Association Between Cerebral Microbleeds and Neurological Outcomes in Patients Who Underwent Extracorporeal Membrane Oxygenation.

BACKGROUND: Cerebral microbleeds (CMBs) are common and varied in patients receiving extracorporeal membrane oxygenation (ECMO). Here, the authors describe CMB findings in patients receiving ECMO and their association with clinical factors. METHODS AND RESULTS: A total of 138 patients receiving ECMO were enrolled and categorized as venovenous and venoarterial. Blood coagulation profiles during ECMO support and Glasgow Coma Scale (GCS) scores within 7 days were recorded. Patients with CMBs exhibited prolonged activated clotting time (P<0.001), decreased fibrinogen levels (P<0.001), reduced platelet counts (P<0.001), and extended prothrombin time (P<0.001). A significant correlation (P<0.05) was observed between the presence of CMBs and most coagulation parameters among all patients. Patients with venoarterial ECMO had significantly higher activated partial thromboplastin time, activated clotting time, and prothrombin time compared with those with venovenous ECMO (all P<0.05). Patients with a less severe CMB burden exhibited higher GCS scores and better neurological injury outcomes at both 7 and 90 days. CMB burden in all patients with ECMO was significantly correlated (P<0.05) with most blood coagulation profiles and neurological injury. CONCLUSIONS: CMB burdens after ECMO are common, varied, and associated with a variety of clinical conditions. These findings may guide ECMO management.

The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery.

Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms. This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0-2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes. Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h. In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.

Monocyte-to-Albumin Ratio Is Associated With Hematoma Expansion in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Hematoma expansion (HE) after spontaneous intracerebral hemorrhage (ICH) is a severe complication that independently predicts poor prognosis. In this study, we aimed to investigate whether monocyte-to-albumin ratio (MAR), a novel marker of systemic inflammation, could predict HE in patients with ICH. METHODS: We retrospectively assessed the data of patients with ICH. The clinical, imaging, and laboratory test data including, the MAR on admission, were analyzed. A multivariate logistic regression analysis was carried out to explore the relationship between MAR and hematoma growth. The receiver operating characteristic (ROC) curve was employed to investigate the predictive value of MAR for HE after ICH. RESULTS: A total of 246 patients were included in the present study. Multivariate logistic regression analysis demonstrated that the MAR was associated with HE (odds ratio [OR] = 1.179; 95% confidence interval, 1.093-1.272; p = 0.000). ROC curve analysis showed that MAR could predict HE, with an area under the curve of 0.802 (95% CI: 0.744-0.859, p < 0.001). The optimal predictive cutoff value of MAR for HE was 10.01 (sensitivity: 72.43%, specificity: 77.05%). CONCLUSIONS: Our results suggested that a high MAR on admission was associated with an increased risk of HE in ICH patients, and MAR can become an independent predictor of HE in ICH patients.

Plasma Inflammation Markers Linked to Complications and Outcomes after Spontaneous Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) could trigger inflammatory responses. However, the specific role of inflammatory proteins in the pathological mechanism, complications, and prognosis of ICH remains unclear. In this study, we investigated the expression of 92 plasma inflammation-related proteins in patients with ICH (n = 55) and healthy controls (n = 20) using an Olink inflammation panel and discussed the relation to the severity of stroke, clinical complications, 30-day mortality, and 90-day outcomes. Our result showed that six proteins were upregulated in ICH patients compared with healthy controls, while seventy-four proteins were downregulated. In patients with ICH, seven proteins were increased in the severe stroke group compared with the moderate stroke group. In terms of complications, two proteins were downregulated in patients with pneumonia, while nine proteins were upregulated in patients with sepsis. Compared with the survival group, three proteins were upregulated, and one protein was downregulated in the death group. Compared with the good outcome group, eight proteins were upregulated, and four proteins were downregulated in the poor outcome group. In summary, an in-depth exploration of the differential inflammatory factors in the early stages of ICH could deepen our understanding of the pathogenesis of ICH, predict patient prognosis, and explore new treatment strategies.

