Small vessels
Large vessels and cavities
Temporary
Absorbable gelatin sponge: Gelfoam
Absorbable gelatin sponge (torpedo)
Permanent
Particles
Coils
Biological glues
Plugs (AVP)
Onyx
Thrombin
Sclerosing agents
The choice of an embolic agent depends on the anatomy of the target, the desired interaction with the surrounding parenchyma, and the sustainability of the desired occlusion. The following questions must be answered first:
1.
Is the desired occlusion a temporary or a permanent one?
2.
At what level on the vascular tree: truncal or distal parenchymal?
3.
Does one wish to preserve the viability of the downstream tissues?
The balance between safety and effectiveness must be systematically analyzed. Finally, the cost is another parameter that must be taken into account.
Autologous clots (for which the lysis is too rapid to obtain a clinical success), larguable balloons (which are at risk of migrating when deflated), and heated contrast agents (which caused severe pain) are today very seldom used.
Guide wire fragments or joining silk threads (2–0 or 3–0) have been sometimes used, especially for aneurysms or voluminous false aneurysms. Although their low cost is an advantage, they cannot however be used alone as it is difficult to position them and then control their landing; repositioning them is also very complicated. We do not use them.
1.1.1 Absorbable Gelatin Sponge (Gelfoam)
(a)
Technical Characteristics
Absorbable gelatin sponge is derived from purified porcine gelatin (Gelfoam®, Pharmacia & Upjohn; Gelita-Spon®, Gelita Medical; Curaspon®, CuraMedical, etc.).
It ensures a temporary occlusion obtained through a mechanical obstruction and platelet adhesion. It is reabsorbed in 3–4 weeks, allowing a recanalization from 3 weeks to 3 months post-procedure: it is thus largely used in preoperative settings or to treat hemorrhages (trauma, GI hemorrhages, postpartum hemorrhages, etc.). Downstream ad integrum restitution can be expected once homeostasis is obtained. It can also be used as a complement of permanent agents (e.g., coils).
The other advantages are its usability and low cost.
(b)
Instructions for Use
Available in pledgets of 1 or 10 mm in thickness, in precut cubes of 2 or 4 mm, in cylinders, in particles, or as a powder, it can be injected after dilution or in fragments. Dilution is carried out in a saline and water-soluble iodine contrast agent (ICM), using 3-way feeding taps and two Luer-Lock syringes. The desired viscosity is obtained according to the size of the manually cut fragments and the mixing procedures. By using small-size diluted fragments, the injection can take place through a 2.7 French microcatheter.
Tips and Tricks
First use fragments of increasing size to ensure a distal embolization.
A “torpedo” can allow a temporary proximal embolization: 3 mm wide by 10–15 mm long strip, rolled up and then inserted in a Luer-Lock syringe and vigorously injected through a diagnostic catheter (minimum 4 Fr).
Gelatin sponge can complete a coil or plug occlusion, in order to obtain hemostasis, especially in case of coagulation disorders.
Pitfalls
The powder form is the easiest to prepare, providing quickly homogeneous mixtures, but it gives very distal embolizations. In our team we have observed complications of embolization with powders in the treatment of postpartum hemorrhages such as necrosis and endometritis and have since abandoned their use when carrying out temporary embolizations.
Air is often contained in the contrast-gelatin mixture and should not be interpreted on the CT scan as a sign of post-procedure infection.
(c)
Future Developments
Several manufacturers are trying to develop absorbable microspheres (some of which are made of gelatin), of various sizes and absorption times.
1.1.2 Microparticles
Initially used to treat arteriovenous malformations, vascular traumatisms, and tumors [2, 3], particles allow distal parenchymal devascularization. They can be injected into the flow through a catheter or a microcatheter. They are characterized by their size, composition, and coating; the latter two determine their elasticity, rigidity, and aggregation ability as well as their interaction with adjacent parenchyma (inflammatory reaction of variable intensity).
Occlusion occurs through a mechanical obstruction, a stasis thrombus, and an inflammatory reaction. This occlusion of the distal capillary bed can induce tissue ischemia and necrosis.
(a)
Technical Characteristics
Composition
Historically the particles were derived from polyvinyl alcohol (PVA) surgical hemostatic sponges. Depending on the way they were cut, they produced elements of variable and irregular forms. The aggregation of these particles was important, making the assessment of the injected aggregates difficult and leading to more proximal embolizations than those planned [2].
The first evolution concerned the calibration of these particles (Contour®, Boston Scientific) so as to obtain a range of particles of various sizes by increments 200 μ (calibrated particles). Then spherical particles appeared, made of PVA (Contour SE®, Boston Scientific; Bead Block®, Terumo Biocompatible) and of tris-acryl (Embosphère® and Medical Embogold®, Biosphere), characterized by a lower adhesion factor enabling more distal embolizations.
More recently, hydrogel spheres with a fixed gauge have been developed (the variation being less than 5 % of the nominal gauge), covered with a polymer (Polyzen-F) limiting their aggregation (Embozen®, CeloNova) (Table 1.2).
Table 1.2
Characteristics of available microparticles
Particles
Composition
Diameters (μm)
Presentation
Color
PVA Foam®
PVA particles
90–2,800
1 ml bottle
No
Bead Block®
PVA spheres
100–1,200
1 or 2 ml syringe
Colored
Contour®
PVA particles
45–1,180
1 or 2 ml bottle
No
Contour SE®
PVA spheres
100–1,200
1 or 2 ml syringe
No
Embosphere®
Tris-acryl spheres
40–900
Bottle or syringe
No
Embogold®
Tris-acryl spheres
40–1,200
1 or 2 ml syringe
Colored
Embozen®
Hydrogel
40–1,300
1 or 2 ml syringe
Colored
Elasticity, Rigidity
The elasticity is the capacity of the particle to return to its initial form after a deformation such as an injection through a microcatheter. The rigidity is the capacity of the sphere to preserve its form in spite of a compression.
The rigidity and the elasticity of the PVA particles (Contour SE®) are more limited than those of the tris-acryl (Embosphere®), which results in a more distal embolization of the deformed PVA particles, more particularly when injected through a microcatheter. Thus, to establish an equivalent embolization level, the caliber of the tris-acryl must be lower than that of the PVA [4, 5]. In the same way, in order to obtain an equivalent occlusion level, the diameter of hydrogel-polyzene spheres chosen must be higher than that of tris-acryl particles.
Interactions with the Adjacent Parenchyma
The intensity of the inflammatory response which conditions the occurrence of a post-embolization syndrome varies according to the extension of the necrosis, the nature, and the size of the particles. Particles of less than 300 μ result in a much more significant inflammation. Over 500 μ, the size is no longer a determining factor [3]. After embolization using PVA, an acute inflammatory reaction mediated by polynuclear neutrophils is observed (more marked with particles than with spheres), which gradually gives way to a predominantly giant cells reaction. With tris-acryl spheres, the initial inflammation is limited, then giving way to a more intense delayed lymphocytic reaction [4].
The composition of the microspheres allows their combination with other therapeutic agents (cytotoxics, anti-inflammatory drugs). These loaded particles allow a targeted and progressive delivery of the associated agent. Various drug-fixing methods are used: ionic link between a positively charged particle and the negative doxorubicin (cd. Bead®, biocompatible Terumo), passive hydrophilic link between ibuprofen and Bead Block, or a combination of both (Hepasphere®). The fixation capacities and the release kinetics depend on the particles and the associated agents. Microparticles can also be loaded with isotopes (yttrium 90), thus allowing a selective in situ radiation therapy.
(b)
Instructions for Use (Table 1.3)
Before injection, the particles are diluted with a saline and ICM, according to ratios specified by the manufacturer (generally isovolume saline/ICM), in order to obtain a homogeneous suspension. To limit the risk of aggregation, dilutions are more important with the smaller particles (100–500 μ) (diluted up to 100× their volume) than with the larger ones (up to ×10) [2]. Prefilled syringes facilitate this operation, which can be carried out with a 3-way tap and a standard Luer-Lock syringe. The mixture can be obtained with the prefilled syringe and a 10 ml syringe, but the injections during embolization are generally carried out using syringes of 1 or 3 ml (Medallion® Merit), given that they take place in microcatheters.
The initial particle diameter is selected according to the topography but also to the nature of the target: for a tumor embolization, the size of the tumor, its vascularization, and the risk of intra-tumoral arteriovenous shunts must be taken into account. In this indication, very-small-caliber particles would more readily induce necrosis by occluding the most distal vessels. Particles of progressively increasing diameter are then selected, to the “end point” which is sometimes difficult to establish: the most commonly used criterion is a reflux or an off-target embolization. Initially the goal of embolization with PVA was to obtain a complete exclusion of the embolized segment. Today with calibrated particles, the aim is to slow down the flow and obtain the “dead-tree” pattern.
In order to maintain the patency of the microcatheter, an arterial purge with saline (via a Y valve) must be carried out.
Table 1.3
Recommended diameter of the catheter internal lumen (according to the manufacturers’ instruction notice)
Particles (μ) | 45–120 | 100–300 | 300–500 | 500–700 | 700–900 | 900–1,200 | 1,300 |
|---|---|---|---|---|---|---|---|
PVA foam | 0.018″ | 0.044″ | |||||
Contour® | 2.4 Fr | 2.7 Fr | 4 Fr | ||||
Contour SE® | 0.021″ | 0.024″ | 0.035″ | ||||
Embosphere | 0.008″ | 0.013″ | 0.018″ | 0.023″ | 0.027″ | 0.035″ | |
Embogold® | 0.008″ | 0.013″ | 0.018″ | 0.023″ | 0.027″ | 0.035″ | |
Embozen® | 0.004″ | 0.013″ | 0.018″ | 0.023″ | 0.027″ | 0.0 35″ | 0.038″ |
Bead Block® | 0.010″ | 0.014″ | 0.021″ | 0.023″ | 0.035″ | ||
Tips and Tricks
The use of microparticles requires a rigorous management of the tools (syringes, catheters, cups, etc.), to avoid unexpected injections. The methods vary according to the centers, but in all cases the embolization material (syringes and cups) must be clearly identified. Some particles are naturally colored.
To obtain a homogeneous suspension, the ICM/saline ratio is variable, but generally if the particles float in the mixture, then the quantity of ICM is excessive. However, the choice of a heterogeneous suspension can be deliberate, so as to progressively inject the required quantity of particles.
Control angiography (after having rinsed the microcatheter) depicts flow redistribution in the collateral networks, which are in some cases only secondarily unmasked. These ICM injections must be carried out with limited pressure, so as not to cause any reflux.
To benefit from the blood flow, the carrier catheter can sometimes be withdrawn, leaving only the microcatheter in place and thus authorizing a better washing by the arterial flow.
The last angiographic control must be carried out after a delay of 3–5 mn, to ensure a stabilized end point (Table 1.4).
Table 1.4
Dilution of the microparticles
Particles
500 μ
>500 μ
Dilution
×100 to ×1,000
×10
ICM/saline
50/50 % adapted to the volume and the radio opacity
If particles float = too much ICM
Pitfalls
Catheter obstruction frequently occurs when particles are not sufficiently diluted or if the catheter is not regularly rinsed.
Microspheres of small caliber should not be used in the presence of arteriovenous shunts.
A hyperpressure injection exposes to endothelium damage, to off-target reflux, and to the opening of anastomoses which can also induce off-target embolization; it can also deform the Embospheres (tris-acryl).
The occurrence of a vasospasm distal to the microcatheter can artificially limit the volume of the target and lead to an early revascularization. A careful catheterization, the comparison with images obtained on global injections, and sometimes an injection of vasodilator are helpful in overcoming this limit.
(c)
Future Prospects
A challenging indication of loaded particles could be the implantation of cells such as hepatic transplantation of small Langerhans islets by percutaneous catheterization of the portal vein to treat some cases of type I diabetes patients.
Little is known about the particle-tissue interactions. This embolization agent constitutes a foreign body which induces an inflammatory reaction which up until now has undoubtedly been underestimated. It causes the release of mediators, leads to a vascular wall remodeling, and results into an extravascular migration and a stimulated angiogenesis. It evolves into intolerance (chronic inflammation, immunity), modifies the environment of the absorbable materials, and lastly can limit the diffusion of the drugs carried by the loaded particles. The histological assessment can only be carried out at a late stage: progress in molecular biology will undoubtedly allow an earlier evaluation of these intolerance phenomena and bring about an evolution in the embolization agents, particularly loaded particles.
1.1.3 Liquid Agents
1.1.3.1 Biological Glues
(a)
Technical Characteristics
Biological glues were initially used to embolize cerebral arteriovenous malformations.
The polyethylene glycol and the aldehydes used in surgery have only very rare endovascular applications [5]. To embolize, cyanoacrylates (Trufill®, Cordis; Histoacryl® Braun; Glubran2®, GEM; Neuracryl, Prohold Technologies) are predominantly used. They are made up of an ethylene molecule coupled with a cyanogen group and an ester. Depending on the associated ester, several agents were initially proposed (isobutyl, n-butyl, 2-hexyl cyanoacrylate); the occurrence of sarcomas in animals resulted in abandoning the isobutyl group. The contact of ionic substances (saline, water, plasma, blood cells, epithelium) initiates the polymerization, starting from the ethylene groups, by releasing heat energy. An inflammatory reaction accompanies the polymerization. The length of the hydrocarbon chain proportionally increases the speed of the polymerization and decreases the importance of the exothermic reaction and the cellular toxicity. Thus, Glubran®, compared to Histoacryl®, polymerizes more slowly, is less painful with the injection, and causes a less marked inflammatory reaction [6]. In spite of a Glubran exothermic reaction which is less marked (<45°), the reduction of the pain remains limited [7].
It should be noted that complete absorptions, which possibly leads to recanalizations, have been described.
To facilitate their visibility, the glues can be mixed with metallic powders (tantalum or tungsten) or with radiopaque oils (Lipiodol®, Guerbet or Ethiodol®, Savage Laboratories) [8]. These radiopaque oils also contribute to slowing down the speed of the polymerization in a linear way. In vitro, polymerization speeds with a glue/Lipiodol ratio between 1:1 and 1:4 spread over 1 and 4 s.
The injection causes an acute inflammatory response of the vessel and the perivascular tissues, evolving into a chronic organized granuloma within a month. The embolization can be permanent if it fills the entire arterial volume. Colonization by neocapillaries within the embolized vessels has been described [5, 6].
(b)
Instructions for Use
To carry out the embolization, the microcatheter should to be positioned as close as possible to the target (less than 1 cm). The correct positioning is verified by a control angiogram. The microcatheter is led via a diagnostic catheter or a delivery/carrier catheter: they ensure the stability of the catheterization and allow a fast withdrawal of the microcatheter after injection of the glue; they must be rinsed continuously (purge). Gloves must be changed when preparing the glue. The volume, the speed of the injection, and the viscosity (glue/Lipiodol ratio) are adapted according to a prior test injection (supposed volume of glue = volume of injected ICM – dead volume of the catheter). The microcatheter is then rinsed by a nonionic solution (dextrose or glucose 5 %); the physiological saline solution is contraindicated because it initiates polymerization. This volume is then pushed by the dextrose serum or 5 % glucose solution, through a lateral path in a three-way tap via a 3 ml Luer-Lock syringe. The glue injection is performed through the tap, distally with the help of an l ml Luer-Lock syringe. A high flow rate exposes the patient to a reflux, while slow one induces a fragmented embolization. The lateral way allows the dextrose injection to be given by a 3 ml Luer-Lock syringe. The volume of the glue is often lower than the evaluated ICM volume, and in vivo polymerization occurs more rapidly in vitro [9]. After the injection of the desired volume, the catheter is either removed using an aspiration or carefully rinsed using dextrose according to the evaluated flow established at the time of the test injection.
Tips and Tricks
Procedure is generally safer with a microcatheter, even when catheterization is easily carried out.
The use of coated hydrophilic microcatheters facilitates the injection by limiting friction within the catheter [10].
The viscosity can be increased by adding glacial acetic acid [11].
In complex indications such as tumor embolizations, where the evaluation of the adequate volume is difficult, the embolization can be carried out using the “sandwich” technique, by repeated injections of a low volume of nBCA-Lipiodol mixture, separated by serum glucose injections [12].
In order to limit the risk of a retrograde embolization, it is necessary to (1) inject slowly, in order to prevent a reflux; (2) withdraw the catheter in time by maintaining an aspiration; and (3) avoid rinsing the dead volume.
Pitfalls
With an antegrade embolization, the principal risks are the obstruction of the internal lumen, the clogging up of the distal end of the catheter, and the mobilization of proximal fragments in contact with the catheter.
