Duan ZW, Li ZN, Zhai YJ, Liu TF, Zhang CC, Hu T, Wei XE, Rong LQ, Liu HY. Effects of glycemic indicators on early neurological outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. World J Diabetes 2025; 16(3): 94491 [DOI: 10.4239/wjd.v16.i3.94491]
Corresponding Author of This Article
Hai-Yan Liu, Doctor, PhD, Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, No. 32 Meijian Road, Xuzhou 221006, Jiangsu Province, China. sjnklhy0722@163.com
Research Domain of This Article
Clinical Neurology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Zuo-Wei Duan, Zhi-Ning Li, Yu-Jia Zhai, Teng-Fei Liu, Cui-Cui Zhang, Xiu-E Wei, Liang-Qun Rong, Hai-Yan Liu, Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
Ting Hu, Department of Neurology, Medical School of Nanjing University, Xuzhou 221006, Jiangsu Province, China
Co-corresponding authors: Zhi-Ning Li and Hai-Yan Liu.
Author contributions: Duan ZW and Li ZN conceived and designed the study; Hu T collected the data; Duan ZW, Liu TF, and Zhang CC analyzed the data, and drafted and revised the manuscript; Zhai YJ and Wei XE participated in drafting the manuscript; Rong LQ and Liu HY reviewed the manuscript and provided critical revision and final editing; All authors contributed to the article and approved the submitted version.
Supported by the Foundation of Jiangsu Provincial Commission of Health and Family Planning, No. QNRC2016353; and the Commission of Health and Family Planning Xuzhou, No. KC22206.
Institutional review board statement: The study was approved by the Ethic Committee of the Second Affiliated Hospital of Xuzhou Medical University, No. 2020122501.
Informed consent statement: All the authors listed have approved the submitted manuscript.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The data underlying this article will be shared on reasonable request to the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hai-Yan Liu, Doctor, PhD, Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, No. 32 Meijian Road, Xuzhou 221006, Jiangsu Province, China. sjnklhy0722@163.com
Received: March 27, 2024 Revised: October 1, 2024 Accepted: December 9, 2024 Published online: March 15, 2025 Processing time: 300 Days and 1.3 Hours
Abstract
BACKGROUND
Stress hyperglycemia (SH) is a common phenomenon that is present in about 50% of patients with acute ischemic stroke (AIS). It is thought to be a main risk factor for poor functional outcome among patients with AIS undergoing intravenous thrombolysis (IVT).
AIM
To investigate the predictive value of glycemic indicators for early neurological outcomes (ENOs) in patients with AIS treated with IVT.
METHODS
We retrospectively reviewed a prospectively collected database of patients with AIS who underwent IVT at the Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, between January 2017 and June 2022. ENO included early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or increase in the National Institutes of Health Stroke Scale (NIHSS) score between baseline and 24 hours after IVT. We analyzed the associations between glycemic indicators [including admission hyperglycemia (AH), fasting blood glucose (FBG), and SH ratio (SHR)] and ENO in all patients and in subgroups stratified by diabetes mellitus (DM).
RESULTS
A total of 819 patients with AIS treated with IVT were included. Among these, AH was observed in 329 patients (40.2%). Compared with patients without AH, those with AH were more likely to have a higher prevalence of DM (P < 0.001) and hypertension (P = 0.031) and presented with higher admission NIHSS scores (P < 0.001). During the first 24 hours after IVT, END occurred in 208 patients (25.4%) and ENI occurred in 156 patients (19.0%). Multivariate mixed logistic regression analyses indicated that END was independently associated with AH [odds ratio (OR): 1.744, 95% confidence interval (CI): 1.236-2.463; P = 0.002]. Subjects were classified into four groups representing quartiles. Compared with Q1, patients in the higher quartiles of SHR (Q2: OR: 2.306, 95%CI: 1.342-3.960; P = 0.002) (Q3: OR: 2.284, 95%CI: 1.346-3.876; P = 0.002) (Q4: OR: 3.486, 95%CI: 2.088-5.820; P = 0.001) and FBG (Q3: OR: 1.746, 95%CI: 1.045-2.917; P = 0.033) (Q4: OR: 2.436, 95%CI: 1.476-4.022; P = 0.001) had a significantly higher risk of END in the overall population. However, none of the glycemic indicators were found to be associated with ENI in patients with or without DM.
