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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3733_Библиотеки_им_академика_М_И_Перельмана.pdf
P
Section C Particulate Agents
6
Polyvinyl Alcohol Particles
Ajita Deodhar • John A. Kaufman
olyvinyl alcohol (PVA) is one of the oldest, particulate embolic
materials providing inexpensive, permanent occlusion of blood
vessels. It is a water-soluble, colorless synthetic polymer made from
polyvinyl acetate through partial or full hydrolysis to remove the acetate
groups. The extent of hydroxylation determines the physical, chemical, and
mechanical properties of the PVA.1 Typically, PVA is highly soluble in water
but resistant to most organic solvents, which allows it to be used for many
applications, including paper manufacturing, cosmetics, household sponges,
food packaging, and medical devices.2 The first ever medical use of PVA was
reported by Grindlay3 in 1949 at the Mayo Clinic as a prosthesis after
pneumonectomy. Since then, it has found multiple medical applications such
as cardiac surgery, skin grafting, embolic material, artificial cartilage,
artificial tear replacement, etc.2 Its nontoxic, inert properties have been well
established over the last several decades. Tadavarthy et al.
4,5
was the first to
report the use of PVA as an embolic material in the mid-1970s. It was used to
treat patients with cervical carcinoma, hemangiosarcoma of the liver,
hemangioendothelioma of the neck and forehead, and an arteriovenous
malformation of the spine.
DEVICE/MATERIAL DESCRIPTION
PVA is most commonly available as an intrinsically nonvisible occlusive
agent that is typically used in combination with contrast to be
radiographically visible. The preparation of PVA particles first involves its
conversion into a foam that can absorb water and become readily
compressible. Historically, sheets or blocks of dried foam were shaved to
yield irregular particles of varying sizes. The resulting shavings or particles
were then passed through sieves with sequentially smaller holes to separate
them into various sizes.
6
Given the irregular configuration of each individual
particle, it was possible for larger particles to pass through small holes
depending on its orientation as it passes through the sieve. This explains why
there was variability in early particle preparations.7 Today, PVA is supplied
as a preparation of irregular or spherical particles within a standardized size
range (Fig. 6.1), although the potential for size variability still exists within
the nonspherical preparations. This is a potential issue when using particulate
PVA because the presence of smaller particles than anticipated may lead to
uncontrolled distal embolization (with tissue infarction), whereas the
presence of larger particles than anticipated may lead to proximal
embolization (with potential recanalization).
PVA is extremely resilient and compressible with excellent memory,
allowing it to regain its shape and size once it comes in contact with body
fluids.7 In fact, due to its inherent memory, PVA particles have the potential
to expand approximately 4 to 15 times once they come in contact with
solution and can therefore occlude blood vessels slightly larger than the
internal diameter of the catheter.7 In addition, the particles have a tendency to
clump together when suspended in saline. Therefore, the effective size of this
agent is often larger than that of the individual dried particles, which can
contribute to a more proximal occlusion than intended.8 This property can
also increase the risk of microcatheter occlusion during delivery.
MECHANISM OF ACTION
The administration of PVA particles initially leads to slow flow due to
adherence of the particles to the vessel wall.9 This ultimately leads to an
inflammatory reaction, a foreign body reaction, and thrombosis.
10–12
PVA is
a nonbiodegradable embolic agent that has traditionally been thought to lead
to a permanent vascular occlusion.7 This occurs with organization of
thrombus, disappearance of the inflammatory infiltrate, and ingrowth of
connective tissue resulting in fibrosis. However, luminal recanalization after
embolization with PVA has been reported as well, which may be due to
resorption of thrombus and/or angiogenesis and capillary regrowth caused by
vascular proliferation inside the organized thrombus.
9,12,13
TECHNIQUE
Before using PVA as an embolic material, particulate PVA should be
reconstituted to allow for radiographic visualization during delivery. This can
be achieved by adding contrast, barium sulfate 60% or tantalum powder. To
decrease particle clumping, albumin, dextran, absolute alcohol, or absorbable
gelatin foam may be added to the saline suspension.
2
PVA embolization uses a flow-directed technique and is performed
under fluoroscopic guidance. During embolization, it is therefore necessary to
monitor the administration at all times to quickly recognize when antegrade
flow is slowing and vascular occlusion has taken place. Failure to recognize
the slowing and changing direction of flow can increase the possibility of
nontarget embolization due to particle reflux out of the target vessel. Given
the tendencies of these particles to clump, arterial occlusion may occur faster
than anticipated. In addition, frequent catheter flushing is recommended to
minimize the possibility of catheter occlusion.
CLINICAL APPLICATIONS
PVA finds application wherever particulate embolization of a permanent
nature is required. In general, this includes gastrointestinal or internal
hemorrhage secondary to trauma, anticoagulation, etc.; therapeutic or
presurgical tumor embolization; and embolization of uterine fibroids (uterine
artery embolization).
