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208
6 Side Eects andTreatment Methods ofFiller Procedures
Prevention
In order to prevent intra-arterial ller injections,
it is recommended to inject at the supraperiosteum level where there is the least amount of
blood vessels.
Using a cannula can never guarantee safety.
According to literature, a large number of blindness accidents occurred after ller or fat transplantation using cannula, and even reported when
a 2mm diameter cannula was used.
HA llers also do not guarantee safety. In
addition to HA llers, ocular complications have
been reported by various llers such as corticosteroids, parafn, silicone oil, and bovine collagen. In cases of blindness caused by HA ller,
hyaluronidase can be injected by the retrobulbar
injection technique to dissolve emboli in the central retinal artery. This has been proven effective
in animal experiments.
Location
Ocular complications are more likely to occur in
the eyebrow, forehead, and nose areas where the
branches of the ophthalmic artery are distributed.
Since ICA and ECA are anastomosed, it may also
be caused by arteries in other parts of the face
(temple, nasolabial fold, anterior cheeks, perioral
area, etc.).
6.2.4 Vascular Complication:
Pulmonary Embolism
Recently, blindness and cerebral infarction have
been emphasized as fatal complications after
ller injection. This is caused by ller material or
autologous fat injected into the arteries. Another
fatal side effect caused by intravenous injection is
pulmonary embolism.
According to the literature, pulmonary embolism occurs after the injection of autologous fat
or ller in the facial region, and some have
resulted in death.
In addition, there are reports of pulmonary
embolism by injection of the vulva and vaginal
llers for perineal rejuvenation.
Mechanism
Pulmonary embolization after the ller procedure
mainly occurs at the temporal region because of
the relatively large diameter of the sentinel vein
and middle temporal vein in the temple. The sentinel vein is about 2 mm in diameter, and the
middle temporal vein is about 5mm in diameter.
When ller is injected into these veins, the emboli
may move from the supercial temporal vein ->
external jugular vein -> heart -> pulmonary
artery, eventually causing pulmonary embolism
(See Sect. 5.1.3 temple).
Prevention
In order to prevent the occurrence of pulmonary
embolism by ller injection in the temple, it is
necessary to be aware of the depth and movement
of the sentinel vein and middle temporal vein.
The sentinel vein is more supercial than the TPF
(temporoparietal fascia), that is, it travels in the
subcutaneous layer and penetrates the TPF and
deep temporal fascia (DTF). It is then connected
to the middle temporal vein in the layer between
the supercial and deep layers of the DTF.
To prevent ller injection into these large
veins, two other methods are recommended
besides subcutaneous layer injection.
The rst method is injection into the supercial layer. It is injected into the space between
TPF and DTF, which has the least distribution of
large veins. Filler with a medium viscoelasticity
is injected using a cannula. A small amount of
ller is effective and is the safest way to inject
(See Sect. 5.1.3 temple).
The second method is to inject into the deep
layer. Inject into the space between the temporalis muscle and the supraperiosteum. Use a ller
with a high viscosity and inject with a needle.
Many practitioners often prefer to inject into
the subcutaneous fat layer. This is because there is
anxiety about deep injections and having little
condence in the injection layer. Since the sentinel
vein runs for a distance in the subcutaneous fat
layer, it is likely for a physician to damage the sentinel vein and cause bleeding while injecting in the
subcutaneous fat layer using a needle or cannula.
6.2 Treatment andPrevention ofVascular Complication
209
Therefore, it is necessary to know the location
and pathway of the sentinel vein before injecting
carefully.
6.2.5 Prevention ofVascular
Complication
6.2.5.1 Procedural Tips toReduce
Vascular Complications
Vascular complications after a ller procedure
can result in fatal sequelae, so utmost care must
be taken when treating facial areas. There are
several tips to reduce vascular complications:
• Choose proper tools (ller, syringe, cannula/
needle).
• Visualize the anatomical structure.
• Inject gently and in small volumes (4R).
: Remove and reinsert injection tools ->
Recheck with an aspiration test -> Retrograde
injection
• Feel the injection force and volumizing
resistance.
• Check the patient’s response (sharp pain, neu-
rologic symptom).
Choose Proper Tools (Filler, Syringe,
Cannula/Needle)
Fillers that can be dissolved in the case of side
effects are limited to hyaluronic acid llers, so
beginners should start with hyaluronic acid llers
to be safe.
