Vascular Reactivity to Hypercapnia Is Impaired in the Cerebral and Retinal Vasculature in the Acute Phase After Experimental Subarachnoid Hemorrhage

Objective: Impaired cerebral blood flow (CBF) regulation, such as reduced reactivity to hypercapnia, contributes to the pathophysiology after aneurysmal subarachnoid hemorrhage (SAH), but temporal dynamics in the acute phase are unknown. Featuring comparable molecular regulation mechanisms, the retinal vessels participate in chronic and subacute stroke- and SAH-associated vessel alterations in patients and can be studied non-invasively. This study is aimed to characterize the temporal course of the cerebral and retinal vascular reactivity to hypercapnia in the acute phase after experimental SAH and compare the potential degree of impairment.Methods: Subarachnoid hemorrhage was induced by injecting 0.5 ml of heparinized autologous blood into the cisterna magna of male Wistar rats using two anesthesia protocols [isoflurane/fentanyl n = 25 (Sham + SAH): Iso—Group, ketamine/xylazine n = 32 (Sham + SAH): K/X—Group]. CBF (laser speckle contrast analysis) and physiological parameters were measured continuously for 6 h. At six predefined time points, hypercapnia was induced by hypoventilation controlled via blood gas analysis, and retinal vessel diameter (RVD) was determined non-invasively.Results: Cerebral reactivity and retinal reactivity in Sham groups were stable with only a slight attenuation after 2 h in RVD of the K/X—Group. In the SAH Iso—Group, cerebral and retinal CO2 reactivity compared to baseline was immediately impaired starting at 30 min after SAH (CBF p = 0.0090, RVD p = 0.0135) and lasting up to 4 h (p = 0.0136, resp. p = 0.0263). Similarly, in the K/X—Group, cerebral CO2 reactivity was disturbed early after SAH (30 min, p = 0.003) albeit showing a recovery to baseline after 2 h while retinal CO2 reactivity was impaired over the whole observation period (360 min, p = 0.0001) in the K/X—Group. After normalization to baseline, both vascular beds showed a parallel behavior regarding the temporal course and extent of impairment.Conclusion: This study provides a detailed temporal analysis of impaired cerebral vascular CO2 reactivity starting immediately after SAH and lasting up to 6 h. Importantly, the retinal vessels participate in these acute changes underscoring the promising role of the retina as a potential non-invasive screening tool after SAH. Further studies will be required to determine the correlation with functional outcomes.

Elevated Glucose-Potassium Ratio Predicts Preoperative Rebleeding in Patients With Aneurysmal Subarachnoid Hemorrhage

Introduction: Recent reports revealed that higher serum glucose-potassium ratio (GPR) levels at admission were significantly associated with poor outcomes at 3 months following aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to investigate the association between GPR and the risk of rebleeding following aSAH.Methods: This single-center retrospective study of patients with aSAH was conducted in our hospital between January 2008 and December 2020. Patients meeting the inclusion criteria were divided into the rebleed group and the non-rebleed group. Univariate and multivariate analyses were implemented to assess the association between risk factors of rebleeding and outcomes.Results: A total of 1,367 patients experiencing aSAH, 744 patients who met the entry criteria in the study [mean age (54.89 ± 11.30) years; 60.50% female patients], of whom 45 (6.05%) developed rebleeding. The patients in the rebleed group had significantly higher GPR levels than those of patients without rebleeding [2.13 (1.56–3.20) vs. 1.49 (1.23–1.87); p < 0.001]. Multivariable analysis revealed that higher mFisher grade and GPR were associated with rebleeding [mFisher grade, odds ratios (OR) 0.361, 95% CI 0.166–0.783, p = 0.01; GPR, OR 0.254, 95% CI 0.13–0.495, p < 0.001]. The receiver operating characteristics (ROCs) analysis described that the suitable cut-off value for GPR as a predictor for rebleeding in patients with aSAH was determined as 2.09 (the area under the curve [AUC] was 0.729, 95% CI 0.696–0.761, p < 0.0001; the sensitivity was 53.33%, and the specificity was 83.98%). Pearson correlation analysis showed a significant positive correlation between GPR and mFisher grade, between GPR and Hunt–Hess grade (mFisher grade r = 0.4271, OR 0.1824, 95% CI 0.3665–0.4842, p < 0.001; Hunt–Hess grade r = 0.4248, OR 0.1836, 95% CI 0.3697–0.4854, p < 0.001). The patients in the poor outcome had significantly higher GPR levels than those of patients in the good outcome [1.87 (1.53–2.42) vs. 1.45 (1.20–1.80); p < 0.001]. Multivariable analysis demonstrated that GPR was an independent predictor for poor prognosis. The AUC of GPR was 0.709 (95% CI 0.675–0.741; p < 0.0001) (sensitivity = 77.70%; specificity = 55.54%) for poor prognosis.Conclusion: Higher preoperative serum GPR level was associated with Hunt–Hess grade, mFisher grade, rebleeding, and unfunctional outcome, and that they predicted preoperative rebleeding and the 90-days outcome of non-diabetic patients with aSAH, who had potentially relevant clinical implications in patients with aSAH.

Chemical Angioplasty with Nitroglycerin for Vasospasm after Subarachnoid Hemorrhage: Case Series and Review

Introduction Vasospasm is a common and potentially devastating complication in patients with subarachnoid hemorrhage, causing high morbidity and mortality. There is no effective and consistent way to prevent or treat cerebral vasospasm capable of altering the morbidity and mortality of this complication. Animal and human studies have attempted to show improvement in aneurysmal vasospasm. Some sought their prevention; others, the treatment of already installed vasospasm. Some achieved only angiographic improvement without clinical correlation, others achieved both, but with ephemeral duration or at the expense of very harmful associated effects. Endovascular techniques allow immediate and aggressive treatment of cerebral vasospasm and include methods such as mechanical and chemical angioplasty. These methods have risks and benefits. Objectives To analyze the results of chemical angioplasty using nitroglycerin (GTN). In addition, to perform a comprehensive review and analysis of aneurysmal vasospasm. Methods We describe our series of 77 patients treated for 8 years with angioplasty for vasospasm, either mechanical (with balloon), chemical (with GTN) or both. Results Eleven patients received only balloon; 37 received only GTN; 29 received both. Forty-four patients (70.1%) evolved with delayed cerebral ischemia and 19 died (mortality of 24.7%). Two deaths were causally related to the rupture of the vessel by the balloon. The only predictors of poor outcome were the need for external ventricular drainage in the first hours of admission, and isolated mechanical angioplasty. Conclusions Balloon angioplasty has excellent results, but it is restricted to proximal vessels and is not without complications. Chemical angioplasty using nitroglycerin has reasonable but short-lived results and further research is needed about it. It is restricted to vasospasm angioplasties only in hospitals, like ours, where better and more potent vasodilator agents are not available.

2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats

A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood–brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1β and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway.