Delayed Cerebral Ischemia Patients Research Articles

The disorders of blood oxygen transport function, hemostasis indicators and endothelium functional state in patients with ruptured arterial aneurysms and the development of delayed cerebral ischemia

Introduction. Rupture of cerebral aneurysms (CA) with the development of intracranial hemorrhage (ICH), complicated in some cases by vascular spasm and delayed cerebral ischemia (DCI), is due to the complex multifactorial genesis of the disease, including changes in the blood oxygen transport function (BOTF), activation of endothelial cells with a release of vasoregulators, reactive oxygen species, inflammatory proteins, as well as disturbances in the hemostasis system.Purpose – to study the indicators of BOTF, primary and secondary hemostasis and the content of some vasoregulatory metabolites in the pre- and postoperative periods in patients with ruptured CA with the development of DCI and without DCI.Materials and methods. The group with DCI included 45 patients; in the group without DCI were 14 people. Clinical-neurological and neuroimaging examinations were carried out, and parameters of BOTF, primary and secondary hemostasis, nitrate/nitrite, angiotensin-converting enzyme (ACE), and PAI-1 concentrations in venous blood were studied before and on days 10–12 after microsurgical clipping of the CA.Results. We diagnosed mild neurological disorders according to the NIHSS scale, confirmed by neuroimaging studies of the brain in the group of DCI patients. It was shown an increase in thrombin-dependent platelet aggregation velocity to 30.6 (24.3; 32.4) AU/min at norm 21.8 (20.3; 24.9) (U, p=0.009) before surgery; and after surgery it was up to 37.4 (30; 44.7) relative to the norm (U, p=0.001). Before surgery, the following was observed: PT shortening to 11.6±0.7 sec at norm 13.2±1.1 (t, p˂0.001), fibrinogen concentration increasing to 4.35 (3.8; 4.8) g/L at norm 3.9 (3.6; 4.1) g/L (U, p = 0.01) and PAI-1 up to 3.9 (2.6; 4.8) ng / mL at norm 2 .7 (2.2; 4.1). After surgery, PT was 11.9±1.1 (t, p˂0.001); fibrinogen - 4.4 (3.9; 4.8) (U, p=0.024), PAI-1 - 4.6 (4.1; 6.7) (U, p=0.0004) respectively. Before surgery, p50 was increased to 28.1 (26.2; 31.6) mm Hg at norm 25.2 (24.3; 26.8) (U, p=0.025); after surgery, it was up to 28.5 (26.8; 30.7) (U, p=0.03) and the ratio of nitrates/nitrites to ACE was reduced to 0.12 (0.08; 0.15) at norm 0.22 (0.15; 0.32) (U, p˂0.001); after - up to 0.11 (0.08; 0.19) (U, p˂0.001) respectively.Conclusion. There has been revealed significant disorders of primary and secondary hemostasis with fibrinolysis inhibition, a decrease in the affinity of hemoglobin to oxygen at the p50 rate and an imbalance of the content of vasoregulatory metabolites in patients with DCI before and after aneurysm clipping, which can be considered as significant factors in the development of DCI after aneurysmal ICH.

The oxygen reactivity index indicates disturbed local perfusion regulation after aneurysmal subarachnoid hemorrhage: an observational cohort study

