Percutaneous embolization is an effective way of treating hemorrhagic conditions and of eliminating the vascular supply of mass lesions. Embolization can be performed either as a definitive treatment or as an adjunct to subsequent surgical management. Safe and effective application of embolic therapy requires high-level catheter skills, familiarity with the embolic agent being used, and knowledge of any agent-specific delivery considerations. This article reviews the features of the most commonly used embolic agents and discusses important general considerations for embolization procedures.

The first transcatheter embolizations were performed in the 1930s to occlude carotidcavernous fistulae. ¹ The carotid arteries were exposed surgically, and muscle, fat, or fascia were used as embolic agents. In 1968, autologous clot was first described as an embolic agent to occlude a spinal arteriovenous malformation (AVM). ² This technique was quickly adopted for use in gastrointestinal hemorrhage, ³ genitourinary bleeding, ⁴ and traumatic hemorrhage from pelvic fractures. ⁵ In the 1970s, three new types of embolic material were introduced for permanent intravascular occlusion: glue, ⁶ mechanical devices (such as stainless steel coils), ⁷ and the first form of polyvinyl alcohol foam. ⁸

Vessel occlusion is achieved either by direct mechanical occlusion alone or by a combination of mechanical obstruction and the establishment of a framework for thrombus formation. Glue is an example of a direct mechanical agent. Polymerization of the glue forms a cast that plugs the treated vessel directly. On the other hand, coils, with their fibers, provide a matrix for thrombus formation in addition to their mechanical obstruction.

Over the last decades, multiple variations of these embolic materials--as well as other, entirely new embolic agents--have been introduced. While each agent has its utility, no single embolic agent is suitable for all indications. Rather, for each case, one must choose the one that is most appropriate for that patient from among the available agents.

This article reviews the most commonly used embolic agents, with emphasis on their specific applications and delivery features and will offer practical tips for safe embolization.

Embolic materials

Autologous clot

The obvious advantages of autologous clot are its immediate availability, absence of cost, and lack of adverse reaction. Embolization with autologous clot is simple: aspirate roughly 20 mL of the patient's blood and allow it to clot, then discard the supernatant and reintroduce the clot through the catheter. If desired, the clot can be opacified by adding sterile tantalum powder. The major drawback is its rapid lysis time, which can lead to recanalization within 6 to 12 hours. This problem can be partially overcome by modification of the autologous clot.

The modified clot is produced by withdrawing 20 to 30 mL of the patient's blood and then adding 500 to 1000 U thrombin and 250 to 500 mg aminocaproic acid (Amicar, Immunex Corporation, Raleigh, NC) to the blood. Aminocaproic acid promotes cross linking of the fibrin precipitate and formation of a more stable thrombus. ⁹ Again, the supernatant is discarded and the clot is injected through the catheter. This modification delays recanalization for approximately 24 hours. Because even the modified thrombus provides only a very short occlusion time, autologous clot is rarely used today. In certain circumstances in which a short-term occlusion is all that is needed, autologous clot should be considered. Such an application could be the treatment of a high-flow priapism.

Absorbable bioprosthetic material

The most widely used absorbable bioprosthetic material is gelatin sponge (Gelfoam, Pharmacia & Upjohn Co., Kalamazoo, MI). Gelfoam is available in powder and sheet form. Particles of Gelfoam powder measure 40 to 60 µm in diameter and produce a very peripheral occlusion. Because of the very distal occlusion and the potential resulting complication of tissue infarction, the powder form is used infrequently. The Gelfoam sheets can be cut into pledgets of the desired size, usually 1 to 3 mm. The pledgets are then suspended in a mixture of contrast and saline and are injected through a catheter with a small syringe, typically 1 or 3 mL in size. Since Gelfoam floats in fluid, the syringe is held nose up.

