Intra-arterial nimodipine for the treatment of refractory delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients. METHODS: To assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011-2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5). RESULTS: Out of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q1: 51.6 to Q3: 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients. CONCLUSION: Intra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up. TRIAL REGISTRATION NUMBER: German Clinical Trial Register DRKS00030505.

Effect of isolated intracranial hypertension on cerebral perfusion within the phase of primary disturbances after subarachnoid hemorrhage in rats.

Introduction: Elevated intracranial pressure (ICP) and blood components are the main trigger factors starting the complex pathophysiological cascade following subarachnoid hemorrhage (SAH). It is not clear whether they independently contribute to tissue damage or whether their impact cannot be differentiated from each other. We here aimed to establish a rat intracranial hypertension model that allows distinguishing the effects of these two factors and investigating the relationship between elevated ICP and hypoperfusion very early after SAH. Methods: Blood or four different types of fluids [gelofusine, silicone oil, artificial cerebrospinal fluid (aCSF), aCSF plus xanthan (CX)] were injected into the cisterna magna in anesthetized rats, respectively. Arterial blood pressure, ICP and cerebral blood flow (CBF) were continuously measured up to 6 h after injection. Enzyme-linked immunosorbent assays were performed to measure the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in brain cortex and peripheral blood. Results: Silicone oil injection caused deaths of almost all animals. Compared to blood, gelofusine resulted in lower peak ICP and lower plateau phase. Artificial CSF reached a comparable ICP peak value but failed to reach the ICP plateau of blood injection. Injection of CX with comparable viscosity as blood reproduced the ICP course of the blood injection group. Compared with the CBF course after blood injection, CX induced a comparable early global ischemia within the first minutes which was followed by a prompt return to baseline level with no further hypoperfusion despite an equal ICP course. The inflammatory response within the tissue did not differ between blood or blood-substitute injection. The systemic inflammation was significantly more pronounced in the CX injection group compared with the other fluids including blood. Discussion: By cisterna magna injection of blood substitution fluids, we established a subarachnoid space occupying rat model that exactly mimicked the course of ICP in the first 6 h following blood injection. Fluids lacking blood components did not induce the typical prolonged hypoperfusion occurring after blood-injection in this very early phase. Our study strongly suggests that blood components rather than elevated ICP play an important role for early hypoperfusion events in SAH.

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

BACKGROUND: Cerebral 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. METHODS: ORx 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). RESULTS: PRx 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). CONCLUSIONS: PRx 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.

Opening a window to the acutely injured brain: Simultaneous retinal and cerebral vascular monitoring in rats.

Many recent research projects have described typical chronic changes in the retinal vasculature for diverse neurovascular and neurodegenerative disorders such as stroke or Alzheimer's disease. Unlike cerebral vasculature, retinal blood vessels can be assessed non-invasively by retinal vessel analysis. To date, there is only a little information about potential simultaneous reactions of retinal and cerebral vessels in acute neurovascular diseases. The field of applications of retinal assessment could significantly be widened if more information about potential correlations between those two vascular beds and the feasibility of non-invasive retinal vessel analysis in acute neurovascular disease were available. Here, we present our protocol for the simultaneous assessment of retinal and cerebral vessels in an acute setting in anesthetized rats using a non-invasive retinal vessel analyzer and a superficial tissue imaging system for laser speckle contrast analysis via a closed bone window. We describe the experimental set-up in detail, outline the pitfalls of repeated retinal vessel analyses in an experimental set-up of several hours, and address issues that arise from the simultaneous use of two different assessment tools. Finally, we demonstrate the robustness and variability of the reactivity of retinal vessels to hypercapnia at baseline as well as their reproducibility over time using two anesthetic protocols common for neurovascular research. In summary, the procedures described in this protocol allow us to directly compare retinal and cerebral vascular beds and help to substantiate the role of the retina as a "window to the brain."

Aneurysmal Subarachnoid Hemorrhage in Hospitalized Patients on Anticoagulants-A Two Center Matched Case-Control Study.

Objective-Direct oral anticoagulants (DOAC) are replacing vitamin K antagonists (VKA) for the prevention of ischemic stroke and venous thromboembolism. We set out to assess the effect of prior treatment with DOAC and VKA in patients with aneurysmal subarachnoid hemorrhage (SAH). Methods-Consecutive SAH patients treated at two (Aachen, Germany and Helsinki, Finland) university hospitals were considered for inclusion. To assess the association between anticoagulant treatments on SAH severity measure by modified Fisher grading (mFisher) and outcome as measured by the Glasgow outcome scale (GOS, 6 months), DOAC- and VKA-treated patients were compared against age- and sex-matched SAH controls without anticoagulants. Results-During the inclusion timeframes, 964 SAH patients were treated in both centers. At the time point of aneurysm rupture, nine patients (0.93%) were on DOAC treatment, and 15 (1.6%) patients were on VKA. These were matched to 34 and 55 SAH age- and sex-matched controls, re-spectively. Overall, 55.6% of DOAC-treated patients suffered poor-grade (WFNS4-5) SAH compared to 38.2% among their respective controls (p = 0.35); 53.3% of patients on VKA suffered poor-grade SAH compared to 36.4% in their respective controls (p = 0.23). Neither treatment with DOAC (aOR 2.70, 95%CI 0.30 to 24.23; p = 0.38), nor VKA (aOR 2.78, 95%CI 0.63 to 12.23; p = 0.18) were inde-pendently associated with unfavorable outcome (GOS1-3) after 12 months. Conclusions-Iatrogenic coagulopathy caused by DOAC or VKA was not associated with more severe radiological or clinical subarachnoid hemorrhage or worse clinical outcome in hospitalized SAH patients.

