Ischemic Subarachnoid Hemorrhage Research Articles

Multimodality Monitoring for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Mini Review.

Aneurysmal subarachnoid hemorrhage is a disease with high mortality and morbidity due in large part to delayed effects of the hemorrhage, including vasospasm, and delayed cerebral ischemia. These two are now recognized as overlapping yet distinct entities, and supportive therapies for delayed cerebral ischemia are predicated on identifying DCI as quickly as possible. The purpose of this overview is to highlight diagnostic tools that are being used in the identification of DCI in the neurocritical care settings.

Angiotensin-(1-7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage.

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 AT1R, 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).

Day 2 neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for prediction of delayed cerebral ischemia in subarachnoid hemorrhage.

Recent evidence has suggested that an admission neutrophil-to-lymphocyte ratio (NLR) of ≥ 5.9 predicts delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH). The primary aims of this study were to assess reproducibility and to ascertain the predictive ability of NLR on subsequent days postictus. Secondary aims included identification of additional inflammatory markers. A single-center, retrospective study of all patients aged ≥ 18 years with aSAH between May 2014 and July 2018 was performed. Patient characteristics, DCI incidence, operative features, and outcomes (on discharge and at 3 months postictus) were recorded. C-reactive protein (CRP) and full blood count differentials were recorded on admission and through day 8 postictus or at discharge. In total, 403 patients were included in the final analysis. Ninety-six patients (23.8%) developed DCI with a median time from ictus of 6 days (IQR 3.25-8 days). A platelet-to-lymphocyte ratio (PLR) cutoff ≥ 157 and CRP cutoff ≥ 27 was used in our cohort. In a multiple binary logistic regression model, after controlling for known DCI predictors, day 2 NLR ≥ 5.9 (OR 2.194, 95% CI 1.099-4.372; p = 0.026), day 1 PLR ≥ 157 (OR 2.398, 95% CI 1.1072-5.361; p = 0.033), day 2 PLR ≥ 157 (OR 2.676, 95% CI 1.344-5.329; p = 0.005), and CRP ≥ 27 on days 3, 4, and 5 were predictive of DCI. The results of this study have confirmed the association between NLR and DCI and have demonstrated the predictive potential of PLR and CRP, suggesting that NLR and PLR at day 2, and CRP from day 3 onward, may be better predictors of DCI than those measurements at the time of ictus.

Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning.

BackgroundMany therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection.Methods and ResultsIn this study, we found that hypoxic postconditioning (8% O2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1 −/− mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1‐Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post‐SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1‐dependent fashion.ConclusionsThe present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning‐based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.

Early low cerebral blood flow and high cerebral lactate: prediction of delayed cerebral ischemia in subarachnoid hemorrhage.

OBJECTIVE Delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is one of the major contributors to poor outcome. It is crucial to be able to detect early signs of DCI to prevent its occurrence. The objective of this study was to determine if low cerebral blood flow (CBF) measurements and pathological microdialysis parameters measured at the bedside can be observed early in patients with SAH who later developed DCI. METHODS The authors included 30 patients with severe SAH. The CBF measurements were performed at Day 0-3 after disease onset, using bedside xenon-CT. Interstitial glucose, lactate, pyruvate, glycerol, and glutamate were measured using microdialysis. RESULTS Nine of 30 patients developed DCI. Patients with DCI showed significantly lower global and regional CBF, and lactate was significantly increased in these patients. A high lactate/pyruvate ratio was also detected in patients with DCI. CONCLUSIONS Early low CBF measurements and a high lactate and lactate/pyruvate ratio may be early warning signs of the risk of developing DCI. The clinical value of these findings needs to be confirmed in larger studies.

Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study.

Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62% with IQR -87 to -39%) compared to the control group (median +27% with IQR -32 to +104%, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95% CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI.

Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults

ObjectivesDelayed cerebral infarction (DCI) has a significant impact on mortality and morbidity of patients with subarachnoid hemorrhage (SAH). The aim of this study was to define quantitative EEG (qEEG) parameters for the early and reliable prediction of DCI and compare the validity and time course of qEEG to standard procedures. Methods12 consecutive unselected SAH patients (8 female, mean age 52years, Hunt-and-Hess grade I–IV) were prospectively examined. Continuous six channel EEG monitoring was started within 48h after admission (mean duration 5.2days; range: 2–12days). All raw and unselected EEG signal underwent automated artifact rejection, Short Time Fast Fourier Transformation and a detrending procedure in order to analyze regional spectral power changes in different frequency bands. According to clinical standards, transcranial Doppler sonography (TCD) was performed at least on alternate days and repeat cerebral computer tomography (CCT) as needed. Results6 patients (50%) developed vasospasm/DCI. Decrease of ⩾40% in power persisting over ⩾5h in the alpha band and ⩾6h in the theta band marked the optimal cut-off to detect DCI (sensitivity 89%, specificity 77% for alpha). EEG changes preceded detection of vasospasm/DCI in standard procedures by 2.3days. Changes in the beta and delta band as well as in the alpha/delta ratio demonstrated lower correlation with imminent DCI. ConclusionsFocal reduction in alpha power may represent a valid, observer independent, non-invasive and continuous marker for vasospasm/DCI in SAH patients. SignificanceqEEG indicates imminent ischemia earlier than established diagnostic tools, such as TCD.