The viscosity of the ller affects the force of
injection as well as the degree of correction, so
the choice of viscosity is important. If the injection force needed by a beginner is too strong, the
beginner tends to shake while injecting. If this is
the case, it is advisable to use a ller which is one
level lower than the viscosity recommended for
the treatment site to prevent it from being injected
incorrectly into another space.
The larger the diameter of the syringe barrel,
the stronger the injection force. Beginners are
advised to use a smaller diameter syringe to
inject. Smaller diameters and longer lengths of
the cannula will also increase ejection pressure,
so using a shorter injection tool with a proper
diameter can lower the injection force needed.
Since the cannula and needle are structurally
different, it is recommended to use them appropriately according to the treatment area and depth
of injection (See Sect. 4.4.3 selection of cannula
and needle).
The preference between a cannula and needle
and which one is more helpful in preventing vascular complications is controversial. This will be
covered later in this chapter.
Visualize the Anatomical Structure
Unlike open surgery, ller procedures are performed blind without any eld of view. Therefore,
there is a higher probability of tissue or blood
vessel damage. Therefore, one needs to be aware
of the structures under the skin. The anatomical
structures most often associated with complications are blood vessels (see Sect. 3.1 vasculature). It should be understood that the routes of
blood vessels are not two-dimensional but threedimensional. In other words, one must not only
nd the path of blood vessels, but the depth of the
blood vessels at a specic location must be considered also.
Arterial vessels in the facial area consist of the
ECA origin group and the ICA origin group.
Blindness which is the most lethal side effect of
vascular complications occur when llers are
injected into the central retinal artery which is a
branch of the ICA.However, these two groups of
blood vessels are not completely separated but
are connected to each other. Even if intravascular
ller injection occurs in the ECA, the emboli
may reach the central retinal artery (a branch of
the ICA) resulting in blindness. Therefore, it is
important to know the location of the ICA and its
associated arteries.
Avoiding the location of the associated blood
vessels that cause vascular complications within
the treatment site and then injecting ller into the
vascular-free layer is a shortcut to prevent
complications. With the least distribution of blood
210
6 Side Eects andTreatment Methods ofFiller Procedures
vessels, the generally recommended injection
layer is the supraperiosteum level. However,
there are always anatomical variations, so one
must be sure to familiarize oneself with anatomical knowledge and safe procedural skills.
Inject Gently and in Small Volumes (4R)
: Remove and reinsert -> Recheck with aspiration test -> Retrograde injection
The author has a series of steps to prevent side
effects when treating areas with high possibility
of blood vessel damage. After inserting the injection tool, the ller is not injected immediately.
Remove the injection tool and conrm that there
is no bleeding. ->Next, reinsert the injection tool
through the passage. For example, in the correction of the temple, if a thick, short needle
(23G~25G) is inserted rst for local anesthesia,
the passage is already formed, and the ller needle can be safely inserted through the same passage. ->Then recheck by an aspiration test
whether it is inserted into the vessel or not.
->Inject a small amount of ller slowly with a
retrograde technique.
Feel the injection force and volumizing
resistance
This is a method to check if the ller is properly
injected into the area to obtain a volumizing
effect. When injecting ller into the tissue, the
feeling of injection force is stronger than that of
injection invitro. Feel it with your hands while
injecting ller. Then use your ngertips on the
opposite hand to feel the resistance over the treatment area while injecting. You can also see the
volume increase with your eyes.
If the injection tool is located somewhere
other than where you planned, you will not feel
resistance of volume lling with your opposite
hand. This is often the case when using a long
exible cannula. In such cases, stop the injection
and remove the injection tool. Insert it again into
the correct area.
Check the patient’s response (sharp pain,
neurologic symptoms)
If the treatment site is sufciently localized
for anesthesia, pain will not be felt during the
procedure. In a locally anesthetized state, if the
patient feels sharp pain while the injection tool
is passing through, a vessel or nerve might have
been damaged, and the injection direction
should be changed. If neurological symptoms
occur during or immediately after injection, it
should be suspected that the ller was injected
into a branch of the ICA. After stopping the
injection, one should check for any additional
symptoms (see Sect. 6.2.3 vascular
complication- Blindness).
