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TREATMENT REVIEW

A Review of Current Hemostatic


Agents and Tissue Sealants Used in
Laparoscopic Partial Nephrectomy
I. Galanakis, MD, FEBU, N. Vasdev, MD, MRCS, N. Soomro, MD, FRCS
Department of Urology, Freeman Hospital, Newcastle upon Tyne, United Kingdom

Laparoscopic partial nephrectomy (LPN) is currently considered to be one


of the most challenging procedures in minimally invasive urological surgery.
With an increasing number of renal tumors being managed using LPN, there
is now a further interest in the development of techniques and agents to
reduce complications associated with the procedure. Hemostasis is of paramount importance during LPN, and hemostatic agents and tissue sealants
are now being used commonly during LPN. Despite this, there is a dearth of
prospective, randomized, human trials in current literature that compare the
various agents. This review evaluates hemostatic agents and tissue sealants
being used during LPN as an adjuvant to suturing in human studies.
[Rev Urol. 2011;13(3):131-138 doi: 10.3909/riu0524]
2011 MedReviews, LLC
Key words: Laparoscopic partial nephrectomy Renal tumors Hemostatic agents
Tissue sealants Suturing adjuvant

he first laparoscopic nephrectomy was performed by Clayman and colleagues in 1991 and is now recognized as a major landmark in urology.1
Following this procedure, there has been a gradual global rise in minimally
invasive urological surgery (MIUS) that has led to a rapid increase in research and
techniques within this field. In Europe and the United States, the use of robotic
systems is currently revolutionizing MIUS and it is now envisaged that only a few
open techniques will be reserved for select cases.
Laparoscopic partial nephrectomy (LPN) is considered to be one of the most
technically challenging types of MIUS, with a steep learning curve and potential
for complications.2 With regard to postoperative hemorrhage, a large multiinstitutional, retrospective study was conducted by Gill and colleagues, who

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Hemostatic Agents and Tissue Sealants Used in LPN continued

compared the outcomes of 1028 and


771 patients undergoing open partial
nephrectomy (OPN) and LPN, respectively. Hemorrhage was found in
1.6% and 4.2% of these patients, respectively (P  .0002), despite the
fact that the open procedures had
been reserved for larger and more
centrally located tumors.3
Minimizing blood loss in the
operating field is a key factor during
LPN as even the smallest amount of
bleeding can compromise vision during laparoscopy due to light absorption by blood. More importantly, a
poor view associated with hemorrhage can affect the outcome during
suturing repair. To maximize hemostasis following the excision of the
tumor and to reduce the rate of postoperative hemorrhagic events, a wide
variety of hemostatic tools have been
transferred from open surgery or developed specifically for use during
LPN. This review describes the currently available hemostatic and sealing agents used to achieve parenchymal hemostasis during LPN that have

(approximately 30) that produce fibrin to form a stable hemostatic plug.


The aim of all hemostatic agents is to
act by imitating, promoting, or bypassing specific steps of the coagulation cascade.

The aim of all hemostatic agents is to act by imitating, promoting, or


bypassing specific steps of the coagulation cascade.
Fibrin Sealants or Glues
The idea of promoting hemostasis
using fibrin was first reported by
Bergel in 1909.4 Fibrin sealants, as we
know them today, have been commercially available in Europe and Japan
for over 30 years with a good safety
profile.5 However, it was not until
1998 that the US Food and Drug Administration (FDA) approved their use
due to concerns over the transmission
of infectious disease as these products
were developed from pooled plasma
components.6
Fibrin sealants are designed to
mimic the final steps of the blood
coagulation cascade, forming a stable,

To maximize hemostasis following the excision of the tumor and to reduce


the rate of postoperative hemorrhagic events, a wide variety of hemostatic
tools have been transferred from open surgery or developed specifically for
use during LPN.
been evaluated in human LPN trials
(Table 1) and also discusses agents
being evaluated in animal LPN studies (Table 2).