Impaired Cerebral Autoregulation Is Associated With Vasospasm and Delayed Cerebral Ischemia in Subarachnoid Hemorrhage

Cerebral autoregulation may be impaired in the early days after subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationship between cerebral autoregulation and angiographic vasospasm (aVSP) and radiographic delayed cerebral ischemia (DCI) in patients with SAH. Sixty-eight patients (54±13 years) with a diagnosis of nontraumatic SAH were studied. Dynamic cerebral autoregulation was assessed using transfer function analysis (phase and gain) of the spontaneous blood pressure and blood flow velocity oscillations on days 2 to 4 post-SAH. aVSP was diagnosed using a 4-vessel conventional angiogram. DCI was diagnosed from CT. Decision tree models were used to identify optimal cut-off points for clinical and physiological predictors of aVSP and DCI. Multivariate logistic regression models were used to develop and validate a risk scoring tool for each outcome. Sixty-two percent of patients developed aVSP, and 19% developed DCI. Patients with aVSP had higher transfer function gain (1.06±0.33 versus 0.89±0.30; P=0.04) and patients with DCI had lower transfer function phase (17.5±39.6 versus 38.3±18.2; P=0.03) compared with those who did not develop either. Multivariable scoring tools using transfer function gain>0.98 and phase<12.5 were strongly predictive of aVSP (92% positive predictive value; 77% negative predictive value; area under the receiver operating characteristic curve, 0.92) and DCI (80% positive predictive value; 91% negative predictive value; area under the curve, 0.94), respectively. Dynamic cerebral autoregulation is impaired in the early days after SAH. Including autoregulation as part of the initial clinical and radiographic assessment may enhance our ability to identify patients at a high risk for developing secondary complications after SAH.

Experimental research Effects of ischemic phrenic nerve root ganglion injury on respiratory disturbances in subarachnoid hemorrhage: an experimental study

IntroductionPhrenic nerves have important roles on the management of respiration rhythm. Diaphragm paralysis is possible in phrenic nerve roots ischemia in subarachnoid hemorrhage (SAH). We examined whether there is a relationship between phrenic nerve root ischemia and respiratory disturbances in SAH.Material and methodsThis study was conducted on 5 healthy control and 14 rabbits with experimentally induced SAH by injecting autologous blood into their cisterna magna. Animals were followed up via monitors for detecting the heart and respiration rhythms for 20 days and then decapitaed by humanely. Normal and degenerated neuron densities of phrenic nerve root at the level of C4 dorsal root ganglia (C4DRG) were estimated by Stereological methods. Between the mean numerical density of degenerated neurons of C4DRG and respiratory rate/minute of groups were compared statistically.ResultsPhrenic nerve roots, artery and diaphragm muscles degeneration was detected in respiratory arrest developed animals. The mean neuronal density of C4DRG was 13272 ±1201/mm3 with a mean respiration rate of 23 ±4/min in the control group. The mean degenerated neuron density was 2.240 ±450/mm3 and respiration rhythm was 31 ±6/min in survivors. But, the mean degenerated neuron density was 5850 ±650/mm3 and mean respiration rhythm was 34 ±7/min in respiratory arrest developed animals (n = 7). A linear relationship was noticed between the degenerated neuron density of C4DRG and respiraton rate (r = –0.758; p < 0.001).ConclusionsPhrenic nerve root ischemia may be an important factor in respiration rhythms deteriorations in SAH which has not been mentioned in the literature.

Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage

BackgroundAngiopoietin-1 (Ang-1) and -2 (Ang-2) are keyplayers in the regulation of endothelial homeostasis and vascular proliferation. Angiopoietins may play an important role in the pathophysiology of cerebral vasospasm (CVS). Ang-1 and Ang-2 have not been investigated in this regard so far.Methods20 patients with subarachnoid hemorrhage (SAH) and 20 healthy controls (HC) were included in this prospective study. Blood samples were collected from days 1 to 7 and every other day thereafter. Ang-1 and Ang-2 were measured in serum samples using commercially available enzyme-linked immunosorbent assay. Transcranial Doppler sonography was performed to monitor the occurrence of cerebral vasospasm.ResultsSAH patients showed a significant drop of Ang-1 levels on day 2 and 3 post SAH compared to baseline and HC. Patients, who developed Doppler sonographic CVS, showed significantly lower levels of Ang-1 with a sustained decrease in contrast to patients without Doppler sonographic CVS, whose Ang-1 levels recovered in the later course of the disease. In patients developing cerebral ischemia attributable to vasospasm significantly lower Ang-1 levels have already been observed on the day of admission. Differences of Ang-2 between SAH patients and HC or patients with and without Doppler sonographic CVS were not statistically significant.ConclusionsAng-1, but not Ang-2, is significantly altered in patients suffering from SAH and especially in those experiencing CVS and cerebral ischemia. The loss of vascular integrity, regulated by Ang-1, might be in part responsible for the development of cerebral vasospasm and subsequent cerebral ischemia.

Central conduction time as an index of ischaemia in subarachnoid haemorrhage

Central conduction time (CCT) has been measured in 12 healthy volunteers, and in 16 patients admitted to a neurosurgical unit following subarachnoid haemorrhage. Twelve of the patients were subsequently operated upon for the obliteration of an intracranial aneurysm. CCT has been found to have low standard deviation in control cases, and in the normal side following subarachnoid haemorrhage from aneurysms in the Circle of Willis, and to be prolonged during the development of ischaemic complications, either of the haemorrhage or following surgery. Evidence so far suggests that CCT may be useful as a monitor of developing ischaemia in association with surgery for subarachnoid haemorrhage.