CONCLUSION
Our study demonstrated that glycemic indicators in patients with stroke treated with IVT were associated with the presence of END rather than ENI during the first 24 hours after admission.
Core Tip: The benefit of intravenous thrombolysis (IVT) is due to arterial recanalization and brain tissue reperfusion, which improve neurological outcomes of patients with acute ischemic stroke (AIS) treated with IVT. There is no consensus on the influence of stress hyperglycemia (SH) on the effects of early neurological outcomes in patients with AIS treated with IVT. This study identified predictors of early neurological improvement (ENI) and early neurological deterioration (END) and demonstrated that admission hyperglycemia, fasting blood glucose, and SH ratio in patients with stroke treated with IVT are associated with END rather than ENI during the first 24 hours after admission.
Citation: Duan ZW, Li ZN, Zhai YJ, Liu TF, Zhang CC, Hu T, Wei XE, Rong LQ, Liu HY. Effects of glycemic indicators on early neurological outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. World J Diabetes 2025; 16(3): 94491
Acute ischemic stroke (AIS) has become a significant economic burden for both families and society due to its high incidence, disability, and mortality[1-3]. Currently, intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) within 4.5 hours has proven to be the most effective pharmacological treatment for patients with AIS[4,5]. The benefits of IVT are attributed to arterial recanalization and brain tissue reperfusion, which improve neurological outcomes for patients with AIS treated with IVT[6-8]. However, individual differences in early neurological outcomes (ENOs) after IVT therapy are considerable. While some patients exhibit significant neurological improvement, others experience minimal benefits or even neurological deterioration[7-10]. ENO after IVT, including early neurological improvement (ENI) and early neurological deterioration (END), have been reported as independent predictors of prognosis at 3 months[11,12]. ENI is associated with good clinical outcomes, whereas END increases the likelihood of disability and mortality[13-16]. Therefore, identifying predictors of ENO and implementing targeted interventions are crucial for improving overall outcomes in patients with AIS treated with IVT.
Stress hyperglycemia (SH) is a common phenomenon present in about 50% of patients with AIS and is considered a major risk factor for poor functional outcomes among those undergoing IVT[17-19]. However, most previous studies have defined SH based on fasting blood glucose (FBG) or random BG (RBG) levels without accounting for baseline glucose levels[20-22]. The SH ratio (SHR), a novel index introduced by Roberts et al[23], is defined as admission glucose divided by the estimated average glucose concentration derived from glycosylated hemoglobin (HbA1c). SHR has been reported to be a superior glycemic indicator for clinical outcomes in AIS compared to other absolute hyperglycemia measures[22,23]. Nonetheless, there is no consensus regarding the influence of SH on ENO in patients with AIS treated with IVT[17-23].
Therefore, this study investigated the incidence of ENO and its association with admission BG, FBG, and SHR in patients with AIS following IVT. We further explored whether these associations differed between patients with and without diabetes mellitus (DM).
MATERIALS AND METHODS
Patient selection
We conducted a retrospective review of a prospectively collected database of patients with AIS at the Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University (Xuzhou, China), between January 2017 and June 2022. The inclusion criteria were as follows: (1) Age of 18 years or older; and (2) IVT performed with IV rt-PA (dose of 0.9 mg/kg, not exceeding 90 mg) within 4.5 hours of symptom onset. We excluded patients who met any of the following criteria: (1) Pre-stroke modified Rankin scale ≥ 3; (2) Receipt of further endovascular therapy; (3) Conditions affecting HbA1c levels, including malignant tumors, autoimmune diseases, major organ failure, or the presence of an active infection; and (4) Incomplete clinical data. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Xuzhou Medical University.
