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Background: Hyperventilation resulting in hypocapnic alkalosis (HA) is frequently encountered in spontaneously breathing patients with acute cerebrovascular conditions. The underlying mechanisms of this respiratory response have not been fully elucidated. The present study describes, applying the physical-chemical approach, the acid-base characteristics of cerebrospinal fluid (CSF) and arterial plasma of spontaneously breathing patients with aneurismal subarachnoid hemorrhage (SAH) and compares these results with those of control patients. Moreover, it investigates the pathophysiologic mechanisms leading to HA in SAH., Methods: Patients with SAH admitted to the neurological intensive care unit and patients (American Society of Anesthesiologists physical status of 1 and 2) undergoing elective surgery under spinal anesthesia were enrolled. CSF and arterial samples were collected simultaneously. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (PCO 2 ), weak noncarbonic acids (A TOT ), and pH were measured in CSF and arterial blood samples., Results: Twenty spontaneously breathing patients with SAH and 25 controls were enrolled. The CSF of patients with SAH, as compared with controls, was characterized by a lower SID (23.1 ± 2.3 vs. 26.5 ± 1.4 mmol/L, p < 0.001) and PCO 2 (40 ± 4 vs. 46 ± 3 mm Hg, p < 0.001), whereas no differences in A TOT (1.2 ± 0.5 vs. 1.2 ± 0.2 mmol/L, p = 0.95) and pH (7.34 ± 0.06 vs. 7.35 ± 0.02, p = 0.69) were observed. The reduced CSF SID was mainly caused by a higher lactate concentration (3.3 ± 1.3 vs. 1.4 ± 0.2 mmol/L, p < 0.001). A linear association (r = 0.71, p < 0.001) was found between CSF SID and arterial PCO 2 . A higher proportion of patients with SAH were characterized by arterial HA, as compared with controls (40 vs. 4%, p = 0.003). A reduced CSF-to-plasma difference in PCO 2 was observed in nonhyperventilating patients with SAH (0.4 ± 3.8 vs. 7.8 ± 3.7 mm Hg, p < 0.001)., Conclusions: Patients with SAH have a reduction of CSF SID due to an increased lactate concentration. The resulting localized acidifying effect is compensated by CSF hypocapnia, yielding normal CSF pH values and resulting in a higher incidence of arterial HA., (© 2022. The Author(s).)

Intracranial aneurysms (IAs) are very rare in children, and the characteristics of the T-cells in the IA wall are largely unknown. A comatose 7-years-old child was admitted to our center because of a subarachnoid hemorrhage due to a ruptured giant aneurysm of the right middle cerebral artery. Two days after the aneurysm clipping the patient was fully awake with left hemiparesis. T-cells from the IA wall and from peripheral blood of this patient were analyzed by multi-dimensional flow cytometry. Unbiased analysis, based on the use of FlowSOM clustering and dimensionality reduction technique UMAP, indicated that there was virtually no overlap between circulating and tissue-infiltrating T-cells. Thus, naïve T-cells and canonical memory T-cells were largely restricted to peripheral blood, while CD4 - CD8 - T-cells were strongly enriched in the IA wall. The unique CD4 + , CD8 + and CD4 - CD8 - T-cell clusters from the IA wall expressed high levels of CCR5, Granzyme B and CD69, displaying thus characteristics of cytotoxic and tissue-resident effector cells. Low Ki67 expression indicated that they were nevertheless in a resting state. Among regulatory T-cell subsets, Eomes + Tr1-like cells were strongly enriched in the IA wall. Finally, analysis of cytokine producing capacities unveiled that the IA wall contained poly-functional T-cells, which expressed predominantly IFN-γ, TNF and IL-2. CD4 + T-cells co-expressed also CD40L, and produced some IL-17, GM-CSF and IL-10. This report provides to our knowledge the first detailed characterization of the human T-cell compartment in the IA wall., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moschetti, Vasco, Clemente, Galeota, Carbonara, Pluderi, Locatelli, Stocchetti, Abrignani, Zanier, Ortolano, Zoerle and Geginat.)

Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin-angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor AT 1 R, and a counterbalancing system, presented in humans as Ang-(1-7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1-7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson's disease, and depression. In the presence of SAH, Ang-(1-7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1-7)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Annoni, Moro, Caruso, Zoerle, Taccone and Zanier.)

Background: Intracranial pressure (ICP) monitoring is essential after subarachnoid hemorrhage (SAH) to prevent secondary brain insults and to tailor individualized treatments. Optic nerve sheath diameter (ONSD), measured using ultrasound (US), could serve as a noninvasive bedside tool to estimate ICP, avoiding the risks of hemorrhage or infection related to intracranial catheters. The aims of this study were twofold: first, to explore the reliability of US for measuring ONSD; second, to establish whether the US-ONSD can be considered a proxy for ICP in SAH patients early after bleeding. For the first aim, we compared the ONSD measurements given by magnetic resonance imaging (MRI-ONSD) with the US-ONSD findings. For the second aim, we analyzed the relationship between US-ONSD measurements and ICP values., Methods: Adult patients with diagnosis of aneurysmal SAH and external ventricular drainage system (EVD) were included. Ten patients were examined by MRI to assess ONSD, and the results were compared to the diameter given by US. In 20 patients, the US-ONSD values were related to ICP measured simultaneously through EVD. In ten of these patients, we explored the changes in the US-ONSD at the time of controlled and fairly rapid changes in ICP after cerebrospinal fluid (CSF) drainage., Results: US-ONSD measurements at the bedside were accurate, very similar to the diameters measured by MRI (the mean difference in the Bland-Altman plot was 0.08 mm, 95% limits of agreement: - 1.13; + 1.23 mm). No clear relationship was detectable between the ICP and US-ONSD, and a linear regression model showed an angular coefficient very close to 0 (p > 0.05). US-ONSD and ICP values were in agreement after CSF drainage and shifts in ICP in a limited number of patients., Conclusions: US-ONSD measurement does not accurately estimate ICP in SAH patients in the intensive care unit.

Objectives: To describe mean intracranial pressure after aneurysmal subarachnoid hemorrhage, to identify clinical factors associated with increased mean intracranial pressure, and to explore the relationship between mean intracranial pressure and outcome., Design: Analysis of a prospectively collected observational database., Setting: Neuroscience ICU of an academic hospital., Patients: One hundred sixteen patients with subarachnoid hemorrhage and intracranial pressure monitoring., Interventions: None., Measurements and Main Results: Episodes of intracranial pressure greater than 20 mm Hg lasting at least 5 minutes and the mean intracranial pressure for every 12-hour interval were analyzed. The highest mean intracranial pressure was analyzed in relation to demographic characteristics, acute neurologic status, initial radiological findings, aneurysm treatment, clinical vasospasm, and ischemic lesion. Mortality and 6-month outcome (evaluated using a dichotomized Glasgow Outcome Scale) were also introduced in multivariable logistic models. Eighty-one percent of patients had at least one episode of high intracranial pressure and 36% had a highest mean intracranial pressure more than 20 mm Hg. The number of patients with high intracranial pressure peaked 3 days after subarachnoid hemorrhage and declined after day 7. Highest mean intracranial pressure greater than 20 mm Hg was significantly associated with initial neurologic status, aneurysmal rebleeding, amount of blood on CT scan, and ischemic lesion within 72 hours from subarachnoid hemorrhage. Patients with highest mean intracranial pressure greater than 20 mm Hg had significantly higher mortality. When death, vegetative state, and severe disability at 6 months were pooled, however, intracranial pressure was not an independent predictor of unfavorable outcome., Conclusions: High intracranial pressure is a common complication in the first week after subarachnoid hemorrhage in severe cases admitted to ICU. Mean intracranial pressure is associated with the severity of early brain injury and with mortality.

