Intra-arterial Research Articles

A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation.

Background Tirapazamine's (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ's safety and tolerability in rats by first injecting into the left hepatic artery and then performing a hepatic artery ligation, which recapitulates the transarterial embolization used clinically. Research design and methods: Forty-six rats in five groups were respectively injected with 0, 0.25, 0.50, 1.0, or more than 1.5mL IA of TPZ (0.7mg/mL) into the left hepatic artery and then subjected to hepatic artery ligation under laparotomy. Blood samples were collected four times daily up to day 15 after which the rats were euthanized and necropsied. The toxicity profile of IA injection of TPZ followed by hepatic artery ligation was then assessed. Results No significant changes to the rats' body weight and serum total bilirubin were observed. Serum alanine aminotransferase (ALT) levels increased slightly but remained below 100U/L one day after treatment for most rats. Three rats in Groups 3 and 4 exhibited an over two-fold transient elevation of ALT. All ALT recovered to the baseline at day 14. Liver tissues were collected on day 15 using H&E staining. One rat in Group 3 showed ischemic coagulative necrosis in its liver tissue. Other sporadic pathological changes not related to TPZ doses were observed in Groups 2, 3, 4, and 5. Conclusion TPZ by IA injection followed by embolization is tolerated up to 7mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver.

HSPA12B Expression as an Epigenetic Signature Following Ischemic Stroke: Heat Shock Protein Mini Review

Stroke is a cardiovascular condition that caused by a clot or obstruction that prevents blood from flowing to the brain. Neural cells within the occluded area undergo cell death within minutes, and the results are often permanent, making stroke one of the leading causes of serious longterm disability. Stroke is a complex disorder that requires innovative solutions to attenuate the effects of stroke and improve clinical outcomes. Traditionally, stroke treated by relieving vascular occlusions and restoring blood flow to the infarcted tissue (necrotic tissue; core infarct) and the surrounding tissue at risk (penumbra). This technique known as thrombolysis, utilizing both chemical and mechanical modes. Chemical thrombolysis utilizes a catheter that administers medication to the clot site, which includes a multitude of treatments that include intravenous (IV) thrombolysis with recombinant tissue plasminogen activator, or rTPA, and intra-arterial (IA) therapies that aim to directly remove the occlusive clot and reestablish blood flow through recanalization.

Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention.

Rationale: Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop D2O as a novel contrast agent for guiding endovascular neurointervention.Methods: Animal studies were approved by institutional ACUC and conducted using an 11.7 T Bruker Biospec system and a 3T Siemens Trio clinical scanner for rodent and canine imaging, respectively. The locally selective blood brain barrier opening (BBBO) in rat brains was obtained by intraarterial (IA) injection of mannitol. The dynamic T2w* EPI MRI sequence was used to study the trans-catheter perfusion territory by IA administered SPIO before mannitol administration, whereas a dynamic T1w FLASH sequence was used to acquire Gd contrast-enhanced MRI for assessing BBBO after injection of mannitol. The contrast generated by D2O assessed by either EPI or FLASH methods was compared with the corresponding results assessed by SPIO or Gd. The utility of D2O MRI was also demonstrated to guide drug delivery to glioma in a mouse model. Finally, the clinical utility of D2O-MRI was demonstrated in a canine model.Results: Our study has shown that the contrast generated by D2O can be used to precisely delineate trans-catheter perfusion territory in both small and large animals. The perfusion territories determined by D2O-MRI show moderate correlation with those by SPIO-MRI (Spearman coefficient r = 0.5234, P < 0.001). Moreover, our results show that the perfusion territory determined by D2O-MRI can successfully predict the areas with BBBO after mannitol treatment similar to that assessed by Gd-MRI (Spearman coefficient r = 0.6923, P < 0.001). Using D2O-MRI as imaging guidance, the optimal infusion rate in the mouse brain was determined to be 150 µL/min to maximize the delivery efficacy to the tumor without serious off-target delivery to the brain parenchyma. The enhanced drug delivery of antibodies to the brain tumor was confirmed by fluorescence imaging.Conclusion: Our study demonstrated that D2O can be used as a negative MRI contrast medium to guide endovascular neurointervention. The established D2O -MRI method is safe and quantitative, without the concern of contrast accumulation. These qualities make it an attempting approach for a variety of endovascular procedures.