BackgroundCerebral autoregulation (CA) can be impaired in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). The Pressure Reactivity Index (PRx, correlation of blood pressure and intracranial pressure) and Oxygen Reactivity Index (ORx, correlation of cerebral perfusion pressure and brain tissue oxygenation, PbtO2) are both believed to estimate CA. We hypothesized that CA could be poorer in hypoperfused territories during DCI and that ORx and PRx may not be equally effective in detecting such local variances.MethodsORx and PRx were compared daily in 76 patients with aSAH with or without DCI until the time of DCI diagnosis. The ICP/PbtO2-probes of DCI patients were retrospectively stratified by being in or outside areas of hypoperfusion via CT perfusion image, resulting in three groups: DCI + /probe + (DCI patients, probe located inside the hypoperfused area), DCI + /probe− (probe outside the hypoperfused area), DCI− (no DCI).ResultsPRx and ORx were not correlated (r = − 0.01, p = 0.56). Mean ORx but not PRx was highest when the probe was located in a hypoperfused area (ORx DCI + /probe + 0.28 ± 0.13 vs. DCI + /probe− 0.18 ± 0.15, p < 0.05; PRx DCI + /probe + 0.12 ± 0.17 vs. DCI + /probe− 0.06 ± 0.20, p = 0.35). PRx detected poorer autoregulation during the early phase with relatively higher ICP (days 1–3 after hemorrhage) but did not differentiate the three groups on the following days when ICP was lower on average. ORx was higher in the DCI + /probe + group than in the other two groups from day 3 onward. ORx and PRx did not differ between patients with DCI, whose probe was located elsewhere, and patients without DCI (ORx DCI + /probe− 0.18 ± 0.15 vs. DCI− 0.20 ± 0.14; p = 0.50; PRx DCI + /probe− 0.06 ± 0.20 vs. DCI− 0.08 ± 0.17, p = 0.35).ConclusionsPRx and ORx are not interchangeable measures of autoregulation, as they likely measure different homeostatic mechanisms. PRx represents the classical cerebrovascular reactivity and might be better suited to detect disturbed autoregulation during phases with moderately elevated ICP. Autoregulation may be poorer in territories affected by DCI. These local perfusion disturbances leading up to DCI may be more readily detected by ORx than PRx. Further research should investigate their robustness to detect DCI and to serve as a basis for autoregulation-targeted treatment after aSAH.

Whole-brain CT Perfusion at Admission and During Delayed Time-window Detects the Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage.

To evaluate the utility of computed tomography perfusion (CTP) both at admission and during delayed cerebral ischemia time-window (DCITW) in the detection of delayed cerebral ischemia (DCI) and the change in CTP parameters from admission to DCITW following aneurysmal subarachnoid hemorrhage. Eighty patients underwent CTP at admission and during DCITW. The mean and extreme values of all CTP parameters at admission and during DCITW were compared between the DCI group and non-DCI group, and comparisons were also made between admission and DCITW within each group. The qualitative color-coded perfusion maps were recorded. Finally, the relationship between CTP parameters and DCI was assessed by receiver operating characteristic (ROC) analyses. With the exception of cerebral blood volume (P=0.295, admission; P=0.682, DCITW), there were significant differences in the mean quantitative CTP parameters between DCI and non-DCI patients both at admission and during DCITW. In the DCI group, the extreme parameters were significantly different between admission and DCITW. The DCI group also showed a deteriorative trend in the qualitative color-coded perfusion maps. For the detection of DCI, mean transit time to the center of the impulse response function (Tmax) at admission and mean time to start (TTS) during DCITW had the largest area under curve (AUC), 0.698 and 0.789, respectively. Whole-brain CTP can predict the occurrence of DCI at admission and diagnose DCI during DCITW. The extreme quantitative parameters and qualitative color-coded perfusion maps can better reflect the perfusion changes of patients with DCI from admission to DCITW.

Bioinformatics Analysis of Autophagy and Mitophagy Markers Associated with Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage.