For more distal embolization (though not as distal as the powder), a slurry of Gelfoam can be created by macerating the pledgets with two syringes and a three-way stopcock: the more passes the Gelfoam makes through the stopcock, the more it is fragmented and the smaller the pieces become. Alternatively, if a very proximal occlusion is desired, Gelfoam "torpedoes" can be formed by compressing and rolling strips of Gelfoam, which are then loaded into the nozzle of a 1- or 3-mL syringe (Figure 1).

Gelfoam embolization provides a temporary occlusion lasting approximately 3 to 6 weeks. For this reason, Gelfoam is often used for embolization of pelvic trauma ¹⁰ or postpartum hemorrhage, ¹¹ especially when there are multiple punctuate bleeding sites from various branches of the internal iliac artery. In such situations, embolization should be initiated with Gelfoam slurry to achieve a relatively distal level of occlusion and then followed by Gelfoam pledgets or torpedoes.

Alternative absorbable embolic bioprosthetic materials include oxidized cellulose (Oxycel, Parke-Davis, Detroit, MI) and microfibrillar collagen (Avitene, Avicon Inc., Fort Worth, TX). Oxycel creates a matrix for thrombus formation. Because it has no clear advantage over Gelfoam and its filmy nature makes it more difficult to handle, Oxycel is rarely used anymore. Avitene is injected as a thick paste and its efficacy in causing platelet aggregation and activation leads to quick hemostasis. It must be used with great care because of its potential for causing severe granulomatous arteritis and extensive tissue infarction secondary to distal occlusion.

Nonabsorbable particles

Polyvinyl alcohol (PVA) is essentially a plastic sponge that is fragmented and then filtered to a certain size range. Although PVA is available in sizes between 50 and 2000 µm, the typical size ranges used clinically are 300 to 500 µm or 500 to 700 µm. Smaller particles have a significant risk of tissue infarction due to their distal level of occlusion. Larger particles may occlude the delivery catheter because PVA--being hydrophobic--has a tendency to flocculate. The particles are mixed in a 1:1 contrast:saline solution and are suspended through a three-way stopcock. If PVA particles are floating, more saline can be added to obtain a homogeneous suspension; conversely, if the particles are sinking, more contrast can be added. In order to avoid blockage of the catheter and to obtain evenly distributed emboli, the material should be resuspended immediately prior to injection. Nonuniform delivery can lead to particle aggregation, which, in turn, results in a more proximal occlusion than intended. This aggregation generally resolves with time (usually several minutes), so embolization at the intended occlusion level can be continued.

PVA is used predominantly for tumor embolization, either for preoperative devascularization or as definitive treatment, such as in uterine fibroid embolization. ¹² In addition, PVA can be used when treating hemorrhage of a vascular bed with multiple small branches. An example of such bleeding is hemoptysis in patients with chronic inflammatory lung disease. Bleeding can usually be stopped by particulate bronchial artery embolization. ¹³ Prior to bronchial embolization, the presence of a spinal artery originating from the treated vessel should be excluded. ¹⁴

An alternative to PVA particles are microspheres (Embosphere, BioSphere Medical, Rockland, MA). Embospheres are precisely calibrated, spherical, hydrophilic, microporous beads made of an acrylic copolymer, which is then cross-linked with gelatin. The hydrophilic surface prevents aggregation, allowing a more predictable, uniform vessel occlusion than PVA, as well as easier delivery through small catheters. The latter feature is enhanced by the material's elasticity, which allows temporary deformation during delivery. Like PVA, Embospheres are suspended in a 1:1 contrast:saline mixture. The indications for embospheres are similar to PVA; however, to date, the main applications are neurointerventional procedures and uterine fibroid embolizations. ¹⁵

Because no aggregation occurs with Embospheres, their use is slightly different from that of PVA. First, the particle size selected in any given application should generally be one size larger than what would be employed with PVA. Second, Embospheres effectively occlude the vessel at the target diameter, but, because they don't aggregate, they don't occlude vessels with larger diameters. Therefore, embolization may be stopped before stasis in the feeding artery is achieved.

