Onyx (Ethylene-vinyl Alcohol Copolymer) in Peripheral Applications

Abstract

Onyx is a nonadhesive liquid embolic agent approved for the treatment of brain arteriovenous malformations. Here, the use of Onyx is discussed in different peripheral procedures. The Onyx's features, its manipulation, technical details, tips, and tricks are presented followed by illustrative cases.

Onyx was initially promised as a dialysis matrix for separating immunoglobulins from albumin¹ and then as a matrix for controlled release of chemotherapeutics (Miyazaki, 1985). First described in 1990,² Onyx is an elastic polymer comprised of ethylene-vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulfoxide (DMSO) with micronized tantalum powder. The latter provides contrast for fluoroscopic visualization. The Food and Drug Administration (FDA) approved Onyx in 2005 for the treatment of arteriovenous malformations (AVMs). It is classified as a liquid, nonadhesive, nonabsorbable, permanent embolic agent³ that can be used off-label for small and large vessels. It was developed by Microtherapeutics; currently, it is distributed by the Ev3 company (Plymouth, MN), which was acquired in 2010 by Covidien (Mansfield, MA). The name Onyx is originated from the onyx stone, which is dark colored and is found mainly in Brazil.

Onyx is perceived by some interventionists as an expensive and complex embolic agent. Nowadays, it is one of the least popular embolic agents used among the interventional radiology community globally, and it has been used mainly for the treatment of peripheral AVMs and abdominal aorta stent graft-related endoleaks.^4,5,6 In fact, it is relatively simple to use as long the correct technical details and recommendations are followed. Neurointerventionists have used it for many years in the management of intracranial aneurysms and AVMs,^7,8,9 and the incidence of complications is relatively low. While Onyx is currently only approved for the treatment of intracranial AVM, this review seeks to describe some off-label peripheral applications for which this promising embolic agent may be used.

Institutional review board approval is not required at our institution for this type of article.

ONYX LIQUID EMBOLIC SYSTEMS FEATURES

Onyx is classified as a liquid, nonabsorbable, injectable and permanent, somewhat unique, embolic agent. As it is nonadhesive, it is easier and safer to deliver, with low risk of sticking to the microcatheter tip and yet is viscous enough to allow for controlled deployment.^10,11 These features are important especially in treatment of peripheral AVMs with variable nidus sizes and number of pedicles.

It is available in three different relative viscosities: Onyx 18 (with 6% of EVOH), Onyx 34 (with 8% of EVOH), and Onyx 500 (recommended for giant intracranial aneurysms). The first formulation is almost twice as viscous as the second one. In theory, higher viscosity (Onyx 34) offers better control while the embolic agent is injected. This is critical when the microcatheter tip is close to the target lesion (or inside of it) and when a very controlled Onyx injection is desired, with minimal chance of nontarget embolization. Examples are the renal artery aneurysm Onyx embolization using a remodeling technique or in AMV Onyx embolization when the pedicle is close to an important vascular branch that needs to be preserved. On the other hand, a lower viscosity formulation (Onyx 18) is preferred when a complex peripheral AVM nidus is distant from the microcatheter tip, as it allows the liquid embolic agent to flow deeper with consequently more appropriate nidus embolization.

Typically, the Onyx package includes three 1-cc delivery syringes (two labeled for Onyx use and one for DMSO), one 1.5-cc vial of Onyx and one 1.5-cc vial of DMSO. Currently, to obtain access to this embolic agent it is necessary to have a neurointerventionalist at the same medical institution from whom Onyx may be borrowed. The EV3 company recommends using any of the delivery microcatheters: Marathon™, Rebar^®, or UltraFlow™ HPC (EV3). They have been extensively tested regarding their compatibility with DMSO (theoretical risk of melting down the nontested microcatheters), and their dead space volume is provided in the microcatheter package (dead space = volume necessary to fill up the lumen of the microcatheter completely).

A significant advantage of Onyx over glue is that it may be injected for a long period (20–60 minutes). In addition, there is low risk of having the microcatheter stuck in the target area as long as the recommended technique is followed (Table 1).

Table 1.

General Steps for the Use of Onyx

1. Shake the Onyx vial for at least 20 minutes.

2. Compatible microcatheter is advanced up to the target area. Diagnostic angiogram is performed.

3. The microcatheter is flushed with normal saline solution.

4. Check the microcatheter dead space and load it up slowly with DMSO (over 60–90 seconds). No fluoroscopy is needed at this point.