If the treatment area turns pale within a few
minutes after the procedure, consider the possibility of vasoconstriction caused by both epinephrine and ller emboli. If it is caused by
anesthesia, the anesthetized area feels more
bloated than the other areas. If ller is injected
into a blood vessel, the pain can be severe when
penetrating the vessel walls, accompanied by
neurological symptoms or pale skin within minutes. In this case, follow up under bed rest for
about 30min after the procedure. If skin discoloration is getting wider, consider intravascular
complications. However, if the discoloration is
improving and no additional symptoms occur,
one can conclude that the vasoconstriction was
caused by epinephrine.
The tips above are generally well-known.
However, further discussion of controversial
issues is needed.
• Is the aspiration test useful just before ller
injection?
• Which is more safe, cannula or needle?
• Does the diameter of the needle help to reduce
vascular complications?
6.2.5.2 Prevention ofVascular
Complications: Aspiration Test
(Fig.6.1)
An aspiration test prior to ller injection is a
widely used method, yet there is a lack of proof
of effectiveness. There are several factors to
consider.
• What is the appropriate diameter of the needle
for the blood to be aspirated?
a
b
6.2 Treatment andPrevention ofVascular Complication
211
Fig. 6.1 aspiration test —in vitro. (a) Plunger was with-
drawn under negative pressure (Restylane Perlane syringe
connected with 27G/13mm needle). Blood was aspirated
in 1s. (b) Plunger was withdrawn under negative pressure
The larger the diameter of the needle, the easier blood is aspirated and vice versa. When a
needle with a small diameter is used, the blood
aspiration test may be false negative. When
this needle is located in a blood vessel, the
backow of blood may not occur. If ller
already exists in the middle of the needle
lumen, blood aspiration may not occur in the
needle lumen due to the viscosity of the ller.
Thus, the smaller the needle diameter and the
(Restylane Perlane syringe connected with 25G/40mm
cannula). Blood was not aspirated even after 10s. This
means the probability of a false-negative aspiration test
during procedure
A closer look at the research mentioned in the
articles showed some effectiveness in aspiration
tests when it is performed using shorter needles
with a large diameter rather than with cannulas.
Nevertheless, it is recommended to conduct an
aspiration test rst when treating areas where
large vessels exist. It is also advisable to stop the
injection and reinject at another location if blood
aspiration is positive regardless of false
positives.
higher the viscosity of the ller, the higher the
probability of a false-negative aspiration test.
• Even if the needle is located in the blood vessel, the wall of the blood vessel may adhere
(occlude) to the needle tip due to negative
pressure of suction, and thus blood may not be
aspirated.
• Even if the needle is not actually inside a blood
vessel, it may cause false positives if blood is
at the end of the needle due to damage of a vessel while reaching the layer to be injected.
• After the aspiration test, the needle is moved
due to error or shaking leading to improper
positioning. This may cause damage to blood
vessels, even if the test is actually negative.
6.2.5.3 Prevention ofVascular
Complications: Needle vs
Cannula
In the past, there has been a tendency to think that
cannulas are less at risk to cause vascular damage
compared to needles. However, according to the
papers that reported vascular complications, the
number of vascular complications caused by needles is not more than by cannula and sometimes
even caused more often by cannulas. This is controversial to date and requires continued research.
Needles and cannulas are structurally different. Needles are pointed and rigid. A cannula is
blunt and exible. The cannula is theoretically
blunt and therefore may be less likely to pene-
Despite these reasons, many doctors routinely
perform aspiration tests during the procedure and
sometimes experience backow of blood.
The literature reported to date points out the
limitations of the effectiveness of the aspiration
test.
trate blood vessels, but unlike rigid needles, it can
be bent so the cannula tip can be located in an
unwanted layer or position.
For example, if you inject into the periosteum,
it is easy to place the needle exactly on the
periosteum. However, in the case of a cannula,
212
6 Side Eects andTreatment Methods ofFiller Procedures
because it is exible, the ller can be injected in
a layer other than the periosteum, i.e., in a blood
vessel-rich layer. Also, due to the preconception
that cannulas are safer than needles, there is a
possibility of being more aggressive and careless
than injecting with a needle.
Nevertheless, the cannula is recommended for
beginners, and advanced practitioners are advised
to use a needle and cannula appropriately. When
using a cannula, it is recommended to inject
using one as short and rigid as possible (See Sect.
4.3 selection of cannula and needle).