Demographic and clinical assessment
We analyzed baseline demographics, medical histories, cardiovascular risk factors, laboratory and neuroimaging data, time from symptom onset to IV rt-PA treatment, stroke severity, and etiology in this study. Hypertension was defined as blood pressure ≥ 140/90 mmHg or the use of antihypertensive medications. DM was defined as FBG ≥ 126 mg/dL, a positive ≥ 75 g oral glucose tolerance test result, or the use of insulin or oral hypoglycemic agents. Current cigarette smoking was defined as smoking at present or having quit within the last 6 months. Alcohol abuse/overuse was defined as an intake exceeding 80 g/day or having quit drinking within the last 6 months. Atrial fibrillation was defined based on a past medical history of atrial fibrillation confirmed in medical records. A history of stroke (transient ischemic attack and/or stroke) and cardiovascular disease was also analyzed.
According to our imaging protocol, the selection of magnetic resonance imaging (MRI) scanning during the first 24 hours after admission, using either a 1.5-T MRI scanner (Signa; GE, Fairfield, CT, United States) or 3.0-T MRI scanner (Magnetom Avanto; Siemens, Munich, Germany), largely depended on availability to ensure a prompt evaluation. The imaging protocol included T1-weighted imaging, T2-weighted imaging, diffusion-weighted imaging, fluid-attenuated inversion recovery, and three-dimensional time-of-flight magnetic resonance angiography (MRA). The status of the responsible artery was evaluated using either MRA or computed tomography angiography. Stroke etiology was classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria as large artery atherosclerosis, small artery occlusion, cardioembolic, or others[24]. All patients underwent a computed tomography scan without contrast enhancement or an MRI scan at 24 hours after thrombolysis, or at any other time when the patient experienced clinical worsening.
Assessment of BG levels
Glycemic indicators, including admission BG, FBG, and SHR, were analyzed. Admission BG was monitored shortly after admission, prior to IV rt-PA treatment. FBG and HbA1c (%) were measured within 24 hours after hospitalization, during the morning hours (range: 06:00-08:00) after an overnight fast. According to previous studies, admission hyperglycemia (AH) was defined as admission BG ≥ 7.8 mmol/L, regardless of diabetic status[25]. SHR was calculated using the following formula: FBG (mg/dL)/HbA1c (%)[23].
Stroke severity and outcome measures
Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). ENI was defined as a decrease of ≥ 4 points in NIHSS score or an NIHSS score of 0 at 24 hours after IVT[26,27]. END was defined as an increase of at least 2 points in NIHSS score or death within the first 24 hours after IVT[14,15,28]. The evaluation of ENO was conducted by investigators who were blinded to the imaging information.
Statistical analyses
Statistical analyses were performed using the Statistical Product and Service Solutions software package (version 24.0; IBM Co., Armonk, NY, United States). Patients were classified into the ENI group, END group, and neither ENI nor END group. Baseline characteristics were compared using the Mann-Whitney U test, χ² test, one-way analysis of variance, or Kruskal-Wallis test, as appropriate. Continuous variables are expressed as the mean and standard deviation or median interquartile range (IQR), while categorical variables are expressed as counts (percentages).
To express FBG and SHR as categorical variables, subjects were classified into one of four groups representing quartiles, with the first quartile considered the reference group. The “neither ENI nor END group” was also considered the reference group for multivariate mixed logistic regression models. These models adjusted for all confounding variables with P ≤ 0.1 in univariate analysis to analyze the predictive value of glycemic indicators for END and ENI for all patients, as well as for those grouped based on diabetes diagnosis. Two-tailed P < 0.05 was considered statistically significant.
RESULTS
Our study population consisted of 819 AIS patients (mean age: 67.11 ± 11.85 years; 64.2% men) treated with IVT. The median NIHSS score on admission was 8 points (IQR: 4-13), and the average admission serum glucose, FBG, and HbA1c of the study sample were 8.31 ± 3.68 mmol/L, 6.76 ± 2.63 mmol/L, and 6.48 ± 1.68 mmol/L, respectively. Among them, hypertension was present in 506 patients (61.8%), DM in 278 patients (33.9%), coronary heart disease in 123 patients (15.0%), atrial fibrillation in 137 patients (16.7%), current smoking in 285 patients (34.8%), and alcohol use in 211 patients (25.8%). One hundred and eighty-one patients (22.1%) had a history of stroke or transient ischemic attack.