Another therapeutic option for embolization with microspheres was introduced during the 2002 Society of Cardiovascular & Interventional Radiology (SCVIR) meeting. Ceramic microspheres have been embedded with the beta emitter Yttrium-90 (TheraSphere, MDS Nordion, Kanata, Canada) to provide internal radiation of hepatic malignancies. ¹⁶ Because of the small mean diameter of the TheraSpheres (25 µm), the radioactive particles are distributed within the tumor for local radiation therapy without significant embolization of blood flow. The major potential complication is radiation pneumonitis secondary to particles that are shunted to the lungs. Therefore, before using this technique, significant intrahepatic arteriovenous shunting should be ruled out by pulmonary scintigraphy after injection of technetium-99m macroaggregated albumin into the proper hepatic artery.

Coils

The first embolic coils consisted of pieces of stainless steel guidewires onto which strands of wool had been woven to add a matrix for thrombus formation. Because of concerns about perivascular reactions, polyester fibers (Dacron, DuPont, Wilmington, DE) have since been substituted for wool. Installation of thrombin into the cartridge in which the coil is constrained before delivery can further increase the thrombogenicity of a coil. In addition to stainless steel, coils are also available in platinum. Stainless-steel coils are best suited for high-flow applications due to their high radial force, which helps prevent dislodging. Platinum coils, on the other hand, are highly visible under fluoroscopy and are much softer than stainless steel. This facilitates accommodation of the coil to the vessel.

Appropriate sizing is important to ensure occlusion of the vessel at the intended location. A coil that is too small will be carried distally by flowing blood, while a coil that is too large will form an elongated, sinusoidal shape, rather than a tight "nest." An elongated, open configuration decreases the effectiveness of thrombus formation. In addition, an oversized coil can force the delivery catheter back, even displacing it out of the target vessel. Nonetheless, in situations in which distal embolization must absolutely be avoided, such as in cases of pulmonary AVMs (Figure 2), the initial "anchoring" coil should be oversized by several millimeters deliberately.

For delivery, coils are loaded from their carrier sheath into the catheter by pushing with the back end of a guidewire. The coil must be advanced far enough into the catheter so that later it can be easily pushed through the catheter and into the target vessel with the floppy end of a straight guidewire or a dedicated "coil pusher." Alternatively, small coils can be pushed through the catheter with hydraulic pressure. With this method, the coil essentially is injected into the vessel with a 1- or 3-mL syringe.

This technique is required for microcatheter liquid coils (Liquid Coil, Boston Scientific, Fremont, CA). Liquid coils can be cut to any desired length (Figure 3) and can be retrieved by suction with a 20-mL syringe before complete delivery. Liquid coils occlude small arteries very effectively by forming a dense cast in the vessel (Figure 4). Occasionally, a straight or C-shaped microcoil is placed first to avoid a too distal injection of a liquid coil.

One disadvantage of most coils is that they cannot be retrieved once they are extruded from the catheter tip. The most commonly used retrievable coil is the Gugliemi detachable coil (GDC) system (Boston Scientific, Fremont, CA). The coil is welded to the pusher wire and can be placed and retracted repeatedly until optimal positioning is achieved. Once the coil is in the desired position, the wire is attached to a battery device that sends a current along the wire. The current melts the welded connection between the coil and the wire and detaches the coil without any force. GDCs are mainly used for treatment of intracranial aneurysms, ¹⁷ but can also be used in other locations where high precision and retrievability is required.

Embolization with coils produces a focal occlusion, leaving the vessel distal to the coil patent, similar to surgical ligature. Therefore, coils are utilized in almost any application in which precise vessel occlusion--but not tissue ablation--is necessary. Applications for coil embolization include treatment of hemorrhage, occlusion of arteriovenous fistulas, ¹⁸ and preoperative or pre-stent graft vessel occlusion. ¹⁹

Detachable balloons

The use of detachable balloons is an efficient way of achieving immediate mechanical vessel occlusion. The balloon is delivered to the target site, inflated until it achieves a seal against the vessel wall, and then released from the delivery/inflation catheter. All detachable balloon systems, therefore, consist of the balloon, a delivery/inflation catheter, and an introducer catheter. The newer balloons are made of silicone and are attached to the delivery catheter by a self-sealing valve. The balloons come in various shapes and sizes, and with valves that release from the delivery/inflation catheter at one of three predetermined levels of force: low, medium, or high.