Hemostasis
Hemostasis is a rather complex
process. The injury of a blood vessel
triggers the following sequence:
(1) vessel constriction to reduce blood
flow; (2) adherence of circulating
platelets to the vessel wall at the site
of the trauma; and (3) platelet activation and aggregation, coupled with
an intricate series of enzymatic reactions involving coagulation proteins

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plastic, oral, and maxillofacial


surgery.9 However, more and more
urologic applications are being
reported. The use of fibrin sealants
in renal injuries or OPN has been
evaluated with good immediate and

physiologic fibrin clot that assists


hemostasis and wound healing. These
agents work best in a dry surgical
field. Fibrin sealants essentially contain human fibrinogen and humanor bovine-derived thrombin. Further
components include antifibrinolytic
agent (eg, aprotinin), calcium chloride, and factor XIII.7 They can be
manufactured from pooled blood or
single-source donors or can be made
specifically from the patients own
blood.7,8
Fibrin glues have initially been
used in a variety of settings including cardiac, vascular, reconstructive

REVIEWS IN UROLOGY

long-term results.10,11 With regard to


LPN, Pruthi and colleagues were the
first to report their experience with
the use of TISSEEL (Baxter Healthcare
Corporation, Westlake Village, CA), in
15 patients undergoing hand-assisted
LPN for renal tumor (mean size,
2.7 cm).12 In all cases, electrocauterization and argon-beam coagulation followed by the application of TISSEEL
was successful in obtaining strict
hemostasis of the surgical bed, with
no evidence of acute or delayed hemorrhage.12 On the other hand, Johnston and colleagues reported that the
use of fibrin glues may offer adequate
hemostasis in patients undergoing
LPN when the collecting system or
renal sinus is not entered, but in case
of entering, a sutured bolster is
recommended.13 In support, a recent,
randomized animal study, which
compared various tissue sealants
(FLOSEAL Hemostatic Matrix, Baxter
Healthcare; Quixil Solutions for
Sealant, Ethicon, Somerville, NJ;
TISSUCOL, Baxter Healthcare) with
conventional suturing during LPN,
emphasized the need for suturing in
cases where the urinary tract
opened.14 Nevertheless, in 2007, Porpiglia and coworkers published results
to the contrary. They prospectively
compared two groups of patients,
similar in baseline characteristics,
undergoing LPN: group A (n  24)
received parenchymal suture, whereas
group B (n  20) received parenchymal suture with fibrin glue (TISSUCOL)
and collagen fleece (TissuFleece E;

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REVIEWS IN UROLOGY
Activates the conversion
of fibrinogen to fibrin

TachoSil (Nycomed)

LPN, laparoscopic partial nephrectomy.

Human
fibrinogen
and thrombin
fleece

Glutaraldehyde
crosslinks bovine
albumin to cell
proteins at wound
site to form a strong
adhesive

BioGlue (Cryolife)

Provides matrix for


clotting initiation

SURGICEL/
TABOTAMP (Ethicon),
Oxycel (Becton
Dickinson)

Oxidized
regenerated
methylcellulose

Glutaraldehydebased adhesives

Provides a matrix
for clot formation
and activates
autologous thrombin

Vivostat
(Vivostat A/S)

FloSeal
(Baxter Healthcare),
SURGIFLO (Ethicon)

Idem

TISSEEL/TISSUCOL
(Baxter Healthcare),
Hemaseel HMN
(Haemacure Corp.)
EVISEL/Quixil
(Ethicon)

Fibrin glues

Gelatin-based
sealant

Activates the
conversion of
fibrinogen to fibrin

Product

Category

Mechanism
of Action

Human

No

No

Autologous

Autologous

Human

Fibrinogen

Human

No

No

Human

Autologous

Human

Thrombin

Human,
pooled

Bovine
albumin

Synthetic

Human,
pooled

Autologous
plasma

Human,
pooled

Source

Table 1
Hemostatic and Sealing Agents Currently Used in LPN and
Evaluated in Human LPN Studies

No need for preparation


or reconstitution
Use even in bleeding
disorders
Rather difficult to apply
laparoscopically

Rapid polymerization
No suture after solidification
Dry field preferred
Bovine product
Quite expensive

Ease of use
Low pH:
(i) antimicrobial effect,
(ii) not used with biologic
agents (thrombin),
(iii) may increase surrounding
tissue inflammation

Contains bovine products


Surgiflo porcine gelatin
Requires blood in the field
Not a sealing agent

Dry field
Sequential application
Autologous only source

Dry field
Sequential application
Requires thawing.
Spray delivery system
for Tisseel (DUPLOSPRAY
MIS) Possible allergic reactions
Hemaseel HMN is expected
No aprotinin in EVICEL

Comments

33-36

42, 43

13, 39, 40

24-30,
44, 45

17,18

12, 13, 15,


17, 18, 44,
45, 52

References

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Hemostatic Agents and Tissue Sealants Used in LPN continued

Table 2
Hemostatic and Sealing Agents Evaluated as Adjuncts During LPN and
Evaluated Only in Animal LPN Studies
Category