Of the 278 patients (33.9%) with a history of DM, 329 patients (40.2%) had AH. Baseline demographic and clinical variables based on the presence of AH are summarized in Table 1. Compared with patients without AH, those with AH were more likely to have a higher prevalence of DM (P < 0.001) and hypertension (P = 0.031) and presented with a higher admission NIHSS score (P < 0.001).
Table 1 Baseline characteristics of patients with acute ischemic stroke, mean ± standard deviation, n (%).
Characteristics
Admission hyperglycemia, n = 329
Without admission hyperglycemia, n = 490
P value
Age in years
68.47 ± 11.85
67.30 ± 11.84
0.165
Female
124 (37.7)
169 (34.5)
0.349
Coronary heart disease
53 (16.1)
70 (14.3)
0.474
Smoking
112 (34.0)
173 (35.3)
0.710
Drinking
84 (25.5)
127 (25.9)
0.901
Atrial fibrillation
59 (17.9)
78 (15.6)
0.449
History of TIA-S
77 (23.4)
104 (21.2)
0.461
Hypertension
218 (66.3)
288 (58.8)
0.031
Diabetes mellitus
149 (45.3)
129 (26.3)
< 0.001
Initial NIHSS, median (IQR)
9 (4, 14)
7 (4, 12)
< 0.001
Stroke subtype
0.076
Large artery atherosclerosis
116 (35.3)
157 (32.0)
Small artery disease
122 (37.1)
208 (42.4)
Cardioembolism
54 (16.4)
56 (11.4)
Others
37 (11.2)
69 (14.1)
Systolic blood pressure in mmHg
157.42 ± 23.65
156.59 ± 24.25
0.628
Diastolic blood pressure in mmHg
90.36 ± 15.03
90.94 ± 13.04
0.553
White blood cell counts as × 109
8.59 ± 3.04
8.26 ± 2.91
0.114
Platelets as × 109
208.49 ± 61.80
208.19 ± 59.92
0.945
Activated partial thromboplastin time in seconds
32.57 ± 7.95
32.85 ± 4.72
0.529
Prothrombin time in seconds
14.89 ± 17.33
14.27 ± 16.27
0.602
Total cholesterol in mmol/L
4.27 ± 1.62
4.16 ± 1.28
0.275
Triglyceride in mmol/L
1.71 ± 2.95
1.61 ± 3.43
0.669
Low-density lipoprotein in mmol/L
2.92 ± 1.01
2.80 ± 0.86
0.087
High-density lipoprotein in mmol/L
1.20 ± 0.44
1.22 ± 0.40
0.453
Door-to-needle treatment in minutes
33.14 ± 21.15
31.97 ± 20.46
0.430
Onset-to-treatment in minutes
146.83 ± 50.87
142.02 ± 49.12
0.176
During the first 24 hours after IVT, END was observed in 208 patients (25.4%) and ENI was observed in 156 patients (19.0%). The baseline characteristics of patients with AIS according to ENO are shown in Table 2. Statistical differences were observed in the following variables: Age (P < 0.001), female sex (P = 0.013), atrial fibrillation (P < 0.001), hypertension (P = 0.010), initial NIHSS (P < 0.001), stroke subtype (P = 0.015), SBP (P = 0.038), FBG (P < 0.001), SHR (P < 0.001), and AH (P < 0.001).
Table 2 Demographics and clinical characteristics of the patients with acute ischemic stroke according to early neurological outcomes, mean ± standard deviation, n (%).