Associations of serum Dickkopf-1 levels with disease severity and 90-day Prognosis after spontaneous intracerebral hemorrhage: results from the prospective cohort study.

Dickkopf-1 (DKK-1) may be involved in inflammatory response and secondary brain injury after acute brain injury. We gauged serum DKK-1 levels and further assessed its correlation with disease severity and investigated its predictive value for 90-day prognosis in patients with spontaneous intracerebral hemorrhage (sICH). Serum DKK-1 levels were measured in 128 sICH patients and 128 healthy controls. The severity of sICH was assessed using the Glasgow Coma Scale (GCS) scores and hematoma volumes. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90 days after stroke. Multivariate analysis was performed to identify associations of serum DKK-1 levels with disease severity, early neurological deterioration (END) and poor prognosis. Receiver operating characteristic curve (ROC) was built to investigate the prognostic predictive capability. The serum DKK-1 levels of patients were significantly higher than those of controls (median, 4.74 ng/mL versus 1.98 ng/mL; P < 0.001), and were independently correlated with hematoma volumes (ρ = 0.567, P < 0.001; t = 3.444, P = 0.001) and GCS score (ρ = -0.612, P < 0.001; t = -2.048, P = 0.043). Serum DKK-1 significantly differentiated patients at risk of END (area under ROC curve (AUC), 0.850; 95% confidence interval (CI), 0.777-0.907; P < 0.001) and poor prognosis (AUC, 0.830; 95% CI, 0.753-0.890; P < 0.001), which had similar prognostic ability, as compared to GCS scores and hematoma volumes. Subsequent Logistic regression model affirmed that GCS score, hematoma volume, and serum DKK-1 levels were independently associated with END and poor prognosis at 90 days after sICH. The models, which contained them, performed well using ROC curve analysis and calibration curve analysis. Serum DKK-1 levels are markedly associated with disease severity, END and 90-day poor prognosis in sICH. Hence, serum DKK-1 is presumed to be used as a potential prognostic biomarker of sICH.

Letter to the Editor: Serum secretoneurin as a promising biomarker for predicting poor prognosis in intracerebral hemorrhage: a prospective cohort study.

Intracerebral hemorrhage is characterized by the occurrence of hemorrhage at the brain parenchymal region. This causes disruption to blood-brain barrier, cerebral edema, hematoma and microvascular failure which results in neurological dysfunction or even death. The article "Serum secretoneurin as a promising biomarker for predicting poor prognosis in intracerebral hemorrhage: A prospective cohort study" elucidates the potential role of secretoneurin as a promising biomarker for detecting acute brain injury. This is the first report about the significant increase in the level of serum secretoneurin after intracerebral hemorrhage. Authors have demonstrated the correlation of serum secretoneurin levels with the hematoma volume and Glasgow Coma Scale (GCS) scores. The work reported will be beneficial to both clinicians and researchers in determining the relationship between serum secretoneurin levels and intracerebral hemorrhage.

The relationship between HbA1c and the activities of daily living in complex chronic patients with and without intracerebral hemorrhage.

