Intra-arterial Injection Research Articles

Correction to: Immediate and delayed hypersensitivity after intra-arterial injection of iodinated contrast media: a prospective study in patients with coronary angiography.

The original version of this article, published on 01 April 2019, unfortunately contained a mistake. The presentation of Fig. 1 was incorrect. The corrected figure is given below.

Blue Dye Embolization of Renal Tumor: A New Technique to Improve Tumor Localization During Laparoscopic Partial Nephrectomy.

Purpose: To improve the tumor localization during laparoscopic surgery, we describe an innovative technique involving superselective intra-arterial injection of blue dye in tumoral vessels to color the tumor before surgical enucleation. Materials and Methods: The dye injection was performed at the same time as superselective embolization, immediately before laparoscopic surgery in a hybrid operating room. We used this new treatment sequence on 50 consecutive patients. Results: The selective intra-arterial injection of an emulsion of blue dye and lipiodol was feasible in 46 (92%) cases and well tolerated, followed by superselective embolization of the tumor vessels with glue or coils. The tumor was easily localized during surgery due to the blue coloration. Tumor coloration was not associated with postoperative complication, especially allergic reaction or renal failure. Pathologic analysis of the tumor was not modified by the coloration and all tumors had negative surgical margins. Conclusions: The preoperative dye localization is a feasible, safe, and accurate procedure. This combined approach reduces the difficulty of surgery and increases patient safety.

Safety and Efficacy of Intra-arterial Tirofiban Injection During Mechanical Thrombectomy for Large Artery Occlusion.

The safety and effect of intra-arterial (IA) tirofiban, a glycoprotein IIb/IIIa inhibitor, during the stent retriever mechanical thrombectomy (MT) was investigated. From January 2015 to May 2019, a total of 327 patients underwent mechanical thrombectomy of large artery occlusions (LAO). Patients were classified into two groups: MT with IA tirofiban (MTT) group and MT only (MTO, without IA tirofiban) group. Clinical outcomes, radiological results, and various complications, such as post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding, and hemorrhagic transformation of infarct were evaluated by comparing the MTT group and MTO group. In addition, subgroup analysis was performed for patients who underwent MT with prior intravenous (IV) tissue plasminogen activator (t-PA). The MTT group needed a lower mean number of stent passes and showed a re-occlusion rate as compared with the MTO group (P=0.038 and 0.022, respectively). Between the two groups, there were no statistically significant differences in post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding complications, or hemorrhagic transformation of infarct (P = 0.511, 0.397, 0.429, and 0.355, respectively). In the subgroup analysis, similar findings were observed. The use of IA tirofiban during MT seems to be safe and potentially more effective than only MT without IA tirofiban, even in patients who used IV t-PA before MT.

Evaluation & Management of Accidental Intra-Arterial Injection in the Ante-Cubital Fossa

Introduction: Intra-arterial drug injection is a rare, but a potentially serious medical emergency. It is most commonly seen as an iatrogenic complication when administering an intravenous medication. Accidental Intra-arterial injection was defined as an intravenous injection administered in the upper limb for any illness, which was followed by sudden severe pain in the limb followed by bluish discoloration of any part of the affected limb. Aim: The aim of the study is to identify the risk factors early on for limb amputation following intra-arterial injection. Also, to assess the efficacy of the various modalities of the treatments administered, and establish a standardized treatment plan for intra-arterial injection to achieve limb salvaging. Materials and methods: A total of twelve cases of accidental intra-arterial injection were studied for the efficacy of early evaluation and management of each. The patients were studied based on Rutherford Classification, clinical history, and Doppler findings. Results: Ten out of the twelve patients presented early and limb salvation was achieved. Conservative treatment and upper limb Fasciotomy proved to aid with the limb salvation. However, two out of the twelve patients presented after 12 hours with complains of blackening of the digits. In these patients, limb salvation was not achieved and Ray’s amputation was performed. All the patients recovered well, with proper functioning of the upper limb. Conclusion: Early evaluation and management of a case of accidental intra-arterial injection is of utmost importance due to its serious complications. Lastly, all medical professionals must be regularly trained in order to prevent such mishaps from happening.

