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.

Mitigation of Blood Load Impact in Patients with Subarachnoid Hemorrhage by Cisternal Lavage

<b><i>Object:</i></b> The initial amount of subarachnoid and ventricular blood is an important prognostic factor for outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this comparative study of an unselected aSAH-population, we assess the modifiability of these factors by implementation of blood clearance by cisternal lavage. <b><i>Methods:</i></b> All patients with aSAH treated in our department between October 2011 and October 2019 (8 years, <i>n</i> = 458) were included in our study. In the first 4-year period (BEFORE, <i>n</i> = 237), patients were treated according to international guidelines. In the second 4-year period (AFTER, <i>n</i> = 221), cisternal lavage methods were available and applied in 72 high-risk patients (32.5%). The cisternal and ventricular blood load was recorded by the Hijdra score. Multivariable regression models were used to assess the prognostic significance of risk factors, including blood load, in relation to common aSAH characteristics in both study groups. <b><i>Results:</i></b> Worse neurological outcomes (mRS &#x3e; 3) occurred in the BEFORE population with 41.45% versus 30.77% in the AFTER cohort, 6 months after aSAH (HR: 1.59, 95% CI 1.08–2.34, <i>p</i> = 0.01). Admission WFNS grade, comorbidities (Charlson Comorbidity Index), herniation signs, concomitant intracerebral hemorrhage, and the development of delayed cerebral infarction were strongly associated with poor outcome in both study groups. Intraventricular and cisternal blood load and, particularly, a cast fourth ventricle (Cast 4) represented strong prognosticators of poor neurological outcome in the BEFORE cohort. This effect was lost after implementation of cisternal lavage (AFTER cohort). <b><i>Conclusion:</i></b> Cisternal and ventricular blood load – in particular: a Cast 4 – represent important prognosticators in patients with aSAH. They are, however, amenable to modification by blood clearing therapies.

Relationship Between Baroreflex and Cerebral Autoregulation in Patients With Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Introduction: Common consequences following aneurysmal subarachnoid hemorrhage (aSAH) are cerebral vasospasm (CV), impaired cerebral autoregulation (CA), and disturbance in the autonomic nervous system, as indicated by lower baroreflex sensitivity (BRS). The compensatory interaction between BRS and CA has been shown in healthy volunteers and stable pathological conditions such as carotid atherosclerosis. The aim of this study was to investigate whether the inverse correlation between BRS and CA would be lost in patients after aSAH during vasospasm. A secondary objective was to analyze the time-trend of BRS after aSAH.Materials and Methods: Retrospective analysis of prospectively collected data was performed at the Neuro-Critical Care Unit of Addenbrooke's Hospital (Cambridge, UK) between June 2010 and January 2012. The cerebral blood flow velocity (CBFV) was measured in the middle cerebral artery using transcranial Doppler ultrasonography (TCD). The arterial blood pressure (ABP) was monitored invasively through an arterial line. CA was quantified by the correlation coefficient (Mxa) between slow oscillations in ABP and CBFV. BRS was calculated using the sequential cross-correlation method using the ABP signal.Results: A total of 73 patients with aSAH were included. The age [median (lower-upper quartile)] was 58 (50–67). WFNS scale was 2 (1–4) and the modified Fisher scale was 3 (1–3). In the total group, 31 patients (42%) had a CV and 42 (58%) had no CV. ABP and CBFV were higher in patients with CV during vasospasm compared to patients without CV (p = 0.001 and p &lt; 0.001). There was no significant correlation between Mxa and BRS in patients with CV, neither during nor before vasospasm. In patients without CV, a significant, although moderate correlation was found between BRS and Mxa (rS = 0.31; p = 0.040), with higher BRS being associated with worse CA. Multiple linear regression analysis showed a significant worsening of BRS after aSAH in patients with CV (Rp = −0.42; p &lt; 0.001).Conclusions: Inverse compensatory correlation between BRS and CA was lost in patients who developed CV after aSAH, both before and during vasospasm. The impact of these findings on the prognosis of aSAH should be investigated in larger studies.

