Use Of Tissue Sealants And Hemostatic Agents

Use of Tissue Sealants Use of Tissue Sealants and Hemostatic Agents in and Hemostatic Agents in

SurgerySurgery

Martha K. Terris, M.D.Martha K. Terris, M.D.

Medical College of GeorgiaMedical College of Georgia

HemostasisHemostasis“life in the balance”“life in the balance”

Bleeding Bleeding to Deathto Death

Clotting Clotting to Deathto Death

CVACVAMIMIDVTDVTPEPE

TraumaTraumaSurgerySurgeryAnticoagulationAnticoagulationHemophiliaHemophilia

Why Use Hemostatic AgentsWhy Use Hemostatic Agents

• Minimize blood lossMinimize blood loss• Improve visualizationImprove visualization• Save operative timeSave operative time• Reduce or avoid transfusionReduce or avoid transfusion• Manage anticoagulated patientManage anticoagulated patient• Avoid conversion of lap proceduresAvoid conversion of lap procedures• Prevent leakage of non-bloody fluidsPrevent leakage of non-bloody fluids• Decrease post-op drainage and infectionDecrease post-op drainage and infection• Decrease hospital length of stayDecrease hospital length of stay

A Century of HemostasisA Century of Hemostasis1900 1950 20001900 1950 2000

Clamps Clips Sutures Direct Compression Bone waxClamps Clips Sutures Direct Compression Bone wax

Electrocautery Laser Argon beamElectrocautery Laser Argon beam

ORC Gelatin ThrombinORC Gelatin Thrombin

Flowable gelatinFlowable gelatin

Fibrin SealantsFibrin Sealants

Synthetic SealantsSynthetic Sealants

Surgeons today have an Surgeons today have an impressive set of tools to impressive set of tools to manage intra-operative manage intra-operative bleeding. But how do you bleeding. But how do you know what to use?know what to use?

History of HemostasisHistory of Hemostasis

Prior to 1900 Prior to 1900

Prior to 1950Prior to 1950

Factors in Choosing a Factors in Choosing a Hemostatic AgentHemostatic Agent

• Product costProduct cost• AvailabilityAvailability• StorageStorage• Procedural applicabilityProcedural applicability• Format (sponge, fabric, Format (sponge, fabric,

powder, paste, liquid)powder, paste, liquid)• PreparationPreparation• DeliveryDelivery

• Speed to hemostasisSpeed to hemostasis• Durability of hemostasisDurability of hemostasis• Source (bovine, porcine, Source (bovine, porcine,

human, plant)human, plant)• ImmunogenicityImmunogenicity• Impact on infection/healingImpact on infection/healing• Absorption rateAbsorption rate• SwellingSwelling

Hemostasis and Sealing MarketHemostasis and Sealing Market• CollagenCollagen

• INSTAT MCH (Microfibrillar INSTAT MCH (Microfibrillar Collagen Hemostat) - J&JCollagen Hemostat) - J&J

• Avitene MCH – Davol Avitene MCH – Davol (Bard)(Bard)

• ORC (Oxidized ORC (Oxidized Regenerated Cellulose)Regenerated Cellulose)• Surgicel – J&J/EthiconSurgicel – J&J/Ethicon

• GelatinGelatin• Gelfoam – Pfizer/BaxterGelfoam – Pfizer/Baxter• Surgifoam – J&JSurgifoam – J&J

• Flowable GelatinsFlowable Gelatins• Floseal - BaxterFloseal - Baxter• Surgiflow - J&JSurgiflow - J&J

• ThrombinThrombin• Thrombin – King PharmaThrombin – King Pharma

• Evithrom – J&JEvithrom – J&J

• Recothrom – ZymogeneticsRecothrom – Zymogenetics

• Fibrin SealantsFibrin Sealants• Tisseel – BaxterTisseel – Baxter

• Evicel – J&JEvicel – J&J

• Synthetic SealantsSynthetic Sealants• Bioglue – CryolifeBioglue – Cryolife

• Duraseal – TycoDuraseal – Tyco

• CoSeal – BaxterCoSeal – Baxter

• Omnex – J&J/Ethicon (Europe Omnex – J&J/Ethicon (Europe only)only)

• LifeBond – (FDA approval LifeBond – (FDA approval pending)pending)

Materials Properties/HandlingMaterials Properties/Handling• Mechanism of actionMechanism of action

• Passive (aides platelet plug formation)Passive (aides platelet plug formation)• Active (aides fibrin clot formation)Active (aides fibrin clot formation)