BACKGROUND: Associations between HbA1c and adverse outcomes in ischemic and hemorrhagic stroke have been confirmed. It is still unclear whether HbA1c is related to the activities of daily living (ADL) score in complex chronic patients (CCP) with and without intracerebral hemorrhage (ICH). AIM: The associations between HbA1c and ADL (Barthel score) in CCP with ICH and without ICH were evaluated, respectively. METHODS: We have analyzed data from a previous cohort study involving in 3594 CCPs without a ICH history at baseline, who were followed up for 5 years to assess ICH episode. RESULTS: One hundred sixty-one ICH case were detected in a total of 3594 patients during the period of follow up for 5 years. Our nonlinear analysis suggested positive trends on the association between HBA1c and Barthel score in ICH and non-ICH patients, respectively. The multivariate linear regression analysis showed that elevated HbA1c was positively associated with a higher Barthel score among all study population (ß = 1.25, 95% CI: 0.92, 1.59; P < 0.0001) with adjusted age and sex. Among non-ICH patients, increased HbA1c was still positively associated with an increased Barthel score (ß = 1.24, 95% CI: 0.90, 1.58; P < 0.001). However, HbA1c appeared to have no any relationship with Barthel score in ICH patients (ß = 1.87, 95% CI: -0.07, 3.82; P = 0.0613) after adjustment for age and sex. By additionally using sensitivity analysis, we still observed that the strong relationship was still existed in non-ICH patients (ß = 0.90, 95% CI: 0.56, 1.24; P < 0.001) but not in ICH patients (ß = 1.88, 95% CI: -0.10, 3.86; P = 0.0649). CONCLUSION: We observed for the first time that elevated HbA1c is associated with better ADL in CCPs without ICH but not in those with ICH. This interesting discovery contradicts the traditional adverse effects of elevated HbA1c.

Identification of immune-related biomarkers for intracerebral hemorrhage diagnosis based on RNA sequencing and machine learning.

Background: Intracerebral hemorrhage (ICH) is a severe stroke subtype with high morbidity, disability, and mortality rates. Currently, no biomarkers for ICH are available for use in clinical practice. We aimed to explore the roles of RNAs in ICH pathogenesis and identify potential diagnostic biomarkers. Methods: We collected 233 individual blood samples from two independent cohorts, including 64 patients with ICH, 59 patients with ischemic stroke (IS), 60 patients with hypertension (HTN) and 50 healthy controls (CTRL) for RNA sequencing. Differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were performed to identify ICH-specific modules. The immune cell composition was evaluated with ImmuneCellAI. Multiple machine learning algorithms to select potential biomarkers for ICH diagnosis, and further validated by quantitative real-time polymerase chain reaction (RT-PCR). Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were performed to evaluate the diagnostic value of the signature for ICH. Finally, we generated M1 and M2 macrophages to investigate the expression of candidate genes. Results: In both cohorts, 519 mRNAs and 131 lncRNAs were consistently significantly differentially expressed between ICH patients and HTN controls. Gene function analysis suggested that immune system processes may be involved in ICH pathology. ImmuneCellAI analysis revealed that the abundances of 11 immune cell types were altered after ICH in both cohorts. WGCNA and GSEA identified 18 immune-related DEGs. Multiple algorithms identified an RNA panel (CKAP4, BCL6, TLR8) with high diagnostic value for discriminating ICH patients from HTN controls, CTRLs and IS patients (AUCs: 0.93, 0.95 and 0.82; sensitivities: 81.3%, 84.4% and 75%; specificities: 100%, 96% and 79.7%, respectively). Additionally, CKAP4 and TLR8 mRNA and protein levels decreased in RAW264.7 M1 macrophages and increased in RAW264.7 M2 macrophages, while BCL6 expression increased in M1 macrophages but not in M2 macrophages, which may provide potential therapeutic targets for ICH. Conclusions: This study demonstrated that the expression levels of lncRNAs and mRNAs are associated with ICH, and an RNA panel (CKAP4, BCL6, TLR8) was developed as a potential diagnostic tool for distinguishing ICH from IS and controls, which could provide useful insight into ICH diagnosis and pathogenesis.

The effectiveness of early systemic inflammatory indices in predicting advanced intraventricular hemorrhage in preterm infants.