The balloon can either be placed through a prepositioned introducer catheter or be "floated" to target site with the blood stream. Once the balloon is in the desired location, it is filled with contrast. Because silicone acts as a semipermeable membrane, osmotic pressure may cause a silicone balloon to rupture if filled with a hypertonic solution. ²⁰ Consequently, the preferred contrast agent is one with an osmolarity close to that of blood, such as iodixanol (Visipaque, Amersham Health, Princeton, NJ). After inflation, balloon detachment is accomplished by pulling back on the delivery catheter, relying on friction against the vessel wall to hold the balloon in place. In some cases, one may choose to stabilize the balloon using an outer coaxial catheter as the inner one is retracted. The more firmly the balloon is attached to the catheter, the lower the chance of a premature, inadvertent release of the balloon. However, balloons that are more firmly attached require more force to detach from the inflation catheter. If the force is greater than that generated by contact with the vessel wall, the balloon will be displaced from its desired location without releasing.

Long-term vascular occlusion appears to occur reliably if the balloon remains inflated for at least 3 weeks. ²¹ Detachable balloons are a suitable alternative to coils for treating high-flow arterial venous fistulas, such as pulmonary AVM or carotid cavernosal fistulas. Advantages of detachable balloons include retrievability before detachment and a near absence of artifacts on subsequent magnetic resonance imaging. ²²

Sclerosant agents

Unlike the previously described embolic agents, which by virtue of their size are arrested at a precapillary level, liquid sclerosants can pass to the capillary level and through to the venous circulation. This feature makes them desirable agents when tissue destruction is warranted, such as for complete ablation of tumors, solid organs, veins, or vascular malformations. ²³ Sclerosing agents cause protein denaturation, leading to endothelial destruction and vascular occlusion. Occlusion by sclerosants is usually permanent. The most frequently used sclerosing agent is absolute alcohol. As with other liquid agents, serious complications related to necrosis of normal tissue can occur if alcohol is introduced inadvertently into a normal vascular territory. ²⁴ An appropriate embolization technique is therefore especially important.

The example of renal ablation further illustrates the special features of sclerosants. In such cases, an occlusion balloon is placed into the renal artery distal to the adrenal and gonadal branches. Contrast is then injected through the inflated balloon to determine the volume of alcohol needed to fill the renal vasculature (usually between 6 and 10 mL). After the contrast is allowed to wash away, the balloon is reinflated for alcohol injection. The balloon remains filled for a few minutes to allow thrombosis to occur. The catheter is then aspirated before the balloon is deflated to remove any alcohol remaining in the artery in order to prevent reflux into the aorta. This step is critical because alcohol is less dense than blood, and will therefore float along the anterior aspect of the aorta. Potentially, any refluxing material could enter more caudal anterior arteries; in most individuals, this is the inferior mesenteric artery. Colonic infarction secondary to renal artery ablation with alcohol has been reported. ²⁵ On the other hand, small volumes of alcohol that wash through the tumor are harmless because they are diluted rapidly in the renal venous system.

Other sclerosing agents include sodium tetradecyl sulfate (Sotradecol, Elkins Sinn, Cherry Hill, NJ) and polidocanol (Aethoxysklerol, Kreussler and Co., Chemische Fabrik, Wiesbaden, Germany). Sotradecol is an ionic detergent mostly used for varicocele embolization. During injection into the gonadal vein, the inguinal ring must be compressed to prevent reflux into the scrotum, which could cause testicular infarction. ²⁶ Aethoxysklerol, a solvent and nonionic emulsifier, is used predominantly for sclerosis of varicose veins.