Stroke transfers for thrombectomy in the era of extended time

Background and purposeThe Dawn and Extend Intra-Arterial (IA) acute stroke intervention trials have proven the benefit of thrombectomy in a select group of patients up to 24 h since their last known well time (LKWT) or time of symptom onset. Following the issuance of new treatment guidelines for large vessel occlusion strokes, we reviewed the paradigm shift effect on transfers for possible thrombectomy in a rural state. HypothesisExtended time window for thrombectomy increases the need for better identification of potential transfers for thrombectomy in rural states with few hospitals capable of 24/7 interventional thrombectomy. MethodsWe analyzed all transfers to a comprehensive stroke center (CSC) from January to December 2018 which were specifically transferred for possible further intervention. This time period was selected in accordance with the change in American Heart Association (AHA) guidelines for extended time windows in mechanical thrombectomy (MT) care. ResultsA total of 132 patients were transferred for possible thrombectomy and advanced imaging. Thirty-four % patients underwent diagnostic angiogram with 33% patients having successful MT. Of the excluded patients 19% had large core infarcts by the time they arrived at hub hospital, 1.5% had hemorrhagic conversion, 32% had stroke without treatable occlusion not amenable for thrombectomy or cortical strokes on follow-up imaging, and 13.5% did not have stroke or LVO on follow-up imaging. ConclusionSince the AHA’s change in time window guidelines for mechanical thrombectomies, there has been an increased effort in identifying good candidates with computerized tomography angiography (CTA). To avoid undue burden on stroke systems of care, CTA identification of these patients at the spoke hospitals is key along with timely transport to appropriate thrombectomy capable sites. Given the rural nature of this state along with limited resources, selection of patients is a practical issue, especially for avoiding futile transfers, which might be true for large areas of the USA.

EXTH-66. NEO100 TRANSIENTLY OPENS UP THE BLOOD BRAIN BARRIER VIA TIGHT JUNCTION INHIBITION

Abstract The blood brain barrier (BBB) prevents effective entry of nearly all therapeutics to the central nervous system (CNS), preventing effective treatment of brain-related malignancies. Intracarotid mannitol injection has been the main technique to transiently open up the BBB, with its attendant variability and complications. A more direct and better tolerated method is needed to open up the BBB. We present our discovery that intraarterial (IA) injection of NEO100, a cGMP-quality form of perillyl alcohol (POH), transiently opens up the BBB in a safe and reversible manner. We used in-vitro models of MDCK1 and patient derived brain endothelial cell (BEC) + astrocyte barriers to determine that NEO100 increased FITC-antibody diffusion across the in-vitro BBB model and decreased trans-epithelial/endothelial electrical resistance (TEER). NEO100 effects on transcellular and paracellular pathways were studied using western blot, flow cytometry, HPLC, fluorescent probes, microarray analysis, and transmission electron microscopy. In-vivo studies were performed using ultrasound-guided intracardiac administration of NEO100 in mice with subsequent intravenous delivery of non-BBB permeable therapeutic agents. We determined that NEO100 transiently disrupts the transcellular pathway by permeabilizing BEC membranes, and the paracellular pathway via delocalization of tight junction proteins. In vivo IA NEO100 administration caused an effective dose- and time-dependent BBB permeabilization, which was reversible and well tolerated by the mice. This was evidenced by the spreading of Evans blue dye, and of therapeutics with different molecular weights, ie methotrexate, anti-PD-1 antibody, and CAR-T cells in the brain. Our results demonstrate that IA NEO100 is able to open the BBB in a controlled and reversible manner, allowing it to facilitate drug delivery to the CNS.

On-demand degradable embolic microspheres for immediate restoration of blood flow during image-guided embolization procedures

