Author: mrtnsmits

Maarten Smits, Max Seidensticker
UMC Utrecht and LMU Hospital Munich

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Principle of embolization

This article is about therapeutic embolization, in which a part of the blood circulation is impeded by the introduction of embolization agents.
An embolus is defined as “Undissolved material carried by the blood and impacted in some part of the vascular system (…)” (Dictionary.com).
The indications for embolization can be grossly categorized into bleeding control, occlusion of pathologic vasculature, and tissue ablation. See table 1.


a. Coaxial catheterization technique using a 4-6F catheter that accomodates a 1.5-3F microcatheter that can be used to negotiate further in the vascular system. b. Example of a microcatheter (Progreat® [Terumo]).

 

Catheterization

Access to the vessel to be embolized can be obtained by direct puncture (superficial varicose veins, fistula or malformation) or indirectly via an endovascular approach. We will focus on the endovascular approach. The target vessel should be catheterized with a catheter that is able to negotiate the vasculature and allow passage of the embolization agent.
Microcatheters are most suitable for this purpose. These catheters usually have a straight tip and a typical outer diameter (OD) of 1.5-3 French (F). They can be advanced coaxially through a larger supporting catheter (OD 4-6 F) in order to reach deep in the vasculature. Guiding sheaths or guiding catheters can be used for support as well.

 


Two types of anti-reflux catheters. a-b. Cone-shaped Surefire infusion system® [Surefire Medical]. The deployed tip is faintly visible (see radiopque markers at the arrow). c-d. Occlusafe® microcatheter featuring a balloon at the tip [Terumo].
A stable position of the entire coaxial system is key when administering the embolization agent to minimize the risk of non-target embolization. Exciting developments in this field are the anti-reflux catheters that use either a cone- or umbrella-shaped tip (e.g. Surefire infusion system®, Surefire Medical Inc.), or a balloon (Occlusafe®, Terumo) to prevent reflux of embolization agent and thus non-target embolization. These catheters are mainly used for chemoembolization or radioembolization.

 

Example of microcatheters with a detachable tip, Sonic Fusecath® [Balt extrusion]

 

When using agents like histoacryl or ethylene-vinyl alcohol (Onyx®) there is a risk that the microcatheter gets stuck in the embolus. Leaving a microcatheter inside the body (after cutting off the external part) causes surprisingly little symptoms, and the catheter will eventually be integrated in the vessel wall. This is of course not a desirable situation. To overcome this issue, manufacturers have developed catheters with a detachable tip akin to a lizard’s tail (e.g. Apollo® [Medtronic] and Sonic® [Balt]). The tip breaks off when the tip is fixed in an embolus and the rest of the catheter is pulled outwards, leaving only a small part of the catheter in situ.

Embolization agents

There is a large variety of agents available to perform embolization, ranging from autologous blood clot to devices like coils or vascular plugs, see Table 2.
Choosing the embolization agent depends on the indication and the experience at hand. Each agent has its specific advantages and disadvantages. Factors influencing the choice of material comprise the size of the target vessel, flow velocity, and duration of embolization (permanent/temporary).

Autologous blood clot

In acute situations, the patient’s own blood can be used for embolization. A small amount of blood is withdrawn and kept for a few minutes after which thrombus has formed and can be reinjected at the point of hemorrhage. This form of embolization is temporary.

Schematic display of thrombin injection in a false aneurysm.

Thrombin

Thrombin is well known for embolizing false aneurysms (aneurysm spurium), particularly in the groin after femoral arterial puncture. This technique - first described in 1986 – consists of direct, ultrasound guided injection of thrombin in the false aneurysm. The primary success rate is about 90%. Aneurysms should have a small neck to avoid spill of thrombin into the femoral artery which can cause femoral artery thrombosis (0.5-1% risk).

 

The neck of the aneurysm should be identified. This neck should ideally be narrow relative to the overall size of the false aneurysm to avoid spill of thrombin in the femoral artery. See video.

 
Thrombin is injected under ultrasound-guidance. The ultrasound probe can be used to compress the neck of the false aneurysm. However, a little inflow of blood is needed to evenly spread the thrombin through the aneurysm.

