Anesthesia management for endovascular treatment.

PURPOSE OF REVIEW: The review highlights recent data regarding the safety and efficacy of endovascular treatment of cerebrovascular disease and concerns in anesthesia management. RECENT FINDINGS: Ongoing trials, including the Barrow Ruptured Aneurysm Trial and the International Subarachnoid Aneurysm Trial II, are aimed at improving understanding of the applicability of the International Subarachnoid Aneurysm Trial data and the roles of surgical clipping and endovascular treatment in the broad general patient population of ruptured aneurysms. Two recent studies in unruptured brain arteriovenous malformation management - ARUBA (a multicenter, randomized clinical trial) and the Scottish population-based cohort study - concluded that conservative medical management is superior to interventional therapy (including endovascular embolization) in preventing death or stroke. Three randomized clinical trials failed to prove the superiority of endovascular therapy to standard care for acute ischemic stroke, but pointed out to the need and direction of future trials. Studies of anesthesia for acute ischemic stroke suggested that inadequate brain perfusion may contribute to poorer outcome. SUMMARY: Recent data further support the role of endovascular coiling for ruptured aneurysm in broader patient populations. Further studies are needed to investigate the proper management of unruptured arteriovenous malformations, and the key factors in endovascular therapy and anesthesia management associated with stroke outcome.

An Update of Neuroanesthesia for Intraoperative Brain Mapping Craniotomy.

The perioperative multidisciplinary team approach has probably been best exemplified by the care of awake craniotomy patients. Advancement in anesthesia and meticulous perioperative care has supported the safety and complexity of the surgical and mapping efforts in glioma resection. The discussions in this review will emphasize on anesthetic and perioperative management strategies to prevent complications and minimize their effects if they occur, including current practice guidelines in anesthesia, updates on the applications of anesthetic medications, and emerging devices. Planning the anesthetic and perioperative management is based on understanding the pharmacology of the medications, the goals of different stages of the surgery and mapping, and anticipating potential problems.

The Impact of the Global SARS-CoV-2 (COVID-19) Pandemic on Neuroanesthesiology Fellowship Programs Worldwide and the Potential Future Role for ICPNT Accreditation.

BACKGROUND: The COVID-19 pandemic is an international crisis placing tremendous strain on medical systems around the world. Like other specialties, neuroanesthesiology has been adversely affected and training programs have had to quickly adapt to the constantly changing environment. METHODS: An email-based survey was used to evaluate the effects of the pandemic on clinical workflow, clinical training, education, and trainee well-being. The impact of the International Council on Perioperative Neuroscience Training (ICPNT) accreditation was also assessed. RESULTS: Responses were received from 14 program directors (88% response rate) in 10 countries and from 36 fellows in these programs. Clinical training was adversely affected because of the cancellation of elective neurosurgery and other changes in case workflow, the introduction of modified airway and other protocols, and redeployment of trainees to other sites. To address educational demands, most programs utilized online platforms to organize clinical discussions, journal clubs, and provide safety training modules. Several initiatives were introduced to support trainee well-being during the pandemic. Feelings of isolation and despair among trainees varied from 2 to 8 (on a scale of 1 to 10). Fellows all reported concerns that their clinical training had been adversely affected by the coronavirus disease 2019 (COVID-19) pandemic because of decreased exposure to elective subspecialty cases and limited opportunities to complete workplace-based assessments and training portfolio requirements. Cancellation of examination preparation courses and delayed examinations were cited as common sources of stress. Programs accredited by the ICPNT reported that international networking and collaboration was beneficial to reduce feelings of isolation during the pandemic. CONCLUSION: Neuroanesthesia fellowship training program directors introduced innovative ways to maintain clinical training, educational activity and trainee well-being during the COVID-19 pandemic.

Nitric oxide in vascular endothelial growth factor-induced focal angiogenesis and matrix metalloproteinase-9 activity in the mouse brain.

BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) can induce matrix metalloproteinase (MMP)-9 activities and focal angiogenesis. We hypothesized that VEGF activation of cerebral MMP-9 would require nitric oxide participation. METHODS: We compared the in vivo effects of: (1) N(G)-monomethyl-l-arginine, a nonspecific nitric oxide synthase inhibitor; (2) L-N(6)-(1-iminoethyl)lysine, an inducible nitric oxide synthase selective inhibitor; and (3) doxycycline, a known nonspecific inhibitor of MMP in the mouse brain, using in situ zymography and endothelial marker CD31. 3-nitrotyrosine was used as a surrogate for nitric oxide activity. Inflammatory cell markers CD68 and MPO were used to confirm leukocyte infiltration. RESULTS: VEGF-stimulated MMP-9 activity expressed primarily around cerebral microvessels. N(G)-monomethyl-l-arginine suppressed cerebral angiogenesis (P<0.05), especially those microvessels associated with MMP-9 activation (P<0.02) induced by VEGF, comparable to the effect of doxycycline. L-N(6)-(1-iminoethyl)lysine showed similar inhibitory effects. 3-nitrotyrosine confirmed nitric oxide levels in the brain. Compared with the lacZ control, VEGF increased inflammatory cell infiltration, especially macrophages, in the induced brain angiogenic focuses. CONCLUSIONS: Inhibition of nitric oxide production decreased MMP-9 activity and focal angiogenesis in the VEGF-stimulated brain. Both specific and nonspecific inhibition of nitric oxide synthase resulted in similar reductions, suggesting that VEGF-stimulated cerebral MMP activity and angiogenesis are predominantly mediated through inducible nitric oxide synthase, a specific nitric oxide synthase isoform mediating inflammatory responses.

Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

OBJECTIVE: We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation. METHODS AND RESULTS: BM from GFP donor mice was isolated and transplanted into lethally irradiated recipients. Four weeks after transplantation, groups of mice received adeno-associated viral vector (AAV)-VEGF or AAV-lacZ gene (control) injection and were euthanized at 1 to 24 weeks. BMDCs were characterized by double-labeled immunostaining. The function of BMDCs was further examined through matrix metalloproteinase (MMP)-2 and -9 activity. We found that capillary density increased after 2 weeks, peaked at 4 weeks (P<0.01), and sustained up to 24 weeks after gene transfer. GFP-positive BMDCs infiltration in the angiogenic focus began at 1 week, peaked at 2 weeks, and decreased thereafter. The GFP-positive BMDCs were colocalized with CD45 (94%), CD68 (71%), 5% Vimentin (5%), CD31/von Willebrand factor (vWF) (1%), and alpha-smooth muscle actin (alpha -SMA, 0.5%). Infiltrated BMDCs expressed MMP-9. MMP-9 KO mice confirmed the dependence of the angiogenic response on MMP-9 availability. CONCLUSIONS: Nearly all BMDCs in the angiogenic focus showed expression for leukocytes/macrophages, indicating that BMDCs minimally incorporated into the neovasculature. Colocalization of MMPs with GFP suggests that BMDCs play a critical role in VEGF-induced angiogenic response through up-regulation of MMPs.

Feasibility of minocycline and doxycycline use as potential vasculostatic therapy for brain vascular malformations: pilot study of adverse events and tolerance.

BACKGROUND: Tetracyclines may be useful in preventing pathological vascular remodeling, thus decreasing the risk of spontaneous hemorrhage from brain vascular malformations. METHODS: Arteriovenous malformation (AVM) and intracranial aneurysm patients undergoing noninvasive management were treated with minocycline or doxycycline (200 mg/day) up to 2 years in a prospective open-label safety pilot trial. The primary outcome was to compare dose-limiting intolerance, defined as treatment-related dose reduction or withdrawal between the agents. RESULTS: Twenty-six patients with AVMs (n = 12) or aneurysms (n = 14) were recruited. Adverse event rates were similar to other reported trials of these agents; 4 of 13 (31%) minocycline and 3 of 13 (23%) doxycycline patients had dose-limiting intolerance (hazard ratio = 3.1, 95% CI = 0.52-18.11, log rank p = 0.70). CONCLUSIONS: It is feasible to propose a long-term trial to assess the potential benefit of tetracycline therapy to decrease hemorrhagic risk in brain vascular malformations.

Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Human brain arteriovenous malformation tissue displays increased levels of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase (MMP)-9, a tissue protease associated with various intracerebral hemorrhage (ICH). We hypothesized that increased MMP-9 was associated with ICH induced by vascular endothelial growth factor hyperstimulation and that this effect could be attenuated by nonspecific MMP inhibition. METHODS: We used a mouse model with adenoviral vector-mediated vascular endothelial growth factor transduction in the brain. The association of MMP-9 expression and the brain tissue hemoglobin levels, an index of ICH, after stereotactic injection of adenoviral vector-mediated vascular endothelial growth factor into caudate putamen was assessed. A dose-response study with adenoviral vector-mediated vascular endothelial growth factor and a time course study at both 24 and 48 hours postinjection were performed. Effects of minocycline, a nonspecific MMP inhibitor, and pyrrolidine dithiocarbamate, an upstream regulator of MMPs, on MMP-9 activity and thereby the degree of ICH were also tested. RESULTS: Adenoviral vector-mediated vascular endothelial growth factor at the higher dose and at 48 hours induced MMP-9 levels 6-fold (n=6, P=0.02) and increased brain tissue hemoglobin (43.4+/-11.5 versus 30.3+/-4.1 mug/mg, n=6, P=0.003) compared with the adenoviral vector control. Immnunostaining was positive for MMP-9 around the cerebral vessels and the hemorrhagic areas. Minocycline and pyrrolidine dithiocarbamate administration suppressed vascular endothelial growth factor-induced MMP-9 activity (n=6, P=0.003 and P=0.01, respectively) and the associated increases in hemoglobin levels (n=5-6, P=0.001 and P=0.02, respectively). CONCLUSIONS: Vascular endothelial growth factor-induced ICH is associated with increased MMP-9 expression. Suppression of MMP-9 by minocycline or pyrrolidine dithiocarbamate attenuated ICH, suggesting the therapeutic potential of MMP inhibitors in cerebral vascular rupture.

Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation.

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.

Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model.

BACKGROUND AND PURPOSE: A number of central nervous system (CNS) disorders are associated with abnormalities in or activation of angiogenesis, including vascular malformations. To test the hypothesis that the nonspecific matrix metalloproteinase (MMP) inhibitor, doxycycline, suppresses vascular endothelial growth factor (VEGF)-induced cerebral angiogenesis through inhibition of MMPs, we used a mouse model with enhanced cerebral angiogenesis induced by focal hyperstimulation of VEGF from adenovirus DNA (AdVEGF) transduction. METHODS: The time course study of MMP activity was performed at 7 and 14 days after AdVEGF transduction. MMP activity and expression were examined by zymography and immunohistochemistry, respectively. As an index of cerebral angiogenesis, microvessel counting was performed in the brains of 3 groups of mice (n=6): (1) control; (2) AdVEGF only; and (3) AdVEGF plus doxycycline (30 mg/kg per day). RESULTS: Brain MMP-9 activities increased 4-fold (883+/-137 versus 179+/-179; 1-sided P<0.001) at 7 days after AdVEGF transduction. VEGF transduction increased vessel counts by 19% (255+/-27 versus 215+/-15, 1-sided P<0.01). Doxycycline treatment decreased MMP-9 activity (89+/-72 versus 883+/-137; 1-sided P<0.001) and cerebral microvessel number (231+/-17 versus 255+/-27; 1-sided P<0.05). CONCLUSIONS: Doxycycline is effective in decreasing stimulated cerebral MMP-9 activity and parenchymal angiogenesis. The decrease in MMP-9 activity is associated with decreased microvessel counts. Brain pathophysiological processes that involve abnormally enhanced angiogenesis may be amenable to manipulation by MMP inhibitors, including tetracycline derivatives.

