State-of-the-Art Review

Clinical and Applied

Thrombosis/Hemostasis
Hemostats, Sealants, and Adhesives II: 16(5) 497-514
ª The Author(s) 2010
Reprints and permission:
Update As Well As How and When to Use sagepub.com/journalsPermissions.nav
DOI: 10.1177/1076029610363589
the Components of the Surgical Toolbox http://cath.sagepub.com

William D. Spotnitz, MD, MBA1, and

Sandra Burks, BSN, RN, CCRC1

Abstract
The goal of this submission is to describe how and when to best use hemostats, sealants, and adhesives as well as to compare their
characteristics and to update the surgical toolbox with respect to any new products approved by the Food and Drug Adminis-
tration (FDA) as of this date (November 2009). The materials will be presented in 3 major groups each containing specific cate-
gories: (1) hemostats; mechanical, active, flowable, and fibrin sealant, (2) sealants; fibrin sealant, polyethylene glycol polymer, and
albumin and glutaraldehyde, (3) adhesives; cyanoacrylate, albumin and glutaraldehyde, and fibrin sealant. The categories will be
used for comparisons based on safety, efficacy, usability, and cost. Recommendations with respect to how and when to best use
these materials will be presented. A review of the recent literature is also provided with respect to the most recent uses of these
materials in specific surgical specialties.

Keywords
hemostats, sealants, adhesives, applications, techniques

Introduction from tissues such as cerebrospinal fluid (CSF) from the cen-
tral nervous system but may also be capable of preventing
As the challenges facing surgeons in the 21st century increase,
the leakage of blood from blood vessels. Finally, adhesives
knowledge of the available components for the surgical tool-
are glues which are capable of bonding various tissues
box,1 which can assist in the technical performance of an oper-
together including a variety of surfaces such as skin or mus-
ation becomes more important. The demands for smaller more
cle and are also capable of bonding blood vessels together.
minimally invasive procedures,2 reduced use of transfusions,3
It is useful to know in which of these 3 groups a Food
and reduced costs4 create greater hurdles than ever for today’s
and Drug Administration (FDA) approved product (as of
practicing surgeon. Hemostats, sealants, and adhesives are November 2009) belongs because this knowledge helps in
components of the surgical toolbox, which may help manage
clarifying how to best use the material. A classification sys-
these challenges.1
tem for these materials based on groups, categories, classes,
Surgery is a branch of medicine in which knowledge, judg-
and products is provided (Figure 1). This system will be used
ment, clinical experience, and technical skill are required for
throughout this review. The categories will be used to pres-
success. Training in medical school and residency facilitates
ent information comparing safety, efficacy, usability, and
development of these talents for surgeons. During this educa-
cost. Generic classes of agents will be used to describe how
tional process, significant time is spent in mastering each of
and when to best use these materials with respect to specific
the required elements including the ability to meticulously cut specialties and procedures.
and carefully sew. The goal of this review is to enhance these
skills by increasing knowledge with respect to some of the
surgical adjuncts that may enhance the performance of oper-
ations. This article will not only describe, compare, and con-
trast the available materials but also emphasize how they are
best used. 1
University of Virginia Health System, Charlottesville, VA, USA
To most clearly cover this topic, some definitions should
be provided. Topical hemostats are materials that stop bleed- Corresponding Author:
William D. Spotnitz, Surgical Therapeutic Advancement Center, Department
ing by causing blood to clot and thus require blood to be of Surgery, University of Virginia Health System, PO Box 801370,
present to satisfy their clotting function. Sealants are agents Charlottesville, VA 22908, USA
that can prevent the leakage of potentially nonclotting fluids Email: [email protected]

497
498 Clinical and Applied Thrombosis/Hemostasis 16(5)

may have some advantages in efficacy whereas the function

of porcine gelatins may be improved by combination with topi-
cal thrombin.11 A major advantage of mechanical agents is
their ease of use or usability. They are immediately available
on opening the product’s package requiring no special storage,
preparation, or reconstitution by operating room personnel.
Their application to a bleeding site is straightforward, requiring
only direct pressure by the surgeon. These agents are relatively
inexpensive, although price premiums may exist for those
thought to have particular advantages.
The active hemostat category consists of 3 available stand-
alone forms of thrombin and is differentiated into classes based
on the source of the plasma used to create these hemostats
(Figure 2). The individual manufacture’s products in each class
within the active category have been previously presented in
detail.1 Each functions by providing concentrated thrombin
Figure 1. Nomenclature for classifying topical hemostats, sealants,
and adhesives. capable of rapidly converting fibrinogen into a fibrin clot. The
rate of clot formation is proportional to the thrombin concentra-
tion. The safety profile of each of the 3 classes, bovine plasma,
UpDate and Comparison of FDA-Approved pooled human plasma, and recombinant, is different (Figure 3),
Agents although none of the 3 forms of thrombin should ever be
injected intravascularly. Antibody formation associated with
Hemostats the use of bovine thrombin potentially leading to coagulopathy
The commercial products currently available for use by sur- and rarely death has resulted in a black box warning, the FDA’s
geons in the United States in the hemostat group may be highest level of concern, being placed on the material’s pack-
divided into 4 categories (Figure 2) based on their functional age insert.12 Pooled human plasma thrombin has a potential
characteristics: mechanical, active, flowable, and fibrin sealant. risk of viral or prion (the agent responsible for Creutzfeldt-
The materials in the mechanical category act predominantly Jakob disease) disease transmission due to the multiple units
by forming a barrier to stop the flow of blood as well as by cre- of blood used in manufacturing each lot of product.13 Genetic
ating a surface on which blood may more rapidly clot. The engineering used to produce recombinant thrombin reduces the
mechanical category can be further organized into 4 descriptive risks of antibody formation and eliminates the risk of known
generic classes (Figure 2): porcine gelatin, bovine collagen, disease transmission. Allergic reactions to hamster or snake
oxidized regenerated cellulose, and polysaccharide spheres. proteins used in manufacturer of the recombinant product are
The individual manufacture’s products in each class within the listed as potential dangers.14 The efficacy of all 3 classes of
mechanical category have been previously presented in detail.1 stand-alone thrombin which each contain about 1000 IU/mL
Two new brands of polysaccharide spheres (Hemostase MPH, is functionally the same.13,15 Each is equally effective for local
Cryolife; Vitasure, Orthovita; Figure 2) are now commercially or diffuse bleeding. Bovine thrombin and recombinant throm-
available in addition to the originally marketed product (Arista bin are provided as room temperature lyophilized powders that
AH, Medafor, Minneapolis, Minnesota).5 The mechanical need reconstitution,12,14 whereas the human pooled thrombin is
agents as a class are relatively safe with swelling and infection fully mixed but requires thawing prior to prompt use or storage
being 2 notable risks of several listed in their package inserts thawed in a refrigerator for no longer than 1 month.13 These
(Figure 3). Thus, the manufacturers recommend removal of products can be applied locally or sprayed over a large area.
mechanical agents if possible after achieving hemostasis. One The stand-alone thrombins can also be combined with absorb-
of the products in the bovine collagen class (Ultrafoam, John- able gelatin sponge12-14 to enhance efficacy and ease of appli-
son & Johnson, Somerville, New Jersey) is suggested to poten- cation. A kit (Gelfoam Plus, Baxter, Hayward, California) has
tially have less risk of collagen fibril swelling due to the use of been recently introduced, which provides a porcine gelatin
ethyl alcohol in the manufacturing process,6 and all products in sponge and a lower concentration of lyophilized human pooled
the oxidized regenerated cellulose class (Surgicel, Surgical thrombin (125 IU/mL) that does not require refrigeration
Microfibrillar, Surgicel Nu-knit, Johnson & Johnson) are sug- together in a single package.16 Finally, the cost of the stand-
gested to reduce the risk of infection by creating an acid bacter- alone thrombins is intermediate, but there may be some varia-
icidal environment.7 However, this same decrease in pH may tion among products within the category based on safety profile
inactivate stand-alone thrombins or fibrin sealants containing differences.17
thrombin when used conjointly with oxidized regenerated cel- The flowable category represents a combination of mechan-
lulose.7 The mechanical hemostats may be useful for the most ical materials and thrombin. Thus, these products work by
minimal bleeding. They may also have some variance in their mechanically obstructing the flow of blood and actively con-
efficacy. Bovine collagens8,9 and polysaccharide spheres10 verting fibrinogen in blood into fibrin at the site of bleeding.

498
Spotnitz and Burks 499

Figure 2. Food and Drug Administration approved topical hemostats.