Evaluation and management of accidental intra-arterial injection in the antecubital fossa

Introduction: Intra-arterial (IA) drug injection is a rare, but a potentially serious medical emergency. It is most commonly seen as an iatrogenic complication when administering an intravenous (IV) medication. Accidental IA injection was defined as an IV injection administered in the upper limb for any illness, which was followed by sudden severe pain in the limb followed by bluish discoloration of any part of the affected limb. Aim: The aim of the study is to identify the risk factors early on for limb amputation following IA injection, to assess the efficacy of the various modalities of the treatments administered, and to establish a standardized treatment plan for IA injection to achieve limb salvaging. Materials and Methods: A total of 12 cases of accidental IA injection were studied for the efficacy of early evaluation and management of each. The patients were studied based on Rutherford classification, clinical history, and Doppler findings. Results: Ten out of the twelve patients presented early, and limb salvation was achieved. Conservative treatment and upper limb fasciotomy proved to aid with the limb salvation. However, two out of the twelve patients presented after 12 h with complains of blackening of the digits. In these patients, limb salvation was not achieved and Ray's amputation was performed. All the patients recovered well, with proper functioning of the upper limb. Conclusion: Early evaluation and management of a case of accidental IA injection is of utmost importance due to its serious complications. Finally, all medical professionals must be regularly trained to prevent such mishaps from happening.

Continuous stellate ganglion block for the effective management of ischemic pain following compartment syndrome of upper limb due to accidental intra-arterial injection

In the present era of advanced medicine and patient safe practice, accidental intra-arterial injection of drugs is a rare occurrence. Compartment syndrome (CS) is one of its most detrimental complications, which leads to loss of circulation, ischemia, myonecrosis, nerve damage, and limb loss. Rapid recognition and emergent fasciotomy to relieve the compartment pressure are imperative to prevent irreversible damage. Sympathetic blockade is one of the most common interventions used in the management of early stages of CS, which interferes with the pain cycle and improves distal flow by vasodilatation. We report a complicated case of CS of the right upper limb following accidental intra-arterial injection. The patient suffered with persistent ischemic pain despite surgical decompression, which was successfully managed by continuous stellate ganglion block.

Facial Blanching after Local Anesthesia Injection: Clinico-anatomical Correlation-Review of Literature.

Facial blanching as a complication of local anesthesia is reported in dentistry. Inadvertent arterial penetration and subsequent vasospasm has been accepted as the mechanism of this phenomenon. Most cases occur after inferior alveolar nerve block injection. In this article, five cases are reported after Gow-Gates injection, maxillary nerve block via greater palatine foramen, inferior alveolar nerve block, and maxillary buccal infiltration. It is the largest case series in this topic. Also, clinico-anatomical correlation between facial–mucosal blanching and the site of intra-arterial injection is explained. To the best of our knowledge, partial blanching of the face subsequent to buccal infiltration is reported for the first time in this article. Cutaneous surgeon should be aware of this complication and should not carry out unnecessary treatment.

INNERVATION OF THE MEDIAN NERVE MOTOR BRANCHES IN THE FOREARM AND ITS CLINICAL SIGNIFICANCE.

ABSTRACTObjective: To analyse the anatomical variations of the median nerve motor branches in the elbow region.Methods: Twenty upper limbs of 10 adult male cadavers were prepared by intra-arterial injection of a solution of 10% glycerol and formaldehyde. All cadavers belonged to the institution anatomy laboratory. Results: We found a great variability within the distribution of median nerve branches leading to forearm muscles. Only three limbs (14%) presented the normal standard of innervation described in anatomy treatises. The pronator teres muscle (PTM), flexor carpi radialis (FCR), palmaris longus (PL), and the flexor digitorum superficialis (FDS) received exclusive innervation from the median nerve in all forearms. The anterior interosseous nerve (AIN) also originated from the median nerve in all dissected limbs. Conclusion: A thorough understanding of the anatomy of the median nerve branches is important for performing surgeries such as: approach to the proximal third of the forearm, alleviation of pronator teres and anterior interosseous nerve compression syndromes, and distal nerve transfers. It also enables a better understanding the recovery of muscle function after a nerve injury. Level of Evidence IV, Case series.