Anesthesia for endovascular neurosurgery and interventional neuroradiology.

This article outlines the roles of the anesthesiologist in the management of patients undergoing invasive endovascular procedures to treat vascular diseases, primarily of the central nervous system. This practice is usually termed interventional neuroradiology or endovascular neurosurgery. The article emphasizes perioperative and anesthetic management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.

Anestesia en neuroradiología intervencionista / Anesthesia for interventional neuroradiology

Interventional Neuroradiology (INR) is firmly established in the management of cerebrovascular diseases. The aim of this manuscript is to present the author's critical review of the literature and interpretation emphasizing perioperative and anesthetic management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.

La Neuroradiología Intervencionista (NRI) está firmemente establecida en el manejo de la patología cerebrovascular. El objetivo del presente manuscrito es presentar una revisión crítica de la literatura e interpretación por parte del autor, enfatizando las estrategias perioperatorias y anestésicas para prevenir complicaciones y minimizar sus efectos en caso de que estas se presenten. La planeación de la gestión anestésica y perioperatoria se fundamenta en comprender las metas de la intervención terapéutica y anticiparse a los problemas potenciales.

Anesthetic concerns in patients with known cerebrovascular insufficiency.

This review outlines the perioperative anesthesia considerations of patients with vascular diseases of the central nervous system, including occlusive cerebrovascular diseases with ischemic risks and various cerebrovascular malformations with hemorrhagic potential. The discussion emphasizes perioperative management strategies to prevent complications and minimize their effects if they occur. Planning the anesthetic and perioperative management is predicated on understanding the goals of the therapeutic intervention and anticipating potential problems.

Management of brain arteriovenous malformations.

PURPOSE OF REVIEW: This review highlights recent data regarding factors associated with brain arteriovenous malformation hemorrhage and different treatment options. RECENT FINDINGS: More risk factors were identified in association with intracranial hemorrhage, including age at initial diagnosis of arteriovenous malformation, co-existing extranidal aneurysms and genetic factors. Patients with unruptured arteriovenous malformations were found to be more susceptible to worsening in neurological function after microsurgery compared with those presenting with hemorrhagic arteriovenous malformation. Radiosurgery has achieved satisfactory obliteration of deep arteriovenous malformations, but with increased actuarial hemorrhage rates from the first to the fifth year. Although the Intraoperative Hypothermia for Aneurysm Surgery Trial failed to show a significant neurological improvement, the superior efficiency of endovascular cooling has offered optimism in cerebral protection during neurovascular surgeries by shortening the time to achieve hypothermia and rewarming. A multi-center trial (ARUBA) has been proposed to test the hypothesis that, for unruptured brain arteriovenous malformations, there is no difference between interventional and conservative management. Recent studies have also shown the promise of using tetracyclines to decrease the rate of spontaneous arteriovenous malformation rupture. SUMMARY: The recent identification of clinical and genetic factors associated with brain arteriovenous malformation hemorrhage, as well as studies on treatment outcomes, will help risk stratification in management choices. Future studies are needed to identify arteriovenous malformation patients at the greatest risk of spontaneous hemorrhage and to develop specific medical therapies.

Physiologic monitoring and anesthesia considerations in acute ischemic stroke.

Acute ischemic stroke is considered a neurologic emergency. The perioperative anesthesia management of acute ischemic stroke is challenging owing to the dynamic pathophysiology of the disease itself and the patients' comorbid factors and conditions. Herein, the authors review preoperative assessment, intraoperative and postoperative physiologic monitoring, and anesthesia management, with a focus on the control of the cerebrovascular and cardiovascular circulations. Issues specific to anesthesia monitoring and management in the radiology suite are emphasized.