Degradable embolic agents that provide transient arterial occlusion during embolization procedures have been of interest for many years. Ideally, embolic agents are visible with standard imaging modalities and offer on-demand degradability, permitting physicians to achieve desired arterial occlusion tailored to patient and procedure indication. Subsequent arterial recanalization potentially enhances the overall safety and efficacy of embolization procedures. Here, we report on-demand degradable and MRI-visible microspheres for embolotherapy. Embolic microspheres composed of calcium alginate and USPIO nanoclusters were synthesized with an air spray atomization and coagulation reservoir equipped with a vacuum suction. An optimized distance between spray nozzle and reservoir allowed uniform size and narrow size distribution of microspheres. The fabricated alginate embolic microspheres crosslinked with Ca2+ demonstrated highly responsive on-demand degradation properties in vitro and in vivo. Finally, the feasibility of using the microspheres for clinical embolization and recanalization procedures was evaluated with interventional radiologists in rabbits. Digital subtraction angiography (DSA) guided embolization of hepatic arteries with these embolic microspheres was successfully performed and the occlusion of artery was confirmed with DSA images and contrast enhanced MRI. T2 MRI visibility of the microspheres allowed to monitor the distribution of intra-arterial (IA) infused embolic microspheres. Subsequent on-demand image-guided recanalization procedures were also successfully performed with rapid degradation of microspheres upon intra-arterial infusion of an ion chelating agent. These instant degradable embolic microspheres will permit effective on-demand embolization/recanalization procedures offering great promise to overcome limitations of currently available permanent and biodegradable embolic agents.

Thrombolytic Salvage of the Frostbitten Upper Extremity: A Systematic Review.

Vascular thrombosis secondary to frostbite can lead to ischemic tissue damage in severe cases. Threatened extremities may be salvaged with thrombolytics to restore perfusion; however, current data are limited to single institution case series. The authors performed a systematic review to determine the efficacy of thrombolytic therapy in treating upper extremity frostbite. PubMed, EBSCO, and Google Scholar were queried using the keywords "thrombolytics," "frostbite," "fibrinolytics," and "tPA." Exclusion criteria were failure to delineate anatomic parts injured, failure to report number of limbs salvaged, animal studies, and non-English language publications. Thrombolytic therapy was defined as intraarterial (IA) or intravenous (IV) administration of tissue plasminogen activator (tPA), alteplase, urokinase, streptokinase, or any tPA derivative. A total of 42 studies were identified, with 13 satisfying inclusion criteria. Eight studies reported catheter-directed IA thrombolysis, four reported systemic IV administration, and 1 reported both methods. A total of 157 patients received thrombolytics. In all, 73 upper extremity digits were treated by IA route and 136 digits were treated by IV route. Overall upper extremity digit salvage rate was 59%. There was a significantly higher salvage rate in digits treated by the IA route compared to the IV route. Thrombolytics, particularly when administered by the intra-arterial route, are emerging as a promising treatment of severe frostbite of the upper extremity, increasing digit salvage rates.

NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics.

Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood-brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol. In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan's blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells. NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells. We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.

Treatment of the acute thromboembolic event during endovascular embolization of intracranial aneurysm

ObjectiveThe study aimed to discuss the treatment of acute thromboembolic event (TE) during endovascular embolization of intracranial aneurysms. MethodsBetween April 2013 and April 2019, 158 patients with 167 intracranial aneurysms were treated with endovascular embolization in our hospital, in which 9 cases of acute TEs occurred during the embolization procedures. The clinical data, radiological findings and treatments of the 9 patients were reviewed and analyzed. ResultsThe TEs occurred at the aneurysmal neck in 3 patients, at distal part of the parent artery in 3, in the stent in 2, and at the proximal part of the parent artery in 1. Intra-arterial (IA) infusion of tirofiban were performed in 6 patients, mechanical thromboectomy (MT) with a stent in 2 patients, and combined use of the two methods in 1 patients. According to the modified Thrombolysis In Cerebral Infarction (mTICI) score, 7 patients had recanalization of 2b/3a, 1 patients had recanalization of 1, and 1 patients had recanalization of 0. At discharge, the mRS score was 0 in 3 patients, 1 in 3 patients, and 2, 3, 4 in 1 patient each. 6 months after the endovascular treatment, the mRS score was 0 in 5 patients, 1 in 2 patients, and 3 in 1 patient. ConclusionsIA tirofiban and MT are effective remedies for the acute TE during endovascular embolization of intracranial aneurysm, reasonable selection of which may improve the prognosis of patients.

Sodium Cholate Bile Acid-Stabilized Ferumoxytol-Doxorubicin-Lipiodol Emulsion for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma

PurposeTo develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC). Materials and MethodsFerumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models. ResultsDOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion. ConclusionsSC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Thrombolysis for Central Retinal Artery Occlusion in 2020: Time Is Vision!