A variety of coil shapes: a. Nester® coil [Cook Medical], b. Complex helical coil [Boston Scientific], c. Straight Hilal® coil [Cook Medical], d. Figure 8 coil [Boston Scientific], e.  Vortx coil [Boston Scientific], f. Vortx Diamond coil [Boston Scientific], g. Multi-curled Hilal® coil [Cook Medical], h. AZUR® framing coil [Terumo]

Coils

Coils are probably the most used type of embolic agent. Coils are braided wires generally made of platinum or stainless steel that can be loaded into a catheter and will coil into shape when released out of the catheter or sleeve. Coils come in a large variety of shapes and sizes fit for specific situations. Most coils have protruding fibers to enhance thrombosis.
Common thicknesses of coils are: 0.014”, 0.018”, 0.035” and 0.038”. Microcatheters will generally only accomodate 0.014” and 0.018” coils. Other important dimensions of coils are their length (mostly in the range of 1-10cm) and their diameter when deployed (range of 1-20mm). As a general rule, the diameter of the coil should be oversized about 20% compared to the vessel diameter as measured on DSA.

Indications:
- Traumatic hemorrhage
- Aneurysms
- Varices (in certain cases)
- Arteriovenous fistulas

 

Case of embolization for acute hemorrhage from a branch of the left hepatic artery (arrow). This was iatrogenic injury after abdominal surgery. A combination of Gelfoam, straight- and figure-8 coils was used. No more extravasate after embolization (B).

 

 

Coil packaging [Boston Scientific].

Saline-flush Technique.

Coil delivery

Coils often come packaged in a protective sheath (see figure). The coil is inserted by placing the sheath in the back end of the catheter. Then, the plunger that comes with the coil, is pushed all the way into the back end of the sheath containing the coil. The coil is then loaded into the catheter.
From there on, coils can be pushed through the catheter using a coil pusher. Alternatively, pushing the coil with a saline bolus is a fast way to deliver coils (saline-flush technique).

Coiling techniques

Packing coils in a large calliber vessel can be challenging. Here are a few techniques that can be used.

 

In the standard (coaxial) technique, coils are densely packed by pushing and pulling the microcatheter forward and backward.

In the anchor technique, a side branch is used to anchor the first coil which is intentionally protruding into the mother vessel. This provides an anchor for following coils.

In the scaffold technique, an oversized coil with high radial force is placed first. This coil will stay in position due to its high radial force. The scaffold created this way can be filled with smaller and softer coils. The scaffold technique is particularly usefull in large or high-flow vessels.

 

a. Interlock™ system [Boston scientific], b. Concerto™ system [ev3], c. InZone® Detachement system [Stryker], d. Axium™ Instant Detacher [ev3].

Detachable coils

Conventional coils are deployed once pushed out of the catheter. Incorrectly placed coils can cause serious complications and can be hard to retrieve. Several types of detachable coils have been developed to enable more controlled coil-embolization. Detachable coils are helpful for embolization in high-flow vessels, embolization close to the origin of a vessel, and for aneurysms when dense coil packing is desired. Detachable coils can be retracted and redeployed a number of times until satisfactory placement is reached and the coil is detached.
There are several types of detachable coils that have their own method of detaching. Some coils are locked onto the pusher and are released when the coil is fully pushed out of the catheter. Most detachable coils work with some kind of detacher that mechanically or electronically activates a release mechanism (see images for examples).

a. Dense coil packing in the gastroduodenal artery prior to yttrium-90 radioembolization. b. The attempt to embolize up to the origin of the gastroduodenal artery led to a coil protruding into the proper hepatic artery (arrow). c. Embolization up to the origin of a vessel is easier controlled using detachable coils (different case then a and b, using Interlock®[Boston Scientific]).

a-c. PCOM aneurysm embolized using detachable coils

Several types of vascular plugs: A-C. Amplatzer plugs [St. Jude Medical], D. Microvascular plug system [ev3]

 

 

Deploying an Amplatzer plug

 

Plugs

Vascular plugs are devices made of a nitinol mesh that expand into their original shape when deployed. Plugs can be used as alternatives to coils for controlled embolization of a large vessel, vessel wall defect or pseudoaneurysm. A single plug can be used to embolize a vessel that would otherwise require multiple coils. Vascular plugs are detachable.

