Embolization of the Pancreas Using Microspheres: A Proof-of-Safety Study (PDF)

LABORATORY INVESTIGATION Embolization of the Pancreas Using Microspheres: A Proof-of-Safety Study in a Porcine Model Brendan Cline, MD, R. Ryan Meyerhoff, MD, PhD, Jeffrey Everitt, DVM, and Charles Y. Kim, MD ABSTRACT Purpose: To evaluate safety and impact of particle embolization on pancreatic...

LABORATORY INVESTIGATION Embolization of the Pancreas Using Microspheres: A Proof-of-Safety Study in a Porcine Model Brendan Cline, MD, R. Ryan Meyerhoff, MD, PhD, Jeffrey Everitt, DVM, and Charles Y. Kim, MD ABSTRACT Purpose: To evaluate safety and impact of particle embolization on pancreatic function in a pig model. Materials and Methods: Embolization of the dorsal pancreatic artery using 100–300-μm particles was performed on 14 Yorkshire pigs. Baseline and post-embolization glucose tolerance testing results and serum amylase/lipase levels were obtained. Pigs were observed for 2 weeks to assess for behavioral signs of pain/distress, bowel changes, and changes to intake/ output. After 2 weeks, euthanasia and necropsy with gross and histopathologic assessment of the pancreas were performed. Results: Embolization was technically successful in all pigs. All animals survived the 2-week follow-up without evidence of pain/distress. There were significant increases in amylase and lipase at 24 and 48 hours (P <.001), which normalized by 2 weeks. There was minimal change in glucose tolerance testing at 2 weeks. Bowel habits were unchanged without diarrhea. At necropsy, all examined pancreases had fibrosis in the distal body and tail, without gross evidence of ongoing inflam- mation. On histopathologic evaluation, all pancreases demonstrated fibrosis in the embolized portions without evidence of active inflammation in treated or adjacent pancreatic tissue. Conclusions: Particle embolization of the pancreas was feasible and tolerated by all tested pigs with transient amylasemia, lipasemia, and mildly impaired glucose tolerance but without clinical or histopathologic evidence of acute pancreatitis and no evident impact on pancreatic endocrine or exocrine function. Although particle-based transarterial embolization is with complex endocrine and exocrine functions, potential commonly used for treatment of tumors in multiple organs alterations in pancreatic functionality are unknown. There- including liver, kidney, and bone, embolization of pancre- fore, the purpose of this study was to explore the safety of atic cancers has not been reported, presumably related to particle embolization of the pancreas in a porcine model fear of inducing ischemic pancreatitis. Animal and in vitro with assessment of impact on pancreatic function. studies (1–4) in the transplant literature have suggested that the primary mechanism of tissue injury in ischemic pancreatitis is oxidative damage during reperfusion (so- MATERIALS AND METHODS called reperfusion injury). However, recent retrospective Animal Preparation and Baseline studies (5,6) of outcomes following limited pancreatic embolization with coils or glue for treatment of pancreatic Assessment hemorrhage found no subsequent development of moderate This study was approved by the Institutional Animal Care and or severe pancreatitis. Although these data raise the Use Committee. Fourteen female adolescent Yorkshire pigs hypothesis that transarterial embolization of the pancreas weighing between 45 and 55 kg were acquired from a research can be employed safely with low risk of inducing pancre- supply farm and housed in a vivarium. Per institutional proto- atitis, the concern for major morbidity and mortality asso- col, each pig was allowed to acclimate to the vivarium for at ciated with acute pancreatitis limits exploration of potential least 2 days. Animals were fed twice daily with high-calorie dry treatment and palliative roles of embolization-based strate- animal feed and were monitored daily by study personnel and gies in patients for treatment of pancreatic tumors, bleeding, vivarium staff. Animals were fasted overnight before emboli- and endocrine dysfunction. Furthermore, as a vital organ zation. Weights were obtained from each pig on the day of the procedure. All procedures were performed under general anesthesia. © SIR, 2024 J Vasc Interv Radiol 2024; 35:1544–1550 Animals were initially sedated using a mixture of 22 mg/kg https://doi.org/10.1016/j.jvir.2024.06.034 of ketamine and 1.1 mg/kg of acepromazine via Volume 35 Number 10 October 2024 1545 RESEARCH HIGHLIGHTS STUDY DETAILS The safety and feasibility of ischemic-intent particle Study type: Animal study embolization of the pancreas were evaluated in a pig model to assess potential oncologic treatment or endocrine modulation. Fourteen pigs underwent particle embolization of the dorsal pancreatic artery and were monitored for 2 weeks after the procedure without behavioral change or change in intake/output. At necropsy and pathologic analysis, there was ischemia and fibrofatty replacement of embolized pancreatic tissue compatible with ischemia. However, there was no evidence of acute or chronic inflammation in adjacent tissue. intramuscular injection. Pigs were then endotracheally intubated, and anesthesia was maintained using isoflurane with dose adjusted by veterinary anesthesia staff based on Figure 1. A schematic diagram of the porcine pancreas with monitoring parameters. Venous blood samples were first overlaid relevant arterial anatomy. The porcine pancreas is obtained from the common femoral vein for baseline serum similar in structure to human pancreas, with the addition of a amylase and lipase analysis. After obtaining blood samples bridge of tissue (B) between the duodenal lobe (analogous to for baseline serum insulin and glucose levels, each pig then the human pancreatic head) and splenic lobe (analogous to the human pancreatic body/tail). The dorsal pancreatic underwent glucose tolerance testing via a 0.5-mg/kg intra- artery (blue arrow) arises from the splenic artery (red venous dextrose bolus. Repeat serum insulin and glucose arrowhead) and supplies the distal pancreas (shaded). measurements were obtained serially at 2, 5, 10, 30, and 60 minutes following dextrose administration. Blood glucose measurements were obtained using a conventional gluc- were removed, and hemostasis was achieved using ometer (Accu-Chek Performa; Roche, Basel, Switzerland). manual pressure. Serum insulin, amylase, and lipase measurements were At the conclusion of each embolization procedure, 0.2 performed by the veterinary referral laboratories at Idexx mg/kg of buprenorphine SR was administered for pain (Westbrook, Maine) and the Cornell University Veterinary control in the immediate postprocedural period, with no School (Ithaca, New York). additional pain control administered during the monitoring period. The animals were awakened from anesthesia and Pancreatic Embolization Technique returned to the vivarium. Using common femoral artery access with a 5-F vascular sheath, celiac arteriography was performed with a 5-F Postprocedural Monitoring Hinck Headhunter catheter (Terumo, Tokyo, Japan) or a Following embolization, animals were observed for 2 5-F Mikaelsson catheter (AngioDynamics, Latham, New weeks for any evidence of pain or distress such as hyper- York) depending on anatomy. The dorsal pancreatic artery activity or change in food intake by the vivarium staff and was selected using a 2.4-F Progreat microcatheter (Terumo). study personnel at least twice daily. Levels of activity, The dorsal pancreatic artery was chosen as an embolization intake, and output were observed. They were also examined target because of its size, similar to the size of the human daily for evidence of access site hemorrhage. Based on a dorsal pancreatic artery, both facilitating cannulation and previously published model of pancreatitis in pigs, blood ensuring that a substantial portion of the pancreas could be samples for repeat amylase and lipase levels were drawn at embolized (7). 24 and 48 hours after embolization (8). Before each blood After angiography confirmed catheter location in the draw, animals were sedated using ketamine and acepro- proximal dorsal pancreatic artery (Figs 1, 2), embolization mazine as previously described. Animals were also weighed was performed using 100–300-μm Embosphere at the conclusion of the 2-week monitoring period to microspheres to complete stasis (Merit Medical, South determine mean daily weight gain following embolization. Jordan, Utah). Angiography to determine adequate Bowel habits were also monitored. No animals were embolization was performed approximately 2 minutes excluded from analysis. after embolization. Embolic was prepared by diluting the After the 2-week monitoring period, the pigs were contents of the Embosphere syringe to 20 mL with weighed and again placed under general anesthesia. Base- addition of 50% contrast and 50% saline. Complete line samples were collected before repeat glucose tolerance embolization required a mean of 2 mL of dilute embolic. testing using the same protocol as above. Although main- Following embolization, the arterial and venous sheaths tained under general anesthesia, animals were then 1546 Pilot Study of Pancreatic Embolization in Pigs Cline, et al JVIR Figure 2. (a) Celiac arteriogram demonstrating the dorsal pancreatic artery (blue arrow), (b) dorsal pancreatic arteriogram via microcatheter before embolization, and (c) stasis in the dorsal pancreatic artery following embolization. euthanized using 150 mg/kg of potassium chloride and correction. The serum amylase and lipase values before bilateral thoracotomy. embolization and at 24 and 48 hours and 2 weeks were compared by repeated-measures analysis of variance fol- Necropsy and Pathology Evaluation lowed by pairwise comparisons using Tukey’s honest sig- nificant difference test. Statistical significance was defined After euthanasia, pancreatic explant was performed by 2 by a P value of