The individual manufacture’s products in each class within the thorough coverage of the local wound using a substance that
flowable category have been previously presented in detail.1 easily conforms to the topography of the underlying tissues.
There are 2 classes in this category (Figure 2). The first consists Evidence suggests that a flowable may be more effective than
of a combination of absorbable bovine gelatin particles with the combination of a porcine gelatin sponge with thrombin.18,19
pooled human thrombin and the second consists of absorbable Preparation of a flowable product requires reconstitution of the
porcine gelatin particles that may be combined with any of the thrombin which must then be mixed with the absorbable gelatin
3 stand-alone thrombins described earlier. Recently, the manu- particles. Thus, about 3 minutes are required for operating
facturer of the absorbable gelatin has gained approval to pack- room staff to get the material ready prior to use.20,21 The flow-
age this originally stand-alone product (Surgiflo, Johnson and ables are easy to apply and are extruded from a syringe much
Johnson, Somerville, New Jersey) with a form of lyophilized like a tooth paste with a thickened consistency that allows the
pooled human thrombin (Evithrom, Johnson and Johnson, hemostat to stay in place at the site of bleeding. Because the
Somerville, New Jersey) that can be stored at room tempera- products contain thrombin without fibrinogen, they require
ture. The combination may be obtained with a long flexible tip. direct contact with blood as a fibrinogen source for conversion
The safety (Figure 3) concerns of flowables represent those of into fibrin. Pressure may be rapidly placed directly onto the
the mechanical and active groups consisting for the first class flowable at the bleeding site by the surgeon using a moist saline
predominantly of swelling and viral or prion disease transmis- (nonbloody) gauze or pad for a period of 2 minutes. Removal of
sion and for the second class of swelling and the risk associated the gauze or pad avoids clot disruption as the hemostat does not
with the particular stand-alone thrombin that is chosen.17 The stick to the nonbloody saline-soaked gauze or pad which does
flowables are most effective for localized bleeding as they not contain fibrinogen. The cost of flowables is higher,
allow for mechanical slowing of blood flow, rapid conversion although some cost savings may be possible by using the por-
of fibrinogen into fibrin by the action of thrombin on blood, and cine gelatin21 with a separate stand-alone thrombin as opposed

499
500 Clinical and Applied Thrombosis/Hemostasis 16(5)

Figure 3. Comparison of characteristics of topical hemostats.

to the bovine gelatin and human pooled plasma thrombin pro- occur in blood. There are 3 classes in this category (Figure 2).
vided by the manufacturer in a single kit.20 If this cost-saving These are pooled human plasma, individual human plasma
strategy is used, it is necessary to carefully choose the proper with bovine collagen and bovine thrombin, and individual
volume of stand-alone thrombin to mix with porcine gelatin human plasma alone. The individual manufacture’s products
to get the desired consistency (not too thick and cakey nor too in each class within the fibrin sealant category have been
thin and watery) and to instruct the operating room personnel in previously presented in detail.1 The safety concerns associated
a method to reliably reproduce the mixture in all subsequent with fibrin sealant include those previously discussed including
preparations. This careful effort is necessary to avoid inconsis- viral or prion disease transmission with pooled human plasma
tency that can decrease effectiveness and satisfaction with a derivatives; antibody formation with bovine thrombin and
flowable hemostat. swelling with bovine collagen; and the need for an intact native
The final category among the topical hemostats is fibrin coagulation system and avoidance of any type of anticoagulant
sealant. This material has a unique, powerful, and sometimes with individual human plasma (Figure 3). One of the pooled
confusing role because it has separate FDA approvals as a human plasma products (Tisseel, Baxter, Westlake Village,
hemostat, sealant, and adhesive. Fibrin sealant consists of California) contains synthetic aprotinin that can also be a
2 components. It contains concentrated fibrinogen and potential source of allergic reactions.22 Fibrin sealant is effec-
thrombin which on mixing create a fibrin clot. The concentra- tive for the control of local as well as diffuse bleeding as it can
tion of fibrinogen is proportional to clot strength whereas the be applied locally using a syringe-like applicator or sprayed
concentration of thrombin is proportional to the rate of clot over a larger area using a gas-driven device. Although the
formation. Fibrin sealant works by increasing the rate of blood fibrin sealants were originally approved for specific individual
clot formation by providing higher concentrations of both bleeding indications, one of the products (Evicel, Johnson and
fibrinogen and thrombin at a bleeding site than would normally Johnson, Somerville, New Jersey) has now been approved by

500
Spotnitz and Burks 501

Figure 4. Food and Drug Administration approved topical sealants.

the FDA with a broad label for broad surgical hemostasis.23 The product is approved to seal the colon at the time of colost-
The concerns raised clinically about fibrin sealant usability are omy closure22 and it (Tisseel, Baxter, Westlake Village, Califor-
mainly associated with the difficulty of reconstitution by hos- nia) has been previously presented in detail.1 In addition, the
pital staff and a potential learning curve for surgeons with safety profiles of the fibrin sealant category with respect to
respect to the techniques of application.24 The available pooled pooled human plasma-derived materials and the operating room
human plasma fibrin sealants may require thawing or mixing staff preparation complexities associated with it as well as its rel-
and the individual human plasma products require processing atively expensive cost have already been reviewed under the sec-
the patients own blood. Fibrin sealant products are among the tion on hemostats. Fibrin sealant is a moderate strength sealer
more costly topical hemostatic materials. (Figure 5) and is most effective when it is applied by the
surgeon to as dry a field as possible.22 This is particularly impor-
tant when applied to the normally moist serosal surface of the
Sealants outer bowel wall or parenchymal tissues of abdominal viscera.
The materials approved for use as sealants are divided into 3 cate- The PEG polymer category has 2 classes of materials: the first
gories (Figure 4): fibrin sealant; polyethylene glycol (PEG) poly- is 2 PEGs together; and the second is a PEG with trilysine amine
mer; and albumin with glutaraldehyde. The sealants work by (Figure 4). The individual manufacture’s products in the 2 classes
forming a barrier that is impervious to the flow of most liquids. within the PEG polymer category have been previously presented
The fibrin sealant category has already been discussed under in detail.1 This category consists of synthetic materials and the
the hemostat group. Additional comments will be provided here major safety risk (Figure 5) is swelling25,26 which varies from
with respect to the role of fibrin sealant as a sealer (Figure 5). It 400% (Coseal, Baxter, Fremont, California) down to 50%
should be noted that only 1 fibrin sealant product which is in the (Duraseal, Covidien, Mansfield, Massachusetts). The products
pooled human plasma class has an on label approval as a sealant. are approved for vascular sealing to prevent blood loss and

501
502 Clinical and Applied Thrombosis/Hemostasis 16(5)

Figure 5. Comparison of characteristics of topical sealants. PEG indicates polyethylene glycol.

sealing of the dura to prevent CSF loss. They are moderately the material contains glutaraldehyde, it is possible to cause
strong. The rate of immediate vascular sealing was more than significant nerve or muscle necrotic injury using this
doubled using the 2 PEG polymer25 as compared to the use of a sealant.27-29 Adhesive embolism,30 limitation of aortic growth,31
hemostat25 and dural sealing was achieved 98% of the time using and pseudoaneurysm27 formation have also been reported with
the single PEG with trilysine amine sealant.26 The efficacy of this type of material. This product is a strong tissue sealant, which
both types of PEG polymers is improved by applying to a dry has been approved for sealing of large blood vessel anastomoses
field and by allowing an adequate time (60 seconds) for polymer- and is also indicated as an adhesive in aortic dissection for
ization. The PEG polymer category of products is moderately reattaching the layers of the aorta.27,32,33 The sealant is quickly
easy to prepare with time required to reconstitute the powdered prepared by operating room personnel as it comes prepackaged
PEGs and to assemble the provided applicators. Application is in applicator syringes and is applied by the surgeon after priming
straightforward with manual spray devices. The dural sealant of the applicator. This category is relatively more expensive.
also uses Federal Food, Drug, & Cosmetic Act (FD&C) blue
No 1 dye to provide a blue color that assists with accurate place-
ment of the sealant. This category is relatively more expensive. Adhesives
The final category of sealants consists of albumin and The commercial products approved as adhesives can be divided
glutaraldehyde. The generic class can be described as bovine into 3 categories (Figure 6): cyanoacrylate; albumin and glutar-
serum albumin cross linked using 10% glutaraldehyde aldehyde; and fibrin sealant. They vary significantly in their
(Figure 4). The single manufacture’s product in this class has functional strength and surgical indications. However, each is
been previously presented in detail.1 The major safety concerns designed to glue 1 type of tissue to another.
(Figure 5) associated with the use of this category relate to the The cyanoacrylates are approved to hold the skin edges
potential for tissue necrosis and adhesive embolism. Because together and may also function as a barrier against bacterial

502
Spotnitz and Burks 503

Figure 6. Food and Drug Administration approved topical adhesives.