Objectives: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome., Methods: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activity was measured, along with that of other LCP initiators (mannose-binding lectin, ficolin-2, and ficolin-1), C3 activation products, and soluble C5b-9 terminal complex, in a prospective cohort of 39 patients with SAH and 20 healthy controls. The following parameters were recorded: SAH severity, assessed using the World Federation of Neurosurgical Societies grading scale; vasospasm, defined as neuro-worsening with angiographic confirmation of vessel narrowing; cerebral ischemia, defined as hypodense lesion on CT scan performed before discharge; and 6-month outcome, assessed using the Glasgow Outcome Scale., Results: In patients, no changes were detected for ficolin-3 compared with controls. Notably, however, ficolin-3-mediated functional LCP activity was reduced. Low levels of plasma ficolin-3 and ficolin-3-mediated functional LCP activity were related to SAH severity, vasospasm, and cerebral ischemia. Moreover, ficolin-3 functional LCP activity was decreased in patients with unfavorable outcome., Conclusion: Our data provide evidence that LCP is activated after SAH and that the actual plasma concentrations of ficolin-3 reflect the severity of brain injury as evaluated by clinical and structural parameters. These results support the idea that ficolin-3-mediated functional LCP activity may be targeted to control injury progression in SAH.

Background: Vasospasm and other secondary neurological insults may follow subarachnoid haemorrhage (SAH). Biomarkers have the potential to stratify patient risk and perhaps serve as an early warning sign of delayed ischaemic injury., Methods: Serial cerebrospinal fluid (CSF) samples were collected from 38 consecutive patients with aneurysmal SAH admitted to the neurosurgical intensive care unit. We measured heart-fatty acid-binding protein (H-FABP) and tau protein (τ) levels in the CSF to evaluate their association with brain damage, and their potential as predictors of the long-term outcome. H-FABP and τ were analysed in relation to acute clinical status, assessed by the World Federation of Neurological Surgeons (WFNS) scale, radiological findings, clinical vasospasm, and 6-month outcome., Results: H-FABP and τ increased after SAH. H-FABP and τ were higher in patients in poor clinical status on admission (WFNS 4-5) compared with milder patients (WFNS 1-3). Elevated H-FABP and τ levels were also observed in patients with early cerebral ischaemia, defined as a CT scan hypodense lesion visible within the first 3 days after SAH. After the acute phase, H-FABP, and τ showed a delayed increase with the occurrence of clinical vasospasm. Finally, patients with the unfavourable outcome (death, vegetative state, or severe disability) had higher peak levels of both proteins compared with patients with good recovery or moderate disability., Conclusions: H-FABP and τ show promise as biomarkers of brain injury after SAH. They may help to identify the occurrence of vasospasm and predict the long-term outcome.

Purpose: To investigate plasma and cerebrospinal fluid (CSF) concentrations of pentraxin 3 (PTX3), a prototypic long pentraxin protein induced by proinflammatory signals, in subarachnoid hemorrhage (SAH), and its relation with SAH-associated vasospasm., Methods: Serial plasma and CSF samples were collected from 38 consecutive SAH patients admitted to the Neurosurgical Intensive Care. PTX3 concentrations were analyzed in relation to clinical status and clinical vasospasm (defined as neuro-worsening and angiographic confirmation of vessel narrowing). Since neutrophils are an important source of preformed PTX3, myeloperoxidase (MPO) in CSF was measured to assess the correlation with CSF PTX3 and establish whether blood contamination was the determinant of PTX3 increase., Results: PTX3 was elevated in all SAH patients both in plasma and CSF. Acute peak (first 48 h after SAH) CSF PTX3 was significantly higher in patients who later developed vasospasm [median 13.6 (range 2.3-51.9) ng/ml] compared to those who did not [3.2 (0.1-50.5) ng/ml, p = 0.03]. The temporal pattern of CSF PTX3 in patients with vasospasm was triphasic with a peak during the first 48 h after SAH, a subsequent decrease in the following 48-96 h and a secondary significant increase with the occurrence of vasospasm. A loose correlation between CSF PTX3 and MPO was observed (r(2) = 0.13), indicating that following SAH there is a brain production of PTX3., Conclusions: Acute increased concentrations of PTX3 in CSF but not in plasma are related to the occurrence of vasospasm, indicating that measurement of CSF PTX3 associated with the clinical evaluation can improve early diagnosis of this complication.

