Method of Intra-Arterial Drug Administration in a Rat: Sex Based Optimization of Infusion Rate

BACKGROUND: Endovascular thrombectomy is the process of removing a blood clot and re-establishing blood flow in patients with emergent large vessel occlusion. The technique provides an opportunity to deliver therapeutics directly to the site of injury. The intra-arterial (IA) route of drug administration in the mouse was developed to bridge the gap between animal stroke treatments and clinical stroke therapy. Here, we adapted the IA method for use in rats, by investigating various flow rates to optimize the IA injection through the internal carotid artery (ICA). METHODS: Male and female Sprague-Dawley rats (∼4 months of age) were subjected to placement of micro-angio tubing at the bifurcation of the common carotid artery for injection into the ICA. We evaluated a range of infusion rates of carbon black ink and its vascular distribution within the brain. RESULTS: Optimal injection rates in males was 4-6 μl/min and 2-4 μl/min in females. The IA injection using these sex-specific rates resulted in appropriate limited dye delivery to only the ipsilateral region of the brain, without inducing a subarachnoid hemorrhage. CONCLUSION: Upon adapting the IA administration model to rats, it was determined that the rate of infusion varied between males and females. This variability is an important consideration for studies utilizing both sexes, such as in ischemic stroke studies

Internal Carotid Artery Stenosis: A Novel Surgical Model for Moyamoya Syndrome

Moyamoya is a cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries. There are two forms: Disease and Syndrome, with each characterized by the sub-population it affects. Moyamoya syndrome (MMS) is more prominent in adults in their 20’s-40’s, and is often associated with autoimmune diseases. Currently, there are no surgical models for inducing moyamoya syndrome, so our aim was to develop a new animal model to study this relatively unknown cerebrovascular disease. Here, we demonstrate a new surgical technique termed internal carotid artery stenosis (ICAS), to mimic MMS using micro-coils on the proximal ICA. We tested for Moyamoya-like vasculopathies by fluorescently labelling the mouse cerebrovasculature with Di I for visualization and analysis of vessel diameter at the distal ICA and anastomoses on the cortical surface. Results show a significant narrowing of the distal ICA and anterior cerebral artery (ACA) in the Circle of Willis, as observed in humans. There is also a significant decrease in the number of anastomoses between the middle cerebral artery (MCA) and the ACA in the watershed region of the cortex. While further characterization is needed, this ICAS model can be applied to transgenic mice displaying co-morbidities as observed within the Moyamoya syndrome population, allowing a better understanding of the disease and development of novel treatments

Evaluation of headache severity after aneurysmal subarachnoid hemorrhage

AbstractObjectiveThe most common complaint from patients after subarachnoid hemorrhage (SAH) is headache. The headache appears to be persistent and often severe. Although this problem is pervasive in the care of SAH patients, very little data have been published to describe the nature and severity of the headache nor is there evidence-based guidance on the appropriate treatment of headache due to SAH.MethodsThis was a retrospective medical record review of adults with aneurysmal SAH. Basic demographics, along with pain scores and analgesic medication administration, were collected. Patients with early vasospasm (within 7days of ictus) were compared with patients with no vasospasm.ResultsThe patient population was characteristic of the typical SAH population. Approximately 31.5% of patients exhibited early vasospasm. These patients had higher pain scores (median 8/10) than did patients without vasospasm (median 6/10) and required more analgesics such as acetaminophen/butalbital/caffeine. Treatment success with any analgesic used in this population was minimal. The pain scores associated with headache increased over the first 7days in both groups.ConclusionsHeadache after SAH is persistent and treatment refractory. There may be an association with development of vasospasm and worsening of headache. Novel treatment strategies to attenuate headache in this population are needed

