Increased peripheral leukocyte aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis: A study based on clinical evidence.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.

Early tirofiban administration after intravenous thrombolysis in acute ischemic stroke (ADVENT): Study protocol of a multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Nearly half of patients with acute ischemic stroke who undergo intravenous thrombolysis (IVT) fail to achieve excellent functional outcomes. Early administration of tirofiban after IVT may improve patient outcomes. OBJECTIVE: To evaluate the efficacy and safety of early tirofiban administration after intravenous tenecteplase in patients with acute ischemic stroke. METHODS AND DESIGN: The ADVENT trial is a multicenter, randomized, parallel-controlled, double-blind clinical trial. A total of 1084 patients undergoing IVT without subsequent endovascular treatment will be recruited from multiple hospitals in China. Subjects will be randomized in a 1:1 ratio to receive tirofiban or placebo, which will be infused within 6 h after IVT until 24 h after IVT, at 0.4 µg/kg/min for 30 min and then at 0.1 µg/kg/min. The primary efficacy outcome is the proportion of patients with excellent functional outcomes (modified Rankin Scale (mRS) ⩽ 1) at 90 days. Secondary outcomes include the proportion of patients with favorable functional outcomes (mRS ⩽ 2) at 90 days and neurological functional assessments evaluated during hospitalization. Symptomatic intracranial hemorrhage will be the primary safety outcome. Mortality and other adverse events will be recorded. DISCUSSION: This pivotal trial will provide important data on the early administration of antiplatelet therapy after IVT and may promote progress in treatment standards. TRIAL REGISTRY: ClinicalTrials.gov (NCT06045156).

Safety and efficacy of remote ischemic conditioning for spontaneous intracerebral hemorrhage (SERIC-ICH): A multicenter, randomized, parallel-controlled clinical trial study design and protocol.

BACKGROUND: Previous studies have revealed that remote ischemic conditioning (RIC) may have a neuroprotective function. However, the potential benefit of RIC for patients with ICH remain unclear. OBJECTIVE: The primary aim of this study is to assess the safety and efficacy of RIC for patients with ICH. METHODS: The Safety and Efficacy of RIC for Spontaneous ICH (SERIC-ICH) is an ongoing prospective, randomized, multicenter, parallel-controlled, and blinded-endpoint clinical trial. The study will enroll an estimated 2000 patients aged ⩾18 years within 24 h after ICH onset, with National Institutes of Health Stroke Scale ⩾6 and Glasgow Coma Scale ⩾8 upon presentation. The patients will be randomly assigned to the RIC or control groups (1:1) and will be treated with cuffs inflated to a pressure of 200 or 60 mmHg, respectively, twice daily for 7 days. Each RIC treatment will consist of four cycles of arm ischemia for 5 min, followed by reperfusion for another 5 min, for a total procedure time of 35 min. The primary efficacy outcome measure is the proportion of patients with good functional outcomes (modified Rankin scale 0-2) at 180 days. The safety outcome measures will include all adverse events and severe adverse events occurring in the course of the study. DISCUSSION: RIC is an inexpensive intervention and might be a strategy to improve outcomes in patients with ICH. The SERIC-ICH trial will investigate whether RIC treatment can be applied as an adjuvant treatment in the acute phase of ICH and identify safety issues.

Heart Rate Variability in Patients with Spontaneous Intracerebral Hemorrhage and its Relationship with Clinical Outcomes.

BACKGROUND: Although abnormal heart rate variability (HRV) is frequently observed in patients with spontaneous intracerebral hemorrhage (ICH), its time course and presentation of different indices remain unclear, and few studies have focused on its association with clinical outcomes. METHODS: We prospectively recruited consecutive patients with spontaneous ICH between June 2014 and June 2021. HRV was evaluated twice during hospitalization (within 7 days and 10-14 days after stroke). Time and frequency domain indices were calculated. A modified Rankin Scale score ≥ 3 at 3 months was defined as a poor outcome. RESULTS: Finally, 122 patients with ICH and 122 age- and sex-matched volunteers were included. Compared with controls, time domain and absolute frequency domain HRV parameters (total power, low frequency [LF], and high frequency [HF]) in the ICH group were significantly decreased within 7 days and 10-14 days. For relative values, normalized LF (LF%) and LF/HF were significantly higher, whereas normalized HF (HF%) was significantly lower, in the patient group than in the control group. Furthermore, LF% and HF% measured at 10-14 days were independently associated with 3-month outcomes. CONCLUSIONS: HRV values were impaired significantly within 14 days after ICH. Furthermore, HRV indices measured 10-14 days after ICH were independently associated with 3-month outcomes.

Heart Rate Variability Parameter Changes in Patients With Acute Ischemic Stroke Undergoing Intravenous Thrombolysis.

Background Autonomic dysfunction has been revealed in patients with acute ischemic stroke and is associated with poor prognosis. However, autonomic nervous system function assessed by heart rate variability (HRV) and its relationship with clinical outcomes in patients undergoing intravenous thrombolysis (IVT) remain unknown. Methods and Results Patients who did and did not undergo IVT between September 2016 and August 2021 were prospectively and consecutively recruited. HRV values were measured at 1 to 3 and 7 to 10 days after stroke to assess autonomic nervous system function. A modified Rankin scale score ≥2 at 90 days was defined as an unfavorable outcome. Finally, the analysis included 466 patients; 224 underwent IVT (48.1%), and 242 did not (51.9%). Linear regression showed a positive correlation of IVT with parasympathetic activation-related HRV parameters at 1 to 3 days (high frequency: ß=0.213, P=0.002) and with both sympathetic (low frequency: ß=0.152, P=0.015) and parasympathetic activation-related HRV parameters (high frequency: ß=0.153, P=0.036) at 7 to 10 days after stroke. Logistic regression showed HRV values and autonomic function within 1 to 3 and 7 to 10 days after stroke were independently associated with 3-month unfavorable outcomes after adjusting for confounders in patients who underwent IVT (all P<0.05). Furthermore, addition of HRV parameters to conventional risk factors significantly improved risk-predictive ability of 3-month outcome (the area under the receiver operating characteristic curve significantly improved from 0.784 [0.723-0.846] to 0.855 [0.805-0.906], P=0.002). Conclusions IVT positively affected HRV and autonomic nervous system activity, and autonomic function assessed by HRV in acute stroke phase was independently associated with unfavorable outcomes in patients undergoing IVT.

Effectiveness of butylphthalide on cerebral autoregulation in ischemic stroke patients with large artery atherosclerosis (EBCAS study): A randomized, controlled, multicenter trial.

Finding appropriate drugs to improve cerebral autoregulation (CA) in patients with acute ischemic stroke (AIS) is necessary to improve prognosis. We aimed to investigate the effect of butylphthalide on CA in patients with AIS. In this randomized controlled trial, 99 patients were 2:1 randomized to butylphthalide or placebo group. The butylphthalide group received intravenous infusion with a preconfigured butylphthalide-sodium chloride solution for 14 days and an oral butylphthalide capsule for additional 76 days. The placebo group synchronously received an intravenous infusion of 100 mL 0.9% saline and an oral butylphthalide simulation capsule. The transfer function parameter, phase difference (PD), and gain were used to quantify CA. The primary outcomes were CA levels on the affected side on day 14 and day 90. Eighty patients completed the follow-up (52 in the butylphthalide group and 28 in the placebo group). The PD of the affected side on 14 days or discharge and on 90 days was higher in the butylphthalide group than in the placebo group. The differences in safety outcomes were not significant. Therefore, butylphthalide treatment for 90 days can significantly improve CA in patients with AIS.Trial registration: ClinicalTrial.gov: NCT03413202.

DL-3-n-butylphthalide Attenuates Cerebral Ischemia-Reperfusion Injury by Inhibiting Mitochondrial Omi/HtrA2-Mediated Apoptosis.

BACKGROUND: Ischemic stroke is a major cause of death and disability worldwide and results from inadequate cerebrovascular blood supply; mitochondrial dysfunction plays an essential role in its pathogenesis. DL-3-n-butylphthalide (NBP) is an effective medicine for ischemic stroke that reduces cell apoptosis and improves long-term prognosis. OBJECTIVE: Whether and how NBP regulates mitochondria-associated apoptosis in cerebral ischemia- reperfusion injury remains unclear. METHODS: Male Sprague Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) stroke and treated with low (20 mg/kg) or high (80 mg/kg) concentrations of NBP. The Omi/HtrA2 inhibitor UCF-101 was used as a positive control. Cerebral infarction, neuron injury and neuronal apoptosis were assessed to determine the efficacy of NBP compared to UCF-101. We assessed the expression of the Omi/HtrA2 signaling pathway by western blotting and tested the mRNA expression of mitochondrial metabolism-related genes by PCR. RESULTS: Compared to the MCAO group, both low and high concentrations of NBP substantially improved cerebral infarction, neuron injury, and neuronal apoptosis; high concentrations of NBP were more potent than low concentrations. The expression of proteins of the mitochondrial Omi/HtrA2 signaling pathway, including Omi/HtrA2, XIAP, PARL, OPA1, CHOP, and ClpP, was inhibited in the NBP group. CONCLUSION: Overall, early application of NBP attenuated cerebral ischemia-reperfusion injury by inhibiting mitochondrial Omi/HtrA2-mediated apoptosis in rats. Our study supports a novel neuroprotective mechanism of NBP, making it a promising therapeutic agent for ischemic stroke.

Safety and efficacy of remote ischemic conditioning combined with intravenous thrombolysis for acute ischemic stroke: A multicenter, randomized, parallel-controlled clinical trial (SERIC-IVT) Study design and protocol.