Mechanism of Action

Source

Comments

References

Fibrin glue

Activates the conversion of


fibrinogen to fibrin

Bovine collagen and


Dry field
thrombin  patient-derived No aprotinin
fibrinogen
Viral infections

46, 47

Hemostatic fibrin
sealant powder

Mixture of lyophilized human


fibrinogen and thrombin prepared
as a fine powder; when activated
by exposure to moisture, it
immediately forms a dense
fibrin clot

Human

Ease of use
Uniform application
Lack of preparation time
Not yet commercially
available
Good results

48

Polyethylene
glycol hydrogel

Two synthetic polyethylene glycol


polymers that mix and crosslink
in wound site

Synthetic

Does not require


47, 49
patients blood
Is not exothermic, does not
cause inflammation or infection
Contradictory results in studies
Expensive

Cyanoacrylates

Liquid monomers form polymers


in the presence of water and in
turn a cyanoacrylate bridge,
binding the wound edges together

Synthetic

Rapid polymerization
Dry field preferred
Useful but only as an additive
Glubran use is reported in
humans,40 no data available

50

Granulated
mineral

Nonwoven gauze impregnated with


kaolin that absorbs the smaller water
granules, leaving the larger clotting
factors and platelets in the wound

Synthetic

Efficacy also in sealing


in a single, small study
Ease of use and inexpensive
Exothermic
Dry field

51

LPN, laparoscopic partial nephrectomy.

Baxter Healthcare).15 The authors concluded that the suturing was the key
component for hemostasis in patients
undergoing LPN and sealants did not
influence their results significantly.15
An important landmark in the field
of hemostatic agents was the development of CROSSEAL (Ethicon) in 2003.
This fibrin sealant was manufactured
entirely from nonanimal components
and lacked, therefore, the bovine aprotinin and, as a consequence, avoided
the potential allergic reactions or
prion infections associated with bovine
products.16 CROSSEAL was replaced in
2006 by Evicel Fibrin Sealant
(Ethicon). This was an identical

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sealant except it lacked the tranexamic acid (a fibrin clot stabilizer) that
has been associated with neurologic
complications.7
Vivostat (Vivostat A/S, Alleroed,
Denmark) is an autologous, plateletenriched, fibrin sealant applicator
system that utilizes 120 mL of the patients blood, which is processed
overnight. Schips and colleagues published their results with 10 patients
undergoing LPN (mean tumor size,
2.7 cm).17 After tumor excision and
placement of two sutures, Vivostat
was applied and there was no acute or
delayed hemorrhage. Likewise, Gidaro
and colleagues have recently reported

REVIEWS IN UROLOGY

similar results with 28 patients undergoing LPN (mean tumor size, 2.5 cm),
although they also applied suture and
bolster in 67% and 80% of patients,
respectively.18
There is much research ongoing in
the development of newer fibrin
sealants for application during LPN
and, despite the fact that many preliminary animal studies are favorable,
outcomes in human patients and in
large series need to be evaluated.
Gelatin-Based Sealants
The first gelatin-based sealant
(Gelfoam, Baxter Healthcare)) was
used in 1945. A further revolution in

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Hemostatic Agents and Tissue Sealants Used in LPN

this field was the introduction of


FloSeal in 1999.19 The FloSeal Matrix
consists of a bovine-derived gelatin
matrix component with a calcium
chloride solution and a humanderived thrombin component.20 When
FloSeal is applied to the bleeding surface, its granules allow high concentrations of thrombin to react rapidly
with the patients fibrinogen and form
a mechanically stable fibrin clot. As
blood percolates through the gelatin
matrix, the granules swell approximately 20% within 10 minutes, reducing blood flow and providing
gentle tamponade, conforming to the
wounds shape. The clot is reabsorbed
after 6 to 8 weeks.20,21 The unique
characteristic of FloSeal is the requirement for the presence of blood at
its application site for activation. As
with fibrin sealants, there is a treatment risk of developing bovine
spongiform encephalitis or IgEmediated anaphylaxis.22,23 Moreover,
injection of FloSeal directly into
medium to large vessels can theoretically cause thromboembolic events.23
The use of FloSeal for urologic
surgery has been mainly in trauma
and partial nephrectomy (laparoscopic or open) where it has been
assessed on animal models and case
series. With regard to LPN, the first
report of using FloSeal as an adjunct,
efficacious haemostatic agent was
made by User and Nadler.24 Richter
and colleagues reported their use of
FloSeal in a case series of 25 patients
undergoing partial nephrectomy (15
OPN, 10 LPN) for small renal tumors
(mean size, 2.8 cm). In this series,
FloSeal provided immediate and
durable hemostasis, without the need
for suturing.25 Gill and coworkers
published a prospective study comparing 63 patients undergoing LPN
using FloSeal with 68 patients undergoing LPN without the use of
FloSeal.26 The results showed that the
adjunctive use of FloSeal substantially