penetration. These materials are for external use only. The immediately available for use in easily stored containers with
cyanoacrylate category can be further subdivided into 2 generic integrated applicators. They are easily applied by surgeons, but
classes either octyl or butyl cyaonacrylate based on the chemical their viscosity varies with each product with some being
structure of these synthetic compounds. The individual manufac- higher (Dermabond High Viscosity, Johnson and Johnson, Som-
ture’s products in each class within the cyanoacrylate category erville, New Jersey) than others. Care should be used to avoid
have been previously presented in detail.1 This category of adhe- the flow of these adhesives onto sensitive-dependent structures
sives is relatively safe (Figure 7) as long as they are reserved for such as the eye. They are relatively inexpensive.
external use, and care is used to avoid getting this strong adhe- The albumin and glutaraldehyde category has 1 single class
sive in unintended areas. Foreign body reaction has been of product. Bovine serum albumin with 10% glutaraldehyde
reported34 particularly if the product gets into subcutaneous tis- (Figure 6) has already been discussed in the section on sealants.
sues.35 They can create a sensation of warmth on exothermic The single manufacture’s product in this class has been previ-
polymerization that may be interpreted by some patients as a ously presented in detail.1 It is included here as an adhesive
painful stimulus. These materials are very strong adhesives, but because it is approved for attachment of the intimal and adven-
their strength as a skin closure device is limited by the strength of titial layers of the aorta during the repair of aortic dissection.27
the superficial layers of the dermis to which they are applied. In comparison to other adhesives (Figure 7), it may be associ-
Because the superficial dermis is always in the process of exfo- ated with tissue injury, emboli, and pseudoaneurysm forma-
liation and can tear away from deeper dermis, the role of this tion. This adhesive is strong as well as moderately easy to
adhesive in providing a sole method of skin closure is limited. use and relatively expensive.
Hence, the products are approved as adjuncts and should be used The final category under the adhesives is fibrin sealant. Only
with some form of deeper dermal sutures. Some recent data sug- the pooled human plasma generic class of fibrin sealant has a
gests superiority of octyl over butyl cyanoacrylate in terms of recently approved product for use as an adhesive (Figure 6). This
wound burst strength and flexibility.36 Cyanoacrylates are new product (Artiss, Baxter, Westlake Village, California) is

503
504 Clinical and Applied Thrombosis/Hemostasis 16(5)

Figure 7. Comparison of characteristics of topical adhesives.

approved for the attachment of skin grafts to underlying wound Mechanical Hemostats
bed at the time of burn graft surgery and can replace staples in this
These materials are desirable because of their ease of storage,
indication. The product’s safety, efficacy, usability, and cost are
preparation, and application as well as their relatively lower
similar to the manufacturer’s previously approved fibrin sealant
cost. However, the operator should not be fooled into thinking
product (Tisseel, Baxter, Westlake Village, California) which has
that their proper use is automatic. Mechanical hemostats are
been reviewed in the past in detail.1 One significant difference is
often applied dry to a wet field and are then removed when
that the new adhesive product37 contains a much lower concentra-
bleeding has ceased and the field is dry. This sequence is actu-
tion of thrombin (5 IU/mL), which allows the fibrin sealant to
ally similar to that used by surgeons when using wet to dry dres-
polymerize more slowly. The thrombin concentration in fibrin sea-
sings to debride infected fibrinous tissue or necrotic wounds.
lant influences the rate of conversion of fibrinogen into fibrin. The
This reliable process assures that removal of the dry dressing
lower thrombin concentration results in a longer 60-second poly-
will achieve wound debridement and removal of underlying
merization time, which allows for a skin graft to be properly placed
undesirable debris. Unfortunately, this same process means that
and adjusted prior to adhesive fixation. In comparison to other
removal of a mechanical agent after achieving hemostasis with-
adhesives (Figure 7), this material is of moderate strength, may
out wetting it will similarly result in removal and debridement of
be more complex to prepare and use, and is relatively expensive.
underlying clot as well as a resumption of bleeding. Thus, it is
important to removing mechanical agents to wet them prior to
removal to leave intact clot behind and achieve maximum ben-
Suggestions efit. This wetting technique may be achieved by using a saline-
Authors specific suggestions are provided in the following sec- filled syringe with a blunt nose cannula to irrigate precisely at
tions for use of topical hemostats, sealants, and adhesives, and the interface between the mechanical agent and the clot as the
these are summarized in Figure 8. mechanical agent is being removed.

504
Spotnitz and Burks 505

Figure 8. Authors’ specific suggestions for the use of categories of products. PEG indicates polyethylene glycol.

Active Hemostats formed clot and removal may cause significant clot disruption.
Adding saline to the field after the bleeding has stopped prior to
These agents are most frequently used in liquid form which is
any attempts at removal of the sponge, gauze, or pad may facil-
excellent for product delivery over large areas with diffuse ooz-
itate the maintenance of hemostasis. Combining thrombin with
ing of blood. For localized bleeding, application of these liquids
an absorbable gelatin powder may be useful as it results in putty-
may be challenging as the liquid tends to be washed away by
like material that can be used to caulk a bleeding site. Because
active bleeding or drip away due to the effects of gravity and the
the acid environment of oxidized regenerated cellulose may
topography of the wound. In addition, it may be difficult to
inactivate thrombin, prolonged exposure of these 2 agents prior
combine the use of pressure, a mainstay of surgical hemostasis
to actual use should be avoided.
with a liquid. Thus, the lesson to applying these agents for more
active local bleeding is delivery in combination with one of the
mechanical agents, an absorbable gelatin sponge or powder, or a
soaked operating room gauze or laparotomy pad. When using an Flowable Hemostats
absorbable sponge in conjunction with thrombin, it is important The flowables combine many of the best characteristics of the
that the sponge not be sopping wet but rather be gently squeezed mechanical and active agents providing a hemostat that is capa-
prior to use to remove excess thrombin. The sponge should be ble of getting into the depths of a wound, adjusting to wound
moist with thrombin but still able to absorb some blood into its topography, providing a mechanical barrier, and actively clot-
interstices to allow both the mechanical action of the sponge and ting blood. Therefore, it may be helpful to assure that the prod-
the active clotting mechanism of the thrombin to come into uct is carefully applied down into lacerations and irregular
effect. In this setting, removal of the absorbable sponge may surfaces by gentle spreading and not just applied to the top
sometimes be difficult as it becomes incorporated into the layers of an irregular wound where blood may be appearing

505
506 Clinical and Applied Thrombosis/Hemostasis 16(5)

but may not be originating. These agents can easily be com- applied as liquids which polymerize quickly but may still tend
bined with pressure because their cream of wheat-like consis- to drip away from the intended site of application unless the
tency can be compressed with a saline-soaked gauze or effects of gravity and topography are anticipated in advance
laparotomy pad for several minutes to allow for successful by the surgeon.
clot formation. It is important to remember that the gauze or
pad should be soaked with saline and not any blood. If the Albumin and Glutaraldehyde
gauze or pad contains blood, the blood will react with the
flowable forming a clot and the sticky clot will be dislodged This is a very strong sealant and adhesive that needs to be
when the gauze or pad is removed. Additional flowables can applied carefully and as sparingly as possible. Critical zones
be reapplied with the blunt nosed applicator tip that needs of the operative field should be protected by walling off with
to be positioned in such away that the new material is bur- removable sponges or pads to avoid injuring delicate tissues
rowed under previously applied product so that the new mate- such as nerves or occluding blood vessels such as coronary
rial comes into direct contact with blood that provides the arteries. Using large volumes of the material should be avoided
fibrinogen necessary for the flowable to create clot. Any not and may increase the potential complications of its use includ-
clotted flowable matrix can be removed with a stream of ing muscle necrosis, embolus, and delayed pseudoaneurysm
saline used in combination with a discard sucker once hemos- formation. The applicators need to be primed by a small
tasis has been achieved. amount of product release outside of the field to get the process
of albumin cross-linking by glutaraldehyde initiated. Finally, a
discard sucker should always be present to immediately
Fibrin Sealant remove any unwanted liquid material before it polymerizes and
As a 2-component liquid material containing fibrinogen and becomes adherent.
thrombin, fibrin sealant also may benefit by combination with
an absorbable gelatin sponge to assure delivery of the liquids to Cyanoacrylates
a local site of active bleeding and allow the fibrin sealant to be
These materials are also very strong adhesives approved at the
combined with the significantly beneficial effects of manual
moment only for topical external use. Skin edges should be
pressure. In this case, however, because the agent contains both
kept approximated for at least 30 seconds following application
concentrated fibrinogen and thrombin, the sponge will not be
to allow for complete curing of the cyanoacrylate. Multiple
removable and will need to be left in place as it is glued into
layers should be used for octyl cyanocrylates whereas butyl
the wound by a fibrin sealant clot. When using fibrin sealant
cyanoacrylates should used more sparingly. Cyanoacrylates
to prevent seroma formation between flaps, it is important to
need to be applied after careful planning and positioning to
assure rapid sealing of the tissues and contact of the flaps to
avoid run off of the liquid cyanoacylate to unwanted locations
be glued together. This adherence can be facilitated by placing
particularly if being used on the face. They should be used as an
a closing lattice work of sutures prior to applying the fibrin sea-
adjunct to wound closure in combination with deep dermal
lant and bringing the flaps into apposition with pressure appli-
sutures and not as the only means of closing wounds as dehis-
cation immediately after sealant placement so that the flaps are
cence is possible. Their ability to function as a temporary bar-
in contact while the sealant is still polymerizing. Disruption of
rier capable of protecting wounds from serous or lymphatic
the formed flap adhesions should then be carefully avoided
fluid leakage and from external sources of bacteria is also a
when handling the wound. Disruption after the placement of
desirable characteristic that may be useful in reducing wound
fibrin sealant could actually make seroma accumulation worse
infection rates.
than without any fibrin sealant application. In this setting, the
disrupted fully polymerized fibrin sealant will function as an
antiadhesive, preventing flap adherence and thereby maintain-
ing a potential space for seroma formation. When using fibrin
Recent Literature Reports of Specialty
sealant as an adhesive to apply skin grafts, avoid too thick a Specific Safety, Efficacy, and Application
layer of sealant, which can prevent diffusion of nutrients to the Techniques
graft from the underlying muscle bed. In our hands, fibrin sea- Selected recent reports on the use of hemostats, sealants, and
lant has been a very powerful agent because it is the only mate- adhesives in specific surgical specialties are provided below.
rial approved by the FDA as a hemostat, sealant, and adhesive,
but it does require some patience and persistence as the surgeon
gets used to its many characteristics.
Abdominal Surgery
Several recent studies evaluated the comparative safety and
efficacy of topical agents in animal models of abdominal sur-
Polyethylene Glycol Polymers gery. The safety of multiple different hemostats, sealants, and
The available materials can be used most effectively by adhesive were evaluated in a laboratory rat cecal adhesion
assuring that the tissues to be sealed are as dry and free of blood model.38 Materials evaluated included oxidized regenerated
or fluid as possible. These agents, themselves, are initially cellulose, polysaccharide spheres, bovine collagen with human