RATIONALE: Remote ischemic conditioning (RIC) combined with intravenous thrombolysis (IVT) may improve functional outcomes in patients with acute ischemic stroke (AIS). AIM: To assess the efficacy and safety of RIC combined with IVT for AIS. METHODS AND DESIGN: SERIC-IVT is a multicenter, randomized, parallel-controlled, blinded endpoint clinical trial. A total of 558 patients with AIS who underwent IVT therapy will be randomly assigned 1:1 to receive RIC or sham-RIC plus standard medical therapy. The cuff pressures of the RIC group and the sham-RIC group will be 200 mm Hg and 60 mm Hg, respectively, performed twice a day for seven consecutive days. STUDY OUTCOMES: The primary efficacy outcome is the proportion of patients with a favorable functional outcome as defined as a modified Rankin Scale ⩽ 1 at 90 days. Safety outcomes include mortality and adverse events within 90 days. SAMPLE SIZE ESTIMATES: A sample size of 558 patients with AIS (279 in each group) will allow detection of a shift of 13.14% toward favorable functional outcome at 90 days (modified Rankin Scale ⩽ 1) with 5% significance and 80% power. DISCUSSION: RIC is a promising adjuvant treatment for AIS. SERIC-IVT will inform on whether RIC treatment combined with IVT improves functional outcomes in AIS patients and identify any safety issues.

Safety and efficacy of remote ischemic conditioning combined with endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion of anterior circulation: A multicenter, randomized, parallel-controlled clinical trial (SERIC-EVT): Study protocol.

RATIONALE/AIM: Many patients undergoing successful recanalization after endovascular thrombectomy (EVT) do not have a good outcome; additional neuroprotection might benefit this group. Remote ischemic conditioning (RIC) stimulates endogenous protective mechanisms and may have a neuroprotective in acute brain ischemia. The safety and efficacy of RIC combined with endovascular thrombectomy (SERIC-EVT) trial is investigating the safety and efficacy of RIC for patients with acute ischemic stroke (AIS) who underwent EVT due to large vessel occlusion of the anterior circulation. METHODS: SERIC-EVT is a multicenter, randomized, parallel-controlled, and blinded endpoint clinical trial. Patients are recruited from 10 hospitals in Jilin Province, Northeast China. Patients with anterior circulation AIS undergoing EVT due to large vessel occlusion are randomized in a 1:1 ratio to RIC or sham-RIC. Participants will receive standard medical treatment and an inflation pressure of 200 mmHg (RIC group) or 60 mmHg (sham-RIC group) twice daily for seven consecutive days. STUDY OUTCOMES: The primary outcome is the proportion of patients with modified Rankin Scale (mRS) score of 0-2 on day 90. Secondary outcome measures include the National Institute of Health Stroke Scale, Barthel Index, and mRS scores obtained at 24 h, 7 days, 30 ± 3 days, and 90 ± 3 days post-EVT, recanalization rate, expanded Thrombolysis in Cerebral Infarction score, and symptomatic intracranial hemorrhage post-EVT. Mortality and all adverse events, including skin changes and pain scores, within the first 90 days will be used as safety outcome measures. SAMPLE SIZE ESTIMATES: Based on previous studies, we estimate a 14% difference in functional independence (the mRS ⩽2) between RIC and sham-RIC groups. Considering a significance level of 5% and power of 80%, and one-fifth of patients lost to follow up, the planned sample size is 498 patients (249 per group). DISCUSSION: RIC might be a strategy that improves 3-month clinical outcomes in AIS patients who have undergone EVT due to large vessel occlusion of anterior circulation. SERIC-EVT will determine whether this is the case.

Circulating Insulin-Like Growth Factor 1 Levels and Migraine Risk: A Mendelian Randomization Study.

INTRODUCTION: Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method. METHODS: A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively. RESULTS: Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842-0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882-0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization-Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses. CONCLUSION: This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines.

Remote ischemic conditioning combined with intravenous thrombolysis for acute ischemic stroke.

OBJECTIVE: The objective of this study was to investigate the safety and efficacy of remote ischemic conditioning (RIC) combined with intravenous thrombolysis (IVT) in the treatment of acute ischemic stroke (AIS). METHODS: Patients with AIS who underwent IVT were enrolled and 1:1 randomized to the RIC group and sham-RIC group in this study. RIC (or sham-RIC) was performed twice within 6-24 h of IVT. The subjects in the two groups were followed up for 90 days. The safety outcome included the ratio of hemorrhagic transformation (HT), adverse events during the follow-up, blood pressure within the first 24 h after IVT, and laboratory tests 24 h after IVT. The efficacy outcome included the modified Rankin Scale (mRS) score, National Institute of Health Stroke Scale (NIHSS) score during the follow-up, and level of high-sensitivity C-reactive protein (hs-CRP) tested 24 h after IVT. RESULTS: Forty-nine patients (24 in the RIC group and 25 in the sham-RIC group) were recruited. No significant difference was observed in the ratio of HT, adverse events, blood pressure, coagulation function or liver function between groups. In addition, there was no significant difference in mRS score and NIHSS score during the follow-up between groups. However, patients in the RIC group exhibited a significant lower level of hs-CRP compared with the control group (P = 0.048). INTERPRETATION: RIC combined with IVT is safe in the treatment of AIS. The neuroprotective and anti-inflammatory effects of this therapy warrant further study on a larger scale.