6.2.5.4 Prevention ofVascular
Complications: Diameter
ofInjection Tool
Large diameter injection tools are less likely to
penetrate blood vessels and be placed in the vessels, while smaller diameter injection tools are
more likely to be placed in the vessels. For example, it is more likely that a 2~30G cannula may
penetrate a 1 mm diameter vessel and place it
inside compared to a 23G cannula.
The author prefers a 23G cannula when injecting ller into the deep layer, and uses a 25G~27G
cannula when injecting into dermal wrinkles
where only relatively small blood vessels are
present. 23~25G is preferred when injecting a
large amount of ller using a needle, and 30G is
used when injecting dermal wrinkles.
Some claim that since a thin cannula is exible, it is more likely to proceed without penetration of blood vessels. This means that a thick
cannula is rigid enough to penetrate the vessels.
This is controversial.
In cases where the injection tool is located
inside a vessel, the claim that a smaller diameter
tool produces a higher ejection pressure leading
to faster movement of the ller to the central retinal artery causing blindness has not been demonstrated to date. The theory that the ller mass
does not travel at high speed in the blood vessels
like a bullet under ejection pressure but rather
moves inside the vessels toward the eyeball in a
single le line is more prevalent. The difference
in the possibility of ocular complications according to the diameter of the injection tool and
injection pressure needs to be veried through
further studies.
6.3 Use ofHyaluronidase
forDegeneration ofFillers
6.3.1 How toUse Hyaluronidase
6.3.1.1 Hyaluronic Acid Turnover
The proper use of hyaluronidase requires an
understanding of the turnover process of hyaluronic acid. The turnover of hyaluronic acid has
a half-life of 24–48h. Hyaluronic acid llers are
products that have a longer duration due to the
cross-linking process. However, empirically, we
can see that the duration of the ller is different
for each facial area and injection depth. The
half- life of hyaluronic acid ller is shortened in
the dermis of the face, which is known to be
higher in hyaluronidase. On the other hand, the
half-life of hyaluronic acid ller is longer at low
hyaluronidase concentrations in deeper layers.
Clinicians have been empirically aware that the
duration of hyaluronic acid ller injected into
the deep facial area is much longer than when
administered in the dermis level. We hope to see
more research about ller duration according to
injection depth and the injection site in the near
future.
Hyaluronidase is widely distributed in animal
testes and skin, and a total of six kinds are known.
Hyaluronidase in the anterior head of sperm is
known to play an important role in the passage of
hyaluronic acid-rich ovary ECM. Therefore,
hyaluronidase extracted from bovine testes is
widely used in research.
The most active human hyaluronidases are
HYAL1 and HYAL2.
HYAL2 breaks down large molecular weight
hyaluronic acid into 20 KDa size fragments.
HYAL1 additionally degrades hyaluronic acid
to the size of its tetra-saccharide. It is then further
broken down to monosaccharides and removed
from the body by the function of the
hyaluronidase families (β-glucuronidase,
β-N-acetylglucosaminidase).
6.3 Use ofHyaluronidase forDegeneration ofFillers
213
The pharmacokinetics and pharmacodynamics of hyaluronidase are not well-known. The
half-life of hyaluonidase in the blood is 2min,
and it quickly loses its activity. However, it is
known to work much longer in tissue. The process of inactivation of hyaluronidase is also not
well-known. Empirically, it is a common opinion
among clinicians that the ability to decompose
hyaluronic acid llers seems to last for several
hours or more. H.J.Kim etal. studied the action
time of hyaluronidase by injecting hyaluronidase
into rats to dissolve the hyaluronic acid ller. In
other words, after using hyaluronidase, it was
investigated how much time interval is needed to
reinject hyaluronic acid ller into the same site.
In an experiment with a rat, 0.2cc of hyaluronic
acid ller was injected per site, and 600IU of
hyaluronidase was injected per site to dissolve
the ller. Then, the ller was reinjected at 30min
1h, 3h, 6h, 12h, 24h, 2days, 4days, 7days,
and 14days, respectively. In each experimental
group, histological examination of the site was
performed 1h after each secondary injection. In
this experiment, the enzyme activity of hyaluronidase was found to have disappeared 6h after
hyaluronidase injection.
