Gary P. Siskin • Tara Murray • Marcelo Guimaraes
PRINCIPLES OF EMBOLIZATION THERAPY
Embolization is defined as the intentional endovascular occlusion of an artery or vein.1 Presently, this procedure has been applied to almost every organ of the body for various indications. The procedure is performed by percutaneously delivering embolic agents into a target vascular system either through selective catheterization or direct puncture of the target organ/vessel. The correct use of embolization techniques require an in-depth knowledge of the clinical condition being treated, the available and appropriate embolic agents and delivery systems (catheters, microcatheters, and guiding catheters), the anticipated postprocedure patient care, and the potential complications of the procedure.
As a general rule for the practice of any percutaneous interventional therapy, every clinical situation must be thoroughly reviewed to help determine how and when to proceed with the embolization procedure. Review of any available imaging is paramount to plan the procedure approach and technique to be used. In general, an embolization procedure should be able to resolve the clinical problem in a single procedure because repeat procedures may not be possible. This is often the case in emergency situations, when alternatives may be limited and rapid decisions need to be made to use embolic therapy sooner rather than later. Ultimately, the final decision to perform an embolization procedure lies with the physician responsible for performing the procedure after an appropriate risk–benefit analysis has been made.
From a historical perspective, the initial agents used for embolization and the procedural indications have significantly changed over time.
The concept of therapeutic vascular occlusion actually began in 1933 when Hamby and Gardener treated a carotid cavernous fistula at surgery by embolizing the fistula with small fragments of muscle via arteriotomy.2Doppman and Newton have been credited with performing the first percutaneous therapeutic embolization procedures.3,4 In 1968, these early interventionalists published separate case reports describing their independent experience with percutaneous embolization of spinal cord arteriovenous malformations. Doppman et al.3 used 3-mm stainless steel pellets for embolization, and Newton and Adams4 used lead pellets and small fragments of muscle.
In the early 1970s, experience with peripheral embolization was initially gained as a treatment option for acute gastrointestinal bleeding.5 During that time, the indications expanded into the treatment of gastroesophageal varices, arteriovenous fistulas and malformations, control of hemoptysis, treatment of varicocele, and ablation of tumors or organs.6 Initially, autologous clot was used as the embolic agent for these indications, but other agents were introduced during this time. The use of gelfoam for endovascular occlusion grew in popularity but was actually first reported as an embolic agent by Speakman7 in 1964. In 1974, Tadavarthy et al.8 reported the first use of polyvinyl alcohol (PVA) as an embolic agent, and Serbinenko9 reported on the use of detachable balloons to treat intracerebral aneurysms. In 1975, Gianturco et al.10 reported on the development and use of the first coils: the cotton-tail device consisting of eight cotton threads attached to a 3-mm body of steel and the wool-tail device consisting of four wool fibers attached to a 5-cm length of guidewire. The wool-tail device design eventually transformed into the stainless steel coil in 1976, and in time, the thrombogenic wool fibers were replaced with nonantigenic synthetic fibers.11
Since that time, the basic tools of embolization have undergone significant development and improvement. New coil configurations, including detachable coils and vascular plugs, have been developed to increase the safety and effectiveness of coil embolization for both neurovascular and peripheral vascular applications.12,13 In addition, experience grew with liquid embolic agents such as cyanoacrylate and Onyx (Covidien, Irvine, California).14 For years, irregularly shaped PVA particles have been the particulate agent of choice. With the maturation of procedures such as chemoembolization and uterine fibroid embolization, new particulate agents were developed, including spherical embolic agents,15 drug-eluting beads,16 yttrium 90 microspheres,17 and soon, bioresorbable spheres.18,19
CLASSIFICATION OF EMBOLIC AGENTS
When looking at all of the available agents for embolization, it is often helpful to classify these agents from a clinical perspective, allowing a particular class or type of embolic agent to be an option for a specific indication or procedure. However, this is easier said than done because it can be difficult to define the terms that are traditionally used for this type of classification system. In addition, there is a significant amount of potential overlap between agents in different categories.
Historically, embolic materials have been grouped in several ways: by physical characteristics (type of material), longevity of vascular occlusion (temporary or permanent), level of occlusion (proximal or distal), pathology being treated, type of delivery technique, cost, and many other alternatives. When attempting to classify these materials clinically, consider that not all materials are available in every angiography suite due to local supply constraints and cost concerns or to marketing and regulatory issues. The availability of various embolic agents to allow for the appropriate performance of embolization procedures for various indications is a requirement for any interventionalist and hospital offering this service.
