Early neurological deterioration in acute ischemic stroke patients after intravenous thrombolysis with alteplase predicts poor 3-month functional prognosis - data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China)

Background We aimed to investigate the risk factors of early neurological deterioration (END) after intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and the relationship between END and poor 3-month functional outcomes. Methods Patients who accepted intravenous recombinant rt-PA were enrolled continuously. END was defined as an increase in National Institute of Health Stroke (NIHSS) score ≥ 4 points or death within 24 hours after intravenous thrombolysis. The modified Rankin Scale (mRS) score was recorded to evaluate the functional outcome of stroke, and the poor 3-month prognosis was defined as an mRS score ≥ of 3. Univariate and multivariate analyses were used to analyze the risk factors of END. The relation between END and 3-month functional outcome was analyzed by multivariate logistic regression analysis. Results A total of 1107 patients (mean age, 63.42 ± 11.33 years; 673 males) were included in the final analysis, and 81(7.32%) patients had END. In multivariate analysis, the serum glucose level was significantly associated with END; the odds ratio was 1.10 (95% CI 1.03 to 1.18, p = 0.004). The multivariate logistic analysis showed END has a notable association with the poor 3-month functional recovery even after adjusting for confounding factors; the adjusted OR was 8.25 (95% CI 3.77 to 18.03, p < 0.0001). Conclusions The initial serum glucose level might be an independent risk factor of END, and END might predict a poor 3-month prognosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-022-02737-8.


Introduction
Stroke has become one of the leading causes of death and disability in humans, and there has been a high incidence of stroke in China [1,2]. It has been confirmed that target-vessel revascularization is the most effective method to reduce the disability and mortality of patients. Meanwhile, intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) has been the most economical and convenient treatment [3]. However, some studies have found that some patients still suffered severe neurological deterioration after receiving intravenous thrombolysis, which resulted in prolonged hospitalization and severe adverse prognosis [4]. This study explored the risk factors of early neurological deterioration (END) and the correlation between END and 3-month functional prognosis.

Study population
The data were obtained from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-CHINA) database -a multicenter prospective stroke registry program that enrolled patients who received intravenous tPA within 4.5 hours after symptom onset from May 2007 to July 2012 in China [5]. Some previous pieces of literature have reported the trial design and some results of the study [6,7]. The ethics committee approved the study protocol of Beijing Tiantan Hospital with the Helsinki Declaration. The quality monitoring committee of TIMS-China and the Contract Research Organization independently have been regularly monitoring the registry. All participants had signed written consent.

Definition of END and clinical outcome measurement
END was defined as an increase of NIHSS (National Institute of Health Stroke) score ≥ 4 points or death within 24 hours after intravenous thrombolysis [8]. The primary outcome was poor 3-month functional recovery, expressed as a modified Rankin Scale (mRS) score ≥ 3. The secondary outcomes were sICH (symptomatic intracranial hemorrhage) [9] and mortality at 7 days and 90 days. We used the definitions of sICH in the following three studies: Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) [8], National Institute of Neurological Disorders and Stroke (NINDS) [10], and European Cooperative Acute Stroke Study II (ECASS II) [11].

Statistical analysis
Continuous variables were described by means (standard deviations [SDs]) or medians (interquartile ranges [IQRs]). Categorical variables were presented as frequencies and percentages. The baseline characteristics of patients between the END group and the non-END group were compared by Wilcoxon rank-sum tests for continuous variables and X 2 test for categorical variables. Univariate and multivariate logistic regression was used to estimate the odds ratios (ORs), the corresponding 95% confidence intervals (CIs), and the adjusted ORs with their 95% CI. The multiple ordinal regression was used to test the distribution of mRS at 3-month of patients. SAS software performed all statistical analyses, version 9.4 (SAS Institute Inc., Cary, NC, USA). All P values were two-sided, with P < 0.05 considered statistically significant.

Conclusions:
The initial serum glucose level might be an independent risk factor of END, and END might predict a poor 3-month prognosis.
Keywords: Acute ischemic stroke, Intravenous thrombolysis, Early neurological deterioration, Prognosis the END group was higher than in the non-END group (28.21% vs. 18.69%), there was no difference in the etiology distribution between the two groups. In multivariate analysis, END has a significant correlation with the initial serum glucose level (OR,1.10, 95% CI 1.03-1.18; p = 0.004), taking aspirin within 7 days before thrombolysis (OR, 0.25, 95% CI 0.14-0.44; p < 0.0001), and taking clopidogrel within 7 days before thrombolysis (OR,0.39, 95% CI 0.19-0.82; p = 0.013). The demographics and clinical characteristics at the baseline of subjects in this study were demonstrated in Table 1, and multivariate logistic regression analysis for risk factors of END was shown in Table 2.