Indications:
- High flow vessels
- Large defects

Endoleak repair with a plug post TEVAR. a. DSA from the left subclavian artery shows a small endoleak. An Amplatz plug (14mm x 10mm) was placed in the origin of the subclavian artery (b). c. Volume rendered CTA image shows the position of the plug in relation to the TEVAR stent.
a. Case of a arteriovenous fistula of the suprascapular artery in a young patient years after a wound from a glass incident. b. A 7mm x 20mm balloon was used to obstruct the high flow fistula. c. Coils were added to fully embolize the efferent artery. D. Goldballoon® [Balt extrusion].

Detachable Balloon

The first use of detachable balloons were described by dr. Serbinenko in 1974. Detachable balloons are an excellent tool for obstructing high-flow vessels or fistulas where coils can easily dislodge. The method of detachment can differ, one system works by pushing a larger catheter over the balloon catheter wheras another systems requires gentle traction on the balloon catheter to detach the balloon.

Indications:
- High flow vessels
- Fistulas

Particles

Embolic particles can be devided into spherical and non-spherical particles.
Spherical particles, sometimes called spheres or microspheres, come in several sizes ranging from app. 40 – 1300μm (micron). Some products are advertised to have a tight size callibration which is favorable for controlled embolization. Examples of spherical particles are: Embozene® [Boston Scientific], Embosphere®/Embogold®/Quadrasphere® [Merit Medical Systems], Contour SE™ [Boston Scientific], Bead Block® [BTG], and LC Bead®/DC Bead® [AngioDynamics], see Table.
Microspheres can be used for embolization of tumors as well, especially when containing drugs or radioactive elements. TransArterial ChemoEmbolization (TACE) and Radioembolization (a.k.a. Selective Internal Radiation Therapy, SIRT) are well known examples of embolization for oncologic purposes. Tumor embolization can also be performed with inactive particles, which is referred to as ‘bland’ embolization.

Particles for embolization a-b. Embozene® microspheres [Boston Scientific] c. Embospheres® [merit Medical] d. Bead Block® [BTG-IM] e. LC Bead® [BTG-IM]  f. Contour™ PVA embolization particles [Boston Scientific].

 

 

Poly-vinyl alcohol particles (PVA) are mostly non-spherical, although spherical PVA particles are available as well.  PVA particles are irregularly shaped, can aggregate and the embolization is slightly less predictable then with spherical particles.
Non-target embolization is a great risk of particles. Since particles are very small they can shunt into non-target vessels or through arteriovenous shunts and cause severe complications and even death. Most types of particles are not visible under angiography.
Indications:
- Recurring hemorrhages, access for future embolization needs to be preserved (e.g. nasopharyngeal or bronchial hemorrhage)
- Tumors
- Hemoptysis
- Uterine fibroids

 

Embolization of a uterus myoma. a. DSA pre-embolization b. post-embolization with 700μm Embozene® particles.
Gelfoam® preparation. (figures courtesy of Dr. Orhan Konez)

Gelfoam®

Gelfoam® [Pfizer] is a sterile compressed sponge created from gelatin granules and purified porcine skin. Gelfoam® comes as a layer of foam that should be cut into small pieces and then mixed with contrast solution to create a very thick mixture (slurry) that can be used for embolization.

Gelfoam® is a fast, cheap and reliable embolic agent. Its key characteristic is non-permanent embolization. Gelfoam® is usually completely resorbed in a few weeks.
Indications:
- Traumatic hemorrhage
- Post-partum fluxus
- Uterine fibroids

Liquid embolics

There is a variety of liquid embolics. Liquid embolics can be applied by direct injection into the target region or transcatheter injection. Liquids can be combined with non-liquid embolic agents such as coils or plugs.

 

 

Glue

Cyanoacrylate (Histoacryl®) is similar to glue used for all kinds of purposes in and around the house. It is a monomere that polymerizes when in contact with water or blood. Histoacryl is a blue colored substance that comes in small pipets (see image).
Histoacryl can be diluted with Lipiodol for radiopacity and to prevent immediate solidification. The catheter needs to be primed with 5% glucose water before injection. Then, Histoacryl is slowly injected and a cast will form distal to the catheter tip. After a few seconds the catheter can be retracted with a firm pull. Make sure there is no reflux to prevent non-target embolization or catheter entrapment.
Indications:
- Traumatic or iatrogenic hemorrhage
- Vascular malformations
- Tumor embolization
- Portal vein embolization

 

 

 

a. Aethoxylerol® [Kreusler pharma] b. Dehydrated alcohol injection [Akorn]

Sclerosants

Intravascularly injected sclerosants lead to and inflammatory reaction resulting in endothelial damage and fibrotic obstruction of the vessel or vascular malformation. Sclerosants are indicated to embolize a peripheral vascular bed.
Examples are:
Polidocanol (Aethoxysklerol®), alcohol, detergents, and antibiotics (doxycycline, bleomycine).
Indications:
- Varices
- Vascular malformations
- Tumor embolization

 

 


Onyx® [ev3]

Precipitating agents

There is a category of liquid embolics consisting of ethylene vinyl alcohol copolymers that are dissolved in dimethyl sulfoxide (DMSO) and are mixed with tantalum powder for radiopacity. Examples of available products in this category are: Onyx® [Covidien], SQUID™[Emboflu], and PHIL® [Microvention].
These precipitating agents need to be shaken at least 20 minutes prior to use to obtain a homogeneous mixture of the tantalum powder. Catheters and hubs used need to be compatible with DMSO since standard plastics are dissolved by DMSO. The dead space of the catheter needs to be primed with DMSO before injection.
Once injected into the body, DMSO dissolves and the ethylene vinyl alcohol copolymeres precipitate inside the blood vessels. The embolic agent can be pushed deep into the vascular bed by slow, intermittent injections. Backflow along the catheter can be managed by pausing injection and waiting for a plug to form around the catheter tip. Consequent injections will follow the path of least resistance which is then hopefully away from the catheter and into the target vasculature. Microcatheters with a detachable tip are strongly recommended.
Indications:
- Vascular malformations
- Hemangiomas
- Aneurysms

Various embolic agents in relation to the vessel size that they are capable of embolizing

Choice of material

The choice of embolic agent depends on many factors. Safety is the main factor, therefore experience of the interventionalist with the embolic agent and risk of non-target embolization should always be weighed.
Other factors are the organ or lesion to be embolized, the desired effect of embolization (permanent or temporary), proximal or distal embolization. Availability and costs of the embolic agent are not unimportant either.
Distal embolization (using liquids or small particles) is more likely to cause tissue necrosis since end-arterioles are blocked and collaterals have no way of reaching the vascular bed. Distal embolization carries a high risk of shunting to non-target organs such as the lungs or brain.
Many embolic agents can be combined to increase efficacy.

References

  • 1. Cope C, Zeit R. Coagulation of aneurysms by direct percutaneous thrombin injection. AJR Am J Roentgenol 1986; 147: 383–387.
  • 2. Vascular Embolotherapy - Vol 1. General Principles, Chest, Abdomen and Great Vessels-2006. Springer.
Maarten Smits, UMC Utrecht

Electron microscope image of resin 90Y-microspheres

 

 

Rationale

Radioembolization (RE) is a form of internal radiation therapy for tumors in the liver.

RE is performed with microspheres containing radioactive yttrium-90 or holmium-166 that are administered in the hepatic arteries from an endovascular catheter.

The liver has a dual blood supply. The liver parenchyma relies mostly on the portal vein for blood supply. In contrast, tumors arising in the liver are predominantly fed by the hepatic artery.1,2

Table 1. Tumor types

 

Table 2. Gross selection criteria

Patient selection

RE can be performed in patients with all kinds of tumors in the liver, ranging from primary tumors such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCC) to liver metastases from colorectal carcinoma, breast cancer, neuroendocrine tumors and melanoma, see table 1.