ObjectiveTo evaluate the interactions among differentially expressed autophagy and mitophagy markers in subarachnoid hemorrhage (SAH) patients with delayed cerebral ischemia (DCI). MethodsThe expression data of autophagy and mitophagy-related makers in the cerebrospinal fluid (CSF) cells was analyzed by real-time reverse transcription-polymerase chain reaction and Western blotting. The markers included death-associated protein kinase (DAPK)-1, BCL2 interacting protein 3 like (BNIP3L), Bcl-1 antagonist X, phosphatase and tensin homolog-induced kinase (PINK), Unc-51 like autophagy activating kinase 1, nuclear dot protein 52, and p62. In silico functional analyses including gene ontology enrichment and the protein-protein interaction network were performed. ResultsA total of 56 SAH patients were included and 22 (38.6%) of them experienced DCI. The DCI patients had significantly increased mRNA levels of DAPK1, BNIP3L, and PINK1, and increased expression of BECN1 compared to the non-DCI patients. The most enriched biological process was the positive regulation of autophagy, followed by the response to mitochondrial depolarization. The molecular functions ubiquitin-like protein ligase binding and ubiquitin-protein ligase binding were enriched. In the cluster of cellular components, Lewy bodies and the phagophore assembly site were enriched. BECN1 was the most connected gene among the differentially expressed markers related to autophagy and mitophagy in the development of DCI. ConclusionOur study may provide novel insight into mitochondrial dysfunction in DCI pathogenesis.

Mitochondrial dysfunction associated with autophagy and mitophagy in cerebrospinal fluid cells of patients with delayed cerebral ischemia following subarachnoid hemorrhage

Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n = 21; and non-DCI, n = 35). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2−ΔCt) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade ≥ IV (p = 0.023), DAPK1 (p = 0.003), and BNIP3L (p = 0.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis.

High epileptiform discharge burden predicts delayed cerebral ischemia after subarachnoid hemorrhage

ObjectiveTo investigate whether epileptiform discharge burden can identify those at risk for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). MethodsRetrospective analysis of 113 moderate to severe grade SAH patients who had continuous EEG (cEEG) recordings during their hospitalization. We calculated the burden of epileptiform discharges (ED), measured as number of ED per hour. ResultsWe find that many SAH patients have an increase in ED burden during the first 3–10 days following rupture, the major risk period for DCI. However, those who develop DCI have a significantly higher hourly burden from days 3.5–6 after SAH vs. those who do not. ED burden is higher in DCI patients when assessed in relation to the onset of DCI (area under the receiver operator curve 0.72). Finally, specific trends of ED burden over time, assessed by group-based trajectory analysis, also help stratify DCI risk. ConclusionsThese results suggest that ED burden is a useful parameter for identifying those at higher risk of developing DCI after SAH. The higher burden rate associated with DCI supports the theory of metabolic supply-demand mismatch which contributes to this complication. SignificanceED burden is a novel biomarker for predicting those at high risk of DCI.

Interleukin 6 in cerebrospinal fluid is a biomarker for delayed cerebral ischemia (DCI) related infarctions after aneurysmal subarachnoid hemorrhage

Interleukin 6 (IL-6) is a prominent proinflammatory cytokine and has been discussed as a potential biomarker for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage. In the present study we have analyzed the time course of serum and cerebrospinal fluid (CSF) IL-6 levels in 82 patients with severe aneurysmal subarachnoid hemorrhage (SAH) requiring external ventricular drains in correlation to angiographic vasospasm, delayed cerebral ischemia, secondary infarctions and other clinical parameters. We observed much higher daily mean IL-6 levels (but also large interindividual variations) in the CSF than the serum of the patients with a peak between days 4 and 14 including a maximum on day 5 after SAH. Individual CSF peak levels correlated significantly with DCI (mean day 4–14 peak, DCI: 26,291 ± 24,159 pg/ml vs. no DCI: 16,184 ± 13,163 pg/ml; P = 0.023). Importantly, CSF IL-6 levels differed significantly between cases with DCI and infarctions and patients with DCI and no infarction (mean day 4–14 peak, DCI with infarction: 37,209 ± 26,951 pg/ml vs. DCI, no infarction: 15,123 ± 11,239 pg/ml; P = 0.003), while findings in the latter patient group were similar to cases with no vasospasm (mean day 4–14 peak, DCI, no infarction: 15,123 ± 11,239 vs. no DCI: 15,840 ± 12,979; P = 0.873). Together, these data support a potential role for elevated CSF IL-6 levels as a biomarker for DCI with infarction rather than for DCI in general. This fits well with a growing body of evidence linking neuroinflammation to ischemia and infarction, but (together with the large interindividual variations observed) limits the diagnostic usefulness of CSF IL-6 levels in SAH patients.

Sequence Variation in the DDAH1 Gene Predisposes for Delayed Cerebral Ischemia in Subarachnoidal Hemorrhage.

Delayed cerebral ischemia (DCI) often causes poor long-term neurological outcome after subarachnoidal hemorrhage (SAH). Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) and is associated with DCI after SAH. We studied single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes that are part of the L-arginine–ADMA–NO pathway, and their association with DCI. We measured L-arginine, ADMA and symmetric dimethylarginine (SDMA) in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at admission; follow-up was until 30 days post-discharge. The primary outcome was the incidence of DCI, defined as new infarctions on cranial computed tomography, which occurred in 18 of 51 patients. Clinical scores did not significantly differ in patients with or without DCI. However, DCI patients had higher plasma ADMA and SDMA levels and higher CSF SDMA levels at admission. DDAH1 SNPs were associated with plasma ADMA, whilst AGXT2 SNPs were associated with plasma SDMA. Carriers of the minor allele of DDAH1 rs233112 had a significantly increased relative risk of DCI (Relative Risk = 2.61 (1.25–5.43), p = 0.002). We conclude that the DDAH1 gene is associated with ADMA concentration and the incidence of DCI in SAH patients, suggesting a pathophysiological link between gene, biomarker, and clinical outcome in patients with SAH.

Abstract 13682: Single Nucleotide Polymorphisms in the Ddah1 Gene Are Associated With Delayed Cerebral Ischemia in Patients With Subarachnoid Hemorrhage

Introduction: Delayed cerebral ischemia (DCI) is a major cause of lethality and poor long-term neurological outcome in patients with subarachnoid hemorrhage (SAH). Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are regulators of vascular NO synthesis from L-arginine. We previously reported that elevated concentrations of both, ADMA and SDMA at ICU admission are associated with the incidence of DCI during follow-up. Dimethylarginines (DMAs) are synthesized by PRMT enzymes; ADMA is metabolized by DDAH1 and DDAH2, whilst SDMA is metabolized by AGXT2. Hypothesis: We hypothesized that common genetic variants in genes encoding the core enzymes of DMA metabolism may predispose individuals for the development of DCI after SAH. Methods: We measured L-arginine, ADMA and SDMA in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at ICU admission and followed them for clinical status and neurological outcome until 30 days post-discharge. Single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes were analyzed by PCR, and genotypes were related to biomarker levels and outcome. The primary outcome was the incidence of DCI, which was defined as the appearance of new infarctions on cranial computed tomography or magnetic resonance imaging. Results: 18 out of 51 SAH patients developed DCI. DCI patients did not significantly differ from those without DCI in clinical scores. However, patients who developed DCI had higher plasma ADMA and SDMA levels and higher SDMA levels in CSF at admission. DDAH1 gene variation was associated with plasma ADMA (p=0.02), whilst AGXT2 gene variation was associated with plasma SDMA (p=0.02). There was a strong association of all three DDAH1 SNPs that we analyzed with DCI, with carriers of the minor allele of DDAH1 rs233112 having a significantly increased relative risk of developing DCI (RR=2.61 (1.25-5.43), p=0.002). Conclusions: Sequence variation in the DDAH1 gene is associated with the incidence of DCI in SAH patients, suggesting that SNPs in the DDAH1 gene, which regulates plasma ADMA concentration, significantly influences the risk of cerebral ischemia after subarachnoid hemorrhage.

Characterization of the TCR β Chain CDR3 Repertoire in Subarachnoid Hemorrhage Patients with Delayed Cerebral Ischemia.