506
Spotnitz and Burks 507

pooled plasma thrombin, human pooled plasma fibrin sealant, 2 lidocaine was found to statistically significantly reduce pain
PEG polymer hydrogel, and bovine albumin and glutaraldehyde. following subpectoral breast augmentation procedures.52 The
Adhesion formation was least with polysaccharide spheres and use of 2 PEG polymer hydrogel or albumin and glutaraldehyde
PEG polymer. Adhesion formation as well as tissue necrosis was did not reduce seroma fluid drainage or time to drain removal
greatest using bovine albumin and glutaraldehyde. In another following axillary dissection procedures for treatment of breast
report, a numerical bleeding score analysis using a heparinized cancer in a randomized, prospective, controlled trial of 75
pig model of liver biopsy demonstrated the statistically significant patients.53 Use of these sealants resulted in foreign body tissue
hemostatic superiority of porcine gelatin sponge with human reaction with the need for surgical intervention in some
thrombin as compared to porcine gelatin sponge and saline at patients. Another consecutive case study of using albumin and
multiple time points up to 10 minutes after treatment.39 A third glutaraldehyde in breast cancer surgery found a statistically
model of grade IV-V combined liver and spleen lacerations using significant beneficial effect on the frequency and volume of
10 heparinized pigs with hemorrhagic shock demonstrated that aspirated seromas during the recovery period in 33 treated
bovine gelatin and thrombin (approximately 1.4 mL/pig) was patients as compared to 32 control patients.54 Repeated aspira-
effective at achieving hemostasis in all animals and that clot tions in follow-up were needed in 21.2% of treated patients and
integration was present at 48 hours on histologic examination.40 37.5% of control patients.
The use of surgical adhesives has been described in addi-
tional abdominal surgical indications. Fibrin sealant use was
recently investigated in humans for mesh fixation during ingu-
Burn Surgery
inal hernia repair using both laparoscopic extraperitoneal41 and Recombinant human thrombin was found to achieve hemosta-
intraperitoneal approaches.42 It was found to be less painful sis and facilitate the application of partial or full thickness skin
than staple fixation.42,43 One laboratory animal study supports grafts in burn wound resection surgery in a multisite, single-
the use of large pore, light-weight polypropylene meshes for arm, open-label study of 72 patients.55 Hemostasis was
the best attachment strength when using fibrin sealant for fixa- achieved after conventional control of point source bleeding
tion44 and another suggests that it may even be possible to using spray application of thrombin within 20 minutes in
repair hiatal hernias using fibrin sealant mesh fixation.45 91.5% of patients. The graft failure rate was 6%.
Bovine albumin and glutaraldehyde in combination with poly-
propylene mesh has been used successfully for fundoplication
and crural reinforcement in a series of 35 patients undergoing
Cardiac Surgery
laparoscopic repair of intrathoracic stomach.46 There were Several new reports on the effectiveness of topical hemostats
3 intraoperative conversions, 1 intraoperative complication, during cardiac surgical operations have appeared. A prospec-
and 3 postoperative complications. Follow-up was possible in tive, randomized, multicenter study comparing either human
21 of 25 eligible patients at 1 year or more after the procedure pooled plasma thrombin or bovine thrombin in combination
and the recurrence rate was 9.5% (2 of 21). Finally, the use of with porcine gelatin sponge in 305 patients revealed no differ-
cyanoacrylates for wound closure is summarized in a recent ence in efficacy between the 2 forms of thrombin in cardiac,
review article.47 neuro, or general surgical procedures.56 Efficacy was based
Application of tissue sealants and adhesives to seal pancrea- on those patients achieving hemostasis at 10 minutes. Cessation
tic resections to prevent pancreatic fistulas remains controver- of bleeding with either form of thrombin combined with por-
sial as noted in a recent review.48 A new clinical study cine gelatin sponge occurred in over 70% of patients in 3 min-
suggested that the rate of fistula formation actually may utes or less. Another recent prospective, randomized,
increase following the use of bovine albumin and glutaralde- nonblinded study found significant benefit to using a flowable
hyde at pancreaticojejunostomies and distal pancreatectomy hemostat at active bleeding sites during cardiac surgical oper-
resections.49 A laboratory study suggested that significant pan- ations compared to control mechanical hemostats.57 All hemo-
creatic tissue reactions occur at pancreaticojejunostomies using stats were applied according to manufacturer’s instructions and
cyanoacrylates while lesser pathologic changes occur using specifically following protamine reversal. In this same study,
fibrin sealants or bovine albumin with glutaraldehyde.50 the flowable agent containing bovine collagen and bovine
thrombin was compared to control application of either porcine
gelatin or oxidized regenerated cellulose alone. Statistically
Breast Surgery significant reductions in achievement of hemostasis by more
Safety and efficacy reports on topical agents in breast surgery than 30%, time to hemostasis by more than 3 minutes, overall
have provided valuable new information. A case report in the postoperative bleeding by more than 150 mL, and incidence of
radiologic literature suggested that malignant appearing micro- blood transfusions by more than 18% were noted compared to
calcifications on a mammogram which were actually benign the control agents. The significant improvement in time to
may appear following the use of a flowable consisting of hemostasis was also confirmed in patients undergoing cardiac
bovine gelatin and human pooled plasma thrombin at a previ- surgical procedures using systemic hypothermia. In another
ous lumpectomy site.51 In a randomized, prospective, con- human study, statistically significant data supporting a new
trolled study of 30 patients, fibrin sealant mixed with 3.5% method of application of commercial human pooled plasma

507
508 Clinical and Applied Thrombosis/Hemostasis 16(5)

fibrin sealant in aortic dissection operations suggest that a performed with a flowable or oxidized regenerated cellulose
‘‘rub-and-spray’’ method may be particularly effective.58 The to achieve hemostasis.66 The flowable group using bovine gela-
technique involves first rubbing fibrinogen into needle holes tin and thrombin had statistically significant reductions in
followed by application of spray thrombin with 3 minutes of operative time of 17 minutes as well as time to drain removal
polymerization time prior to reperfusion. Using this method, and hospital discharge. In another report, a flowable consisting
statistically significant reductions were found in the 10 treated of porcine gelatin and bovine thrombin was used in a
fibrin sealant patients as compared to the 10 control patients multicenter, prospective, single-arm study to evaluate its
receiving no fibrin sealant in the number of bleeding needle hemostatic effectiveness in 30 patients undergoing endoscopic
holes, proportion of proximal and distal bleeding needle holes, sinus surgery.67 Hemostasis was achieved in 96.7% of patients
duration of bleeding, and overall blood loss. within 10 minutes with a reported median time to hemostasis of
The use of sealants to prevent postpericardiotomy adhesions 61 seconds. In a laboratory study using a rabbit model of nasal
has remained an area of investigation. A multicenter, prospec- mucosal injury of the maxillary sinus, polysaccharide spheres
tive, observational study evaluating 36 pediatric patients under- were compared with a flowable consisting of bovine gelatin
going staged reoperative congenital cardiac surgery more than and human pooled plasma thrombin.68 Healing at 2 weeks was
3 months after the initial procedure evaluated a hydrogel poly- evaluated by a blinded pathologist. Sinuses treated with bovine
mer consisting of 2 PEGs to seal the anterior mediastinum.59 gelatin and human pooled plasma thrombin showed extensive
Results revealed a reduction in adhesions, although 5 patients loss of cilia, inflammation, and fibrosis compared to the control
sustained serious adverse events potentially related to the sea- untreated sides. The polysaccharide sphere treated sinuses did
lant. However, the use of a PEG and trilysine amine polymer not exhibit these pathologic changes.
hydrogel was investigated in a controlled 7 pig study and was The use of topical adhesive has also been recently investi-
found not to produce any reductions in adhesion formation.60 In gated in head and neck procedures. In a randomized, controlled,
this study, adhesions were measured using a mathematical prospective, single-center study of 146 patients, fibrin sealant
adhesion score at 6 weeks postpericardiotomy which was orig- was evaluated as a method of achieving hemostasis as well as for
inally performed with instillation of intrapericardial blood to sealing the septum and flaps associated with septoplasy and con-
facilitate the creation of adhesions. chotomy.69 Both treatment groups used fibrin sealant, but 1
Several investigations evaluated the use of topical agents as group had no sutures applied to the septum or flaps. Results were
adhesives in cardiac surgery. Using a rodent model of chronic similar in both groups, suggesting that fibrin sealant use may be
ischemic cardiomyopathy, intramyocardial injection of fibrin able to eliminate the need for transeptal suturing. A series of
sealant was found to stop negative remodeling, enhance angio- 80 patients (20 thyroidectomies, 13 submandibular gland resec-
genesis, and reduce infarct size potentially serving as a basis tions, 9 parotidectomies, 6 neck dissections in conjunction with
for treatment of heart failure.61 The use of octyl cyanoacrylate other surgical procedures, 1 lateral rhinotomy, 1 thyroglossal
was evaluated in a prospective, randomized, controlled trial of cyst resection, and 30 open neck biopsies) were evaluated to
106 patients comparing skin closure following saphenous vein compare wound closure using butyl cyanoacrylate to standard
harvesting for coronary artery bypass grafting using the brid- closure with sutures.70 The cyanoacrylate method was faster by
ging technique.62 Statistically significant benefits were found the large factor of 15 and appearance was judged satisfactory
for the skin closures using octyl cyanoacrylate versus subcuti- with no wound complications in either the treated or control
cular sutures in time required to close the leg incisions, cos- groups. Patients were similar with respect to age, gender, and
metic appearance at 1 and 6 weeks, and overall patient incision length. Another prospective, consecutive patient trial
satisfaction. In another study designed to gain incite into the in 100 participants supported the long-term safety and efficacy
use of adhesives in aortic root replacement, the mechanical of butyl cyanoacrylate for closing parotidectomy incisions.71
properties of fibrin sealants, PEG polymer, and albumin and The study included over 7 years of follow-up and the incidence
glutaraldehyde were compared.63 Albumin and glutaraldehyde of hypertrophic scars and keliods was 8% and 9%, respectively,
was found to be significantly stiffer than the other materials as in the butyl cyanoacrylate patients which is thought comparable
well as stiffer than aortic root grafts and native aortic tissue to the rate using suture technique for wound closure.
raising the possibility that it might contribute to anastomotic The use of topical hemostats in oral surgery in patients with
stricture and restriction of physiologic root dilation. Additional compromised hemostasis due to medications or illness such as
potential complications associated with the use of albumin and von Willebrand diseases or hemophilia A has been recently
glutaraldehyde in cardiac operations have been recently reviewed, and these agents were found to allow for effective
reported including valve dysfunction64 and inferior vena caval wound management in many cases.72
compression masquerading as pericardial tamponade.65
Neurosurgery and Orthopedic Surgery
Head and Neck Surgery Meticulous hemostasis has remained a critical issue in neuro-
The use of topical hemostats has been studied lately in head and surgical procedures and topical hemostats have been a useful
neck operations. In a randomized, prospective, nonblinded adjunct. A comparative rat model of neurosurgery with approx-
study, 155 consecutive total thyroidectomy operations were imately 40 animals in each group was used to test efficacy and

508
Spotnitz and Burks 509

safety of bovine collagen, oxidized regenerated cellulose, The leak rate was 2% (2 of 100) for the polymer and 10%
polysaccharide spheres, and bovine gelatin combined with (10 of 100) for fibrin sealant. In another report, the technique
human pooled plasma thrombin.73 All 4 stopped bleeding of using a ‘‘gasket-seal’’ consisting of autologous fascia lata
within 1 minute but only oxidized regenerated cellulose and around a bone buttress in combination with PEG and trilysine
polysaccharide spheres avoided granuloma formation on amine polymer hydrogel to seal the anterior cranial base in
pathologic examination. A minimally invasive method of treat- transnasal minimal access endoscopic procedures has been
ing spontaneous supratentorial intracerebral hemorrhage has described.81 There were no cerebrospinal leaks noted in any
been described using a flowable hemostat.74 After a linear patients including no leakage from lumbar drains placed intrao-
incision and 3 cm craniotomy, hematomas were evacuated and peratively in 5 patients using this method.
bovine gelatin with pooled plasma thrombin was placed in In an orthopedic study, a long-term follow-up after an aver-
31 patients without vascular anomalies or bleeding disorders. age time of more than 12 years was performed in patients
Hemostasis was successfully achieved in all patients and only undergoing Achilles tendon surgical repair using sutures in
1 patient required reexploration. The benefits of this technique 11 patients or fibrin sealant in 31 patients.82 The results
may include a reduction in surrounding brain damage. In a rat revealed superior function, equal strength, and fewer complica-
model of back surgery, topical treatment of 8 animals with bovine tions using fibrin sealant tendon fixation.
gelatin and human pooled plasma thrombin after laminectomy
was compared to no application after laminectomy in 8 control
animals.75 The treated rats had significantly less epidural fibrosis
Obstetric and Gyneclogic Surgery
as well as less fibroblast and inflammatory cell density. The use of flowable agents has been evaluated in multiple
Reports of complications using flowables in patients have gynecologic procedures. A new method of performing laparo-
also appeared in the spine surgery literature. A case report of scopic ovarian cystectomy has been described.83 Hemostasis of
right heart failure and disseminated intravascular coagulation the ovary after stripping of the cyst was performed using a
following the use of a flowable containing porcine gelatin and flowable of bovine gelatin and pooled plasma thrombin without
bovine thrombin to achieve hemostasis in a posterior fusion the need for sutures or electroacautery. The method may have
operation as treatment for scoliosis has recently been pub- reduced thermal and inflammatory injury to the remaining
lished.76 The case suggested that thrombin may have entered ovarian tissue. Another study of laparoscopic stripping of ovar-
the venous circulation causing fatal thrombosis. In addition, a ian endometriomas compared the use of bovine gelatin and
single report of 2 cases of spinal compression secondary to the pooled plasma thrombin in 8 treated cases to 12 control patients
use of flowable of bovine gelatin and human pooled plasma treated with bipolar cautery for achieving hemostasis.84 The
thrombin at the time of pedicle screw insertion due to inadver- times to cessation of bleeding were similar. This method of
tent extravasation of the hemostatic matrix into the spinal canal achieving hemostasis provided a way to potentially reduce fol-
was reported.77 In both instances of epidural spinal cord com- licular damage associated with the use of electrocautery. In a
pression, neurologic symptoms appeared and the patients third report, a randomized, controlled, prospective, single-
required reexploration for removal of the extravasated material. center trial, on the use of bovine gelatin and thrombin for
Fortunately, both patients eventually had complete recoveries bleeding from uterine tissue was described in 50 women under-
with resolution of all symptoms. going abdominal myomectomy.85 Large reductions in intrao-
The use of sealants to prevent CSF leakage has gained wider perative and postoperative bleeding, use of transfusions, and
use in neurosurgery. A report of cervicomedullary compression hospital stay were found.
secondary to an expanding mass consisting of a PEG and trily- The degree of posterior uterine adhesions was significantly
sine amine polymer hydrogel and gelatin sponge has been reduced in 71 patients entered into a prospective randomized
reported.78 The materials were used for dural sealing in a case trial using 2 PEG polymer hydrogel to seal uterine tissues fol-
of posterior fossa decompression and dural augmentation for lowing myomectomy at the time of laparoscopy or laparot-
Chiari malformation type I. The case emphasized the fact that omy.86 Second look procedures at 8 to 10 weeks revealed the
both of these materials swell and should not be used in critical reductions. No intra-abdominal or wound infections occurred
confined spaces. A second report of a complication associated and the numerical occurrence of adverse events was larger in
with this same polymer hydrogel suggested that the material the control group.
may migrate after application and caused cauda equina com-
pression following the performance of a laminotomy and dis-
cectomy.79 Both movement and swelling were documented
Ophthalmologic Surgery
on sequential imaging studies with operative removal on post- Fibrin sealant has been used more frequently in ophthalmology
operative day 10, confirming proximal migration. as is discussed in a review describing the use of this material.87
In a prospective single-armed study using retrospective Fibrin sealant has been used to seal tissues or suture lines, fix
fibrin sealant controls, PEG and trilysine amine polymer hydro- tissues or devices in place, and to completely replace sutures
gel application to seal the dural incision was found to be statis- in a variety of applications. Cyanoacrylates have also been used
tically significantly superior to fibrin sealant at preventing CSF as adhesives for ophthalmologic procedures. Octyl cyanoacry-
leaks following posterior fossa craniotomy or craniectomy.80 late was applied to the upper eyelid for progressive myophathic