 

 

 

There is much discussion about the exact selection criteria for RE. Table 2 lists the gross selection criteria that many centers use.3

More information is available on the websites of the manufacturers of yttrium-90 microspheres: SIR-Spheres(R) and Therasphere(R). QuiremSpheres(R), containing holmium-166 are not commercially available yet.

Aberrant left hepatic artery arising from the left gastric artery (arrow)

Vascular anatomy

Before proceeding with a work-up angiography it is advisable to have a look at the patient’s vascular anatomy. The arterial anatomy of the liver region can vary widely between patients (see figure). A thin slice CT angiography viewed in MIP-mode can help to identify variant anatomy.4,5

Figures from ref 5 with permission from Springer

Work-up procedure in the angiosuite.

Digital subtraction angiography with contrast injection in the common hepatic artery. 
Injection position of 99mTc-MAA in the right hepatic artery after coil embolization of the gastroduodenal artery (long arrow) and the right gastric artery (short arrow). Subsequent injection position in the left hepatic artery. Images reproduced from Smits et al. Eur J Pharm 2013, with permission from Elsevier. 

Work-up angiography

  1. Perform a contrast run from the celiac axis and the superior mesenteric artery (for abberant vessels).
  2. Assess the vascular anatomy. The anatomy should have been assessed on CTA at this point.
  3. Embolization of non-target vessel (see subtopic)
  4. Perform C-arm CT (see subtopic)
  5. Inject 99mTc-MAA at the desired injection positions

Panel a displays a digital subtraction angiography with contrast injection in the common hepatic artery in a breast cancer liver metastases patient. Panel b: 1. common hepatic artery; 2. gastroduodenal artery; 3. right gastric artery; 4. left hepatic artery, 5. right hepatic artery. Tumorous areas are marked with ‘T’, catheter as a white dotted line.

Embolization of non-target vessels

Traditionally, all non-target vessels arising near to the injection position are coil-embolized. These vessels typically include the gastroduodenal artery (GDA) and right gastric artery (RGA). Currently, most centers decide whether or not to close these vessels based on the vascular anatomy (e.g. Where is the origin of the GDA? Is there retrograde flow in the GDA?) and intended injection position(s). Also, the use of an anti-reflux catheter may decrease the risk of back-flow and thus the need of closing the non-target vessels.

 

Cystic artery

The cystic artery can pose a dilemma. The cystic artery often arises from the right hepatic artery and closing this vessel to prevent radiation cholecystitis may be tempting. Closure may however cause ischemic cholecystitis. The consensus of the available literature on this topic seems to be that in case of visually (so no dosimetry needed) high 99mTc-MAA deposition in the gallbladder, one should seek a more distal injection position. If that is not possible, one can choose to (partially) close the cystic artery with coils or gelfoam, preferably at the time of the treatment angio to avoid formation of new collateral vessels.6,7

C-arm CT used to ensure complete tumor coverage. Depicted is a neuroendocrine tumor, supplied by the left- (in red) and right hepatic artery (in blue/green).

Cone-beam CT

One can use the C-arm at the angio suite to acquire cross-sectional CT images. This technique is called C-arm CT or cone-beam CT. The combination of CT with contrast injected via an endovascular catheter can be useful in several ways:

  1. Non-target embolization detection:
    Is there any enhancement of non-target organs?
  2. Selecting the target vessel supplying a tumor
    In case of multiple vessels projecting on top of each other on 2D-angiography, the target vessel can be identified using C-arm CT.
  3. Assessment of the target volume:
    What is the size of the volume that is reached from a certain injection position?
  4. Tumor coverage:
    Is the tumor completely covered? A tumor may be supplied by multiple vessels from within the liver or outside the liver A large variety of parasitic vessels have been described, particularly in HCC. Incomplete tumor coverage will lead to inadequate treatment.

99mTc-MAA SPECT and corresponding 90Y-SPECT. Images reproduced from Smits et al. Eur J Pharm 2013, with permission from Elsevier. 

99mTc-MAA imaging

After injection of 99mTc-MAA at the work-up angio, the distribution is assessed using nuclear imaging.