Characteristics
ENI group, n = 156
Neither ENI nor END group, n = 455
END group, n = 208
P value
Age in years
64.26 ± 11.28
67.94 ± 11.78
70.03 ± 11.88
< 0.001
Female
42 (26.9)
164 (36.0)
87 (41.8)
0.013
Coronary heart disease
23 (14.7)
64 (14.1)
36 (17.3)
0.552
Smoking
54 (34.6)
151 (33.2)
80 (38.5)
0.416
Drinking
43 (27.6)
110 (24.2)
58 (27.9)
0.508
Atrial fibrillation
43 (27.6)
61 (13.4)
33 (15.9)
< 0.001
History of TIA-S
29 (18.6)
104 (22.9)
48 (23.1)
0.501
Hypertension
85 (54.5)
276 (60.7)
145 (69.7)
0.010
Diabetes mellitus
51 (32.7)
150 (33.0)
77 (37.0)
0.554
Initial NIHSS, median (IQR)
6.5 (4, 11)
6 (3, 12)
10 (6, 16)
< 0.001
Stroke subtype
0.015
Large artery atherosclerosis
44 (28.2)
141 (31.0)
88 (42.3)
Small-artery disease
68 (43.6)
191 (42.0)
71 (34.1)
Cardioembolism
29 (18.6)
58 (12.7)
23 (11.1)
Others
15 (9.6)
65 (14.3)
26 (12.5)
Systolic blood pressure in mmHg
154.02 ± 25.15
156.39 ± 24.17
160.25 ± 22.44
0.038
Diastolic blood pressure in mmHg
91.17 ± 14.57
90.53 ± 13.73
90.75 ± 13.68
0.882
White blood cell counts as × 109
8.53 ± 2.95
8.30 ± 3.01
8.50 ± 2.88
0.528
Platelets as × 109
217.56 ± 67.24
205.75 ± 57.21
206.96 ± 62.37
0.103
Activated partial thromboplastin time in seconds
32.67 ± 4.17
32.93 ± 7.04
32.35 ± 5.57
0.525
Prothrombin time in seconds
13.44 ± 14.01
15.56 ± 19.17
13.03 ± 11.95
0.131
Total cholesterol in mmol/L
4.21 ± 1.19
4.18 ± 1.57
4.24 ± 1.24
0.863
Triglyceride in mmol/L
1.40 ± 0.84
1.71 ± 3.63
1.70 ± 3.45
0.577
Low-density lipoprotein in mmol/L
2.76 ± 0.90
2.85 ± 0.97
2.90 ± 0.84
0.326
High-density lipoprotein in mmol/L
1.19 ± 0.28
1.22 ± 0.49
1.19 ± 0.32
0.552
Door-to-needle treatment in minutes
29.46 ± 16.99
33.16 ± 21.84
33.10 ± 20.70
0.137
Onset-to-treatment in minutes
136.92 ± 45.03
144.71 ± 51.09
147.56 ± 50.26
0.117
Fasting blood glucose
< 0.001
First quartile: ≤ 5.09 mmol/L
51 (32.7)
119 (26.2)
33 (15.9)
Second quartile: 5.10-5.90 mmol/L
39 (25.0)
125 (27.5)
42 (20.2)
Third quartile: 5.91-7.66 mmol/L
37 (23.7)
111 (24.4)
57 (27.4)
Fourth quartile: > 7.67 mmol/L
29 (18.6)
100 (22.0)
76 (36.5)
Stress hyperglycemia ratio
< 0.001
First quartile: ≤ 0.85
37 (23.7)
137 (30.1)
29 (13.9)
Second quartile: 0.86-0.98
53 (34.0)
105 (23.1)
48 (23.1)
Third quartile: 0.99-1.16
35 (22.4)
116 (25.5)
54 (26.0)
Fourth quartile: > 1.16
31 (19.9)
97 (21.3)
77 (37.0)
Admission hyperglycemia
53 (34.0)
168 (36.9)
108 (51.9)
< 0.001
Multivariate mixed logistic regression analyses were conducted to explore the predictive value of glycemic indicators for END and ENI, using “neither ENI nor END” as the reference group. END was independently associated with AH [odds ratio (OR): 1.744, 95% confidence interval (CI): 1.236-2.463; P = 0.002]. Regarding FBG and SHR as categorical variables, we classified subjects into four groups representing quartiles. Compared with Q1, END was more frequently observed in Q3 (OR: 1.746, 95%CI: 1.045-2.917; P = 0.033) and Q4 (OR: 2.436, 95%CI: 1.476-4.022; P = 0.001) for FBG. Similarly, patients in the higher quartiles of SHR (Q2: OR: 2.306, 95%CI: 1.342-3.960; P = 0.002) (Q3: OR: 2.284, 95%CI: 1.346-3.876; P = 0.002) (Q4: OR: 3.486, 95%CI: 2.088-5.820; P = 0.001) also had a significantly higher risk of END. However, none of the glycemic indicators were found to be related to the presence of ENI (Table 3).