Some systemic inflammatory indices have been reported to be associated with intracerebral hemorrhage in adults. However, the relationship between systemic inflammatory indices and intraventricular hemorrhage (IVH) in premature neonates is still not completely understood. OBJECTIVE: To evaluate the relationship between systemic inflammatory indices obtained on the first day of life in premature infants and the development of severe IVH. PATIENTS AND METHOD: Premature newborns < 32 weeks of gestational age were included. Eligible patients were divided into 2 groups: Group 1: without IVH or grade I and II hemorrhage, and Group 2: grade III and IV HIV. Demographic characteristics, clinical outcomes, monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), pan-immune inflammation value (PIV), and Systemic inflammation response index (SIRI) were compared between groups. RESULTS: A total of 1176 newborns were included in the study, 1074 in Group 1 and 102 premature babies in Group 2. There was no difference between the groups in terms of the count of leukocytes, neutrophils, monocytes, lymphocytes and platelets (p > 0.05). The values of NLR, MLR, PLR, PIV, SII and SIRI were similar in both groups (p > 0.05). CONCLUSION: While the relationship between inflammation, hemodynamics and IVH is still under discussion, our results show that systemic inflammatory indices have no predictive value for IVH.

"Enhancing prognostic accuracy in intracerebral hemorrhage: the role of serum secretoneurin and emerging biomarkers".

Intracerebral hemorrhage (ICH) is a severe stroke type with high mortality and disability rates, and traditional prognostic tools like the Glasgow Coma Scale (GCS) have limited predictive power. Emerging research suggests that serum secretoneurin could serve as a promising biomarker for ICH. Elevated secretoneurin levels have been associated with poorer outcomes and may offer more precise prognostic insights compared to conventional methods. This biomarker's potential to enhance outcome prediction underscores the need for further research to validate its efficacy and integrate it into clinical practice. Future studies should also explore additional biomarkers and advanced predictive models.

Acute Myocardial Injury in Spontaneous Intracerebral Hemorrhage: A Secondary Observational Analysis of the FAST Trial.

BACKGROUND: Acute myocardial injury is associated with poor outcomes in patients with acute ischemic stroke, but its prognostic significance in patients with spontaneous intracerebral hemorrhage remains unclear. We investigated whether acute myocardial injury and the direction of the cardiac troponin I (cTnI) change (rising versus falling) affect post-intracerebral hemorrhage outcomes. METHODS AND RESULTS: We re-analyzed the FAST (Factor-Seven-for-Acute-Hemorrhagic-Stroke) trial. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of >20%. Logistic regression tested for associations (1) between acute myocardial injury (presence versus absence) and poor outcome (modified Rankin Scale 4-6) and mortality at 15 and 90 days; (2) among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Among the 841 FAST participants, 785 patients were included. Acute myocardial injury was detected in 29% (n=227); 170 had rising cTnI. At 15 and 90 days, respectively, those with acute myocardial injury had higher odds of poor outcome (adjusted odds ratio) ([aOR] 2.3 [95% CI, 1.3-3.9]); and adjusted odds ratio 2.5 [95% CI, 1.6-3.9];, and higher odds of mortality (adjusted odds ratio 2.4 [95% CI, 1.4-4.3]; and adjusted odds ratio 2.2 [CI, 1.3-3.6]) than patients without. There was no interaction between FAST group assignment and myocardial injury, and associations between myocardial injury and outcomes were consistent across group assignments. Rising cTnI was associated with the highest risk of poor outcomes and mortality. CONCLUSIONS: In this secondary analysis of the FAST trial, acute myocardial injury was common and associated with poor outcomes. The direction of the cTnI change might provide additional risk stratification after intracerebral hemorrhage.

Stress hyperglycemia is associated with longer ICU length of stay after endoscopic intracerebral hemorrhage evacuation.