enhanced parenchymal hemostasis


and reduced postoperative hemorrhagic complications to levels comparable with previous contemporary
OPN series.26 Further studies reported
similar positive results.27,28 Weld and
colleagues published their experience
for the first 60 LPN cases performed
by a single surgeon.29 In this series,
the authors described using both
FloSeal and fibrin glue but later
stopped using the fibrin glue. The interesting outcome of this series was
that, despite the exclusion of fibrin
glue in the more recent cases, there
was no clinical or statistical difference in the incidence of bleeding or
leakage.29
SURGIFLO (an evolution of
SURGIFOAM; Ethicon) is another
currently used gelatin matrix thrombin sealant, though of porcine origin.
This agent can also be mixed with
sterile saline instead of thrombin.
Nogueira and colleagues prospectively compared SURGIFLO with
FloSeal in 35 patients undergoing
LPN by a single surgeon and reported
no notable differences in terms of
hemostasis, handling, or ease of
application.30
Accessibility, ease of use, and
effective hemostasis make FloSeal a
popular tool in reducing surgical
morbidity from blood loss in patients
undergoing a LPN.

lacks the bovine aprotinin. Upon


contact with blood or other fluids, the
coagulation factors react to form a
fibrin clot that sticks TachoSil to the
tissue surface, producing an air- and
liquid-tight seal in 3 to 5 minutes. It
is biodegradable and may be applied
directly to the bleeding surface without the need for preparation or reconstitution. Rassweiler and colleagues
reported their positive experience
with the use of TachoComb in LPN.33
An interesting prospective, randomized, multicenter study was published
later by Siemer and colleagues, although it studied use in OPN.34 The
authors compared TachoSil with standard suturing in 185 patients undergoing OPN for small renal tumors and
concluded it was superior to standard
suturing in obtaining intraoperative
control of hemorrhage and equally
well tolerated. Hacker and coworkers
used TachoComb and fibrin glue as
preventive measures for delayed
bleeding in 25 LPN cases.35 Falsaperla
and associates recently reported their
experience with the use of TachoSil in
14 patients who underwent LPN for
small peripheral tumors (mean size,
3.4 cm).36 After suturing the
parenchyma, they applied TachoSil
directly on the bloody surface of the
tumoral bed and found no immediate
or delayed hemorrhage or other complications in any of the patients.

Human Fibrinogen and


Thrombin Fleece
TachoSil (Nycomed, Zurich, Switzerland) is a sterile, ready-to-use absorbable patch for intraoperative
topical application. It consists of an
equine-collagen sponge coated with
the human coagulation factors fibrinogen and thrombin.31 It was
launched in 2004 but only approved
by the FDA in April 2010.32 It is the
evolution of TachoComb (Nycomed),
as it now contains a purely human
coagulation factor component and

Oxidized Regenerated Methylcellulose


Oxidized cellulose was first introduced in 1942 by Frantz, after which
SURGICEL (Ethicon) was launched
into the clinical market in 1960.37
SURGICEL is a plant-based topical
hemostatic made by regenerating
pure plant-derived cellulose into a
knitted fabric that is then oxidized.38
When it is applied topically, it absorbs
blood and becomes a gel covering the
site of vessel injury. Contact with
moisture triggers the breakdown of
cellulose and the release of cellulosic

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acid that lowers the topical pH. That


causes localized vasoconstriction but
also provides bactericidal properties.
However, SURGICELs main hemostatic effect is achieved by providing a
matrix for platelet adhesion, accelerating the creation of the platelet plug
that will form the foundation of the
fibrin clot.37,38
SURGICEL is currently widely used
in LPN, not only for controlling mild
bleeding but also in the form of surgical bolster. Following the excision
of the tumor, SURGICEL is positioned
within a sutured bolster into the defect, achieving approximation and
local compression at the resected site,
as in the open technique.13,39 In a
multi-institutional survey from Europe and the United States (18 centers
with 1347 LPN cases), parenchymal
suturing over bolster of SURGICEL
was consistently used by 16 centers.40
Of the remaining two, one center (50
cases) never performed suturing/
bolstering, using only sealants, and
the other (35 cases) reported variable
use of a bolster suture and/or central
hemostatic suture depending on the
depth of the lesion.
Glutaraldehyde-Based Adhesive
BioGlue (CryoLife, Kennesaw, GA)
was first released in Europe in 1998. It
is a two-component surgical adhesive
composed of solutions of purified
bovine serum albumin (BSA) and
glutaraldehyde.41 The glutaraldehyde
molecules covalently bond (crosslink)
the BSA molecules to each other and
on application to the tissue proteins
at the repair site, creating a flexible
mechanical seal independent of the
bodys clotting cascade. BioGlue begins to polymerize within 20 to 30 seconds and reaches its bonding strength
within approximately 2 minutes.41
Nadler and colleagues were the first
to report their positive experience
with the use of BioGlue in 8 LPN
cases (mean tumor size, 2.8 cm), both