Traditional Classification System
The most common way to classify embolic agents has been to define them as being either temporary or permanent.1 This is helpful when selecting an embolic agent because some applications of embolization, such as trauma, may only require the use of a temporary agent, whereas in other applications, a permanent agent may be more appropriate. When this system is used, the temporary category is small and consists of only gelfoam, collagen, thrombin, and new biodegradable microspheres that are being developed but are not commercially available at this time.18,19 The remaining available agents are considered to be permanent.
When using this classification system, however, the question needs to be asked regarding what one is referring to when using the terms temporary and permanent. This classification system refers to temporary and permanent as terms used to describe the biodegradability of the actual embolic agent. It does not refer to the occlusion caused by the embolic agent because if it does, the group assignment might change for several agents. This can be exemplified with PVA particles. These particles have been classically described as permanent because they are not biodegradable and can be found in embolized tissue years after embolization.20 However, the occlusion caused by PVA particles is not always permanent. Recanalization has been demonstrated, with proposed mechanisms including angiogenesis and capillary regrowth caused by vascular proliferation inside organized thrombus and resorption of the thrombus in between PVA particles found in the vessel lumen after resolution of the initial inflammatory response.21–24 Similarly, gelatin sponge particles are considered to be a temporary embolic agent.25 This has historically been based on the work of Light and Prentice26 in 1945. Later studies have demonstrated the temporary nature of the occlusion induced by gelfoam,27,28 supporting its classification as a temporary embolic agent. However, permanent occlusion after gelfoam embolization has also been described and attributed to dense packing29 and to fibrotic or necrotic changes induced by the gelfoam.30,31 These examples demonstrate the difficulty in using the “temporary versus permanent” classification system unless a clear distinction is made between the temporary and permanent nature of the embolic agent or of the vascular occlusion induced by the embolic agent.
Classification of embolic agents based on the size of the vessel being embolized has also been described.32,33 Although this system can be useful in guiding interventionalists toward the use of appropriate agents, it becomes clear that overlap can exist between these categories. For example, coils are available in various sizes, making them appropriate to use for certain indications in both large and small vessels.
Present Classification System
Various pathologies are treated today by embolization. In general, these can be divided into focal abnormalities (i.e., aneurysms, traumatic injury, arteriovenous fistulae) and more diffuse abnormalities that are treating abnormal vascular beds in part or in their entirety. Focal abnormalities are typically treated by the insertion of mechanical embolic agents at or in close proximity to the abnormality being treated. Diffuse abnormalities, such as tumors and vascular malformations, are typically treated by placing a catheter proximal to the abnormal vascular bed and using a flow-directed embolic agent to embolize the abnormal vasculature. Therefore, it seems useful to classify agents as either mechanical (delivered at the site of a focal vascular abnormality) or flow-directed (delivered by flow from a catheter position proximal to a vascular abnormality (Table 1.1).
Various mechanical agents are available to treat focal vascular abnormalities. The most common agents include coils and plugs. Detachable balloons, which are available in most of the world outside of the United States, can also be used as a mechanical agent to treat focal vascular abnormalities. In theory, they can be used to quickly occlude a vessel at a precise position and have the ability to be repeatedly repositioned as needed. However, they were recalled in the United States due to manufacturing and placement issues and have essentially been replaced with new, detachable coils.
Pushable and detachable coils are available, and both are manufactured in sizes that can be delivered through standard 4-Fr or 5-Fr angiographic catheters or microcatheters. Synthetic fibers are often attached to these coils to increase their thrombogenicity (Fig. 1.1). Pushable coils require a guidewire or dedicated coil pusher to advance the coil through and out of the delivery catheter to the site of the vascular abnormality. Detachable coils are attached to the coil pusher and are released either mechanically or electrically when they are appropriately positioned (Fig. 1.2). Typically, multiple coils are required for embolization, although the hydrogel-coated coils may decrease the number of coils required for occlusion.
Plugs are larger than coils and are able to create a focal occlusion in larger vessels with a single device. Amplatzer Vascular Plugs (St. Jude Medical, Inc., St. Paul, Minnesota) are the most commonly used device in this category (Fig. 1.3).13 Newer products have also recently become available and include the Medusa Vascular Plug (EndoShape, Inc., Boulder, Colorado) and the MVP Micro Vascular Plug System (Reverse Medical Corporation, Irvine, California) (Fig. 1.4). Both of these plugs have received U.S. Food and Drug Administration (FDA) approval in 2013 for use in the peripheral vasculature. The MVP Micro Vascular Plug is a smaller system and is delivered through a microcatheter to occlude small vessels.
