Severe cerebral edema in substance-related cardiac arrest patients.

BACKGROUND: Studies of neurologic outcomes have found conflicting results regarding differences between patients with substance-related cardiac arrests (SRCA) and non-SRCA. We investigate the effects of SRCA on severe cerebral edema development, a neuroimaging intermediate endpoint for neurologic injury. METHODS: 327 out-of-hospital comatose cardiac arrest patients were retrospectively analyzed. Demographics and baseline clinical characteristics were examined. SRCA categorization was based on admission toxicology screens. Severe cerebral edema classification was based on radiology reports. Poor clinical outcomes were defined as discharge Cerebral Performance Category scores > 3. RESULTS: SRCA patients (N = 86) were younger (P < 0.001), and more likely to have non-shockable rhythms (P < 0.001), be unwitnessed (P < 0.001), lower Glasgow Coma Scale scores (P < 0.001), absent brainstem reflexes (P < 0.05) and develop severe cerebral edema (P < 0.001) than non-SRCA patients (N = 241). Multivariable analyses found younger age (P < 0.001), female sex (P = 0.008), non-shockable rhythm (P = 0.01) and SRCA (P = 0.05) to be predictors of severe cerebral edema development. Older age (P < 0.001), non-shockable rhythm (P = 0.02), severe cerebral edema (P < 0.001), and absent pupillary light reflexes (P = 0.004) were predictors of poor outcomes. SRCA patients had higher proportion of brain deaths (P < 0.001) compared to non-SRCA patients. CONCLUSIONS: SRCA results in higher rates of severe cerebral edema development and brain death. The absence of statistically significant differences in discharge outcomes or survival between SRCA and non-SRCA patients may be related to the higher rate of withdrawal of life-sustaining treatment (WLST) in the non-SRCA group. Future neuroprognostic studies may opt to include neuroimaging markers as intermediate measures of neurologic injury which are not influenced by WLST decisions.

Delayed rFGF21 Administration Improves Cerebrovascular Remodeling and White Matter Repair After Focal Stroke in Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is a major comorbidity exacerbating ischemic brain injury and impairing post-stroke recovery. Our previous study suggested that recombinant human fibroblast growth factor (rFGF) 21 might be a potent therapeutic targeting multiple aspects of pathophysiology in T2DM stroke. This study aims to evaluate the potential effects of rFGF21 on cerebrovascular remodeling after T2DM stroke. Permanent distal middle cerebral artery occlusion was performed in heterozygous non-diabetic db/ + and homozygous diabetic db/db mice. Daily rFGF21 administration was initiated 1 week after stroke induction and maintained for up to 2 weeks thereafter. Multiple markers associated with post-stroke recovery, including angiogenesis, oligodendrogenesis, white matter integrity, and neurogenesis, were assessed up to 3 weeks after stroke. Our results showed an impairment in post-stroke vascular remodeling under T2DM condition, reflected by the decreased expression of trophic factors in brain microvessels and impairments of angiogenesis. The defected cerebrovascular remodeling was accompanied by the decreased oligodendrogenesis and neurogenesis. However, delayed rFGF21 administration normalized post-stroke hyperglycemia and improved neurological outcomes, which may partially be via the promotion of pro-angiogenic trophic factor expression in brain microvessels and cerebrovascular remodeling. The better cerebrovascular remodeling may also contribute to oligodendrogenesis, white matter integrity, and neurogenesis after T2DM stroke. Therefore, delayed rFGF21 administration may improve neurological outcomes in T2DM stroke mice, at least in part by normalizing the metabolic abnormalities and promoting cerebrovascular remodeling and white matter repair.

Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy.

Intravenous administration of tissue-type plasminogen activator (IV tPA) therapy has long been considered a mainstay in ischemic stroke management. However, patients respond to IV tPA therapy unequally with some subsets of patients having worsened outcomes after treatment. In particular, diabetes mellitus (DM) is recognized as a clinically important vascular comorbidity that leads to lower recanalization rates and increased risks of hemorrhagic transformation (HT). In this short-review, we summarize the recent advances in understanding of the underlying mechanisms involved in post-IV tPA worsening of outcome in diabetic stroke. Potential pathologic factors that are related to the suboptimal tPA recanalization in diabetic stroke include higher plasma plasminogen activator inhibitor (PAI)-1 level, diabetic atherogenic vascular damage, glycation of the tPA receptor annexin A2, and alterations in fibrin clot density. While factors contributing to the exacerbation of HT in diabetic stroke include hyperglycemia, vascular oxidative stress, and inflammation, tPA neurovascular toxicity and imbalance in extracellular proteolysis are discussed. Besides, impaired collaterals in DM also compromise the efficacy of IV tPA therapy. Additionally, several tPA combination approaches developed from experimental studies that may help to optimize IV tPA therapy are also briefly summarized. In summary, more research efforts are needed to improve the safety and efficacy of IV tPA therapy in ischemic stroke patients with DM/poststroke hyperglycemia.

Dual antiplatelet therapy reduced stroke risk in transient ischemic attack with positive diffusion weighted imaging.

Dual antiplatelet therapy (DAPT) reduced stroke risk in high-risk transient ischemic attack (TIA) patients assessed by ABCD2 score. Patients with positive diffusion-weighted imaging (DWI) were identified as imaging-based high-risk. The present study aims to investigate whether DAPT could reduce stroke risk in TIA with DWI positive. The study enrolled TIA patients within 72 h of onset from the prospective TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischemic stroke at 90-day. The relationship between DAPT and stroke was analyzed in a cox proportional hazards model. The Kaplan-Meier curves of TIA patients with DAPT and monotherapy were plotted. Total of 661 TIA patients were enrolled, 279 of whom were DWI positive and 281 used DAPT. The 90-day stroke risk was higher in patients used monotherapy than those used DAPT in TIA with positive DWI (23.7% vs. 13.4%, p = 0.029). DAPT was associated with reduced stroke risk in TIA patients with positive DWI (hazard ratio [HR] = 0.54; 95% confidence interval [CI], 0.30-0.97; p = 0.037). However, the benefit didn't exist in TIA patients with negative DWI (HR = 0.43; 95% CI, 0.14-1.33; p = 0.142). Early use of DAPT reduced stroke risk in TIA patients with positive DWI.

Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage.

OBJECTIVE: To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia. METHODS: Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied. RESULTS: sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1ß, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial-cadherin fragments. CONCLUSIONS: These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.