From this study, we can see that the guidelines
may have to differ between using hyaluronidase
to dissolve hyaluronic acid in blood vessels and
using it to dissolve hyaluronic acid in other tissues. This is because hyaluronidase quickly loses
its activity when it encounters blood. When using
hyaluronidase for ller side effects such as intravascular ller injection, hyaluronidase should be
administered frequently at short intervals, taking
into account that the activity of hyaluronidase
quickly disappears upon contact with blood.
Hyaluronic acid is decomposed by hyaluronidase into small fragments (Fig. 6.2).
Hydrolyzation of the hexosamidic β (1–4) link in
the disaccharide structure (Fig.6.3). Hyaluronic
acid fragmentation is observed.
Several months after the injection of hyaluronic acid ller, an immune response appears as
a delayed type. The fact that it takes several
months to decompose the cross-linked hyaluronic
acid ller and that fragments of various sizes are
produced during the decomposition process may
suggest that the delayed type of immune response
may be related to the hyaluronic acid ller
fragment.
Further research is required in this area.
The fact that high molecular weight hyaluronic acid has a better effect does not mean that
it would be better as a material for llers.
Attempts have been made to develop products
Fig. 6.2 Action of hyaluronidase
214
yl-D-glucosamine
D-glucur
Hyaluronidase
Hyaluronic Acid
6 Side Eects andTreatment Methods ofFiller Procedures
CH
OH
COOH
OH
OH
onic acid
Fig. 6.3 Site where hyaluronidase acts
O
OH
O
OH
2
N-Acetyl-D-glucosamine
HN
O
O
O
using hyaluronic acid with a molecular weight
much greater than that commonly used in ller
manufacturing. However, some new llers that
have attempted to do so have caused many problems and have been withdrawn from the market.
Generally, hyaluronic acid of 1.5 × 10 ^ 6Da to
2.5 × 10 ^ 6Da is used to produce the ller.
Since ller manufacturing involves the cross-
linking process using a cross-linker, we cannot
apply the results studied with the molecular
weight using free hyaluronic acid without crosslinking to all situations. Be sure to keep this in
mind.
6.3.1.2 Use ofHyaluronidase
The use of hyaluronidase as a dissolving treatment in cases of adverse events after hyaluronic
acid ller is currently off label. There have been
various discussions on how to use hyaluronidase
in the most effective way. Recently, a diverse
group of doctors created a consensus on this topic.
Based on various experimental results, the use
of evidence-based hyaluronidase has been
summarized.
D-glucuronic acid
COOH
O
OH
OH
CH
3
O
OH
CH
OH
2
N-Acet
HN
O
O
CH
3
O
There are dozens of hyaluronidases on the
market today. It is interesting to note that 150–200
USP is used mainly in the United States, while
1500IU is used in Korea.
1 international unit (IU)=1 USP unit.
In the previous studies on the use of hyaluronidase, we recommended about 3–15 units for
0.1cc of ller volume. Of course, there is a difference in recommendation dosage depending on
whether it is a simple nodule, an impending
necrosis, or a vascular accident.
Later consensus recommended high doses of
hyaluronidase—approximately 200–300 IU per
day. If needed to use hyaluronidase repeatedly,
some doctors recommend 1day interval for the
procedure, while some doctors recommend a 1h
interval.
The authors present an evidence-based guideline on the use of hyaluronidase, based on the
experience of clinicians and scientic
experiments.
The principles of proper use of hyaluronidase
can be summarized as follows:
<Method of using hyaluronidase>
6.3 Use ofHyaluronidase forDegeneration ofFillers
215
(1) Prepare for the possibility of hypersensitivity to
hyaluronidase.
(2) Use a sufcient amount of hyaluronidase.
(3) Widely used in all areas where Ischemia is
suspected.
(4) Inject hyaluronidase at 1cm intervals over all the
suspected ischemia area.
(5) Repeat every 15min.
(6) Massage after hyaluronidase injection.
(7) When injecting into a nodule or granuloma, make
sure to penetrate the capsule and inject into the
center of the mass.
The following is the summary of the rationale
for each guideline.
• Theoretical basis of the guidelines
(1) Prepare for the possibility of hypersensitivity
to hyaluronidase.
Some guidelines recommend a skin test.
However, in the clinical eld, skin test is practically easy to do. It is possible to treat the hypersensitivity reaction or use antihistamines and
steroid injections prophylactically.
(2) Use a sufcient amount of hyaluronidase.
The authors performed a hyaluronic acid ller
degradation test.