Ultrasound-guided T2 and T3 paravertebral block versus ultrasound-guided stellate ganglion block in acute upper limb ischemia

Background Accidental intra-arterial injection can cause severe limb ischemia, often resulting in amputation. We reported a number of cases of acute upper limb ischemia with severe pain and ischemia in vascular surgery department for urgent relief of the pain and ischemia. Either ultrasound-guided stellate ganglion block or thoracic paravertebral block was done to protect upper limb from gangrene and amputation. Purpose The aim of the present study is to compare the effect of ultrasound-guided stellate ganglion block with ultrasound-guided thoracic T2 and T3 paravertebral block in relief of pain and ischemia and also to compare the result of the block and complications. Patients and methods Forty American Society of Anaesthesiologists status I–II adult patients 16–60 years of age with acute upper limb ischemia and severe pain were admitted to Vascular Surgery Department of Zagazig University Hospital. They were randomly divided into two groups: group S (n=20) where ultrasound-guided stellate ganglion block was done, and group TPV (n=20), where ultrasound-guided thoracic paravertebral block was done. Both groups received 10 ml bupivacaine (0.25%)+16 mg dexamethasone for relief of the pain and ischemia, and the complications that resulted from the procedure were followed and recorded. Results There was significant decrease in visual analog scale in both groups after the stellate ganglion block and thoracic paravertebral block, with minimal complications with thoracic paravertebral block and relief of pain and ischemia in both groups. Conclusion Thoracic paravertebral block is a good choice in acute upper limb ischemia with rapid relief of the pain and restoration of peripheral perfusion with minimal complications.

Effects of Remote Ischemic Pre-Conditioning to Prevent Contrast-Induced Nephropathy after Intravenous Contrast Medium Injection: A Randomized Controlled Trial.

ObjectiveWe aimed to assess the effects of remote ischemic pre-conditioning (RIPC) on the incidence of contrast-induced nephropathy (CIN) after an intravenous (IV) or intra-arterial injection of contrast medium (CM) in patient and control groups.Materials and MethodsThis prospective, randomized, single-blinded, controlled trial included 26 patients who were hospitalized for the evaluation of the feasibility of transcatheter aortic valve implantation and underwent investigations including contrast-enhanced computed tomography (CT), with Mehran risk scores greater than or equal to six. All the patients underwent four cycles of five minute-blood pressure cuff inflation followed by five minutes of total deflation. In the RIPC group (n = 13), the cuff was inflated to 50 mm Hg above the patient's systolic blood pressure (SBP); in the control group (n = 13), it was inflated to 10 mm Hg below the patient's SBP. The primary endpoint was the occurrence of CIN. Additionally, variation in the serum levels of cystatin C was assessed.ResultsOne case of CIN was observed in the control group, whereas no cases were detected in the RIPC group (p = 0.48, analysis of 25 patients). Mean creatinine values at the baseline, 24 hours after injection of CM, and 48 hours after injection of CM were 88 ± 32 µmol/L, 91 ± 28 µmol/L and 82 ± 29 µmol/L, respectively (p = 0.73) in the RIPC group, whereas in the control group, they were 100 ± 36 µmol/L, 110 ± 36 µmol/L, and 105 ± 34 µmol/L, respectively (p = 0.78). Cystatin C values (median [Q1, Q3]) at the baseline, 24 hours after injection of CM, and 48 hours after injection of CM were 1.10 [1.08, 1.18] mg/L, 1.17 [0.97, 1.35] mg/L, and 1.12 [0.99, 1.24] mg/L, respectively (p = 0.88) in the RIPC group, whereas they were 1.11 [0.97, 1.28] mg/L, 1.13 [1.08, 1.25] mg/L, and 1.16 [1.03, 1.31] mg/L, respectively (p = 0.93), in the control group.ConclusionThe risk of CIN after an IV injection of CM is very low in patients with Mehran risk score greater than or equal to six and even in the patients who are unable to receive preventive hyperhydration. Hence, the Mehran risk score may not be an appropriate method for the estimation of the risk of CIN after IV CM injection.

Iatrogenic intra-arterial injection in the upper limb: A pragmatic guide for the on-call vascular surgeon

Background: Peripheral venous cannulation is one of the most commonly performed procedures to establish venous access in the hospital setting. Inadvertent arterial cannulation is a rare event but can have serious consequences including ischemia and limb loss, especially if medication is administered through the device. Vascular surgeons should have an understanding of the management of this potential complication Methods: We reviewed the risk factors, mechanism, pathophysiology, and management options for inadvertent upper limb arterial cannulation and injection. Results: Inadvertent arterial cannulation and administration of medication has a reported incidence of 1 in 3440 cases. Several risk factors were identified including difficult venous access, difficulty in communication, and aberrant vascular anatomy. Both arterial injury from the misplaced cannula and injection of medication can cause ischemic events through a number of mechanisms. We recommend that patients sustaining an inadvertent arterial injury should have an urgent clinical assessment and be managed according to the degree of upper limb ischemia as per the Rutherford classification. We provide a pragmatic management algorithm to aid the vascular surgeon when encountering such a situation. Conclusion: Iatrogenic arterial injury is a rare but potentially serious complication of peripheral venous cannulation. Prompt recognition and management of ischemic complications is essential for favorable outcomes. Our pragmatic management guide should aid the vascular surgeon in managing this situation.

