In this multicenter retrospective study, we observed that sICH occurred in 2.6% of patients by the mSITS-MOST definition in our research, which is comparable to incidence reported in the TIMS-China trial (2.0%) [5]. However, patients who received only intravenous rt-PA within 4.5 h of AIS onset were recruited for the TIMS-China trial. Furthermore, our report showed that higher NIHSS score, higher white blood cell count on admission, and delayed recanalization treatment were independently associated with sICH after IVT. Our study seems to be the first multicenter retrospective study conducted in northern China to investigate the predictors of sICH with AIS patients treated with rt-PA or UK within 6 h, which may better reflect real-world practices.

Compared with patients without sICH, sICH patients had higher blood glucose on admission in our research (mean 9.1 versus 8.3 mmol/L, P = 0.045) (Table 1). In addition, we found no statistical association between admission blood glucose and increasing the risk of sICH post IVT according to mSITS- MOST criteria (OR = 1.938; P = 0.124) (Table 2), a finding reported in prior studies [13, 14]. However, in previous studies [5, 15], elevated baseline glucose level was shown to be a risk factor for sICH in acute ischemic stroke patients treated with IV rt-PA, in which the sICH was diagnosed based on the European Cooperative Acute Stroke Study II (ECASS-II) definition. Certainly, the mechanism behind this phenomenon requires further research.

High white blood cell (WBC) counts are known to be involved in the inflammatory process of AIS [16]. A study by Tiainen et al. reported that higher WBC counts at admission were significantly associated with sICH in AIS patients treated with IVT [17], and similar findings were obtained in our research. In contrast, another study indicated that elevated WBC counts failed to independently predict sICH [18]. In our research, the best predictor of sICH was the WBC count in blood tests, and a value ≥9000/mm3 indicated a 3.6-fold increased risk for sICH. The different results of previous studies may have been caused by the different times of blood sampling due to the dynamic changes in WBC counts after stroke [19]. The mechanism behind the association between elevated WBC counts and sICH is not completely understood, which may be partly because AIS causes WBCs to migrate into the brain, where they can cause brain edema and injury by initiating inflammatory cascade reactions and releasing inflammatory cytokines [20].

Among the clinical risk factors, DNT and NIHSS scores were independently associated with sICH in our study, and these results are consistent with those of previous studies [5, 13]. The elapsed time from hospital admission to the thrombolytic bolus was defined as door-to-needle time (DNT). The benefit of IVT for patients with AIS is time-dependent. The clinical benefit from IVT declines rapidly (time is brain), and every minute counts [21]. In our report, DNT turned out to be the most reliable predictor of sICH among the other parameters assessed, which revealed that patients with a DNT > 50 min had a 4.5-times higher risk of developing sICH than those with a DNT ≤ 50 min, and the difference was statistically significant (P = 0.003) when adjusted for multivariate analysis.

The National Institutes of Health Stroke Scale (NIHSS) score is a tool used to objectively quantify stroke impairment of the stroke and is the most commonly used stroke outcome scale [22]. Higher NIHSS scores are generally associated with the more severe ischemic stroke, which is reflected by large areas of injured blood vessels that are prone to bleeding after IVT. In our research, a higher initial NIHSS score on admission increased the risk of sICH, which was similar to the findings of previous reports [23, 24]. We found that patients with NIHSS scores > 10 had a 3.4-times higher risk of sICH (using NIHSS scores ≤10 as reference). If a patient that had an acute stroke and receiving IVT has an NIHSS score > 10, the physician must be cautious and should check the patient’s white blood cell count. It is worth noting that the NIHSS-assessed stroke severity was milder in the current study than in previous studies, which may explain why the sICH incidence (2.6%) was lower than that in previous reports [6, 7].

A linear relationship showing that an increasing number of concurrent multiple risk factors is associated with an increased likelihood of having sICH was found. These findings suggest that increased monitoring is needed in order to reduce the risk of sICH after IVT for AIS patients in northern China.

Our study was conducted at multicenter hospitals, which including secondary hospitals and tertiary hospitals, and this is the greatest advantage of this study. Considering the research hospitals were located in rural and urban areas in northern China, care should be taken in comparing these results with those of previous studies because regional and racial characteristics may act as sources of bias.

This study has some limitations. First, as a retrospective study, the data may have generated system biases. Involved centers may have followed different protocols for IVT. Second,pretreatment Alberta Stroke Program Early CT Score (ASPECTS), hyperdense middle cerebral artery signs and other important parameters that may influence the risk of sICH, were not assessed in the present study. Third, the sample size was relatively small, and the obtained findings should be verified in future studies with larger samples.

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