Different concentrations of hyaluronidase
were used to degrade the ller. The temperature
was maintained at 36 degrees Celsius to create an
environment similar to that of an invivo environment. In order to observe the difference in concentration only, the hyaluronidase was mixed
into a 1cc volume (Figs.6.4, 6.5, 6.6, and 6.7).
In the past, the recommended hyaluronidase
dosage for dissolving llers or ller nodules was
3–15 units/0.1 cc. This is assuming that hyaluronidase is correctly injected into the center of
the nodule. However, the same amount of hyaluronidase should not be recommended for
impending necrosis by intravascular ller injection. This is because the ller is expected to dissolve due to the diffusion of hyaluronidase under
the assumption of trans-arterial penetration,
rather than the direct injection of hyaluronidase
into the ller bolus center. In addition, hyaluronidase is rapidly deactivated in contact with blood.
Therefore, the recommended amount of hyaluronidase for dissolving ller/ller nodules and
the amount for impending necrosis by intravascular ller injection should be different. Naturally,
higher doses of hyaluronidase would be required
in the latter.
(3) Inject widely in all areas where ischemia is
suspected.
This is when ischemia occurs in a wide area
from intravascular injection, not for nodule or
granuloma cases.
The ller injected into the vessels are not
formed into an embolus, but advance into the
vessels forming columns (Fig. 6.8). Therefore,
the ller may spread through the vessels in all
parts of the ischemia that appear in the intravascular ller injection case.
Therefore, in intravascular ller injection
cases, the hyaluronidase should be injected into
all areas showing signs of ischemia.
a
Fig. 6.4 Filler dissolution test. Filler 1cc+HU 75units (1cc), 5min, 1h, 24h
b
c
216
6 Side Eects andTreatment Methods ofFiller Procedures
a
Fig. 6.5 Filler dissolution test. Filler 1cc+HU 300units (1cc) 5min, 1h, 24h
a
Fig. 6.6 Filler dissolution test. Filler 1cc+HU 750units (1cc) 5min, 1h, 24h
b
b
c
c
a
Fig. 6.7 Filler dissolution test. Filler 1cc+HU 1500units (1cc) 5min, 1h, 24h
b
Hyaluronidase degrades hyaluronic acid by acting directly on the ller surface. Therefore, direct
contact is necessary. In case of vascular accident by
intravascular injection, ischemia signs appear
according to the route of the facial artery (Fig.6.9).
In cases of impending necrosis by intravascular ller injection, if the hyaluronidase is injected
only into the ller injection site, the progress is
poor. One can improve the clinical course by
Fig. 6.8 Schematic diagram of endovascular ller injec-
tion case
injecting hyaluronidase in all areas suspected of
skin compromise caused by ischemia.
c
6.3 Use ofHyaluronidase forDegeneration ofFillers
Fig. 6.9 Facial artery variation—The route of the left and right facial artery is different
217
(4) Inject at 1 cm intervals over all suspected
ischemia areas.
This is also applicable for cases of impending
necrosis by intravascular injection.
Hyaluronidase not only dissolves hyaluronic
acid at the injection site, but also diffuses to the
periphery. In practice, hyaluronidase is used to
increase the spread of drugs in ophthalmology
and dermatology. This is because dissolving
hyaluronic acid in tissue ECM eliminates the barrier to drug diffusion. However, due to the limited
diffusion range, injection of hyaluronidase at
appropriate intervals is required (Fig.6.10).
In previous studies, hyaluronidase proved to
have trans-arterial penetration (Fig. 6.11). In
other words, in cases of ller side effects via
intravascular injection, the hyaluronic acid ller
can be dissolved by injecting hyaluronidase into
the periphery of the vessel instead of directly
injecting it directly into the blood vessel.
(5) Repeat every 15min.
When dissolving hyaluronic acid ller with
hyaluronidase, one procedure may not be enough
Fig. 6.10 Interval distance of hyaluronidase injection
to dissolve all the llers. Therefore, it is necessary
to clarify what intervals are most effective when
performing repetitive procedures, especially in
serious complication cases such as intravascular
ller injection. As mentioned earlier, hyaluronidase activity in tissues is known to last for several
hours. However, in an emergency case, the duration of maximal effect will be more important
than the total duration of hyaluronidase activity.
Won Lee etal. studied the proper hyaluroni-
dase injection interval after intravascular ller