5. Overwash the microcatheter hub with the residual amount of DMSO.

6. Under fluoroscopy guidance, Onyx is slowly injected. Satisfactory embolization might require several minutes or multiple injections.

7. At the end of the embolization, apply negative pressure in the delivery syringe and the pull out the microcatheter.

8. Control angiogram should be performed through the diagnostic catheter or a new microcatheter.

MECHANISM OF ACTION

DMSO is a solvent and it is part of the final Onyx formulation. It is initially injected very slowly inside the microcatheter lumen, filling its dead space, with the goal to prevent direct contact between Onyx and the bloodstream, which ultimately triggers the solidification process. In analogy, the initial injection of dextrose 5% before glue embolization has the same purpose to avoid triggering the polymerization process. Onyx is injected slowly right after DMSO and once it is delivered outside of the microcatheter, it tends to precipitate (not to polymerize like glue), occupying the target area space slowly and progressively without immediate or quick solidification as glue (N-butyl cyanoacrylate/Trufill; Cordis, Miami, FL) (Table 2). There is a slow solidification process that starts from the “outside-in.” In other words, a solid cast is formed outside with a spongy or foam-like consistency inside, similar to what happens to volcano lava when it cools off. The solidification process, also called copolymerization, starts once Onyx comes in contact with ionic fluids, such as blood or saline solution; it usually takes 5 minutes for the formulations Onyx-18 and Onyx-34 to become solid and stable. Onyx induces a mild inflammatory reaction in the adjacent vessel walls,¹² and as a nonabsorbable embolic agent, the recanalization of the embolized area is nonexistent.

Table 2.

Comparative Features Between Onyx and Glue

	Onyx	Glue
Time to solidification	4–5 minutes	Typically in seconds*
Injection time	Several minutes	Few seconds
Adhesiveness	Low	High
Final consistency	Foam-like substance	Rocky formation
Microcatheter compatibility	Restricted	Universal
Preparation	20-minute shacking	Immediate use
Solidification process	Copolymerization	Polymerization
Pre-embol flushing	DMSO	D5%

DMSO, dimethyl sulfoxide

^*It will depend on the glue concentration.

TECHNICAL DETAILS

A step-by-step approach to the technique is described in Table 1. Initially, the vial of Onyx has to be shaken for at least 20 minutes before the Onyx is aspirated into the delivery syringe. It typically happens while access to the embolization target area is obtained. Homogenous Onyx solution facilitates delivery and guarantees good opacification. Assuming that the diagnostic catheter is as close to the area of interest as possible, a Touhy-borst adaptor is connected in the hub. Coaxially, a DMSO compatible microcatheter is advanced up to the target zone where its working position and stability are checked with hand iodine contrast injection. The microcatheter is flushed with normal saline solution.

At this point, the microcatheter dead space volume should have been checked (information available in the package). Aspirate 1.5 cc of DMSO into its specific syringe. Very slowly, fill up the dead space with DMSO (matching exactly the dead space volume) over a period of 60–90 seconds. If the patient experiences pain, either the DMSO is injected too fast or the dead space volume is wrong. DMSO in high concentration irritates the endothelium. Fluoroscopy is not necessary while DMSO in injected. Overwash the microcatheter hub with the residual amount of DMSO. This maneuver will prevent triggering the copolymerization process before the Onyx reaches the tip of the microcatheter. The Onyx syringe should be already filled at this point, and it is recommended to connect it into the microcatheter hub vertically. Make sure there is no air bubble in the hub because aspiration of the microcatheter before Onyx injection is not permitted. Sometimes a single drop of Onyx may be necessary to fill up a residual gap in the microcatheter hub. Fluoroscopy should be used at all times while Onyx is slowly injected. This will allow adequate and asymptomatic DMSO dilution within the blood stream. Again, if there is pain, the injection rate should be slower because Onyx is displacing DMSO too fast into the blood vessel.

Depending on the size or capacitance of the target area/vessel, multiple injections of Onyx may be required. The Onyx syringes should be simply exchanged without leaving any gaps or air bubble. Again, a small drop of Onyx in the hub of the microcatheter might be needed to avoid discontinuation of the column of Onyx, which should be carefully avoided. There is no need for additional DMSO injections.