Because of polymerization in contact with blood and a physiological saline solution, the internal lumen and the end of the catheter must thoroughly be rinsed by a dextrose serum or a glucose solution.
1.1.3.2 Ethylene Vinyl Alcohol (EVA)
(a)
Technical Characteristics
Ethylene vinyl alcohol (Onyx ®, eV3) is a copolymer which forms a nonadhesive solution when associated with dimethyl sulfoxide (DMSO); this solution progressively polymerizes when it is in contact with ionic materials and blood. Various concentrations of EVA are available (Onyx 18, 20, 34), with a gradually increasing viscosity. It is more easily monitored with fluoroscopy by the adjunction of tantalum powder.
Onyx solidifies, from the periphery towards the center, gradually forming a cast of the vessel (aneurysm, AVM, etc.).
(b)
Instructions for Use
Onyx is prepared in advance by a recomposition of the solution (solvent and powder), then mixed for 20 min in a centrifuge dedicated for this purpose. In this form, the solution is stable for 15–20 min and can be injected into a microcatheter compatible with the DMSO (Table 1.5). The catheter is slowly rinsed with DMSO; the volume used corresponds to the dead volume of the catheter (specified by the manufacturer). After disconnecting the syringe, the end of the catheter is rinsed so as to limit air bubbles at the DMSO-Onyx interface.
Table 1.5
Examples of DMSO-compatiblea microcatheters
Catheter | External diameter (Fr) (proximal/distal) | Internal lumen (″v) | Length (cm) |
|---|---|---|---|
Cantata® (Cook) | 2.5 | 0.021 | 100–150 |
2.8 | 0.025 | ||
Progreat® (Terumo) | 2.4 | 0.022 | 130–150 |
2.7 | 0.025 | 110–130 | |
Progreat Ω® | 2.8 | 0.027 | 130 |
Rebar ™ 18 (eV3) | 2.8/2.3 | 0.021 | 135–158 |
Rebar ™ 27 | 2.8 | 0.027 | 135–150 |
Renegade Hi-Flo® (Boston Scientific) | 3/2.8 | 0.027 | 105–150 |
Onyx is then slowly injected. This second phase must be carried out slowly (<0.5 ml/min), because it initially corresponds to the injection of the DMSO. A rapid injection of the solution exposes to a systemic toxicity. The pulmonary elimination of the DMSO induces a specific a rotten apple breath.
Once in contact with blood, the polymerization is carried out gradually, from the periphery towards the center. A sheath develops around Onyx during its injection, allowing its containment. Onyx is not adhesive; therefore, it is possible to limit its reflux by producing a first “stopper” at the distal end of the catheter. Once this stopper has solidified, the injection can be renewed safely.
This technique can be used to carry out proximal occlusions.
To treat AVM or tumor neovascularizations, the injection can be pursued before solidification, thus allowing the filling of the nidus, the efferents, and the collateral networks.
Tips and Tricks
Control angiogram can be improved by the use of a “negative roadmap” (image subtraction fluoroscopy). After the activation of the road-map function, the first fluoroscopy showing the injected Onyx is used as a mask: the following injections will then appear, after subtraction of the previously injected Onyx.
To avoid vasospasm, the injection must be given slowly (0.5 ml/min).
To limit the volume of the DMSO, the catheters are not rinsed but changed for each injection site.
Pitfalls
Once onyx has been injected, the guide wire should not be reintroduced into the microcatheter, because of a theoretical risk of expulsion of microemboli.
Preoperative “burns” have been described when using electric bistouries or electrocoagulation in patients previously treated with Onyx [15].
Even if Onyx does not have any adhesive property, a limited fragment can remain attached to the catheter’s distal end. It is usually an extension of an intracatheter residue.
1.1.3.3 Sclerosing Agents
Sclerosing agents include absolute alcohol and detergents. Hypertonic saline and glycerol are currently no longer used for embolization. The mechanisms are variable (endothelial cell membrane impairment, surface protein alteration, destruction of the extracellular matrix), but these agents all have a common principle: destruction of the endothelium, which is responsible for the vascular occlusion. This destruction is more or less intense and can extend to the surrounding tissues. The intensity of the reaction is determined by the concentration of the agent and its contact time. The use of detergents is limited, due to the direct and systemic toxicities and to the difficulties in controlling their diffusion.
Absolute Alcohol
(a)
Technical Characteristics
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