Little is known of the adaptive immune response to subarachnoid hemorrhage (SAH). This study was the first to investigate whether T cell receptor (TCR) immune repertoire may provide a better understanding of T cell immunology in delayed cerebral ischemia (DCI). We serially collected peripheral blood in five SAH patients with DCI. High-throughput sequencing was used to analyze the TCR β chain (TCRB) complimentary determining regions (CDR) 3 repertoire. We evaluated the compositions and variations of the repertoire between admission and the DCI period, for severe DCI and non-severe DCI patients. Clonality did not differ significantly between admission and DCI. Severe DCI patients had significantly lower clonality than non-severe DCI patients (p value = 0.019). A read frequency of 0.005% ≤ – < 0.05% dominated the clonal expansion in non-severe DCI patients. Regarding repertoire diversity, severe DCI had a higher diversity score on admission than non-severe DCI. The CDR3 lengths were similar between admission and DCI. Among 728 annotated V-J gene pairs, we found that the relative frequencies of two V-J pairs were different at the occurrence of DCI than at admission, with T cells increasing by over 15%. TCRB CDR3 repertoires may serve as biomarkers to identify severe DCI patients.

Early stage neuroglobin level as a predictor of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

BackgroundThe neuroglobin (Ngb) is well recognized as a potential biomarker for the hypoxic‐ischemic brain injury. However, connection between Ngb and delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is still unclear.ObjectiveTo investigate the relationship between early stage Ngb level of aSAH patient and the occurrence of DCI.MethodsWe evaluated 126 aSAH patients who were enrolled into a prospective observational cohort study. Serum Ngb level on days 1, 2, 3, 5, and 7 after aSAH were determined using a commercial enzyme‐linked immunosorbent assay kit. The relationship between Ngb level and DCI was analyzed.ResultsForty‐six (36.5%) aSAH patients experienced DCI. Patients with DCI had significantly higher Ngb levels than those without (p < .001). Multivariate model analysis revealed that day 3 Ngb level remained a significant factor after adjusting for World Federation of Neurosurgical Societies (WFNS) grade, modified Fisher grade, clipping and Ngb levels on days 1, 2, 5, and 7. Sensitivity, specificity, and Youden index of day 3 Ngb level for identifying DCI were derived as 73.9%, 72.5%, and 0.46, respectively, based on the best threshold of 8.4 ng/ml. Regardless in good‐grade group or in poor‐grade group, patients having day 3 Ngb level > 8.4 ng/ml has a significantly worse DCI survival rate than those having day 3 Ngb level <=8.4 ng/ml (p = .026 and .009, respectively).ConclusionsSerum Ngb level was significantly elevated in DCI patients. Early stage aSAH Ngb level has the potential of being used as a novel DCI occurrence predictor, especially when Ngb level was combined with WFNS grade.

CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage.

Despite the multifactorial pathogenesis of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), augmentation of cerebral blood flow (CBF) is still considered essential in the clinical management of DCI. The aim of this prospective observational study was to investigate cerebral metabolic changes in relation to CBF during therapeutic hypervolemia, hemodilution, and hypertension (HHH) therapy in poor-grade SAH patients with DCI. CBF was assessed by bedside xenon-enhanced CT at days 0-3, 4-7, and 8-12, and the cerebral metabolic state by cerebral microdialysis (CMD), analyzing glucose, lactate, pyruvate, and glutamate hourly. At clinical suspicion of DCI, HHH therapy was instituted for 5 days. CBF measurements and CMD data at baseline and during HHH therapy were required for study inclusion. Non-DCI patients with measurements in corresponding time windows were included as a reference group. In DCI patients receiving HHH therapy (n = 12), global cortical CBF increased from 30.4 ml/100 g/min (IQR 25.1-33.8 ml/100 g/min) to 38.4 ml/100 g/min (IQR 34.2-46.1 ml/100 g/min; p = 0.006). The energy metabolic CMD parameters stayed statistically unchanged with a lactate/pyruvate (L/P) ratio of 26.9 (IQR 22.9-48.5) at baseline and 31.6 (IQR 22.4-35.7) during HHH. Categorized by energy metabolic patterns during HHH, no patient had severe ischemia, 8 showed derangement corresponding to mitochondrial dysfunction, and 4 were normal. The reference group of non-DCI patients (n = 11) had higher CBF and lower L/P ratios at baseline with no change over time, and the metabolic pattern was normal in all these patients. Global and regional CBF improved and the cerebral energy metabolic CMD parameters stayed statistically unchanged during HHH therapy in DCI patients. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was a common occurrence, possibly explained by mitochondrial dysfunction despite improved microcirculation.