Gelfoam is one agent that can straddle the line between mechanical agents and flow-directed agents. Where it becomes assigned is often due to the technique used for preparation. When cut as pledgets or larger torpedoes, it can be considered as a mechanical device because it is often staying in close proximity to the tip of the catheter used for delivery. When gelfoam is cut in smaller pieces or prepared as a slurry by passing it between two syringes through a stopcock, it can become flow directed and travel distal beyond the tip of the catheter.
This category consists of agents that are delivered through a catheter and are then directed beyond the tip of the catheter into an abnormal vascular bed by normal arterial flow. In addition to small gelfoam particles or a gelfoam slurry, the agents in this category include particulate and liquid embolic agents. Because these agents are using normal flow to carry an agent distally, close attention must be paid during their administration to be certain that delivery ceases when forward flow into the abnormal vascular bed is no longer recognized.
Irregularly shaped PVA particles were the initial particulate embolic agent and still remain the standard particulate agent used by most interventionalists (Fig. 1.5). There are disadvantages that are inherent to the use of particulate PVA, including size variability, particle aggregation, and microcatheter occlusion during delivery. This prompted the development of spherical embolic agents, allowing for significant growth in this area during the last two decades.34 Calibrated spherical agents are now available, including PVA-based microspheres, trisacryl gelatin microspheres, and Polyzene-F–based microspheres. These agents are used commonly for procedures such as uterine fibroid embolization and other tumor and organ-based indications. Drug-eluting microspheres (Fig. 1.6) and yttrium 90 microspheres have helped develop an entire subspecialty of interventional oncology. Resorbable microspheres represent a significant future advance in this area, potentially allowing for the creation of temporary, reproducible arterial occlusion with embolization.19,35
Liquid embolic agents are also classified in the category of flow-directed agents, although this can be somewhat variable based on the agent and the amount of dilution used during administration. Sclerosants such as ethanol have been used successfully as an embolic agent for certain tumors and vascular malformations, whereas more mild agents such as sodium tetradecyl sulfate have been used for venous applications such as varicose veins, varicoceles, and pelvic congestion syndrome. Other sclerosants include hypertonic glucose, doxycycline, and OK-432. Agents such as N-butyl cyanoacrylate and Onyx (Fig. 1.7) are playing a growing role in the treatment of cerebral and peripheral arteriovenous malformations.
In conclusion, embolotherapy has gone through significant changes since its development in the late 1960s and early 1970s. The indications for these procedures have greatly expanded, as have the agents available for us. Although classifying these agents does not necessarily change the way they are used, it is important to understand how they work and when they should potentially be used. As new agents are introduced and new indications are established, modern interventional radiology will continue to evolve, resulting in the reorganization of the classification schemes used for embolization.
1. Vaidya S, Tozer KR, Chen J. An overview of embolic agents. Semin Intervent Radiol. 2008;25:204–215.
2. Vitek JJ, Smith MJ. The myth of the Brooks method of embolization: a brief history of the endovascular treatment of carotid-cavernous sinus fistula. J Neurointerv Surg. 2009;1:108–111.
3. Doppman JL, Di Chiro G, Ommaya A. Obliteration of spinal-cord arteriovenous malformation by percutaneous embolization. Lancet. 1968;1:477.
4. Newton TH, Adams JE. Angiographic demonstration and nonsurgical embolization of spinal cord angioma. Radiology. 1968;91:873–876.
5. Rosch J, Dotter CT, Brown MJ. Selective arterial embolization. A new method for control of acute gastrointestinal bleeding. Radiology. 1972;102:303–306.
6. Rosch J, Keller FS. Historical account: cardiovascular interventional radiology. In: Lanzer P, ed. Catheter-Based Cardiovascular Interventions: A Knowledge-Based Approach. Berlin, Germany: Springer-Verlag; 2013:15–26.
7. Speakman TJ. Internal occlusion of a carotid-cavernous fistula. J Neurosurg. 1964;21:303–315.
8. Tadavarthy SM, Knight L, Ovitt TW, et al. Therapeutic transcatheter arterial embolization. Radiology. 1974;111:13–16.
9. Serbinenko FA. Balloon catheterization and occlusion of major cerebral vessels. J Neurosurg. 1974; 41:125–145.
10. Gianturco C, Anderson JH, Wallace S. Mechanical devices for arterial occlusion. Am J Roentgenol Radium Ther Nucl Med. 1975;124:428–438.