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as a hemostatic and as a protective


covering over the tumor resection
site.42 Nevertheless, they underlined
some interesting technical points,
such as the dry surgical field as a prerequisite for the successful adherence
of BioGlue to the application site, the
risk of hardening within the collecting system, and the extreme difficulty
of placing sutures after it has solidified.42 In a larger study, Hidas and
colleagues retrospectively compared
143 patients who underwent traditional sutured OPN with 31 patients
undergoing a sutureless BioGlue
sealing-only procedure. Despite the
retrospective nature of the study, the
patient and tumor characteristics
were similar in both groups. The authors concluded that BioGlue alone
provided adequate hemostasis during
nephron-sparing surgery, and significantly decreased blood loss and the

laparoscopically. Technical modifications and refinements, as well as a


number of hemostatic tools, have
been added to the armamentarium of
urologic surgeons. In particular, hemostatic agents and sealants, with
over 100 years of history, play an
important role. In a recent multiinstitutional LPN study, over 80% of
urologists used sealants as an adjunct.39 Choice is variable from one
surgeon to another and may depend
on individual experience rather than
a strong evidence base.
It is obvious that useful recommendations cannot be made because of
the lack of properly designed,
prospective, randomized human trials. Nevertheless, by no means should
the use of hemostatic agents preclude
proper laparoscopic suturing with
surgical bolsters. There may be examples of small peripheral tumors

By no means should the use of hemostatic agents preclude proper laparoscopic suturing with surgical bolsters.
transfusion rate, as well as the renal
ischemic and operative times.43
Other Agents
A great number of hemostatic and
sealing agents are currently in use in
all surgical specialties and research is
ongoing. Not all of them are, naturally, suitable for LPN. Table 2 briefly
presents the agents that have been
evaluated in LPN-only trials.

Conclusions
OPN is currently considered the gold
standard for the treatment of small
renal cancers. However, the need for
less morbidity without compromising
the oncological and surgical outcome is directing urologists toward
LPN. Centers of excellence have
shown that duplication of established
open surgical principles is possible

REVIEWS IN UROLOGY

that can be treated with the complementary use of sealants and bipolar
coagulation, but in case of a bigger
tumor, when ischemia is required, sutures with bolster are essential. Interestingly, there are authors proposing
that, in the future, to determine a
standard hemostasis technique, rather
than relying on the development of
sealants, we should rely on innovations in suture techniques.15
The search for the ideal efficient
hemostatic agent continues. Until
that day, the urologic surgeon should
have a detailed knowledge of the
available agents and must be sure
that by using them he will have better results than with those using
standard methods. Most importantly,
he must keep in mind that hemostatic
agents and tissue sealants should not
be considered as a surgical alternative

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Hemostatic Agents and Tissue Sealants Used in LPN

technique, but rather as an adjunct to


facilitate and achieve the optimal
surgical outcome.

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Main Points
Fibrin sealants are designed to mimic the final steps of the blood coagulation cascade, forming a stable, physiologic fibrin clot that
assists hemostasis and wound healing. These agents work best in a dry surgical field. Fibrin sealants essentially contain human
fibrinogen and human- or bovine-derived thrombin. Further components include antifibrinolytic agent (eg, aprotinin), calcium
chloride, and factor XIII. They can be manufactured from pooled blood or single-source donors or can be made in specifically from
the patients own blood.
Fibrin glues have been used in a variety of settings including cardiac, vascular, reconstructive plastic, oral, and maxillofacial
surgery. More and more urologic applications are being reported. The use of fibrin sealants in renal injuries or OPN has been evaluated with good immediate and long-term results.
Hemostatic agents and tissue sealants should not be considered as a surgical alternative technique, but rather as an adjunct to facilitate and achieve the optimal surgical outcome.

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