Polymers

The principal feature of embolic polymers (also known as glues) is that they are liquid in a nonionized environment, such as 5% dextrose water (DW5), but polymerize to a solid state almost instantly in an ionized medium, such as blood. This characteristic is particularly useful in treating large, high-flow lesions, such as AVMs. The rate of polymerization--and thereby the depth of polymer penetration into a vascular structure--can be controlled by diluting the glue with nonionic fluids. Ethiodol is ideal for this purpose because it also makes the mixture radiopaque. N-Butyl Cyanoacrylate (Trufill, Cordis Neurovascular Inc., Miami Lakes, FL) is one such agent approved by the Food and Drug Administration.

To avoid premature polymerization, it is critical that all ionic compounds be excluded from contact with the agent. Thus, preparation for glue embolization begins with putting on fresh, dry gloves and carefully flushing the delivery system, including the hub of the catheter, with DW5. The polymer is then mixed with ethiodol at glue:ethiodol ratios of 1:1 to 1:4. As indicated above, polymer dilution depends upon the rate of blood flow in the vessel being treated. Less diluted glue would be used for high-flow arteriovenous fistula, more diluted glue for low-flow AVMs. A more dilute mixture also reduces the likelihood of gluing the catheter to the target vessel.

Glue should be injected with a 1-mL syringe. Generally only a few milliliters of glue are used. As soon as the mixture is injected, the delivery catheter must be removed to prevent it from being glued in place. Because the delivery catheter is removed after each aliquot of glue, embolization must always be performed with a coaxial system to preserve access.

A new biocompatible liquid embolic agent, consisting of ethylene vinyl alcohol copolymer dissolved in dimethyl sulfoxide (Onyx, Micro Therapeutics Inc., Irvine, CA), was introduced recently in Europe. Onyx contains tantalum powder to render it radiopaque. After Onyx is injected into the target lesion, the dimethyl sulfoxide solvent rapidly diffuses away, causing precipitation of the polymer and formation of a spongy cast. The cast solidifies from the outside in. Onyx allows a prolonged, controlled embolization because of its nonadhesive nature. Currently, Onyx is available for investigational use only in the United States.

Practical tips for embolization

Considerations before embolization

The choice of a specific embolic agent for an individual case depends on both the desired level of occlusion and the duration of occlusion required. Splenic artery embolization can be used as an example of different embolization strategies. Proximal occlusion with coils or large Gelfoam pledgets would be appropriate for splenic artery embolization prior to surgical splenectomy, whereas distal embolization with particles should be applied for definitive percutaneous tissue ablation in hypersplenism.

The patient's condition also influences the approach used in embolization. An unstable patient needs a quick life-saving embolization procedure. For example, in the case of pelvic hemorrhage, scattered Gelfoam embolization or embolization of an entire internal iliac artery may be more appropriate than superselective coil embolization. The latter can be performed in a stable patient in whom procedure time is less of an issue. Also, the coagulation status has to be known. Since embolic agents function either by direct mechanical occlusion alone or by additionally providing a framework for thrombus formation as mentioned above, the patient's coagulation status can influence the selection of embolic materials. A detachable balloon leads to immediate vessel occlusion independent of the coagulation status of the patient, whereas vessel occlusion after coil embolization can be prolonged in a coagulopathic patient.

Embolization procedure

A detailed understanding of target anatomy, and especially of potential collaterals, is important for safe and effective embolization. In some cases, embolization proximal and distal to the bleeding site may be required to avoid recurrent bleeding through collateral vessels (Figure 5). Thus, unless a patient is extremely unstable, a detailed high-quality angiogram should be obtained to visualize the vascular supply to the target lesion or bleeding site. In cases of abdominal hemorrhage, angiography should generally start with a nonselective (ie, aortic) injection in order to identify occult anatomic anomalies (such as an accessory renal artery) or any unusual or unexpected bleeding sources (Figure 6).