Table 3 Multivariate analysis of the associations between glycemic indicators and early neurological outcomes in the whole population.
Parameter
Early neurological deterioration
Early neurological improvement
OR
95%CI
P value
OR
95%CI
P value
Admission hyperglycemia
1.744
1.236-2.463
0.002
0.928
0.622-1.383
0.712
Fasting blood glucose
First quartile
Reference
Reference
Reference
Reference
Reference
Reference
Second quartile
1.259
0.739-2.146
0.396
0.724
0.439-1.195
0.207
Third quartile
1.746
1.045-2.917
0.033
0.789
0.471-1.321
0.367
Fourth quartile
2.436
1.476-4.022
0.001
0.713
0.413-1.230
0.224
Stress hyperglycemia ratio
First quartile
Reference
Reference
Reference
Reference
Reference
Reference
Second quartile
2.306
1.342-3.960
0.002
1.875
0.976-2.321
0.067
Third quartile
2.284
1.346-3.876
0.002
1.059
0.618-1.816
0.834
Fourth quartile
3.486
2.088-5.820
0.001
1.293
0.736-2.274
0.372
Multivariate mixed logistic regressions were performed to investigate the association of glycemic indicators with ENO for the subgroups of patients with and without DM. We found that AH and the higher quartiles of SHR and FBG were independently related to END in patients with and without DM. However, none of the glycemic indicators were found to be associated with ENI in patients with or without DM (Table 4).
Table 4 Multivariate logistical regression analyses depicting the association of glycemic indicators and early neurological outcomes in the patients with and without diabetes.
IVT with rt-PA remains the gold standard treatment for AIS as recommended by guidelines[4,5]. However, clinical outcomes are not always satisfactory. Based on the results of the present study, clinical symptoms improved in 156 patients (19.0%), remained unchanged in 455 patients (55.6%), and deteriorated in 208 patients (25.4%) during the first 24 hours after IVT. Our findings are consistent with previous studies that highlighted significant individual differences in the effects of IVT therapy[9,29,30].
ENO serves as an early endpoint that can precisely isolate the effect of IVT itself, independent of subsequent care influences. It is widely acknowledged that a considerable fraction of patients with AIS do not recover or may even deteriorate within 24 hours after IVT; this condition, known as END, is strongly associated with poor outcomes[31]. Therefore, identifying biomarkers that can predict early clinical outcomes in patients with AIS treated with IVT is crucial. Several studies have analyzed prognostic predictors of IVT therapy for AIS, showing that various clinical and biological factors such as older age, initial neurological severity, DM, and blood levels of homocysteine may affect patient prognosis[27,32,33]. Among these, serum glucose levels have garnered significant attention from researchers[19]. However, the impact of hyperglycemia on ENO in patients with AIS remains controversial, as it may act as a contributing factor rather than a direct cause[17-20]. AH is a common phenomenon in the early stages of AIS, even in non-diabetic patients, due to stress-mediated release of cortisol and norepinephrine[34]. According to the SWIFT trial, AH was independently associated with poor early outcomes among patients with AIS[35]. Higher serum glucose levels upon admission were also reportedly linked to lower rates of recanalization in patients with AIS receiving rt-PA IVT, leading to poor functional outcomes[36]. However, other studies did not demonstrated a significant relationship between AH and the risk of symptomatic intracranial hemorrhage, poor outcomes, or mortality after 3 months among patients with AIS[21,22]. In summary, while hyperglycemia may be a factor contributing to END, the conclusions of relevant studies regarding this association remain inconsistent.