Development of a questionnaire to identify persons with a family history of aneurysmal subarachnoid hemorrhage

Background: Preventive screening for intracranial aneurysms is effective in persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH), but for many relatives of aSAH patients, it can be difficult to assess whether their relative had an aSAH or another type of stroke. Aim: We aimed to develop a family history questionnaire for people in the population who believe they have a first-degree relative who had a stroke and to assess its accuracy to identify relatives of aSAH patients. Methods: A questionnaire to distinguish between aSAH and other stroke types (ischemic stroke and intracerebral hemorrhage) was developed by a team of clinicians and consumers. The level of agreement between the questionnaire outcome and medical diagnosis was pilot tested in 30 previously admitted aSAH patients. Next, the sensitivity and specificity of the questionnaire were assessed in 91 first-degree relatives (siblings/children) of previously admitted stroke patients. Results: All 30 aSAH patients were identified by the questionnaire in the pilot study; 29 of 30 first-degree relatives of aSAH patients were correctly identified. The questionnaire had a sensitivity of 97% (95% confidence interval (CI) = 83–100%) and a specificity of 93% (95% CI = 84–98%) when tested in the first-degree relatives of stroke patients. Conclusion: Our questionnaire can help persons to discriminate an aSAH from other types of stroke in their affected relative. This family history questionnaire is developed in the Netherlands but could also be used in other countries after validation.

Efficacy and Safety of Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Tranexamic acid has been shown to reduce rebleeding after aneurysmal subarachnoid hemorrhage; however, whether it can reduce mortality and improve clinical outcomes is controversial. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of the tranexamic acid in aneurysmal subarachnoid hemorrhage. We conducted a comprehensive literature search of PubMed, Embase, Web of Science, and Cochrane Library from inception to March 2021 for randomized controlled trials (RCTs) comparing tranexamic acid and placebo in adults with aneurysmal subarachnoid hemorrhage. The risk of bias was evaluated using the Cochrane Handbook, and the quality of evidence was evaluated using the GRADE approach. This meta-analysis included 13 RCTs, involving 2,888 patients. In patients with aneurysmal subarachnoid hemorrhage tranexamic acid had no significant effect on all-cause mortality (RR = 0.96; 95% CI = 0.84–1.10, p = 0.55, I2 = 44%) or poor functional outcome (RR = 1.04; 95% CI = 0.95–1.15, p = 0.41) compared with the control group. However, risk of rebleeding was significantly lower (RR = 0.59; 95% CI = 0.43–0.80, p = 0.0007, I2 = 53%). There were no significant differences in other adverse events between tranexamic acid and control treatments, including cerebral ischemia (RR = 1.17; 95% CI = 0.95–1.46, p = 0.15, I2 = 53%). At present, routine use of tranexamic acid after subarachnoid hemorrhage cannot be recommended. For a patient with subarachnoid hemorrhage, it is essential to obliterate the aneurysm as early as possible. Additional higher-quality studies are needed to further assess the effect of tranexamic acid on patients with subarachnoid hemorrhage.

Admission Lower Serum Phosphate Ion Levels Predict Acute Hydrocephalus of Aneurysmal Subarachnoid Hemorrhage

Introduction: The relationship between serum phosphate ion (sPi) and the occurrence of acute hydrocephalus (aHCP) in aneurysmal subarachnoid hemorrhage (aSAH) remains largely unknown and controversial. The primary aim of this study was to investigate the association between sPi on admission and aHCP following aSAH.Methods: The study included 635 patients over the age of 19 years diagnosed with aSAH in our institution from September 2012 to June 2018. Data on clinical characteristics, laboratory parameters, treatments, and outcomes were collected and analyzed. The association between lower sPi levels and aHCP was assessed in univariate and multivariate analyses. Propensity-score matching (PSM) analysis was performed to reduce significant differences in baseline characteristics between the aHCP group and non-HCP group.Results: The overall incidence of aHCP following aSAH was 19.37% (123/512). Lower sPi levels were detected in patients with aHCP compared with those without [0.86 (0.67–1.06) vs. 1.04 (0.84–1.21) mmol/L] in the univariate analysis. In the multivariate analysis, lower sPi level, high modified Fisher (mFisher) grade, and high Hunt-Hess grade were associated with aHCP [odds ratios (OR) 1.729, 95% confidence interval (CI) 1.139–2.623, p = 0.01; mFisher OR 0.097,95% CI 0.055–0.172, p &lt; 0.001; Hunt-Hess, OR 0.555, 95% CI 0.320–0.961, P = 0.036]. After PSM, the matched aHCP group had a significantly lower sPi level than the matched non-aHCP group [0.86 (0.67–1.06) vs. 0.94 (0.76–1.12) mmol/L, p = 0.044]. The area under the curve (AUC) of the sPi level and the logistic regression model based on these predictors (sPi, Hunt-Hess grade, and mFisher grade) was 0.667 and 0.840 (sensitivity of 88.6% and specificity of 68.4%) for predicting aHCP, respectively.Conclusions: Lower sPi levels predict the occurrence of aHCP, and the model constructed by sPi levels, Hunt-Hess grade, and mFisher grade markedly enhances the prediction of aHCP after aSAH.