POTENTIAL COMPLICATIONS
The complications reported in association with embolization using PVA
particles have typically been related to the organ and pathology being
embolized as opposed to the embolic agent itself. However, complications
related to the characteristics of PVA can occur and are typically a function of
flow. As described, the characteristics of PVA particles can lead to particle
clumping, leading to proximal embolization with a potential for subsequent
recanalization and procedural failure. Avoiding particle clumping and
nontarget embolization requires attention to detail while preparing and
delivering PVA.
TIPS AND TRICKS
• PVA particles should be matched to the size of the arteries to be
occluded.
• The particles should be delivered in small aliquots with a 1-mL Luer
lock syringe using road map imaging to monitor for flow and reflux.
• After reaching the desired end point, it is prudent to wait for 5 min
and then perform another angiogram to check for return of flow due
to distal migration of clumped PVA.
• Adding a little 25% albumin to the contrast/saline dilutant (1:20)
minimizes clumping in the syringe. If the delivery catheter is blocked
with particles, it can be cleared with a 1-mL Luer lock saline syringe.
REFERENCES
1. Tubbs RK. Sequence distribution of partially hydrolyzed polyvinyl
acetate. J Polym Sci Part A-1: Polym Chem. 1968;4:623–629.
2. Baker MI, Walsh SP, Schwartz Z, et al. A review of polyvinyl alcohol
and its uses in cartilage and orthopedic applications. J Biomed Mater
Res B Appl Biomater. 2012;100:1451–1457.
3. Grindlay JH, Clagett OT. A plastic sponge prosthesis for use after
pneumonectomy; preliminary report of an experimental study. Proc Staff
Meet Mayo Clin. 1949;24:538.
4. Tadavarthy SM, Knight L, Ovitt TW, et al. Therapeutic transcatheter
arterial embolization. Radiology. 1974;111:13–16.
5. Tadavarthy SM, Moller JH, Amplatz K. Polyvinyl alcohol (Ivalon): a
new embolic material. Am J Roentgenol Radium Ther Nucl Med.
1975;125:609–616.
6. Siskin GP, Englander M, Stainken BF, et al. Embolic agents used for
uterine fibroid embolization. AJR Am J Roentgenol. 2000;175:767–773.
7. Derdeyn CP, Moran CJ, Cross DT, et al. Polyvinyl alcohol particle size
and suspension characteristics. Am J Neuroradiol. 1995;16:1335–1343.
8. Choe DH, Moon HH, Gyeong HK, et al. An experimental study of
embolic effect according to infusion rate and concentration of
suspension in transarterial particulate embolization. Invest Radiol.
1997;32:260–267.
9. Germano IM, Davis RL, Wilson CB, et al. Histopathological follow-up
study of 66 cerebral arteriovenous malformations after therapeutic
embolization with polyvinyl alcohol. J Neurosurg. 1992;76:607–614.
10. Castaneda-Zuniga WR, Sanchez R, Amplatz K. Experimental
observations on short and long-term effects of arterial occlusion with
Ivalon. Radiology. 1978;126(3):783–785.
11. White R, Stranberg JV, Gross G, et al. Therapeutic embolization with
long-term occluding agents and their effects on embolized tissue.
Radiology. 1977;125:677–687.
12. Link DP, Strandberg JD, Virmani R, et al. Histopathologic appearance
of arterial occlusions with hydrogel and polyvinyl alcohol embolic
material in domestic swine. J Vasc Interv Radiol. 1996;7:897–905.
13. Tomashefski JF, Cohen AM, Doershuk CF. Long-term histopathologic
follow-up of bronchial arteries after therapeutic embolization with
polyvinyl alcohol (Ivalon) in patients with cystic fibrosis. Hum Pathol.
1988;19:555–561.
S
7
Spherical Embolic Agents
Alan D. Birney • Gary P. Siskin
ince 1974, polyvinyl alcohol (PVA) particles have been used as a
particulate agent for embolization procedures.1 However, as
experience was gained with this agent, its inherent limitations and
disadvantages were recognized. These include size variability in a given
preparation of particles due to the manufacturing process, particle
aggregation, and microcatheter occlusion during delivery. Spherical embolic
agents were developed in response to these limitations and become
increasingly popular since their introduction.
2
DEVICE DESCRIPTION
Trisacryl Gelatin Microspheres
In 1996, Laurent et al.3 reported on the development of a spherical,
nonresorbable embolization agent. These microspheres (Embosphere
Microspheres; Merit Medical Systems, Inc., South Jordan, Utah) consist of a
trisacryl polymer that is impregnated and embedded with gelatin (Fig. 7.1A).