Several minutes or multiple Onyx injections might be required to obtain satisfactory embolization. In reality, it is possible to inject Onyx slowly, observe its behavior in the target area (which will depend on the blood vessel flow, capacitance), and inject more again. This maneuver may be repeated several times as needed. A gap between injections should be avoided to maintain embolization control and to avoid nontarget embolization.

Because of the cast formation in the front of the microcatheter, pressure builds quickly and there is a tendency of the Onyx, initially, to back flow toward the body of the microcatheter. At this point, the injection must be very slow to allow no more than 10–15 mm of Onyx to move along the tract of the microcatheter (column formation around the microcatheter tip). This part of the embolization procedure is fundamental for safety reasons. The goal is to wait for the creation of a “plug” around the tip of the microcatheter (Fig. 1). Once the plug is organized, it will prevent further back flow of the embolic agent. The Onyx is then delivered only forward in relation to the microcatheter tip. This maneuver also allows safe embolization of target zones that may be “far away” (1 or 2 cm) from the microcatheter tip. In this situation, a less viscous solution (Onyx-18) should be selected as well. Onyx is not an adhesive embolic agent, but there is risk of getting the microcatheter stuck in the working area due to external compression. This is more critical when the Onyx column covering the tip of the microcatheter is longer than 1/2 inch in length. Also, small arteries have low compliance that increases the risk of microcatheter tip adhesion to the embolic agent.

Figure 1.

No more than 10–15 mm of Onyx is allowed to move backward along the tract (arrows) of the microcatheter (column formation around the microcatheter tip). The “plug” formation around the tip prevents further Onyx back-flow.

For obvious reasons, the Onyx “plug” formation technique is unnecessary when there is free antegrade flow in the vessels (in a dead end branch, such as in portal vein embolization) and when the remodeling technique is used (more information about the latter below).

Before removing the microcatheter, negative pressure must be applied in the delivery syringe and the microcatheter may be pulled out without much effort. If there is resistance, consider pulling the microcatheter continuously in small increments in the traction intensity. Typically, the external pressure surrounding the microcatheter tip (that holds it in place) is decreased and the microcatheter is released. Do not pull the microcatheter abruptly as there is a risk of fracture, and it should not be reused. Control angiogram may be performed through the diagnostic catheter or through a new microcatheter as needed.

It is important to emphasize that in the embolization of complex AVMs with multiple feeding branches, multiple sessions might be needed to achieve complete treatment.

REMODELING TECHNIQUE

Typically, the remodeling technique is utilized during the endovascular treatment of aneurysms (especially the ones with large neck), of pseudoaneurysms or of abdominal aorta aneurysms (AAA) type 1 (A or B) endoleaks. The balloon diameter must match the diameter of the target vessel. A DMSO compatible microcatheter may be advanced coaxially through an occlusion balloon or in parallel to an angioplasty balloon catheter. If the latter is selected, a low profile 0.014–0.018” balloon is preferable to accommodate both the balloon catheter and the microcatheter through a single guiding catheter or introducer sheath. The DMSO injection, just before Onyx injection, should be performed while the balloon is deflated. If the DMSO is injected while the aneurysm neck is sealed, it will dilute the Onyx solution and the copolymerization time will be longer and unpredictable. The balloon should be inflated just before the whole DSMO is pushed outside the microcatheter (check the dead space volume) or just before Onyx delivery. The balloon catheter should be inflated with a very diluted iodine contrast solution to optimize Onyx visualization. A control angiogram is performed to exclude flow into the aneurysmal sac followed by Onyx embolization technique as described above. Obviously, there is no need for the “plug” formation as there is full flow control. It is suggested to wait for 4–5 minutes before the balloon is deflated to allow a stable cast formation.

PULLBACK TECHNIQUE

Following the embolization of the main lesion, the microcatheter may be pulled back to leave a “tail” of Onyx. This might be desired after the embolization of an AAA sac (in endoleaks type 1 or 2) when the entry site is embolized in AVMs to embolize the nidus pedicle, or in traumatic pseudoaneurysms with the embolization of the feeding artery. The microcatheter should be retracted very slowly while Onyx is gently injected. Any aggressive maneuver or inadvertent pull of the microcatheter may lead to nontarget embolization or to a loss of control of the embolic agent delivery.