11. Rose SC. Mechanical devices for arterial occlusion and therapeutic vascular occlusion utilizing steel coil technique: clinical applications. AJR Am J Roentgenol. 2009;192:321–324.
12. Guglielmi G. History of the genesis of detachable coils. J Neurosurg. 2009;111:1–8.
13. Wang W, Li H, Tam MD, et al. The Amplatzer Vascular Plug: a review of the device and its clinical applications. Cardiovasc Intervent Radiol. 2012;35:725–740.
14. Guimaraes M, Wooster M. Onyx (ethylene-vinyl alcohol copolymer) in peripheral applications. Semin Intervent Radiol. 2011;28:350–356.
15. Laurent A, Beaujeux R, Wassef M, et al. Trisacryl gelatin microspheres for therapeutic embolization, I: development and in vitro evaluation. AJNR Am J Neuroradiol. 1996;17:533–540.
16. Lewis AL, Gonzalez MV, Lloyd AW, et al. DC Bead: in-vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol. 2006;17:335–342.
17. Yan ZP, Lin G, Zhao HY, et al. An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer. Cancer. 1993;72:3210–3215.
18. Weng L, Rostambeigi N, Zantek ND, et al. An in situ forming biodegradable hydrogel-based embolic agent for interventional therapies. Acta Biomater. 2013;9:8182–8191.
19. Owen RJ, Nation PN, Polakowski R, et al. A preclinical study of the safety and efficacy of Occlusin™ 500 artificial embolization device in sheep. Cardiovasc Intervent Radiol. 2012;35:636–644.
20. Davidson GS, Terbrugge KG. Histopathologic long-term follow-up after embolization with polyvinyl alcohol particles. Am J Neuroradiol. 1995;16:843–846.
21. Germano IM, Davis RL, Wilson CB, et al. Histopathological follow-up study of 66 cerebral arteriovenous malformations after therapeutic embolization with polyvinyl alcohol. J Neurosurg. 1992;76:607–614.
22. Tomashefski JF, Cohen AM, Doershuk CF. Long-term histopathological follow-up of bronchial arteries after therapeutic embolization with polyvinyl alcohol (Ivalon) in patients with cystic fibrosis. Hum Pathol. 1988;19:555–561.
23. Link DP, Strandberg JD, Virmani R, et al. Histopathologic appearance of arterial occlusions with hydrogel and polyvinyl alcohol embolic material in domestic swine. J Vasc Interv Radiol. 1996;7:897–905.
24. Siskin GP, Englander M, Stainken BF, et al. Embolic agents used for uterine fibroid embolization. AJR Am J Roentgenol. 2000;175:767–773.
25. Abada HT, Golzarian J. Gelatin sponge particles: handling characteristics for endovascular use. Tech Vasc Interv Radiol. 2007;10:257–260.
26. Light RU, Prentice HR. Surgical investigation of new absorbable sponge derived from gelatin for use in hemostasis. J Neurosurg. 1945;2:435–455.
27. Barth KH, Strandberg JD, White RI. Long-term follow-up of transcatheter embolization with autologous clot, oxycel, and gelfoam in domestic swine. Invest Radiol. 1977;12:273–280.
28. Gold RE, Grace DM. Gelfoam embolization of the left gastric artery for bleeding ulcer: experimental considerations. Radiology. 1975;116:575–580.
29. Jander HP, Russinovich NA. Transcatheter gelfoam embolization in abdominal, retroperitoneal, and pelvic hemorrhage. Radiology. 1980;136:337–344.
30. Tabata Y, Ikada Y. Synthesis of gelatin microspheres containing interferon. Pharm Res. 1989;6:422–427.
31. Maeda N, Verret V, Eng LM, et al. Targeting and recanalization after embolization with calibrated resorbable microspheres versus hand-cut gelatin sponge particles in a porcine kidney model. J Vasc Interv Radiol. 2013;24:1391–1398.
32. Lubarsky M, Ray CE, Funaki B. Embolization agents—which one should be used when? Part 1: large-vessel embolization. Semin Intervent Radiol. 2009;26:352–357.
33. Lubarsky M, Ray CE, Funaki B. Embolization agents—which one should be used when? Part 2: small-vessel embolization. Semin Intervent Radiol. 2010;27:99–194.
34. Laurent A. Microspheres and nonspherical particles for embolization. Tech Vasc Interv Radiol. 2007;10:248–256.
35. Weng L, Rusten M, Talaie R, et al. Calibrated bioresorbable microspheres: a preliminary study on the level of occlusion and arterial distribution in a rabbit kidney model. J Vasc Interv Radiol. 2013;24:1567–1575.