Severity Assessment in Rats Undergoing Subarachnoid Hemorrhage Induction by Endovascular Perforation or Corresponding Sham Surgery.

INTRODUCTION: Animal models for preclinical research of subarachnoid hemorrhage (SAH) are widely used as much of the pathophysiology remains unknown. However, the burden of these models inflicted on the animals is not well characterized. The European directive requires severity assessment-based allocation to categories. Up to now, the classification into predefined categories is rather subjective and often without underlying scientific knowledge. We therefore aimed at assessing the burden of rats after SAH or the corresponding sham surgery to provide a scientific assessment. METHODS: We performed a multimodal approach, using different behavior tests, clinical and neurological scoring, and biochemical markers using the common model for SAH of intracranial endovascular filament perforation in male Wistar rats. Up to 7 days after surgery, animals with SAH were compared to sham surgery and to a group receiving only anesthesia and analgesia. RESULTS: Sham surgery (n = 15) and SAH (n = 16) animals showed an increase in the clinical score the first days after surgery, indicating clinical deterioration, while animals receiving only anesthesia without surgery (n = 5) remained unaffected. Body weight loss occurred in all groups but was more pronounced and statistically significant only after surgery. The analysis of burrowing, open field (total distance, erections), balance beam, and neuroscore showed primarily an effect of the surgery itself in sham surgery and SAH animals. Only concerning balance beam and neuroscore, a difference was visible between sham surgery and SAH. The outcome of the analysis of systemic and local inflammatory parameters and of corticosterone in blood and its metabolites in feces was only robust in animals suffering from larger bleedings. Application of principal component analysis resulted in a clear separation of sham surgery and SAH animals from their respective baseline as well as from the anesthesia-only group at days 1 and 3, with the difference between sham surgery and SAH being not significant. DISCUSSION/CONCLUSION: To our knowledge, we are the first to publish detailed clinical score sheet data combined with advanced behavioral assessment in the endovascular perforation model for SAH in rats. The tests chosen here clearly depict an impairment of the animals within the first days after surgery and are consequently well suited for assessment of the animals' suffering in the model. A definitive classification into one of the severity categories named by the EU directive is yet pending and has to be performed in the future by including the assessment data from different neurological and nonneurological disease models.

Optimal Cerebral Perfusion Pressure and Brain Tissue Oxygen in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO2) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO2 as an adjunctive monitor for adequate or optimal local perfusion. METHODS: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO2 <20 mmHg. RESULTS: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO2 and deltaCPP (P<0.001) with PbtO2 decrease with deltaCPP <0 mmHg and stable PbtO2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI. CONCLUSIONS: We found a nonlinear relationship between PbtO2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO2. Nevertheless, the nature of PbtO2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO2), which cannot be fulfilled by both measurements interchangeably.

Intraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment Protocol.

BACKGROUND: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IANonly) treatment protocol for refractory DCI in an observational study. METHODS: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IANonly). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5). RESULTS: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IANonly 0.26±0.20 µg/kg per minute, P<0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P<0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P=0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P=0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P=0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P<0.01). CONCLUSIONS: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Clinical Outcome and Prognostic Factors of Patients with Perimesencephalic and Nonperimesencephalic Subarachnoid Hemorrhage.

OBJECTIVE: To demonstrate the clinical outcome of patients with nonperimesencephalic subarachnoid hemorrhage (npSAH) compared with patients with aneurysmal SAH (aSAH) and perimesencephalic SAH (pSAH) and to evaluate predictive value of various clinical and radiological findings in patients with npSAH. METHODS: We retrospectively identified patients with SAH who presented at our institution between 2009 and 2018. We analyzed demographic and clinical data and outcomes. Multivariable analysis was performed for outcome parameters. RESULTS: Of 608 patients with confirmed SAH, 78% had aSAH, and 22% had nonaneurysmal SAH. Nonaneurysmal SAH was perimesencephalic in 30% of cases and nonperimesencephalic in 70%. Initial clinical status (Hunt and Hess score) was significantly worse in patients with aSAH compared with patients with nonaneurysmal SAH. Complications such as delayed cerebral ischemia occurred significantly more often in patients with aSAH. Patients with pSAH had a more favorable clinical course than patients with aSAH or npSAH. There was no significant difference in 30-day mortality between aSAH (29%) and npSAH (28%) patients (P = 0.835). Hunt and Hess score emerged as a strong predictor of unfavorable outcome in both aSAH and npSAH in multivariable regression. CONCLUSIONS: Patients with npSAH had a similar clinical outcome as patients with aSAH, although there were significantly fewer clinical complications in patients with npSAH. Patients with pSAH demonstrated an overall good clinical course. Our multivariable analysis showed that initial Hunt and Hess score was an important predictor for clinical outcome in aSAH as well as npSAH.

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.