Intra-Arterial Combination Therapy for Experimental Acute Ischemic Stroke

Acute ischemic stroke continues to devastate millions of individuals worldwide. Current treatments work to restore blood flow but not rescue affected tissue. Our goal was to develop a combination of neuroprotective agents administered intra-arterially following recanalization to target ischemic tissue. Using C57Bl/6J male mice, we performed tandem transient ipsilateral middle cerebral/common carotid artery occlusion, followed by immediate intra-arterial pharmacotherapy administration through a standardized protocol. Two pharmacotherapy agents, verapamil and lubeluzole, were selected based on their potential to modulate different aspects of the ischemic cascade; verapamil, a calcium channel blocker, works in an acute fashion blocking L-type calcium channels, whereas lubeluzole, an N-methyl-D-aspartate modulator, works in a delayed fashion blocking intracellular glutamate trafficking. We hypothesized that combination therapy would provide complimentary and potentially synergistic benefit treating brain tissue undergoing various stages of injury. Physiological measurements for heart rate and pulse distention (blood pressure) demonstrated no detrimental effects between groups, suggesting that the combination drug administration is safe. Tissue analysis demonstrated a significant difference between combination and control (saline) groups in infarct volume, neuronal health, and astrogliosis. Although a significant difference in functional outcome was not observed, we did note that the combination treatment group had a greater percent change from baseline in forced motor movement as compared with controls. This study demonstrates the safety and feasibility of intra-arterial combination therapy following successful recanalization and warrants further study

Operative Management of Symptomatic, Metachronous Carotid Body Tumors Involving the Skull Base and Its Neurological Sequelae

A 44-year-old morbidly obese woman with a history of right carotid body tumor (CBT) resection presented with a symptomatic, nonfunctional, left Shamblin-III CBT. Abutment of the skull base precluded distal internal carotid artery control for arterial reconstruction, favoring parent vessel sacrifice after an asymptomatic provocative test. She underwent CBT resection with anticipated sacrifice of cranial nerves X and XII and the common carotid artery and its branches, developing baroreceptor failure syndrome and sequelae of cranial nerve sacrifice. When facing a symptomatic, metachronous CBT abutting the skull base, upfront operative intervention with adjuvant radiation for residual tumor optimizes curative resection

Hemorrhagic stroke outcomes of KApSR patients with co-morbid diabetes and Alzheimer’s disease

Background: Vascular risk factors, such as diabetes mellitus (DM), are associated with poorer outcomes following many neurodegenerative diseases, including hemorrhagic stroke and Alzheimer’s disease (AD). Combined AD and DM co-morbidities are associated with an increased risk of hemorrhagic stroke and increased Medicare costs. Therefore, we hypothesized that patients with DM in combination with AD, termed DM/AD, would have increased hemorrhagic stroke severity. Methods: Kentucky Appalachian Stroke Registry (KApSR) is a database of demographic and clinical data from patients that live in Appalachia, a distinct region with increased health disparities and stroke severity. Inpatients with a primary indication of hemorrhagic stroke were selected from KApSR for retrospective analysis and were separated into four groups: DM only, AD only, neither, or both. Results: Hemorrhagic stroke patients (2,071 total) presented with either intracerebral hemorrhage (ICH), n=1,448, or subarachnoid hemorrhage (SAH), n=623. When examining all four groups, subjects with AD were significantly older (AD+, 80.9±6.6 yrs) (DM+/AD+, 77.4±10.0 yrs) than non AD subjects (DM-/AD-, 61.3±16.5 yrs) and (DM+, 66.0±12.5 yrs). A higher percentage of females were among the AD+ group and a higher percentage of males among the DM+/AD+ group. Interestingly, after adjusting for multiple comparison, DM+/AD+ subjects were ten times as likely to suffer a moderate to severe stroke based on a National Institute of Health Stroke (NIHSS) upon admission [odds ratio (95% CI)] compared to DM-/AD- [0.1 (0.02–0.55)], DM+ [0.11 (0.02–0.59)], and AD+ [0.09(0.01–0.63)]. The odds of DM+/AD+ subjects having an unfavorable discharge destination (death, hospice, long-term care) was significant (P Conclusions: In our retrospective analysis utilizing KApSR, regardless of adjusting for age, sex, and comorbidities, DM+/AD+ patients were significantly more likely to have had a moderate or severe stroke leading to an unfavorable outcome following hemorrhagic stroke

Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke

Background: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy. Objective: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization. Methods: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose–response (3.12, 6.25, 12.5, and 25 .ig/.iL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 .ig/.iL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively. Results: Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 .ig/.iL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN. Conclusions: These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy