n, % | 4 (4.49) | 2(5.88) | 2 (3.64) | ||
Bridging rt-PA, n, % | 42 (47.19) | 12(35.29) | 30 (54.55) | 3.125 | 0.077 |
DPT (IQR), min | 150.00 (107.00, 204.00) | 121.50 (99.50, 162.25) | 177.00 (115.00, 233.00) | –2.534 | 0.011 |
LKNPT (IQR), min | 296.00 (207.00, 490.00) | 330.00 (201.50, 556.50) | 290.50 (209.25, 437.50) | –0.717 | 0.473 |
TICI post |
75 (84.27) | 31 (91.18) | 44 (80.00) | 1.98 | 0.159 |
Abbreviations: AT, Admission Temperature; AC, Anterior Circulation; AF, Atrial Fibrillation; CE, Cardioembolic; CKD, Chronic Kidney Disease; CAD, Coronary Artery Disease; DM, Diabetes Mellitus; DPT, Door-to-Puncture Time; LAA, Large Artery Atherosclerosis; LKNPT, Last-Known Normal-to-Puncture Time; PBT, Peak Body Temperature; PC, Posterior Circulation; SVO, Small Vessel Occlusion; SOE, Stroke of Other Etiology; SUE, Stroke of Undetermined Etiology; TICI, Thrombolysis in Cerebral Infarction. |
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
Total = 89 | PBT |
PBT |
p | ||
(n = 34) | (n = 55) | ||||
Pneumonia, n, % | 35 (39.32) | 9 (26.47) | 26 (47.27) | 3.81 | 0.051 |
Urinary tract infection, n, % | 5 (56.18) | 3 (8.82) | 2 (3.64) | 0.31 | 0.579 |
sICH, n, % | 15 (16.85) | 3 (8.82) | 12 (21.82) | 2.53 | 0.112 |
mRS discharge (IQR) | 4 (1.5, 5) | 2 (1.00, 4.00) | 4 (2.00, 5.00) | –3.11 | 0.002 |
Inpatient Mortality/hospice discharge, n, % | 20 (22.47) | 3 (8.82) | 17 (30.91) | 5.88 | 0.015 |
Favorable outcome, n, % | 39 (43.82) | 22 (64.71) | 17 (30.91) | 9.75 | 0.002 |
Mortality at 3 months, n, % | 32 (35.96) | 7 (20.59) | 25 (45.45) | 5.64 | 0.018 |
Poor outcome, n, % | 50 (56.18) | 12 (35.29) | 38 (69.09) | 9.70 | 0.002 |
Favorable outcome: mRS (0–2) at 3 months. Poor outcome: mRS |
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
Crude OR (95% CI) | p-value | Adjusted OR (95% CI) | p-value | |
/ | / | / | / | |
37.3 °C |
1.22 (0.42, 3.54) | 0.71 | 0.90 (0.27, 2.99) | 0.871 |
PBT |
25.66 (5.19, 126.83) | 12.86 (2.40, 68.78) | ||
Female | 0.73 (0.22, 2.40) | 0.606 | ||
NIHSS admission | 1.14 (1.01, 1.28) | 0.024 | ||
DPT | 1.01 (1.00, 1.01) | 0.109 |
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
Crude OR (95% CI) | p-value | Adjusted OR (95% CI) | p-value | |
/ | / | / | / | |
37.3 °C |
1.22 (0.35, 4.20) | 0.755 | 1.52 (0.41, 5.69) | 0.533 |
PBT |
6.66 (2.19, 20.31) | 0.001 | 6.56 (1.75, 24.59) | 0.005 |
Female | 1.97 (0.64, 6.11) | 0.239 | ||
NIHSS admission | 1.03 (0.94, 1.13) | 0.485 | ||
DPT | 1.00 (0.99, 1.01) | 0.612 |
Crude OR (95% CI) | p-value | Adjusted OR (95% CI) | p-value | |
PBT |
/ | / | / | / |
37.3 °C |
0.90 (0.13, 5.82) | 0.911 | 1.16 (0.17, 8.01) | 0.883 |
PBT |
5.17 (1.26, 21.10) | 0.022 | 8.84 (1.70, 46.01) | 0.010 |
Female | 0.77 (0.17, 3.42) | 0.727 | ||
NIHSS admission | 0.93 (0.83, 1.04) | 0.208 | ||
DPT | 1.00 (0.99, 1.01) | 0.650 |
Crude OR (95% CI) | p-value | Adjusted OR (95% CI) | p-value | |
PBT |
/ | / | / | / |
37.3 °C |
1.41 (0.26, 7.64) | 0.691 | 1.16 (0.30, 10.22) | 0.530 |
PBT |
9.04 (2.26, 36.12) | 0.002 | 10.48 (2.04, 53.92) | 0.005 |
Female | 1.61 (0.42, 6.15) | 0.488 | ||
NIHSS admission | 1.04 (0.93, 1.15) | 0.518 | ||
DPT | 1.00 (0.99, 1.01) | 0.356 |
This study found that elevated 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 (
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.
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