509
510 Clinical and Applied Thrombosis/Hemostasis 16(5)

blepharoptosis in 10 consecutive patients to increase the depth Urologic Surgery

of the upper lid crease.88 The placement of hyperdry amniotic
The use of hemostats to achieve hemostasis following
membrane patches using octyl cyanoacrylate for the treatment
partial nephrectomy has been evaluated in several studies.
of corneal perforations or glaucoma bleb leaks was reported to
A continuous series of 35 patients undergoing laparoscopic
be successful in 5 patients.89
partial nephrectomy for renal tumors by a single surgeon at
one institution was used to investigate 2 forms of flowable
hemostats, bovine gelatin or porcine gelatin, both combined
Plastic Surgery with thrombin.96 No differences in efficacy or safety were
Recent reports of the successful use of cyanoacrylates in plastic found. In another report of 20 consecutive patients operated
surgery included a randomized, prospective trial of the use of upon at a single center using a robotic approach to perform
octyl cyanoacrylate for wound closure following bilateral a laparoscopic partial nephrectomy for the treatment of
reduction mammoplasty with the patients serving as their own tumors less than 7 cm described the successful use of
controls.90 In this study, one side was closed with adhesive and bovine gelatin and thrombin to facilitate hemostasis prior
the other with sutures. Statistically significant benefits in terms to capsular closure with running suture and surgical clips.97
of comfort and appearance were found at 6 weeks and 6 months. There were no bleeding complications with follow-up of
In a retrospective study of unilateral cleft lip repair comparing 1 year. Lastly, a laboratory study in pigs has demonstrated
closure using octyl cyanoacrylate in 186 patients with the feasibility of sutureless laparoscopic heminephrectomy
steri-strips in 121 patients, similar hypertrophic scar rates were in 5 pigs.98 Hemostasis was achieved using an argon beam
found.91 There were no infections or need for scar revisions in coagulator as well as flowable of bovine gelatin and human
the cyanoacrylate group which was performed in the most pooled plasma thrombin. Security at the transection site was
recent time period. In this study, historical controls using achieved using a sandwich of decellularized bovine pericar-
steri-strip skin closure had an infection rate of 4% and a scar dium and bovine albumin and glutaraldehyde. No urine
revision rate of 6% in the earlier time period. A series of 8 leaks were demonstrated on pyelography in the 4 week
female patients had high-viscosity octyl cyanoacrylate used for follow-up period.
skin closure following blepharoplasty.92 Application of Another study of challenging renal trauma in 180 hepari-
adhesive was performed with temporary sutures to facilitate nized rats revealed that gelatin in the form of a sponge or
skin edge approximation and placement of the agent. The matrix with or without thrombin or recombinant factor VIIa
sutures were removed immediately after cyanoacrylate achieved hemostasis 100% of the time, whereas polysaccharide
polymerization. Closure time was 6.9 minutes, aesthetic results spheres with or without recombinant factor VIIa achieved
were judged to be very good to excellent, and no complications hemostasis 25% of the time.99 Thrombin and factor VIIa alone
occurred. There was a minor dehiscence rate of 12.5% did not achieve hemostasis in this model. However, using the
(2 eyelids). efficacious combination of gelatin even with the addition of
thrombin or recombinant factor VIIa resulted in re-bleeding
within 60 minutes in 34% of cases, suggesting that additional
Thoracic Surgery agents may be needed to achieve long lasting hemostasis in this
setting.
The use of topical agents to reduce air leaks following lung
resection continued to be evaluated. In a randomized, prospec-
tive, and blinded study, air leak in lung volume reduction
procedures was reduced in frequency by more than 25% and
Vascular Surgery
in duration by 3 days using an autoglous fibrin sealant for rein- A recent publication analyzed hemostats in a vascular subset
forcement of staple lines.93 A specific application technique consisting of 164 patients from a larger randomized, pro-
was used with the fibrin sealant being placed on the deflated spective, multicenter, double blind study.100 The article
lung staple line and extending outward 1 cm laterally at each compared bovine thrombin and human recombinant throm-
side of the staple line. In another study, a polymer consisting bin. In peripheral vascular procedures as well as dialysis
of 2 PEGs was used as a lung sealant to reinforce leaking lung access operations, both forms of thrombin were equally
staple lines following resection in a randomized, prospective effective in achieving hemostasis at 10 minutes. The recom-
controlled trial.94 The sealant decreased the proportion of binant thrombin was statistically significantly better at
patients with air leaks versus control patients at 24 hours to achieving hemostasis at 3 minutes than bovine thrombin,
19.6% versus 40.6% and at 48 hours to 23.5% versus 41.6%. 55% versus 39%.
The duration of air leaks was also statistically significantly The treatment of groin pseudoaneurysm with ultrasound-
reduced in the sealant treated group. Albumin and glutaralde- guided injection of thrombin was recently reviewed and
hyde adhesive has been reported as being capable of creating assessed.101 The technique was judged to be safe, effective, and
a successful seal within 24 hours in a series of 3 patients with cost-beneficial as well as requiring only a brief learning curve.
postoperative brochopleural fistulas using a brochoscopic It was suggested that this method may be approaching standard
approach for adhesive application.95 of care.

510
Spotnitz and Burks 511

Conclusions experimental results in the porcine model. J Urol. 2004;172(3):

1119-1122.
The surgeons’ desire for improved tools to facilitate the techni- 11. Schenk WG III, Goldthwaite CA Jr, Burks S, Spotnitz WD. Fibrin
cal performance of operations continues to drive new research sealant facilitates hemostasis in arteriovenous polytetrafluor-
and development in the field of topical hemostats, sealants, and oethylene grafts for renal dialysis access. Am Surg. 2002;68(8):
adhesives. This article has provided an update on new products; 728-732.
comparisons of categories of agents in terms of safety, efficacy, 12. Thrombin -JMI [package insert]. Bristol, TN: King Pharmaceuti-
usability, and cost; suggestions for how these products may be cal; 2007.
best applied; and a specialty-specific review of the recent liter- 13. Evithrom [package insert]. Somerville, NJ: Johnson & Johnson;
ature in this area. Choices of which materials to use as well as 2007.
when and how to use them need to be made and the information 14. Recothrom [package insert]. Seatlle, WA: Zymogenetics; 2008.
contained here is intended to help with these decisions. 15. Chapman WC, Singla N, Genyk Y, et al. A phase 3,
randomized, double-blind comparative study of the efficacy
Acknowledgment and safety of topical recombinant human thrombin and bovine
There is an existing consulting agreement between the University of thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):
Virginia and Bayer Pharmaceuticals as well as Zymogenetics for the 256-265.
services of the authors.
16. Gelfoam Plus [package insert]. Hayward, CA: Baxter; 2007.
17. Cheng CM, Meyer-Massetti C, Kayser SR. A review of three
Declaration of Conflicting Interests stand-alone topical thrombins for surgical hemostasis. Clin Ther.
The author(s) declared no conflicts of interest with respect to the 2009;31(1):32-41.
authorship and/or publication of this article. 18. Oz MC, Cosgrove DM III, Badduke BR, et al. Controlled clinical
trial of a novel hemostatic agent in cardiac surgery. The Fusion
Funding Matrix Study Group. Ann Thorac Surg. 2000;69(5):1376-1382.
The author(s) received no financial support for the research and/or 19. Weaver FA, Hood DB, Zatina M, Messina L, Badduke B. Gelatin-
authorship of this article. thrombin-based hemostatic sealant for intraoperative bleeding in
vascular surgery. Ann Vasc Surg. 2002;16(3):286-293.
References 20. Floseal [package insert]. Fremaont, CA: Baxter; 2005.
1. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: 21. Surgiflo [package insert]. Somerville, NJ: Johnson & Johnson;
components of the surgical toolbox. Transfusion. 2008;48(7): 2006.
1502-1516. 22. Tisseel [package insert]. Westlake Village, CA: Baxter; 2009.
2. Vistarini N, Aiello M, Mattiucci G, et al. Port-access minimally 23. Evicel [package insert]. Somerville, NJ: Johnson & Johnson;
invasive surgery for atrial septal defects: a 10-year single-center 2008.
experience in 166 patients. J Thorac Cardiovasc Surg. 2010; 24. Wang GJ, Goldthwaite CA Jr, Burks SG, Spotnitz WD.
139(1):139-145. Experience improves successful use of fibrin sealant in total knee
3. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, arthroplasty: implications for surgical education. J Long Term Eff
Angelini GD. Increased mortality, postoperative morbidity, and Med Implants. 2003;13(5):389-397.
cost after red blood cell transfusion in patients having cardiac 25. Coseal [package insert]. Hayward, CA: Baxter; 2006.
surgery. Circulation. 2007;116(22):2523-2524. 26. Duraseal [package insert]. Mansfield, MA: Covidien; 2005.
4. Larsen K, Hansen TB, Thomsen PB, Christiansen T, Søballe K. 27. Bioglue [package insert]. Kennesaw, GA: Cryolife; 2007.
Cost-effectiveness of accelerated perioperative care and rehabili- 28. Fürst W, Banerjee A. Release of glutaraldehyde from an
tation after total hip and knee arthroplasty. J Bone Joint Surg Am. albumin-glutaraldehyde tissue adhesive causes significant in vitro
2009;91(4):761-772. and in vivo toxicity. Ann Thorac Surg. 2005;79(5):1522-1528.
5. Arista AH [package insert]. Minneapolis, MN: Medafor; 2006. 29. Lemaire SA, Ochoa LN, Conklin LD, et al. Nerve and conduction
6. Ultrafoam [package insert]. Davol, Bard. Somerville, NJ: Johnson tissue injury caused by contact with BioGlue. J Surg Res. 2007;
& Johnson; 2002. 143(2):286-293.
7. Surgicel, Surgical Fibrillar, and Surgicel Nu-Knit [package 30. LeMaire SA, Carter SA, Won T, Wang X, Conklin LD, Coselli JS.
insert]. Somerville, NJ: Johnson & Johnson; 2005. The threat of adhesive embolization: BioGlue leaks through
8. Wagner WR, Pachence JM, Ristich J, Johnson PC. Comparative needle holes in aortic tissue and prosthetic grafts. Ann Thorac
in vitro analysis of topical hemostatic agents. J Surg Res. 1996; Surg. 2005;80(1):106-110.
66(2):100-108. 31. LeMaire SA, Schmittling ZC, Coselli JS, et al. BioGlue surgical
9. Coln D, Horton J, Ogden ME, Buja LM. Evaluation of hemostatic adhesive impairs aortic growth and causes anastomotic strictures.
agents in experimental splenic lacerations. Am J Surg. 1983; Ann Thorac Surg. 2002;73(5):1500-1505.
145(2):256-259. 32. Bavaria JE, Brinster DR, Gorman RC, Woo YJ, Gleason T,
10. Murat FJ, Ereth MH, Dong Y, Piedra MP, Gettman MT. Evalua- Pochettino A. Advances in the treatment of acute type A dissec-
tion of microporous polysaccharide hemospheres as a novel tion: an integrated approach. Ann Thorac Surg. 2002;74(5):
hemostatic agent in open partial nephrectomy: favorable S1848-S1852.