Acute nonarteritic central retinal artery occlusion (CRAO) is an eye stroke with poor visual prognosis and no proven effective therapies. Given advances in acute stroke care, thrombolysis in CRAO merits critical re-examination. We review the evidence for intravenous (IV) and intra-arterial (IA) tissue plasminogen activator (tPA) in CRAO management. MEDLINE, Scopus, and Cochrane online databases were systematically searched from 1960 to present, for reports of acute IV or IA therapy with alteplase or tenecteplase in nonarteritic CRAO patients. English language case reports, case series, interventional studies, or randomized controlled trials were included. The study type, age and number of subjects, the regimen administered, the time since symptoms' onset, visual outcome, and safety reports were noted. Use of IV thrombolysis with alteplase was reported in 7 articles encompassing 111 patients, with 54% of them receiving IV tPA within 4.5 hours of symptom onset, and none developing symptomatic intracranial or ocular hemorrhage. Six studies described IA alteplase administration, with only 18 of a total of 134 patients (13.4%) treated within the first 6 hours after visual loss. The reported adverse events were minimal. Visual outcomes post-IV and IA thrombolysis were heterogeneously reported; however, most studies demonstrated benefit of the respective reperfusion therapies when administered very early. We found no reports of tenecteplase administration in CRAO. In 2020, nonarteritic CRAO patients should theoretically receive the same thrombolytic therapies, in the same time window, as patients with acute cerebral ischemia. Eye stroke and teleeye stroke code encounters must include an expert ophthalmologic evaluation to confirm the correct diagnosis and to evaluate for ocular signs that may help guide IV tPA administration or IA management. Future research should focus on developing feasible retinal penumbra imaging studies that, similar to cerebral tissue viability or perfusion imaging, can be incorporated into the thrombolysis decision-making algorithm.

Intra-Arterial Glycoprotein IIb/IIIa Inhibitor Treatment for Symptomatic Intracranial Atherosclerotic Stenosis Presenting as Large Vessel Occlusions.

IntroductionThere is no consensus on the optimal treatment for acute ischemic stroke (AIS) large vessel occlusions (LVOs) or near-occlusions with underlying intracranial atherosclerotic stenosis (ICAS). We report the first American series using intra-arterial (IA) glycoprotein IIb/IIIa inhibitors (GPIs) as a stand-alone revascularization technique for ICAS presenting with large vessel ischemic syndromes.MethodsRecords at two centers of 140 patients presenting with AIS undergoing stroke intervention from January 2017 to June 2019 were retrospectively reviewed. Patients treated with IA GPIs were identified, and baseline factors, imaging, procedural characteristics, hospital course, and outcomes were collected. Six patients with ICAS underlying their acute symptomatic near occlusion or LVO were treated with IA GPI. Four near-occlusions were treated with IA GPI as the first-line therapy, while two LVOs were treated with IA GPI as an adjunct therapy to thrombectomy.ResultsThe mean age was 61.3 years (range 36-79), presentation National Institute of Health Stroke Scale (NIHSS) was 10 (4-18), time from last seen well to treatment was 434.5 minutes (164-1290), and time from groin puncture to revascularization was 67.3 minutes (26-94). Three patients received intravenous (IV) tissue plasminogen activator (tPA), and all patients received an IA weight-based GPI infusion. Five patients had thrombolysis in cerebral ischemia (TICI) 3, and one patient had TICI 2b. The mean discharge NIHSS was 2.5 (0-8). The mean modified Rankin scale was 1.3 (range 0-4) at discharge and .8 at three months. No patients had a postprocedural symptomatic hemorrhage.ConclusionOur results highlight the utility of IA GPI administration as the first-line therapy for symptomatic ICAS near occlusions or as a rescue technique after failed thrombectomy for LVO patients suspected of underlying ICAS.

Intraarterial Peptide Receptor Radionuclide Therapy Using 90Y-DOTATOC for Hepatic Metastases of Neuroendocrine Tumors