Extracellular Mitochondrial Dysfunction in Cerebrospinal Fluid of Patients with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

Mitochondrial dysfunction is related to brain ischemic injury and neural cell death. However, little is known about the association between mitochondrial dysfunction of cerebrospinal fluid (CSF) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). The objective of this study was to investigate whether extracellular CSF mitochondria might serve as a potential biomarker for DCI. CSF samples were serially collected at 1, 3, and 5days following SAH in 33 patients (DCI, n = 12; and non-DCI, n = 21) who underwent coil embolization. To monitor mitochondrial membrane potentials, JC-1 dye was used. The ratio (red/green) of JC-1 was considered as an indicator of intact mitochondrial membrane potential. Flow cytometry was done to analyze extracellular mitochondria particles and their possible cellular origins. DCI patients had lower JC-1 red/green ratios than non-DCI patients at 1day (3.35 [3.20-3.75] vs. 3.70 [3.40-3.95] in non-DCI) and 3days (4.65 [4.45-5.00] vs. 5.10 [4.65-5.30] in non-DCI) after SAH. At 5days after SAH, JC-1 red/green ratio was significantly lower in DCI than that in non-DCI (3.05 [2.90-3.35] vs. 4.20 [4.10-4.50]; p < 0.01) patients. DCI patients had a higher percentage of vWF-positive mitochondria (40.10% [38.25%-44.90%] vs. 30.20% [25.70%-36.68%]) and a lower percentage of GLAST-positive mitochondria particles (26.85% [17.10%-30.00%] vs. 31.60% [26.70%-35.00%]) than non-DCI patients. However, there was no significant difference in CD45-positive (p = 0.369) or CD41/61-positive mitochondrial particles (p = 0.155) between the two groups of patients. Mitochondrial membrane potential could be a marker of DCI. JC-1 ratios seemed to be able to predict future DCI onset. Further studies are needed to determine detailed mechanisms of extracellular mitochondria-mediated cell-to-cell signals in DCI.

Nimodipine-Induced Blood Pressure Changes Can Predict Delayed Cerebral Ischemia.

Background: Early diagnosis of delayed cerebral ischemia (DCI) in patients after aneurysmal subarachnoid hemorrhage (aSAH) still poses a leading problem in neurointensive care. The aim of this study was to analyze the effect of oral Nimodipine administration on systemic blood pressure in patients with evolving DCI compared to patients without DCI.Methods: Systolic (SBP), mean (MAP), and diastolic (DBP) blood pressures were analyzed at the time of Nimodipine administration and additionally 30, 60, and 120 min thereafter on days 1, 3, and 5 after aSAH. Additionally, the 24 h period preceding DCI and in patients without DCI day 10 after aSAH were analyzed. Statistical analysis was performed for SBP, MAP and DBP at time of Nimodipine administration and for the maximal drop in blood pressure after Nimodipine administration.Results: Thirty patients with aSAH were retrospectively analyzed with 17 patients developing DCI (“DCI”) and 13 patients who did not (“Non-DCI”). DCI patients showed a more pronounced rise in MAP and DBP over the examined time period as well as a higher decrease in SBP following Nimodipine administration. A fall of 18 mmHg in SBP after Nimodipine administration showed a sensitivity of 82.4% and specificity of 92.3% for occurrence of DCI.Conclusion: An increase of MAP and DBP after aSAH and a heightened sensitivity to Nimodipine administrations may serve as additional biomarkers for early detection of evolving DCI.