ROAD MAPPING

There are situations, such as during the percutaneous embolization of endoleaks type 2, in which a significant amount of Onyx is required to fill up the AAA sac completely. After the injection of a few millimeters of Onyx and depending on the microcatheter position and dimensions of the lesion under treatment, it may be difficult to visualize in which direction the Onyx is being delivered in a posteroanterior or even in oblique views. To have full control and visualization during the Onyx delivery, road-mapping capability should be used regardless of the amount of Onyx previously injected. Most of the modern angiography suites worldwide have this application. Successive road-mappings may be performed repeatedly every time there is a compromise in the Onyx delivery visualization. However, the most important limitation of this technique is the respiratory-dependent artifact, which blurs the road-mapping image.

POTENTIAL DRAWBACKS

The shaking time may limit the use of Onyx in an emergency situation for some interventionists. However, if the operation is well coordinated and the Onyx embolization-related material is promptly available, it may certainly be used in emergency procedures such as in trauma patients.

Some interventionists advocate the idea that it is required to have specific training to use Onyx. More important than training in Onyx is to have full formal training in catheter-based endovascular techniques—Onyx is only one among several other devices that all interventionists should be familiar with. In addition, probably existing training on glue may be translated to Onyx usage.

Other potential limitations to the spread of Onyx are the current cost and the necessity to be used specifically with DMSO-compatible microcatheters commercialized by EV3.

If the patient complains of smelling like garlic the next day, do not worry. It is the DMSO that gives the garlic-type of smell and usually disappears within 2 days.

CASES

Some illustrative cases showing applications of Onyx in peripheral embolizations are described (Figs. 2,3,4,5,6).

Figure 2.

Right pelvic and proximal lower extremity angiogram demonstrates a complex arteriovenous malformation. An ultra-flow microcatheter was used for the distal selective Onyx (density 34) embolization, as close to the nidus as possible. Control angiogram shows complete exclusion of the lesion and preservation of the common, profunda, and superficial femoris arteries.

Figure 3.

Patient with history of abdominal aorta aneurysm (AAA) stent graft repair. Twelve months follow-up computed tomography angiogram (CTA) shows endoleak type I-A. Microcatheter was inserted, through the suprarenal fixation portion of the stent graft, deep in the AAA sac. It was filled with Onyx using the “pull-back” and the “remodeling” techniques. Immediate control aortogram and 3 months CTA show no evidence of endoleak.

Figure 4.

Patient with upper gastrointestinal bleeding refractory to transjugular intrahepatic portosystemic shunt (TIPS). Portal venogram shows extensive gastroesophageal collateral veins that were treated with Onyx embolization and the bleeding successfully controlled.

Figure 5.

Patient with splenic laceration and intraperitoneal bleeding secondary to a motor vehicle accident (MVA). Selective splenic arteriogram shows the bleeding site, which was successfully controlled with superselective Onyx embolization.

Figure 6.

Patient with history of MVA and right thigh pain. Right common femoral angiogram shows right profunda femoris branch pseudoaneurysm. Initially, microcoils were used to close the pseudoaneurysm outflow vessels and the lesion was treated with Onyx embolization using the “remodeling” technique.

Complications

From the technical standpoint, the difficulties lie in depositing an adequate amount of a liquid embolic agent precisely and in having the microcatheter tip in the right location. Nontarget embolization is always a risk, especially if the correct technique is not followed. Selection of the right Onyx density may provide better control of the embolic agent delivery. Familiarity with embolization procedures is essential. Interventionists with prior exposure to embolization with glue as an embolic agent probably will encounter no difficulties. For those without experience with liquid embolic agents, it is recommended to attend an Onyx embolization workshop before starting to use it. If the interventionist has minimal experience with embolization procedures, the use of Onyx as an embolic agent should not be the way to get started.

Complications such as infection, nontarget embolization, and the microcatheter getting stuck in the target vessel are rare. Skin color change might happen in case of Onyx embolization of shallow lesions, such as in the embolization of superficial AVMs. High flow lesions or aneurysm may be successfully treated under flow control as described above. Tissue infarct after the embolization of solid organs is expected, as it would occur in any other embolization procedure. Most procedures may be performed on an outpatient basis, unless a complication of other medical comorbidities prevents early discharge.

CONCLUSION

Onyx is an effective embolic agent, with several applications in peripheral embolizations and it is relatively simple to use. It is important to balance cost versus benefits when any embolic agent is selected, but at the same time, it would be desirable to have a more liberal use of Onyx in academic institutions to provide the opportunity for future interventionists to be trained in all the existing embolic agents.