Given the high frequency of liver metastases in neuroendocrine tumor patients, we aimed to determine whether hepatic intraarterial administration of 90Y-DOTATOC peptide receptor radionuclide therapy (PRRT) would increase treatment efficacy while reducing systemic toxicity compared with systemic toxicity from intravenous administration as previously reported in the literature. Methods: PRRT-naïve adult neuroendocrine tumor patients with liver-dominant metastases were enrolled in a prospective single-center, open-label pilot study. The patients underwent baseline PET/CT using intravenous 68Ga-DOTATOC. Then, 3.5 ± 0.2 GBq (94.7 ± 5.4 mCi) of 90Y-DOTATOC were administered into the proper hepatic artery over 30 min. The first 5 patients also received intraarterial 68Ga-DOTATOC and underwent PET/CT. All patients were followed for response (RECIST, version 1.1) (primary aim 2, safety) and toxicity (Common Terminology Criteria for Adverse Events, version 4.0) (primary aim 1, efficacy) for at least 6 mo, with optional follow-up for up to 1 y. In the subset of 5 patients who underwent both intravenous and intraarterial 68Ga-DOTATOC PET/CT, tumor SUVmax was compared between intravenous and intraarterial administration for hepatic tumors, intrahepatic tumors, and uninvolved background organs (secondary aim, intravenous vs. intraarterial uptake). Results: The study was terminated after a planned analysis of the first 10 patients because of lack of efficacy. The best response was stable disease in 90% (9/10 patients) and progressive disease in 10% (1/10 patients) at 3 mo, and stable disease in 8 of 10 patients and progressive disease in 2 of 10 patients at 6 mo. One additional patient developed progressive disease after the 6-mo follow-up period but within the optional 1-y follow-up period. No partial response or complete response was observed. The 2 patients with the highest liver tumor burden died within 6 mo of treatment, with treatment considered a possible contributor. Patients who received intraarterial administration failed to demonstrate higher uptake by hepatic metastases than patients who received intravenous administration, with a median intraarterial-to-intravenous SUVmax ratio of 0.81 (range, 0.36-2.09) on a lesion level. Conclusion: Our study found that administration of PRRT via the proper hepatic artery did not reproduce the increase in hepatic tumor uptake that was previously reported. In addition, the single treatment using 90Y-DOTATOC did not induce tumor shrinkage, indicating that more treatment cycles may be required. Possible safety concerns in patients with a high liver tumor burden should inform patient selection for future studies.

P0584A COMPARATIVE STUDY ON THE INCIDENCE OF CONTRAST INDUCED NEPHROPATHY FOLLOWING INTRA-ARTERIAL VERSUS INTRAVENOUS CONTRAST ADMINISTRATION

Abstract BACKGROUND Contrast-induced nephropathy (CIN) / Contrast induced-acute kidney injury (CI-AKI), defined as a relative increase of ≥25% or an absolute increase of ≥0.5 mg/dL in S.Cr levels assessed at 48 hours post procedure, is a well described following an administration of Intra-arterial (IA) iodinated contrast agent, but its occurrence after Intravenous (IV) contrast is being questioned. AIMS To compare the incidence of CIN following IV and IA contrast procedures and to identify its risk factors. METHOD This is a prospective, single center study of 774 patients (449 males and 325 females with mean age of 48.85 ± 14.05 years) who underwent contrast studies with nonionic, low-osmolar iodinated contrast agent (Iomeprol) via IV and IA routes were included in the study. We recorded baseline characteristics along with laboratory parameters; underlying renal injury risk factors; contrast administration volume, type, and route of administration; incidence of CIN and requirement of renal replacement therapy (RRT). Univariate and multivariate models were used to determine predictors of CIN. RESULTS The total incidence of CIN was 14.85% (115 patients). Baseline eGFR was lower for patients undergoing intra-arterial contrast procedures (66.02 ± 23.70 ml/min/1.73m2 vs 71.31±24.07 ml/min/1.73m2, p=0.002). Simple logistic regression showed a statistically significant difference in the rate of CIN in patients who received IV vs. IA iomeprol (6.2% vs 25.1%). The total risk of RRT was 1.7% with the incidence being more in the IA group than the IV group (3.1% vs 0.5%, p=0.005). Advanced age, dehydration and hypotension, CCF, anemia, proteinuria, diabetes mellitus, preexisting renal disease (i.e. baseline serum creatinine&amp;gt;1.5mg/dl), baseline eGFR&amp;lt;60ml/min/1.73m2), use of nephrotoxic antibiotics and route of contrast correlated significantly with CIN. Proteinuria ≥1 g/day and hypoalbuminemia was significantly higher in the intra-arterial group than the intravenous group (p=0.001). CONCLUSION We found that administration of both IV and IA iodinated contrast agents is associated with a risk of CIN with a significant higher risk of CIN as well as RRT following IA contrast. Proteinuria may be a new risk factor for the development of CIN.