Anatomical variations of the terminal branching of the brachial artery

ObjectiveKnowledge regarding arterial variations is important during surgeries, intra-arterial injections, venipuncture and imaging of the upper limb. Our objective was to document brachial artery variations. MethodsWe studied 54 upper limb specimens during routine dissection. The anterior compartment of the arm, cubital fossa and the forearm were dissected and the pathway and the distribution of the brachial artery and its branches were documented. ResultsVariations of the brachial artery anatomy were noted in 3 specimens (5%). Unilateral high bifurcation of brachial artery was noted in two specimens on the left side. In one of these, bifurcation was directly from the axillary artery at the axilla just proximal to the formation of the median nerve. Here the brachial artery divided into its terminal radial and ulnar branches. In the other specimen, the brachial artery bifurcated into radial and ulnar arteries at the level of the mid humerus. In the other specimen, the brachial artery was seen to trifurcate into radial, ulnar and common interosseus arteries at the level of the neck of the radius. ConclusionsHigh brachial artery bifurcation and trifurcation of the brachial artery in the upper arm was noted in this study. Reporting of such variations in different populations is important for the practicing clinician during diagnostic and surgical procedures.

Novel Treatment of Cerebral Vasospasm Using Solitaire Stent Retriever−Assisted Angioplasty: Case Series

Endovascular procedures such as intraarterial (IA) vasodilator injection and balloon angioplasty are used to treat medically refractory cerebral vasospasm. The effects of IA therapy may be short lived and thus require multiple treatments. Balloon angioplasty also has limitations including transient occlusion of the spastic blood vessel, possible endothelial injury, and limited access to proximal vessels. We aim to demonstrate a novel technique using a stent retriever for the management of medically refractory vasospasm, especially in distal vessels. Compared with balloon angioplasty, stent retrievers provide a passive, self-limiting expansion of blood vessels. Other benefits over balloon angioplasty include 1) ability to simultaneously inject IA vasodilators, 2) limited contact and damage to vessel wall, 3) nonocclusive expansion, and 4) technical ease. Fourteen blood vessels from 6 patients with symptomatic vasospasm after subarachnoid hemorrhage were identified. We injected 5 mg of IA vasodilator medication into the vasospastic segments without radiographic improvement in vessel diameter and blood flow. The stent retriever was deployed for 2-5 minutes in each vasospastic segment. Distal anterior and posterior circulation segments were easily accessible with the stent retriever system. It resulted in improved vessel diameter and blood flow with subsequent improvement in neurologic examination. All patients demonstrated radiographic resolution of vasospasm. No procedural-related complications were noted. We demonstrate the safety and efficacy of a novel technique for the treatment of medically refractory cerebral vasospasm using stent retriever angioplasty in distal vessels. Stent angioplasty can be used as an additional tool in the management of subarachnoid hemorrhage-induced cerebral vasospasm.

Anatomical Study of Radial Tunnel and its Clinical Implications in Compressive Syndromes.

Objective The purpose of the present study was to analyze the structures in the radial tunnel that can cause posterior interosseous nerve entrapment. Methods A total of 30 members of 15 adult cadavers prepared by intra-arterial injection of a 10% solution of glycerol and formalin were dissected. All were male, belonging to the laboratory of anatomy of this institution. Results The branch for the supinator muscle originated from the posterior interosseous nerve in all limbs. We identified the Frohse arcade with a well-developed fibrous constitution in 22 of the 30 dissected limbs (73%) and of muscular constitution in 8 (27%). The distal margin of the supinator muscle presented fibrous consistency in 7 of the 30 limbs (23.5%) and muscular appearance in 23 (76.5%). In the proximal margin of the extensor carpi radialis brevis muscle, we identified the fibrous arch in 18 limbs (60%); in 9 (30%) we noticed the arcade of muscular constitution; in 3 (10%) there was only the radial insertion, so that it did not form the arcade. Conclusion The Frohse arcade and the arcade formed by the origins of the extensor carpi radialis brevis are normal anatomical structures in adult cadavers. However, from the clinical point of view, these structures have the potential to cause entrapment of the posterior interosseous nerve.