BACKGROUND: Stress hyperglycemia has been linked to poor outcomes in intracerebral hemorrhage (ICH). Recent studies using the ratio of blood glucose to glycated hemoglobin (HbA1c) as a marker for stress hyperglycemia have demonstrated greater discriminative power in predicting poor outcomes for stroke inpatients compared to blood glucose alone. Therefore, we aimed to investigate whether the preoperative glucose-to-HbA1c ratio is a predictor of postoperative outcomes in patients who have undergone minimally invasive ICH evacuation. METHODS: Retrospective chart review was performed on ICH patients treated with minimally invasive surgery (MIS) in a single health system from 2015 to 2022. Stress hyperglycemia was defined as preoperative glucose-to-HbA1c ratio > calculated-median. Postoperative outcomes including modified Rankin Score (mRS) and length of stay (LOS) were collected. Univariate analyses were conducted to determine associations. Variables with p<0.05 were included in multivariate analyses. RESULTS: Of 192 patients who underwent minimally invasive ICH evacuation and had available glucose data, 96 demonstrated stress hyperglycemia (glucose-to-HbA1c ratio > 1.23). Patients with stress hyperglycemia were more likely to have a history of diabetes (43 % vs. 27 %, p=0.034), IVH (54 % vs. 33 %, p=0.007), higher preoperative hematoma volumes (46.8 ml vs. 38.6 mL, p=0.02), higher postoperative hematoma volumes (6 ml vs. 2.9 mL, p=0.008), smaller evacuation percentages (86.7 % vs. 92.7 %, p=0.048), longer procedure lengths (2.78 hrs vs. 2.23 hrs, p=0.015), and prolonged ICU LOS (9.44 days vs. 5.68 days, p=0.003). In a multivariate analysis, stress hyperglycemia remained predictive of prolonged ICU LOS (OR=2.44; p=0.026) when controlling for initial NIHSS, IVH, time to evacuation, procedure time, and diabetes. CONCLUSIONS: Stress hyperglycemia was strongly associated with prolonged ICU LOS after MIS for ICH. Understanding factors associated with LOS may provide predictive value for a patient's hospital course after minimally invasive ICH evacuation and further guide clinician expectations of recovery.

Serum secretoneurin as a promising biomarker for predicting poor prognosis in intracerebral hemorrhage: A prospective cohort study.

OBJECTIVE: Secretoneurin may play a brain-protective role. We aim to discover the relationship between serum secretoneurin levels and severity plus neurological outcome after intracerebral hemorrhage (ICH). METHODS: In this prospective cohort study, serum secretoneurin levels were measured in 110 ICH patients and 110 healthy controls. Glasgow Coma Scale (GCS) and hematoma volume were used to assess stroke severity. Poor prognosis was defined as Glasgow Outcome Scale (GOS) scores of 1-3 at 90 days after ICH. A multivariate logistic regression model was constructed to determine independent correlation of serum secretoneurin levels with severity and poor prognosis. Under receiver operating characteristic (ROC) curve, prognostic ability of serum secretoneurin levels was assessed. Restricted cubic spline (RCS) model and subgroups analysis were used for discovering association of serum secretoneurin levels with risk of poor prognosis. Calibration curve and decision curve were evaluated to confirm performance of nomogram. RESULTS: Serum secretoneurin levels of patients were significantly higher than those of healthy controls. Serum secretoneurin levels of patients were independently correlated with GCS scores and hematoma volume. There were 42 patients with poor prognosis at 90 days following ICH. Serum secretoneurin levels were significantly higher in patients with poor outcome than in those with good outcome. Under the ROC curve, serum secretoneurin levels significantly differentiated poor outcome. Serum secretoneurin levels ≥ 22.8 ng/mL distinguished patients at risk of poor prognosis at 90 days with a sensitivity of 66.2% and a specificity of 81.0%. Besides, serum secretoneurin levels independently predicted a 90-day poor prognosis. Subgroup analysis showed that serum secretoneurin levels had non-significant interactions with other variables. The nomogram, including independent prognostic predictors, showed reliable prognosis capability using calibration curve and decision curve. Area under the curve of the predictive model was significantly higher than those of GCS scores and hematoma volume. CONCLUSION: Serum secretoneurin levels are strongly related to ICH severity and poor prognosis at 90 days after ICH. Thus, serum secretoneurin may be a promising prognostic biomarker in ICH.