Method of Intra‐Arterial Administration in a transient MCAO Rat model to mimic the treatment of the human patient

Endovascular thrombectomy is routinely performed in patients undergoing a large vessel occlusion. This process not only allows for the removal of a blood clot but also for the selective delivery of potential 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. We have previously shown this delivery method targets the site of injury while blunting systemic effects that have proven problematic with intraperitoneal routes. Here, we adapted the IA method for use in rats, combining it with a clinically relevant large vessel occlusion stroke model (MCAO). Our goal was to characterize variances in the model in order to optimize potential therapeutic delivery methods to the ipsilaterally affected hemisphere. 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 (CCA), with delivery through the internal carotid artery (ICA). We then determined the optimal infusion rate and volume using injection of India ink and evaluation of vascular distribution within the brain and the liver. Importantly, we found the infusion rate and volume varied depending on sex and body weight. India ink was selectively delivered to the ipsilateral side of the brain in males (370–460 g) at 4 μl/min with a max volume of 25 μl and in females (250–300 g) at 2.5 μl/min with a max volume of 25 μl. Following these guidelines, no ink was observed in the liver of these animals, indicating reduced systemic circulation of administered compounds. We then performed a 5‐hour transient MCAO, on male and female Sprague‐Dawley rats (4 months of age), to mimic human stroke, since 5 hours is the average time from the clinical presentation of stroke to the thrombectomy procedure. A silicone coated monofilament was advanced till resistance was felt, occluding the MCA territory. At the 5 hour time point, we removed the monofilament and inserted the mico‐angio tubing at the same entry point on the bifurcation of the CCA. We performed variant injections using different volumes and rates, measuring delivery of dye (India Ink) and rate of induced subarachnoid hemorrhage. A rate of 4 ul/min with a max volume of 25 ul was optimal in males, and a rate of 2.5 ul/min with a max volume of 25 ul was optimal in females. The results showed that, even with a large vessel occlusion, and removal of the monofilament (recanalization), the IA injection using these sex‐specific rates and volumes resulted in appropriate limited dye delivery without ruptured subarachnoid hemorrhage. This IA method is ideally suited for combination with the MCAO stroke model and mirrors the human patient undergoing an endovascular thrombectomy. This model provides an investigative opportunity to test neuroprotective drugs and other pharmacotherapies.Support or Funding InformationUniversity of Kentucky Center for Advanced Translational Stroke Science, Surgery Core

Milrinone for refractory cerebral vasospasm with delayed cerebral ischemia.

Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty. The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm. The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III-V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01-112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0-2) assessed at a median of 4 months (interquartile range 2-8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512). The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood-brain barrier disruption: where are we now, and where we are going.

Intra-arterial (IA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated IA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of IA therapy for the treatment of brain tumors and refinement of its potential applications are necessary. We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSIACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of IA therapy for the treatment of brain tumors. Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the IA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy. IA drug delivery may significantly affect the way treatments are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of IA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, IA therapy may offer significant benefits for the treatment of brain tumors.

Intra-arterial versus standard intravenous administration of lutetium-177-DOTA-octreotate in patients with NET liver metastases: study protocol for a multicenter, randomized controlled trial (LUTIA trial)

BackgroundLutetium-177-DOTA-octreotate (177Lu-DOTATATE) significantly increases survival and response rates in patients with grade I and grade II neuroendocrine tumors (NETs). However, survival and response rates are significantly lower in patients with bulky liver metastases. Increasing the tumor-absorbed dose in liver metastases may improve response to 177Lu-DOTATATE. The LUTIA (Lutetium Intra-Arterial) study aims to increase the tumor-absorbed dose in liver metastases by intra-arterial (IA) administration of 177Lu-DOTATATE, compared to conventional intravenous (IV) administration.MethodsA multicenter, within-patient randomized controlled trial (RCT) in 26 patients with progressive, liver-dominant, unresectable grade I or grade II NET will be conducted. Patients with bilobar bulky disease will be randomly allocated to receive IA treatment into either the left or the right hepatic artery. Using this approach, one liver lobe will be treated intra-arterially (first-pass effect), while the contralateral lobe will receive an intravenous treatment as a second-pass effect. The primary endpoint of this study is the difference in tumor-to-non-tumor ratio of 177Lu-DOTATATE uptake between the two liver lobes on post-treatment SPECT/CT (IA versus IV). Secondary endpoints include absorbed dose in both liver lobes, tumor response, dose-response relationship, toxicity, uptake in extrahepatic lesions, and renal uptake.DiscussionThis multicenter, within-patient RCT will investigate whether IA administration of 177Lu-DOTATATE results in a higher activity concentration in liver metastases compared to IV administration.Trial registrationClinicalTrials.gov, NCT03590119. Registered on 17 July 2018.