Purpose: The contribution of axonal injury to brain damage after aneurysmal subarachnoid haemorrhage (aSAH) is unknown. Neurofilament light chain (NF-L), a component of the axonal cytoskeleton, has been shown to be elevated in the cerebrospinal fluid of patients with many types of axonal injury. We hypothesised that patients with aSAH would have elevated cerebrospinal fluid (CSF) NF-L levels and sought to explore the clinical correlates of CSF NF-L dynamics., Methods: Serial ventricular CSF (vCSF) samples were collected from 35 patients with aSAH for up to 15 days. vCSF NF-L measurements were determined by enzyme-linked immunosorbent assay. NF-L levels were analysed in relation to acute clinical status, radiological findings and 6-month outcomes., Results: vCSF NF-L concentrations were elevated in all patients with aSAH. Patients with early cerebral ischaemia (ECI), defined as a CT hypodense lesion visible within the first 3 days, had higher acute vCSF NF-L levels than patients without ECI. These elevated NF-L levels were similar in patients with ECI associated with intracranial haemorrhage and ECI associated with surgical/endovascular complications. vCSF NF-L levels did not differ as a function of acute clinical status, clinical vasospasm, delayed cerebral ischaemia or 6-month Glasgow Outcome Scale., Conclusions: Elevated vCSF NF-L levels may in part reflect increased injury to axons associated with ECI. However, our results suggest that axonal injury after aSAH as reflected by release of NF-L into the CSF may not play a major role in either secondary adverse events or long-term clinical outcomes.

Background: Heart-type Fatty Acid-Binding Protein (H-FABP) and tau protein (tau) have been shown to be novel biomarkers associated with brain injury and, therefore, they could represent a useful diagnostic tool in patients with subarachnoid hemorrhage (SAH). The goal of this study was to measure H-FABP and tau in cerebrospinal fluid (CSF) following SAH to test the hypothesis that a relationship exists between SAH severity and H-FABP/tau values., Methods: Twenty-seven consecutive SAH patients admitted to our ICU were studied. Serial CSF samples were obtained in every patient starting on the day of SAH and daily for up to 2 weeks post-SAH. H-FABP/tau levels were measured by enzyme-linked immunosorbent assay., Results: Patients with severe SAH showed significantly higher peak levels of H-FABP and tau compared to mild-SAH patients (FABP: p = 0.02; tay: p = 0.002). In addition the peak concentrations of H-FABP and tau in CSF from SAH patients correlated significantly with Glasgow Coma Scale motor score (H-FABP: Spearman r = -0.52, p = 0.006; tau: Spearman r = -0.63, p = 0.0004). Based on outcome at discharge from the hospital, patients were categorized into survivors and non-survivors. Peak concentrations of both proteins in the non-survivors group were significantly higher than in the survivors., Conclusions: H-FABP and tau CSF levels are proportional to SAH severity and may be novel biomarkers that can be used to predict the severity of outcome following clinical SAH.

Background: Postischaemic pyrexia exacerbates neuronal damage. Hyperthermia related cerebral changes have still not been well investigated in humans., Objective: To study how pyrexia affects neurochemistry and cerebral oxygenation after acute brain injury., Methods: 18 acutely brain injured patients were studied at the onset and resolution of febrile episodes (brain temperature > or = 38.7 degrees C). Intracranial pressure (ICP), brain tissue oxygen tension (PbrO2), and brain tissue temperature (Tbr) were recorded continuously; jugular venous blood was sampled intermittently. Microdialysis probes were inserted in the cerebral cortex and in subcutaneous tissue. Glucose, lactate, pyruvate, and glutamate were measured hourly. The lactate to pyruvate ratio was calculated., Results: Mean (SD) Tbr rose from 38 (0.5) to 39.3 (0.3) degrees C. Arteriojugular oxygen content difference (AJD(O2)) fell from 4.2 (0.7) to 3.8 (0.5) vol% (p < 0.05) and PbrO2 rose from 32 (21) to 37 (22) mm Hg (p < 0.05). ICP increased slightly and no significant neurochemical alterations occurred. Opposite changes were recorded when brain temperature returned towards baseline., Conclusions: As long as substrate and oxygen delivery remain adequate, hyperthermia on its own does not seem to induce any further significant neurochemical alterations. Changes in cerebral blood volume may, however, affect intracranial pressure.