511
512 Clinical and Applied Thrombosis/Hemostasis 16(5)

33. Coselli JS, Bavaria JE, Fehrenbacher J, Stowe CL, Macheers SK, fistula following pancreas resection. J Gastrointest Surg. 2008;
Gundry SR. Prospective randomized study of a protein-based tis- 12(5):882-890.
sue adhesive used as hemostatic and structural adjunct in cardiac 50. Lämsä T, Jin HT, Sand J, Nordback I. Tissue adhesives and the
and vascular anastomotic repair procedures. J Am Coll Surg. pancreas: biocompatibility and adhesive properties of 6 prepara-
2003;197(2):243-252. tions. Pancreas. 2008;36(3):261-266.
34. Dragu A, Unglaub F, Schwarz S, et al. Foreign body reaction after 51. Henkel A, Cooper RA, Ward KA, Bova D, Yao K. Malignant-
usage of tissue adhesives for skin closure: a case report and review appearing microcalcifications at the lumpectomy site with the use
of the literature. Arch Orthop Trauma Surg. 2009;129(2):167-169. of FloSeal hemostatic sealant. AJR Am J Roentgenol. 2008;
35. Dermabond High Viscosity [package insert]. Somerville, NJ: 191(5):1371-1373.
Johnson & Johnson; 2003. 52. Zhibo X, Miaobo Z. Effect of sustained-release lidocaine on
36. Singer AJ, Perry LC, Allen RL Jr. In vivo study of wound bursting reduction of pain after subpectoral breast augmentation. Aesthet
strength and compliance of topical skin adhesives. Acad Emerg Surg J. 2009;29(1):32-34.
Med. 2008;15(12):1290-1294. 53. Taflampas P, Sanidas E, Christodoulakis M, Askoxylakis J,
37. Artiss [package insert]. Westlake Village, CA: Baxter; 2008. Melissas J, Tsiftsis DD. Sealants after axillary lymph node dissec-
38. Hoffmann NE, Siddiqui SA, Agarwal S, et al. Choice of hemo- tion for breast cancer: good intentions but bad results. Am J Surg.
static agent influences adhesion formation in a rat cecal adhesion 2009;198(1):55-58.
model. J Surg Res. 2009;155(1):77-81. 54. Athanassiou E, Vamvakopoulos N, Nakopoulou F, et al. Use of
39. Adams GL, Manson RJ, Hasselblad V, Shaw LK, Lawson JH. albumin polymers during breast cancer surgery improves post-
Acute in-vivo evaluation of bleeding with Gelfoam plus saline operative seroma outcome. Surg Technol Int. 2009;18:109-116.
and Gelfoam plus human thrombin using a liver square lesion 55. Greenhalgh DG, Gamelli RL, Collins J, et al. Recombinant
model in swine. J Thromb Thrombolysis. 2009;28(1):1-5. thrombin: safety and immunogenicity in burn wound excision and
40. Leixnering M, Reichetseder J, Schultz A, et al. Gelatin thrombin grafting. J Burn Care Res. 2009;30(3):371-379.
granules for hemostasis in a severe traumatic liver and spleen rup- 56. Doria C, Fischer CP, Wood CG, Li PM, Marra S, Hart J. Phase 3,
ture model in swine. J Trauma. 2008;64(2):456-461. randomized, double-blind study of plasma-derived human throm-
41. Novik B, Hagedorn S, Mörk UB, Dahlin K, Skullman S, bin versus bovine thrombin in achieving hemostasis in patients
Dalenbäck J. Fibrin glue for securing the mesh in laparoscopic undergoing surgery. Curr Med Res Opin. 2008;24(3):785-794.
totally extraperitoneal inguinal hernia repair: a study with a 40- 57. Nasso G, Piancone F, Bonifazi R, et al. Prospective, randomized
month prospective follow-up period. Surg Endosc. 2006;20(3): clinical trial of the FloSeal matrix sealant in cardiac surgery. Ann
462-467. Thorac Surg. 2009;88(5):1520-1526.
42. Fortelny RH, Schwab R, Glaser KS, et al. The assessment of qual- 58. Minato N, Katayama Y, Yunoki J, Kawasaki H, Satou H. Hemo-
ity of life in a trial on lightweight mesh fixation with fibrin sealant static effectiveness of a new application method for fibrin glue,
in transabdominal preperitoneal hernia repair. Hernia. 2008; the ‘‘rub-and-spray method,’’ in emergency aortic surgery for
12(5):499-505. acute aortic dissection. Ann Thorac Cardiovasc Surg. 2009;
43. Ceccarelli G, Casciola L, Pisanelli MC, et al. Comparing fibrin 15(4):265-271.
sealant with staples for mesh fixation in laparoscopic transabdom- 59. Napoleone CP, Valori A, Crupi G, Ocello S, Santoro F, Vouhé P,
inal hernia repair: a case control-study. Surg Endosc. 2008;22(3): Weerasena N, Gargiulo G. An observational study of CoSeal(R)
668-673. for the prevention of adhesions in pediatric cardiac surgery. Inter-
44. Schug-Pass C, Lippert H, Köckerling F. Mesh fixation with fibrin act Cardiovasc Thorac Surg. 2009;9(6):978-982.
glue (Tissucol/Tisseel(R)) in hernia repair dependent on the mesh 60. Pätilä T, Jokinen JJ, Salminen J, Kankuri E, Harjula A. Polygly-
structure-is there an optimum fibrin-mesh combination?- colic acid glue does not prevent intrapericardial adhesions in a
Investigations on a biomechanical model. Langenbecks Arch short-term follow-up. J Surg Res. 2008;148(2):181-184.
Surg. (IN PRESS). 61. Yu J, Christman KL, Chin E, Sievers RE, Saeed M, Lee RJ.
45. Fortelny RH, Petter-Puchner AH,GlaserKS, et al. Fibrin sealant Restoration of left ventricular geometry and improvement of
(Tisseel) for hiatal mesh fixation in an experimental model in left ventricular function in a rodent model of chronic ischemic
pigs. J Surg Res. (IN PRESS). cardiomyopathy. J Thorac Cardiovasc Surg. 2009;137(1):
46. Zehetner J, Lipham JC, Ayazi S, et al. A simplified technique for 180-187.
intrathoracic stomach repair: laparoscopic fundoplication with 62. Krishnamoorthy B, Najam O, Khan UA, Waterworth P,
Vicryl mesh and BioGlue crural reinforcement. Surg Endosc. Fildes JE, Yonan N. Randomized prospective study comparing
2010;24(3):675-679. conventional subcuticular skin closure with Dermabond skin
47. Singer AJ, Quinn JV, Hollander JE. The cyanoacrylate topical glue after saphenous vein harvesting. Ann Thorac Surg. 2009;
skin adhesives. Am J Emerg Med. 2008;26(4):490-496. 88(5):1445-1449.
48. Fingerhut A, Veyrie N, Ata T, Alexakis N, Leandros E. Use of 63. Azadani AN, Matthews PB, Ge L, et al. Mechanical properties of
sealants in pancreatic surgery: critical appraisal of the literature. surgical glues used in aortic root replacement. Ann Thorac Surg.
Dig Surg. 2009;26(1):7-14. 2009;87(4):1154-1160.
49. Fisher WE, Chai C, Hodges SE, Wu MF, Hilsenbeck SG, 64. Goldberg SP, Campbell DN. Mechanical aortic valve dysfunction
Brunicardi FC. Effect of BioGlue on the incidence of pancreatic due to biological glue. Ann Thorac Surg. 2009;88(2):671-672.