What Interventional Radiologists Need to Know About Managing Severe Frostbite: A Meta-Analysis of Thrombolytic Therapy.

OBJECTIVE. The purpose of this study is to review the various techniques and clinical management paradigms using tissue plasminogen activator (tPA) to treat severe frostbite injuries, which are relevant to the interventional radiologist. MATERIALS AND METHODS. A literature search yielded 157 citations, which were manually screened for inclusion criteria of case reports, case series, cohort studies, and randomized prospective studies that reported the use of tPA to treat severe frostbite injuries, of which 16 qualified for review. Data extracted from the studies included authors, journal, year of publication, initial assessment and management of severe frostbite injuries, inclusion and exclusion criteria for tPA therapy, treatment and control group size, different imaging modalities used in evaluation of severe frostbite injuries, tPA treatment protocols, outcomes, and side effects or complications. RESULTS. The analyzed series included 209 patients with 1109 digits at risk of amputation who were treated with intraarterial (IA) or IV tPA (116 and 77 patients, respectively). A total of 926 digits at risk were treated with IA tPA and resulted in amputation of 222 digits, for a salvage rate of 76%. Twenty-four of 63 patients underwent amputation after IV tPA, resulting in a salvage rate of 62%. Both digital subtraction angiography and triple-phase bone scan were used for initial imaging evaluation. Additional concurrent treatment included therapeutic heparin, warfarin, nonsteroidal antiinflammatory drugs, pain management, and light dressings with topical antimicrobial agents. CONCLUSION. Severe frostbite injuries can lead to devastating outcomes with loss of limbs and digits, yet clinical management continues to consist primarily of tissue rewarming, prolonged watchful waiting, and often delayed amputation. Recent studies have shown promising results using both IA and IV tPA to reduce amputation after severe frostbite injuries. Through a meta-analysis of thrombolytic therapy in the management of severe frostbite, this article provides a useful guideline for interventional radiologists including a suggested protocol, inclusion and exclusion criteria, and potential complications.

Abstract WP392: Intravenous Thrombolysis in Therapeutically Anticoagulated and Thrombocytopenic Ischemic Stroke Patients Does Not Increase Hemorrhage Rates

Introduction: IV rt-PA guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. These exclusion criteria may limit thrombolytic therapy to patients who might benefit, especially with the increased use of novel oral anticoagulants (NOACs). The objective of this study is to determine if IV rt-PA is safe, especially in this patient population. Methods: Retrospective analysis of IV rt-PA treated patients receiving oral anticoagulation (warfarin (INR &gt; 1.7)), novel oral anticoagulant (NOAC), therapeutic heparin, low-molecular weight heparin (LMWH), or with thrombocytopenia (platelets &lt; 100K). Patients were treated using SMART criteria (consent obtained for off label rt-PA use). Safety was evaluated by symptomatic intracerebral hemorrhage (sICH) rate ≤36hr after treatment. Results: 81 patients were identified. 35 patients received therapeutic warfarin and 1 had coagulopathy (unclear etiology); mean INR=2.2 (range 1.7-3). 5 received therapeutic IV heparin, 6 full dose (1 mg/kg BID) LMWH, and 22 therapeutic NOACs. 12 had thrombocytopenia (mean platelet count 77K). There was a consistent increase in NOAC use in this cohort; 25% of the patients were taking NOACs from 2012-14, increasing to 71% from 2015-17. Out of all patients, 7 received intra-arterial (IA) rt-PA, and 8 thrombectomy. There were 3 sICH (3.75%), none in patients taking NOACs; for all sICHs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive IA rt-PA, incorrect time of onset). Two developed hematoma at the catheter site with no clinical effect. Conclusions: These data suggest that IV rt-PA can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sICH rates were similar to the NINDS cohort. The use of IV rt-PA in these patients may increase eligibility for acute stroke therapy, particularly where IA therapy is unavailable. Furthermore, preliminary results for patients taking NOACs indicate a good safety profile in this growing subpopulation.