As a general rule, a coaxial catheter system should be used for embolization procedures because this approach permits removal of the inner catheter without losing access. Having this ability is critical should the catheter itself become occluded by embolic material. In addition, the selected catheter should match the planned embolic agent. For particulate embolization, the inner lumen of the microcatheter has to be large enough for the chosen particle size. In addition, because particulate embolization relies upon antegrade blood flow to carry the particles into the target territory, the catheter profile should be low enough to minimize spasm and maximize antegrade flow (in a small vessel, this may require a microcatheter). For coil embolization, side-hole catheters should be avoided because coils can be partially extruded before reaching the catheter tip. Polyurethane catheters should also be avoided because of high friction during coil delivery. In addition, the catheter and coil diameter must be concordant. Obviously, a coil with a diameter larger than the inner diameter of the catheter cannot be introduced, but also delivery of a microcoil through a 0.035-inch catheter must be avoided, because premature coiling in the catheter, with resultant catheter occlusion, may occur. Although dedicated coil pushers exist, any straight guidewire matching the inner diameter of the delivery catheter can be used. Glidewires should be avoided, however, because they can become "sticky" during coil advancement.

Selective catheterization of the target vessel is carried out using standard catheter technique. Once the catheter is in its expected final position, a selective angiogram through the catheter should be performed to ensure that the position is, in fact, correct. It is also critical to be sure that the catheter position is stable. This can be tested with a vigorous saline injection or, for coil embolization, by first advancing the pusher through the catheter without a coil. If an embolization site cannot be accessed transarterially, a direct puncture should be considered. This technique is used increasingly for treatment of type II endoleaks after stent graft placement (Figure 7). ²⁷ When direct access is achieved, an appropriate and stable catheter position should also be verified. The actual embolization is performed under fluoroscopic guidance. During coil embolization, the coil should form its pre-shaped configuration in the vessel. If it does not, but instead begins to form a sinusoidal shape, the catheter should be advanced gently to try to force the coil into the pre-shaped configuration. Alternatively, it may be helpful to "tap" on the coil with the pusher rather than giving continuous forward pressure. During particulate embolization, the particles should be carried away from the catheter by the blood flow. Once reflux is detected, the injection rate must be reduced or the embolization terminated. Reflux detection can be enhanced by using the "negative" road-map if the site of embolization is not moving during respiration. This technique consists of a blind road map image before embolization followed by subtracted images during embolization. Before removing the catheter, effective vessel occlusion should be documented by follow-up angiography.

Consideration after embolization

Most patients experience pain related to ischemia after embolization of solid organs. The pain level tends to increase with more distal embolization secondary to possible tissue infarction. The pain intensity varies markedly between individual patients; therefore, a patient-controlled-analgesia pump is widely used for opiate administration. For severe pain, epidural anesthesia should also be considered. In order to control the pain appropriately, the patient should be admitted overnight to the hospital. Usually the pain decreases after 12 hours, allowing a switch to oral analgesia the next day. Between 10% and 30% of patients experience a postembolization syndrome consisting of pain, fever, nausea, vomiting, and leukocytosis requiring a prolonged hospitalization. In general, these symptoms resolve with symptomatic treatment within a few days. Because the postembolization syndrome can be difficult to distinguish from an infection, prophylactic antibiotics are recommended for solid organ embolization. A single dose just before the procedure is usually enough, but in certain instances--for example, after splenic ablation--a full course of antibiotics is recommended.

Conclusion

Embolotherapy, although known for decades, is a growing treatment modality and a cornerstone of interventional radiology. A combination of catheter skills, profound knowledge of the different embolic agents and their specific characteristics, and understanding of vascular anatomy and disease pathology, together with good clinical judgment, is a prerequisite for successful embolotherapy. The challenge of embolization is to choose an appropriate combination of treatment strategy and embolic agent in each patient.