512
Spotnitz and Burks 513

65. Cavolli R, Kaya K, Elalmis AO. ‘‘Acute pseudo-pericardial tam- 80. Than KD, Baird CJ, Olivi A. Polyethylene glycol hydrogel dural
ponade’’: the compression of the thoracal inferior vena cava—a sealant may reduce incisional cerebrospinal fluid leak after pos-
case report. J Cardiothorac Surg. 2009;4(1):9. terior fossa surgery. Neurosurgery. 2008;63(1 suppl 1):
66. Testini M, Marzaioli R, Lissidini G, et al. The effectiveness of ONS182-ONS6.
FloSeal matrix hemostatic agent in thyroid surgery: a prospective, 81. Leng LZ, Brown S, Anand VK, Schwartz TH. ‘‘Gasket-seal’’
randomized, control study. Langenbecks Arch Surg. 2009;394(5): watertight closure in minimal-access endoscopic cranial base
837-842. surgery. Neurosurgery. 2008;62(5 suppl 2): ONSE342-ONSE343.
67. Woodworth BA, Chandra RK, LeBenger JD, Ilie B, Schlosser RJ. 82. Hohendorff B, Siepen W, Spiering L, Staub L, Schmuck T,
A gelatin-thrombin matrix for hemostasis after endoscopic sinus Boss A. Long-term results after operatively treated Achilles ten-
surgery. Am J Otolaryngol. 2009;30(1):49-53. don rupture: fibrin glue versus suture. J Foot Ankle Surg. 2008;
68. Antisdel JL, Janney CG, Long JP, Sindwani R. Hemostatic agent 47(5):392-399.
microporous polysaccharide hemospheres (MPH) does not affect 83. Ebert AD, Hollauer A, Fuhr N, Langolf O, Papadopoulos T.
healing or intact sinus mucosa. Laryngoscope. 2008;118(7): Laparoscopic ovarian cystectomy without bipolar coagulation or
1265-1269. sutures using a gelantine-thrombin matrix sealant (FloSeal): first
69. Vaiman M, Sarfaty S, Eviatar E. The use of fibrin sealant as a support of a promising technique. Arch Gynecol Obstet. 2009;
glue for septoplasty and conchotomy. Rhinology. 2009;47(3): 280(1):161-165.
297-300. 84. Angioli R, Muzii L, Montera R, et al. Feasibility of the use of
70. Bozkurt MK, Saydam L. The use of cyanoacrylates for wound novel matrix hemostatic sealant (FloSeal) to achieve hemostasis
closure in head and neck surgery. Eur Arch Otorhinolaryngol. during laparoscopic excision of endometrioma. J Minim Invasive
2008;265(3):331-335. Gynecol. 2009;16(2):153-156.
71. Greenhill GA, O’Regan B. Incidence of hypertrophic and keloid 85. Raga F, Sanz-Cortes M, Bonilla F, Casañ EM, Bonilla-Musoles F.
scars after N-butyl 2-cyanoacrylate tissue adhesive had been Reducing blood loss at myomectomy with use of a gelatin-
used to close parotidectomy wounds: a prospective study of thrombin matrix hemostatic sealant. Fertil Steril. 2009;92(1):
100 consecutive patients. Br J Oral Maxillofac Surg. 2009; 356-360.
47(4):290-293. 86. Mettler L, Hucke J, Bojahr B, Tinneberg HR, Leyland N,
72. Reich W, Kriwalsky MS, Wolf HH, Schubert J. Bleeding compli- Avelar R. A safety and efficacy study of a resorbable hydrogel for
cations after oral surgery in outpatients with compromised hae- reduction of post-operative adhesions following myomectomy.
mostasis: incidence and management. Oral Maxillofac Surg. Hum Reprod. 2008;23(5):1093-1100.
2009;13(2):73-77. 87. Panda A, Kumar S, Kumar A, Bansal R, Bhartiya S. Fibrin glue in
73. Ereth MH, Schaff M, Ericson EF, Wetjen NM, Nuttall GA, ophthalmology. Indian J Ophthalmol. 2009;57(5):371-379.
Oliver WC Jr. Comparative safety and efficacy of topical hemo- 88. Osaki TH, Osaki MH, Belfort R Jr, Osaki T, Sant’anna AE,
static agents in a rat neurosurgical model. Neurosurgery. 2008; Haraguchi DK. Management of progressive myopathic blephar-
63(4 suppl 2):369-372. optosis with daily application of octyl-2-cyanoacrylate liquid ban-
74. Gazzeri R, Galarza M, Neroni M, Alfieri A, Esposito S. Minimal dage. Ophthal Plast Reconstr Surg. 2009;25(4):264-266.
craniotomy and matrix hemostatic sealant for the treatment of 89. Kitagawa K, Yanagisawa S, Watanabe K, et al. A hyperdry
spontaneous supratentorial intracerebral hemorrhage. J Neuro- amniotic membrane patch using a tissue adhesive for corneal per-
surg. 2009;110(5):939-942. forations and bleb leaks. Am J Ophthalmol. 2009;148(3):383-389.
75. Dogulu F, Durdag E, Cemil B, Kurt G, Ozgun G. The role of Flo- 90. Nipshagen MD, Hage JJ, Beekman WH. Use of 2-octyl-
Seal in reducing epidural fibrosis in a rat laminectomy model. cyanoacrylate skin adhesive (Dermabond) for wound closure
Neurol Neurochir Pol. 2009;43(4):346-351. following reduction mammaplasty: a prospective, randomized
76. Ferschl MB, Rollins MD. Thromboemboli, acute right heart fail- intervention study. Plast Reconstr Surg. 2008;122(1):10-18.
ure and disseminated intravascular coagulation after intraopera- 91. Wilson AD, Mercer N. Dermabond tissue adhesive versus Steri-
tive application of a topical hemostatic matrix. Anesth Analg. Strips in unilateral cleft lip repair: an audit of infection and hyper-
2009;108(2):434-436. trophic scar rates. Cleft Palate Craniofac J. 2008;45(6):614-619.
77. Buchowski JM, Bridwell KH, Lenke LG, Good CR. Epidural 92. Perin LF, Helene A Jr, Fraga MF. Sutureless closure of the upper
spinal cord compression with neurologic deficit associated with eyelids in blepharoplasty: use of octyl-2-cyanoacrylate. Aesthet
intrapedicular application of hemostatic gelatin matrix during Surg J. 2009;29(2):87-92.
pedicle screw insertion. Spine (Phila Pa 1976). 2009;34(13): 93. Moser C, Opitz I, Zhai W, et al. Autologous fibrin sealant reduces
E473-E477. the incidence of prolonged air leak and duration of chest tube drai-
78. Blackburn SL, Smyth MD. Hydrogel-induced cervicomedullary nage after lung volume reduction surgery: a prospective rando-
compression after posterior fossa decompression for Chiari mized blinded study. J Thorac Cardiovasc Surg. 2008;136(4):
malformation. Case report. J Neurosurg. 2007;106(4 suppl): 843-849.
302-304. 94. D’Andrilli A, Andreetti C, Ibrahim M, et al. A prospective rando-
79. Mulder M, Crosier J, Dunn R. Cauda equina compression by mized study to assess the efficacy of a surgical sealant to treat air
hydrogel dural sealant after a laminotomy and discectomy: case leaks in lung surgery. Eur J Cardiothorac Surg. 2009;35(5):
report. Spine (Phila Pa 1976). 2009;34(4):E144-E148. 817-820.

513
514 Clinical and Applied Thrombosis/Hemostasis 16(5)

95. Ranu H, Gatheral T, Sheth A, Smith EE, Madden BP. Successful physiologic and chronically obstructed porcine kidney. Surg
endobronchial seal of surgical bronchopleural fistulas using Bio- Innov. 2008;15(3):194-202.
Glue. Ann Thorac Surg. 2009;88(5):1691-1692. 99. Björses K, Holst J. Topical haemostatics in renal trauma—an
96. Nogueira L, Katz D, Pinochet R, Kurta JM, Coleman JA. evaluation of four different substances in an experimental
Comparison of gelatine matrix-thrombin sealants used during setting. J Trauma. 2009;66(3):602-611.
laparoscopic partial nephrectomy. BJU Int. 2008;102(11): 100. Weaver FA, Lew W, Granke K, Yonehiro L, Delange B,
1670-1674. Alexander WA; Study Investigators. A comparison of recombi-
97. Ho H, Schwentner C, Neururer R, Steiner H, Bartsch G, nant thrombin to bovine thrombin as a hemostatic ancillary in
Peschel R. Robotic-assisted laparoscopic partial nephrectomy: patients undergoing peripheral arterial bypass and arteriovenous
surgical technique and clinical outcomes at 1 year. BJU Int. graft procedures. J Vasc Surg. 2008;47(6):1266-1273.
2009;103(7):663-668. 101. Hanson JM, Atri M, Power N. Ultrasound-guided thrombin
98. Derweesh IH, Malcolm JB, Diblasio CJ, Mehrazin R, Jackson S. injection of iatrogenic groin pseudoaneurysm: doppler features
Sutureless laparoscopic heminephrectomy: safety and efficacy in and technical tips. Br J Radiol. 2008;81(962):154-63.

514