Trisacryl gelatin microspheres had been initially manufactured in the mid-
1980s for use as a microcarrier for cell cultures.4 These microspheres are
biocompatible, hydrophilic, and deformable. In addition, cellular adhesion to
these microspheres is supported by the presence of denatured collagen on
their surface.
3
,4
Interventionalists instantly accepted these microspheres once they
became commercially available because they successfully addressed the
limitations of particulate PVA. The manufacturing process of these
microspheres enabled a more narrow and reliable range of particles to be
produced.
2,3
In addition, these microspheres did not aggregate, possibly due
to their spherical configuration, the presence of a positive surface charge on
the microspheres, and their hydrophilic nature.
2,5,6
In addition, a more
predictable target occlusion could be achieved due to the fact that these
microspheres did not aggregate. Derdeyn et al.5 demonstrated that trisacryl
gelatin microspheres occlude more distally than PVA particles of matched
size, supporting the absence of aggregation when these microspheres are
used. In fact, the level of vascular occlusion appears to correlate closely with
the diameter of the microspheres used for embolization.
6–8
The narrow size
range of microspheres, their lack of aggregation, and their deformability
minimize the risk of microcatheter occlusion and contribute to the ease of
delivery during administration.
The cellular response to embolization with trisacryl gelatin microspheres
has been described. Macrophages, polymorphonuclear cells, and sparse
lymphocytes have all been described after embolization with these
microspheres, as has vessel recanalization.
3,9–11
Interestingly, these
microspheres often undergo transvascular migration and can be found within
the vessel lumen, within the vessel wall, or completely outside of the vessel
after embolization11; PVA particles are less likely to be found outside of the
vessel. This has been attributed to the inflammatory reaction induced by these
microspheres.
Polyvinyl Alcohol Microspheres
Given the decades of success seen with embolization procedures performed
with particulate PVA, it seems logical that a PVA-based microsphere
(Contour SE Microspheres; Boston Scientific Corporation, Natick,
Massachusetts) would be developed as a next generation embolic agent (Fig.
7.1B). PVA microspheres appear to generate a milder inflammatory response
than both particulate PVA and trisacryl gelatin microspheres.9 After
embolization, neutrophils are acutely seen, but these are ultimately replaced
by macrophages and occasional lymphocytes.
PVA microspheres, like trisacryl gelatin microspheres, address the
disadvantages of particulate PVA with better size uniformity, less
aggregation, and ease of administration. However, many of the inherent
properties differ between these microspheres, including compressibility and
elastic recovery.10 PVA microspheres have been shown to be highly
compressible with a delayed and incomplete elastic recovery, leading to a
more distal embolization when compared to other spherical embolic agents.
7,8
This is felt to be due to change in shape of the particle with compression
during delivery, which allows them to deform and occlude more distally than
intended.
Acrylamido PVA microspheres (Bead Block microspheres;
Biocompatibles, Inc., Oxford, Connecticut) consist of a PVA-based hydrogel
polymer (Fig. 7.1C). Its properties have been shown to be intermediate
between spherical PVA microspheres and trisacryl gelatin microspheres, with
similar compression and nearly immediate subsequent reexpansion when
compared with trisacryl gelatin microspheres.2 These microspheres have been
found to occlude slightly more distal than trisacryl gelatin microspheres,
which is likely due to the slight differences in force required to compress the
microspheres.
Polyphosphazene-Coated PMMA Microspheres
Polyphosphazene-coated polymethylmethacrylate (PMMA) microspheres
(Embozene Microspheres; CeloNova BioSciences, Inc., San Antonio, Texas)
consist of a Polyzene-F shell surrounding a hydrogel core of PMMA (Fig.
7.1D). When PMMA undergoes an alkaline hydrolysis, its structural
flexibility increase, making it an appropriate material to use for an embolic
agent.12 This was theorized as early as 1989 by Jayakrishnan et al.
13
Polyzene-F is a proprietary, biocompatible, and nonresorbable version of the
poly(bis[trifluoroethoxy]phosphazene) (PTFEP) polymer class and is applied
as a thin coating on the PMMA core.14 Polyzene-F has previously been used
in vascular stents where it was found to have an absence of a significant
inflammatory reaction.15 A preclinical evaluation by Stampfl et al.
14
demonstrated similar findings, with only a minimal lymphocyte-mediated
inflammatory reaction noted after embolization in a renal artery model. This
is different from the findings of Verret et al.,12 which noted early recruitment
of phagocytic cells in a uterine artery model. In terms of the distribution of
these microspheres within embolized vasculature, Verret et al.
16
demonstrated that they occlude more distal vessels than similarly sized
trisacryl gelatin microspheres. They attributed this finding to their
compressibility and deformability, enabling them to conclude that
deformability determines the size of the vessel occluded as opposed to the
actual particle size, which potentially makes the level of occlusion
unpredictable with these microspheres.