Clinical outcomes
During the follow-up, 23 patients were excluded because of missing, and there were 1084 patients (97.92%) who had a 3-month mRS score. The proportion of poor function outcomes is 83.54% in the END group and 37.41% in the non-END group (crude OR After adjusting the baseline variables as the history of prior stroke/TIA, initial serum glucose level, fibrinogen, low-density lipoprotein, cholesterol, SBP on admission, DBP on admission, taking aspirin within 7 days before thrombolysis, taking clopidogrel within 7 days before thrombolysis, and TOAST types, END has a statistical correlation with poor 3-month functional outcomes, the adjusted OR was 8.25(95% CI 3.77-18.03; P < 0.0001; Table 3). There was a numerical difference in the distribution of 3-month mRS among patients in the two groups (crude p < 0.0001), and this difference was still significant after adjusting confound factors (adjusted OR 11.74, 95%CI 7.58 to 18.18; P < 0.0001; Fig. 2). Regarding the secondary outcomes, END has a prominent correlation with SICH.

Discussion
Our study aimed to explore the risk factors of END and the relationship between END and poor 3-month functional outcomes. In some studies, the incidence of END was significantly different due to the lack of a unified    . 2 Distribution of modified Rankin scale (mRS) score after intravenous thrombolysis in patients with acute ischemic stroke definition of END, which was from 5.8 to 34.9% [12][13][14][15].
Most studies have defined END as an increasing NIHSS score ≥ 4 points or death within 24 hours after intravenous thrombolysis, which was our study's exact definition of END [8,16]. Our study enrolled 1107 patients accepting intravenous thrombolysis, and 81 (7.32%) patients occurred END. Simonsen et al. studied 569 patients who received reperfusion therapy and found the incidence of END was 5.8% [14].
Concerning the risk factors of END, although some experts generally believe that elderly patients are more prone to END, it has not been confirmed in some studies [10,15]. Some studies also have demonstrated the predictors of END as follows: diabetes [17,18], neurological functional deficits on admission [19], and systolic BP [20][21][22].
There was no statistical difference in age between the END and non-END groups. Still, there were statistical differences in the history of prior stroke/TIA, initial serum glucose level, fibrinogen, low-density lipoprotein, cholesterol, SBP on admission, and DBP on admission between the two groups. However, in the multivariate analysis, our study found the initial serum glucose level was an independent risk factor of END; the odds ratio was 1.10 (95%CI 1.03 to 1.18, p = 0.004).
Our study found that antiplatelet therapy before thrombolysis might be the protective factor for END. The incidence of END in patients taking aspirin could be 0.25 times lower than in patients without aspirin, similar to patients taking clopidogrel within 7 days. Due to the limitation of our research, we had no further study on this result, and it would be a meaningful research focus in the future.
The series of pathophysiological reactions of the brain after intravenous thrombolysis, such as intracranial hemorrhage (ICH) [23,24], malignant edema [25], early recurrent ischemic stroke [12], and early seizures [26], resulted in the aggravation of neurological deficit [20,21]. Meanwhile, SICH had been the leading cause of END. Our study confirmed that the patients in the END group had a higher incidence of ICH than in the non-END group. The incidence of SICH (NINDS) in the END group patients could be 12.53 times higher than patients in the non-END group. Furthermore, END was significantly correlated with mortality at 7 days and mortality at 3 months. Compared the patients with non-END, the mortality at 7 days of patients with END could be 20.92 times higher, and the mortality at 3 months could be 8.06 times higher.
Our study still has some shortcomings. Firstly, our study did not analyze patients separately in anterior circulation stroke (ACS) and posterior circulation stroke (PCS) groups, which has been confirmed there was no significant difference in the incidence of END between ACS and PCS groups in a recent study [27]. Secondly, we also did not perform subgroup analysis based on the time of ICH, although we have realized that patients usually experience hemorrhagic transformation within 24 h after thrombolysis [28]. Thirdly, owing to the lack of records on other complications(i.e., hyperperfusion syndrome, early stroke recurrence) after intravenous thrombolysis, we were still unable to explain the pathological mechanism of END. Fourthly, confounding factors (i.e., mechanical ventilation, fluid resuscitation, decompressive craniectomy) were not eliminated in our study, which may lead to data bias. We look forward to furthering research in the future.

Conclusions
Early neurological deterioration has a high incidence after intravenous thrombolysis, and the initial serum glucose level might be an independent risk factor of END. END might predict a poor 3-month prognosis. It might be essential to understand the underlying mechanism of END.