 

Non-target embolization

Distribution of 99mTc-MAA anywhere outside the liver can be detected with 99mTc-MAA-SPECT and should be resolved before treatment. Regions of interest are the duodenum, stomach, pancreas, falciform ligament and umbilicus. Free pertechnetate can cause diffuse high activity in the stomach simulating non-target embolization. This can be recognized by its characteristic pattern and accompanying high uptake in the thyroid gland. With the growing experience of many IR-teams and the growing use of C-arm CT, non-target embolization is now more and more frequently detected already during angio. Some experts have even gone as far as stating that 99mTc-MAA is only necessary for lung shunt detection.

 

Lung shunt

Hepatopulmonary shunting can be evaluated on planar imaging. In fact, the limit of a maximum 20% lung shunt fraction is based on studies using planar imaging. However, it is clear that attenuation-corrected Single Photon Emission Computed Tomography (SPECT) is far more accurate than planar imaging. Even when using SPECT, it seems that 99mTc-MAA tends to overestimate the amount of lungshunting when compared with the actual microspheres.8

 

 

a. Administration of 90Y-microspheres in the angio-suite. b. Therasphere administration system

Treatment angiography

After the work-up angiography and 99mTc-MAA imaging, the patient returns for the actual treatment procedure. This is generally performed 1 or 2 weeks after the work-up angiography.

In the angiosuite, a microcatheter is placed in the exact same position(s) as where the 99mTc-MAA has been injected. Next, the administration system holding a vial that contains the radioactive microspheres is attached to the microcatheter. The administration system consists of a perspex box for SirSpheres, Theraspheres, and Quiremspheres (perspex absorbes most beta radiation), see images.

The microspheres are brought into suspension and pushed forward through the tubing system and into the microcatheter. Depending on the type of microspheres and type of tumor, one should monitor the forward flow distal to the catheter to avoid reflux.

Post-treatment dosimetry

Post treatment imaging to visualize the distribution of the radioactive microspheres can be useful in order to confirm an adequate dose to the tumors and no non-target deposition.

Post treatment imaging for yttrium-90 microspheres can be performed with Bremsstrahlung SPECT (indirect gamma-emission from decelerating beta-particles) and with PET (32 positrons per million decays), see figure A.

Holmium-166 microspheres on the other hand can be visualized with SPECT (direct gamma-emission) and with MRI (holmium is a paramagnetic element). See figure B.

References

  • 1. Bierman HR, Byron RL, Jr., Kelley KH, et al. Studies on the blood supply of tumors in man. III. Vascular patterns of the liver by hepatic arteriography in vivo. Journal of the National Cancer Institute 1951; 12(1)
  • 2. Dezso K, Bugyik E, Papp V, et al. Development of arterial blood supply in experimental liver metastases. The American journal of pathology 2009; 175(2)
  • 3. Coldwell D, Sangro B, Wasan H, et al. General selection criteria of patients for radioembolization of liver tumors: an international working group report. American journal of clinical oncology 2011; 34(3)
  • 4. van den Hoven AF, Smits ML, de Keizer B, et al. Identifying aberrant hepatic arteries prior to intra-arterial radioembolization. Cardiovascular and interventional radiology 2014; 37(6)
  • 5. van den Hoven AF, van Leeuwen MS, Lam MG, et al. Hepatic arterial configuration in relation to the segmental anatomy of the liver; observations on MDCT and DSA relevant to radioembolization treatment. Cardiovascular and interventional radiology 2015; 38(1)
  • 6. Prince JF, van den Hoven AF, van den Bosch MA, et al. Radiation-induced cholecystitis after hepatic radioembolization: do we need to take precautionary measures? Journal of vascular and interventional radiology : JVIR 2014; 25(11)
  • 7. McWilliams JP, Kee ST, Loh CT, et al. Prophylactic embolization of the cystic artery before radioembolization: feasibility, safety, and outcomes. Cardiovascular and interventional radiology 2011; 34(4)
  • 8. Elschot M, Nijsen JF, Lam MG, et al. ((9)(9)m)Tc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with (1)(6)(6)Ho-microspheres. European journal of nuclear medicine and molecular imaging 2014; 41(10)

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