Management of Intravenous Drug Abusers Groin Pseudoaneurysms: Ligation or Reconstruction? (Systematic Review)

Introduction: Infected femoral pseudo aneurysms are the most common type of infected aneurysm observed in clinical practice, largely explained by increase intravenous drug abuser (IVDU) in the recent years. Management of such a condition remains controversial due to high rate of amputation and disabled claudication after surgical management. The Aim of the review is to critically evaluate different surgical management options of intravenous drug abuser groin pseudoaneurysms. Methods: A systematic review of published literature with regard to the arterial consequences of intravenous drug abuser groin pseudoaneurysms' surgical management options was undertaken using the PUBMED, EMBASE, and Medline databases from January 1980 to January 2019. Search was performed using combination of keywords : ''intravenous drug abuse'', ''pseudo-aneurysm'', ''limb ischaemia'' , ''intra-arterial injection'', "artery ligation" and "bypass surgery". Results: A total of 21 articles were identified covering a total of 529 patients. Selected articles were case reports (n = 5), case series (n = 6) or retrospective studies (n =10). Surgical management consisted of either femoral artery ligation (FAL) and local debridement in 414 cases (78%) or local debridement plus primary revascularisation (LDPR) using Autologous vein/artery graft 38.3%, cryopreserved 1.6% or synthetic graft 60.1% in 115 cases (22%). LDPR group was associated with higher amputation rate 11% compared to FAL group 6%. Mortality rate is 2.6% in LDPR group compared to 0.7% in FAL. However, claudication incidence was higher in FAP 23.4% compared to 7.8% in the LDPR. In the LDPR group, using of vein/artery graft or Patch was associated with the lowest amputation rate (4%) and claudication incidence (2%) with mortality rate of 2%. Conclusion: Primary femoral artery ligation remains the first and safest option for management of intravenous drug abusers' groin pseudoaneurysms. However, in selected patients with an adequate autologous conduit, primary revascularization has a better outcome in term of amputation and claudication rate. Disclosure: Nothing to disclose

Optimization of osmotic blood-brain barrier opening to enable intravital microscopy studies on drug delivery in mouse cortex

Intra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery. Intravital microscopy is increasingly used to capture the dynamics of biological processes at the molecular level in convenient mouse models. However, until now OBBBO has been achieved safely in subcortical structures, which prevented direct insight into the process of extravasation through the skull window. Here, we used our previously developed real-time MRI to adjust the procedure to achieve robust cortical OBBBO. We found that catheter-mediated delivery to the cortex from the ipsilateral carotid artery can be improved by temporarily occluding the contralateral carotid artery. The reproducibility and safety of the method were validated by MRI and histology. This experimental platform was further exploited for studying with intravital microscopy the extravasation of 0.58 kDa rhodamine and 153 kDa anti-VEGF monoclonal antibody (bevacizumab) upon IA injection. Dynamic imaging during IA infusion captured the spatiotemporal dynamic of infiltration for each molecule into the brain parenchyma upon OBBBO. Small-sized rhodamine exhibited faster and higher penetration than the antibody. Histological analysis showed some uptake of the monoclonal antibody after IA delivery, and OBBBO significantly amplified the extent of its uptake. For quantitative assessment of cortical uptake, bevacizumab was radiolabeled with zirconium-89 and infused intraarterially. As expected, OBBBO potentiated brain accumulation, providing 33.90 ± 9.06% of injected dose per gram of brain tissue (%ID/g) in the cortex and 17.09 ± 7.22%ID/g in subcortical structures. In contrast IA infusion with an intact BBB resulted in 3.56 ± 1.06%ID/g and 3.57 ± 0.59%ID/g in the same brain regions, respectively. This study established reproducible cortical OBBBO in mice, which enabled multi-photon microscopy studies on OBBBO and drug targeting. This approach helped demonstrate in a dynamic fashion extravasation of fluorescently-tagged antibodies and their effective delivery into the brain across an osmotically opened BBB.

Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats

BackgroundIschemic stroke is the major cause of long-term severe disability and death in aged population. Cell death in the infarcted region of the brain induces immune reaction leading to further progression of tissue damage. Immunomodulatory function of mesenchymal stem cells (MSCs) has been shown in multiple preclinical studies; however, it has not been successfully translated to a routine clinical practice due to logistical, economical, regulatory, and intellectual property obstacles. It has been recently demonstrated that therapeutic effect of intravenously administered MSCs can be recapitulated by extracellular vesicles (EVs) derived from them. However, in contrast to MSCs, EVs were not capable to decrease stroke-induced neuroinflammation. Therefore, the aim of the study was to investigate if intra-arterial delivery of MSC-derived EVs will have stronger impact on focal brain injury-induced neuroinflammation, which mimics ischemic stroke, and how it compares to MSCs.MethodsThe studies were performed in adult male Wistar rats with focal brain injury induced by injection of 1 μl of 50 nmol ouabain into the right hemisphere. Two days after brain insult, 5 × 105 human bone marrow MSCs (hBM-MSCs) labeled with Molday ION or 1.3 × 109 EVs stained with PKH26 were intra-arterially injected into the right hemisphere under real-time MRI guidance. At days 1, 3, and 7 post-transplantation, the rats were decapitated, the brains were removed, and the presence of donor cells or EVs was analyzed. The cellular immune response in host brain was evaluated immunohistochemically, and humoral factors were measured by multiplex immunoassay.ResultshBM-MSCs and EVs transplanted intra-arterially were observed in the rat ipsilateral hemisphere, near the ischemic region. Immunohistochemical analysis of brain tissue showed that injection of hBM-MSCs or EVs leads to the decrease of cell activation by ischemic injury, i.e., astrocytes, microglia, and infiltrating leucocytes, including T cytotoxic cells. Furthermore, we observed significant decrease of pro-inflammatory cytokines and chemokines after hBM-MSC or EV infusion comparing with non-treated rats with focal brain injury.ConclusionsIntra-arterially injected EVs attenuated neuroinflammation evoked by focal brain injury, which mimics ischemic stroke, and this effect was comparable to intra-arterial hBM-MSC transplantation. Thus, intra-arterial injection of EVs might be an attractive therapeutic approach, which obviates MSC-related obstacles.

Continuous intra-arterial infusion of verapamil for treatment of severe vasospasm after subarachnoid hemorrhage

Delayed cerebral ischemia (DCI) is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Options are limited for treating vasospasm refractory to medical therapy. We present a patient with SAH and refractory vasospasm. After coil embolization of the aneurysm and initial near complete improvement, the patient developed severe DCI causing coma. Medical therapy failed and angiography showed severe vasospasm complicated by chronic occlusion of distal left ICA. Balloon angioplasty of proximal right ICA was attempted but failed, as a micro wire could not be advanced into the distal ICA and proximal ACA, MCA, and basilar arteries. Intra-arterial verapamil injection produced transient improvement but angioplasty could not be performed. Due to severe bilateral cerebral hypoperfusion, continuous intra-arterial verapamil was infused using micro-catheters placed in the right ICA and vertebral artery. After 22 h there was significant improvement in caliber of both vessels and perfusion in both hemispheres without complications.

A Study Comparing the Effects of Targeted Intra-Arterial and Systemic Chemotherapy in an Orthotopic Mouse Model of Pancreatic Cancer

Systemic chemotherapy is the first line treatment for patients with unresectable pancreatic cancer, however, insufficient drug delivery to the pancreas is a major problem resulting in poor outcomes. We evaluated the therapeutic effects of targeted intra-arterial (IA) delivery of gemcitabine directly into the pancreas in an orthotopic mouse model of pancreatic cancer. Nude mice with orthotopic pancreatic tumors were randomly assigned into 3 groups receiving gemcitabine: systemic intravenous (IV) injection (low: 0.3 mg/kg and high: 100 mg/kg) and direct IA injection (0.3 mg/kg). Treatments were administered weekly for 2 weeks. IA treatment resulted in a significantly greater reduction in tumor growth compared to low IV treatment. To achieve a comparable reduction in tumor growth as seen with IA treatment, gemcitabine had to be given IV at over 300x the dose (high IV treatment) which was associated with some toxicity. After 2 weeks, tumor samples from animals treated with IA gemcitabine had significantly lower residual cancer cells, higher cellular necrosis and evidence of increased apoptosis when compared to animals treated with low IV gemcitabine. Our study shows targeted IA injection of gemcitabine directly into the pancreas, via its arterial blood supply, has a superior therapeutic effect in reducing tumor growth compared to the same concentration administered by conventional systemic injection.

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats.

The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 μg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex.NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.