Anemia From Inflammation After Intracerebral Hemorrhage and Relationships With Outcome.

BACKGROUND: Baseline anemia is associated with poor intracerebral hemorrhage (ICH) outcomes. However, underlying drivers for anemia and whether anemia development after ICH impacts clinical outcomes are unknown. We hypothesized that inflammation drives anemia development after ICH and assessed their relationship to outcomes. METHODS AND RESULTS: Patients with serial hemoglobin and iron biomarker concentrations from the HIDEF (High-Dose Deferoxamine in Intracerebral Hemorrhage) trial were analyzed. Adjusted linear mixed models assessed laboratory changes over time. Of 42 patients, significant decrements in hemoglobin occurred with anemia increasing from 19% to 45% by day 5. Anemia of inflammation iron biomarker criteria was met in 88%. A separate cohort of 521 patients with ICH with more granular serial hemoglobin and long-term neurological outcome data was also investigated. Separate regression models assessed whether (1) systemic inflammatory response syndrome (SIRS) scores related to hemoglobin changes over time and (2) hemoglobin changes related to poor 90-day outcome. In this cohort, anemia prevalence increased from 30% to 71% within 2 days of admission yet persisted beyond this time. Elevated systemic inflammatory response syndrome was associated with greater hemoglobin decrements over time (adjusted parameter estimate: -0.27 [95% CI, -0.37 to -0.17]) and greater hemoglobin decrements were associated with poor outcomes (adjusted odds ratio per 1 g/dL increase, 0.76 [95% CI, 0.62-0.93]) independent to inflammation and ICH severity. CONCLUSIONS: We identified novel findings that acute anemia development after ICH is common, rapid, and related to inflammation. Because anemia development is associated with poor outcomes, further work is required to clarify if anemia, or its underlying drivers, are modifiable treatment targets that can improve ICH outcomes. REGISTRATION: https://www.clinicaltrials.gov Unique identifier: NCT01662895.

The clinical value of nutritional and inflammatory indicators in predicting pneumonia among patients with intracerebral hemorrhage.

Immunosuppression and malnutrition play pivotal roles in the complications of intracerebral hemorrhage (ICH) and are intricately linked to the development of stroke-associated pneumonia (SAP). Inflammatory markers, including NLR (neutrophil-to-lymphocyte ratio), SII (systemic immune inflammation index), SIRI (systemic inflammatory response index), and SIS (systemic inflammation score), along with nutritional indexes such as CONUT (controlling nutritional status) and PNI (prognostic nutritional index), are crucial indicators influencing the inflammatory state following ICH. In this study, our objective was to compare the predictive efficacy of inflammatory and nutritional indices for SAP in ICH patients, aiming to determine and explore their clinical utility in early pneumonia detection. Patients with severe ICH requiring ICU admission were screened from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The outcomes included the occurrence of SAP and in-hospital death. Receiver operating characteristic (ROC) analysis, multivariate logistic regression, smooth curve analysis, and stratified analysis were employed to investigate the relationship between the CONUT index and the clinical outcomes of patients with severe ICH. A total of 348 patients were enrolled in the study. The incidence of SAP was 21.3%, and the in-hospital mortality rate was 17.0%. Among these indicators, multiple regression analysis revealed that CONUT, PNI, and SIRI were independently associated with SAP. Further ROC curve analysis demonstrated that CONUT (AUC 0.6743, 95% CI 0.6079-0.7408) exhibited the most robust predictive ability for SAP in patients with ICH. Threshold analysis revealed that when CONUT < 6, an increase of 1 point in CONUT was associated with a 1.39 times higher risk of SAP. Similarly, our findings indicate that CONUT has the potential to predict the prognosis of patients with ICH. Among the inflammatory and nutritional markers, CONUT stands out as the most reliable predictor of SAP in patients with ICH. Additionally, it proves to be a valuable indicator for assessing the prognosis of patients with ICH.