AIS was associated with elevated AH concentrations measured at admission and with elevated FBG concentrations during the morning hours after an overnight fast. However, both metrics have limitations in distinguishing between chronic poor management of background glucose levels and physiological stress responses to AIS[21]. Previous studies have considered absolute hyperglycemia as an observational predictor but overlooked differences in baseline glycemia, a practice that may influence analyses of the association between hyperglycemia and clinical outcomes after stroke[19,21]. SH, defined as transient hyperglycemia in the context of illness, regardless of known diabetes, is a common manifestation found in patients with myocardial infarction, stroke, and other critical illnesses. However, there is no unified definition of SH. Most prior studies have simply used FBG or initial BG at admission to determine the presence of SH, ignoring usual BG levels prior to stroke onset[19-22]. Therefore, when assessing the relationship between SH and outcomes in critical illness, background BG levels should be considered. The SHR was first applied to assess SH by Roberts et al[23] and is reportedly associated with END and poor functional outcomes at discharge in patients with AIS treated with IVT. SHR is regarded as a better predictive biomarker of critical illness than absolute hyperglycemia, as it incorporates HbA1c, which reflects BG levels over the last 2-3 months, along with RBG after stroke. Nevertheless, the association between SHR and clinical outcomes in patients with AIS treated with IVT remains uncertain. Variations in study populations and definitions of SHR may contribute to the heterogeneity of existing studies[21,23,37-39]. Additionally, discrepancies in the inclusion of relevant confounding factors, such as stroke severity, may also affect the predictive value of SHR. In this study, we defined SHR as FBG within 24 hours after hospitalization (mg/dL) divided by HbA1c (%), finding that elevated SHR was associated with poor functional outcomes in AIS following IVT. Subgroup analyses indicated a consistent association in both patients with DM and those without DM. Our findings align with a recent study that identified a higher SHR as a predictor of increased risk of END after IVT[17].
Recently, the underlying pathophysiology of the effect of SH on END remains incompletely understood. SH has been thought to aggravate blood-brain barrier injury by enhancing intracellular acidosis in the ischemic penumbra, leading to mitochondrial dysfunction, energy failure, and increased apoptosis[40]. Additionally, hyperglycemia can impair cerebral autoregulation, resulting in reperfusion injury and lower rates of recanalization in AIS patients receiving rt-PA IVT[41]. Moreover, SH is associated with greater inflammatory and neurohormonal responses, increased induction of endothelial apoptosis, and heightened oxidative stress, which elevate the risks of brain edema and hemorrhage after IVT[42,43]. Studies have also indicated that both acute and chronic hyperglycemia contribute to a prothrombotic shift, potentially facilitating thrombus extension, which is strongly associated with END[44,45]. Consequently, the complex molecular mechanisms and pathological changes may lead to poor outcomes following stroke in the presence of SH.
The results of our study align with previous research suggesting that hyperglycemia is more likely associated with worse outcomes in patients with AIS treated with IVT[17]. Therefore, early BG management in AIS is critical in routine clinical practice. According to several studies, early control of hyperglycemia should ideally be conducted within 12 hours after stroke onset, sustained for more than 48 hours, and aim to achieve BG levels in the range of 140-180 mg/dL[5,46]. However, using RBG or FBG to evaluate SH overlooks background glucose concentrations prior to stroke onset. By contrast, SHR serves as a relative clinical predictor that quantitatively evaluates hyperglycemia. Therefore, SHR is recommended as a substitute for RBG or FBG and may serve as a clinical parameter for the prognosis of patients with AIS treated with IVT.
This study had several limitations. The data were collected from only one hospital, resulting in a limited sample size, which may have introduced selection bias and restricted the generalizability of the results. Additionally, we did not obtain serial serum glucose measurements, which prevented us from assessing the impact of short-term glycemic variability on ENO. We also did not evaluate the influence of early control of hyperglycemia on functional outcomes. Therefore, prospective randomized multicenter studies with larger sample sizes should be conducted to clarify these relationships.
CONCLUSION
In conclusion, our study demonstrated that AH, FBG, and SHR in patients with stroke treated with IVT were associated with the presence of END rather than ENI during the first 24 hours after admission. The results suggest that comprehensive evaluation and appropriate control of BG may be important for patients with AIS receiving IVT.
ACKNOWLEDGEMENTS
The authors would like to thank all of the nurses and doctors who helped in collecting the data from all participating centers.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade D, Grade D
Novelty: Grade B, Grade C
Creativity or Innovation: Grade C, Grade C
Scientific Significance: Grade C, Grade C
P-Reviewer: Cheon DY; Horowitz M; Peng DG S-Editor: Fan M L-Editor: Filipodia P-Editor: Xu ZH
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