High-Resolution MRI Vessel Wall Imaging in Acute Aneurysmal Subarachnoid Hemorrhage : Spatiotemporal Pattern and Clinicoradiologic Implications.

The spatiotemporal pattern of vessel wall changes was investigated on two time point magnetic resonance images (MRI) in patients with aneurysmal subarachnoid hemorrhages (aSAH) and its association with clinicoradiologic severity score and delayed cerebral ischemia (DCI) was analyzed. A total of 32 prospectively enrolled patients with aSAH (mean age 56.94 years; 9male and 23female) underwent vessel wall imaging (VWI) MRI. Of the patients 20 completed two time point MRIs early and late during the admission, 10patients only had early MRI and 2patients only had late MRI. Timing of early MRI had amean of 2.5days (range 1-6days) and late MRI had amean of 10.5 days (range 7-16 days) from time of admission. Spatiotemporal pattern of vessel wall enhancement (VWE), vasospasm, diffusion-weighted imaging (DWI) lesion burden (grade0-III) and infarcts were analyzed against the clinicoradiologic severity score (high-risk: vasograde red and yellow, low-risk: vasograde green) and DCI. On the early MRI, mild VWE alone was significantly more frequent in the high-risk group (36.7% versus 20.0%; P = 0.024). On the late MRI, vasospasm was significantly more frequent in the high-risk group (27.2% versus 4.5%; P = 0.022). Vasospasm infrequently showed mild VWE (6.67% on early MRI and 9.09% on late MRI). Both mild VWE alone on early MRI and on late MRI were significantly associated with development of DCI during the admission (P = 0.034 and P = 0.035, respectively). Mild VWE on early MRI and vasospasm on late MRI were significantly more prevalent in high-risk and DCI patients suggesting VWI might enable imaging of early neuroinflammatory changes which are part of the pathomechanism of vasospasm and DCI.

Angiographic Findings in Refractory Delayed Cerebral Ischemia

Background Delayed cerebral ischemia (DCI) follows a refractory course in a subgroup of patients with aneurysmal subarachnoid hemorrhage (SAH), leading to diffuse ischemic injury. The role of angiographic vasospasm (AV) is unknown. Our goal is to study the angiographic alterations and the clinical profile of refractory DCI patients. Methods Retrospective study of patients with SAH who presented with DCI treated with medical and endovascular therapy, with a refractory evolution, defined as multiple ischemic infarction and brain death. Results Out of a cohort of 336 patients, 7 (2%) developed refractory DCI. The median age of the patients was 48 (38–60) years old. Five patients had ruptured anterior communicating artery (ACoA) aneurysms. Four patients were treated with coil embolization, and three with microsurgical clipping. Angiographic vasospasm was classified as severe in 5 cases. Compromise of bilateral circulation was detected in six patients. Distal circulation vasospasm occurred in five cases. Slow circulatory transit times were observed in three patients. Conclusion Angiographic findings such as bilateral circulatory compromise and distal vasospasm were frequent alterations. Further studies are required to establish the association of these findings with the clinical outcomes.

Burden of cerebral hypoperfusion in patients with delayed cerebral ischemia after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden. Sixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7-10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres. Twenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%-23%, vs 12%, 9%-16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049). The burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions.

Effect of HHH-Therapy on Regional CBF after Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT

BackgroundManagement of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is difficult and still carries controversies. In this study, the effect of therapeutic hypervolemia, hemodilution, and hypertension (HHH-therapy) on cerebral blood flow (CBF) was assessed by xenon-enhanced computerized tomography (XeCT) hypothesizing an increase in CBF in poorly perfused regions.Methods Bedside XeCT measurements of regional CBF in mechanically ventilated SAH patients were routinely scheduled for day 0–3, 4–7, and 8–12. At clinical suspicion of DCI, patients received 5-day HHH-therapy. For inclusion, XeCT was required at 0–48 h before start of HHH (baseline) and during therapy. Data from corresponding time-windows were also collected for non-DCI patients.ResultsTwenty patients who later developed DCI were included, and twenty-eight patients without DCI were identified for comparison. During HHH, there was a slight nonsignificant increase in systolic blood pressure (SBP) and a significant reduction in hematocrit. Median global cortical CBF for the DCI group increased from 29.5 (IQR 24.6–33.9) to 38.4 (IQR 27.0–41.2) ml/100 g/min (P = 0.001). There was a concomitant increase in regional CBF of the worst vascular territories, and the proportion of area with blood flow below 20 ml/100 g/min was significantly reduced. Non-DCI patients showed higher CBF at baseline, and no significant change over time.ConclusionsHHH-therapy appeared to increase global and regional CBF in DCI patients. The increase in SBP was small, while the decrease in hematocrit was more pronounced, which may suggest that intravascular volume status and rheological effects are of importance. XeCT may be potentially helpful in managing poor-grade SAH patients.

Evolution of diffusion tensor imaging parameters after acute subarachnoid haemorrhage: a prospective cohort study.

Few studies assessed diffusion tensor imaging (DTI) changes in the acute phase of subarachnoid haemorrhage (SAH). We prospectively evaluated DTI parameters in the acute phase of SAH and 8-10days after and analysed whether changes could be related to SAH severity or to the development of delayed cerebral ischemia (DCI). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) changes over time were assessed in a prospective cohort of patients with acute SAH. Two MRI studies were performed at <72h (MRI-1) and 8-10days (MRI-2). DTI parameters were recorded in 15 ROIs. Linear mixed regression models were used. Forty-two patients were included. Subtle changes in DTI parameters were found between MRI-1 and MRI-2. At the posterior limb of internal capsule (PLIC), a weak evidence of a 0.02 mean increase in FA (p=0.064) and a 17.55×10-6mm2/s decrease in ADC (p=0.052) were found in MRI-2. Both FA and ADC changed over time at the cerebellum (increase of 0.03; p=0.017; decrease of 34.73×10-6mm2/s; p=0.002, respectively). Patients with DCI had lower FA values on MRI-1 and lower ADC on MRI-2, although not reaching statistical significance, compared to non-DCI patients. DTI parameters on MRI-1 were not correlated to clinical admission scales. ADC and FA values show subtle changes over time in acute SAH at the PLIC and cerebellum although not statistically associated with the severity of SAH or the occurrence of DCI. However, DTI changes occurred mainly in DCI patients, suggesting a possible role of DTI as a marker of DCI.

Computed Tomography Perfusion Deficits during the Baseline Period in Aneurysmal Subarachnoid Hemorrhage Are Predictive of Delayed Cerebral Ischemia

Delayed cerebral ischemia (DCI) is a frequent and fearful complication following aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study is to assess the diagnostic accuracy of computed tomography perfusion (CTP) during an admission baseline period for the prediction of DCI. Fifty-four aSAH cases were screened by baseline CTP within 3 days after aSAH and were reexamined with CTP 7-17 days after aSAH. Relative cerebral blood volume, relative cerebral blood flow (CBF), and relative mean transit time were measured. DCI was confirmed by a combination of noncontrast CT, CTP reexamination, and clinical assessment of neurologic deficits. Quantitative baseline and reexamination CTP data for all patients were compared between DCI and without DCI groups using Student's t-tests. The quantitative baseline and reexamination CTP data of DCI patients were compared using paired Student's t-tests. The χ2 test was used to evaluate incidences of DCI between different baseline relative CBF levels. The optimal cutoff value for each parameter was established by receiver operating characteristic curve analysis. Of the patients included in this study, 33.3% (18 of 54) developed DCI. There was a significant difference in the incidence of DCI among different baseline relative CBF subsets (χ2 = 38.00, P < .05). A relative CBF of .84 had the highest specificity and sensitivity of predicting DCI. CTP parameters during the baseline period can be helpful for the early identification of aSAH patients who are at high risk for DCI.