• Application formatApplication format• FabricFabric

• Woven (suturable vs see-through)Woven (suturable vs see-through)• Non-woven (layers vs peanuts vs cigars)Non-woven (layers vs peanuts vs cigars)

• FlowableFlowable• Paste (spread with fingers)Paste (spread with fingers)• Slurry (apply with syringe)Slurry (apply with syringe)

• LiquidLiquid• Drip (controlled delivery)Drip (controlled delivery)• Spray (broad coverage)Spray (broad coverage)

Site CharacterizationSite Characterization

• Area: large vs smallArea: large vs small• Intensity: light vs heavyIntensity: light vs heavy• Accessibility: open vs confinedAccessibility: open vs confined• Surface type: raw vs smoothSurface type: raw vs smooth

BleedBleed

BleedBleed

Collagen, Collagen, ORCORC

Flowable Flowable GelatinGelatin

ThrombinThrombin

Fibrin Fibrin SealantSealant

BleedBleed

Platelet Platelet inhibitors, inhibitors,

NSAIDS, ASA, NSAIDS, ASA, ClopidogrelClopidogrel

Thrombin Thrombin inhibitors, inhibitors, Heparin, Heparin, WarfarinWarfarin

tPA, tPA, uPAuPA

Trauma, Trauma, Time, Us!Time, Us!

Hemostasis and Sealing Market• Collagen

• INSTAT MCH (Microfibrillar Collagen Hemostat) - J&J

• Avitene MCH – Davol (Bard)

• ORC (Oxidized Regenerated Cellulose)• Surgicel – J&J/Ethicon

• Gelatin• Gelfoam – Pfizer/Baxter• Surgifoam – J&J

• Flowable Gelatins• Floseal - Baxter

• Surgiflow - J&J

• Thrombin• Thrombin – King Pharma

• Evithrom – J&J

• Recothrom – Zymogenetics

• Fibrin Sealants• Tisseel – Baxter

• Evicel – J&J

• Synthetic Sealants• Bioglue – Cryolife

• Duraseal – Tyco

• CoSeal – Baxter

• Omnex – J&J/Ethicon (Europe only)

• LifeBond – (FDA approval pending)

INSTAT INSTAT

Instat Collagen Instat Collagen

(Absorbable Hemostat Sponge)(Absorbable Hemostat Sponge)

Instat MCH (Microfibrillar Collagen Instat MCH (Microfibrillar Collagen Hemostat Powder)Hemostat Powder)

AVITENEAVITENE

Avitene Collagen SpongeAvitene Collagen Sponge

(Absorbable Hemostat Sponge)(Absorbable Hemostat Sponge)

Avitene MCH Flour (Microfibrillar Avitene MCH Flour (Microfibrillar Collagen Hemostat Powder)Collagen Hemostat Powder)

CollagenCollagenINSTAT (J&J) and Avitene (Davol)INSTAT (J&J) and Avitene (Davol)

• Not widely used in urologic surgeryNot widely used in urologic surgery• Plant-derivedPlant-derived• Available as sponge or powderAvailable as sponge or powder• Can be used dry or wet, cut, sutured, Can be used dry or wet, cut, sutured,

wrappedwrapped• Won’t adhere to wet instruments or Won’t adhere to wet instruments or

glovesgloves• Hemostasis in 3-5 minutesHemostasis in 3-5 minutes

Avitene ApplicatorsAvitene Applicators

• Extended applicators available for deeper open or Extended applicators available for deeper open or laparoscopic application of Avitenelaparoscopic application of Avitene

• Use a syringe of air to clear any product still in applicator Use a syringe of air to clear any product still in applicator

Oxidized Regenerated Cellulose Oxidized Regenerated Cellulose (ORC)(ORC)

AdvantagesAdvantages

• Multiple application Multiple application formats (mesh, knit, formats (mesh, knit, fibrillar)fibrillar)

• Plant-derivedPlant-derived• Minimal tissue reactionMinimal tissue reaction• BactericidalBactericidal

DisadvantagesDisadvantages

• Swelling can cause Swelling can cause pressure on adjacent pressure on adjacent structuresstructures

• Impairs bone healingImpairs bone healing

Absorbs FluidsAbsorbs Fluids

Causes platelet plug formationCauses platelet plug formation

$12$12

$15$15

$20$20

How Does SURGICEL Work?How Does SURGICEL Work?

Why is SURGICEL Bactericidal?Why is SURGICEL Bactericidal?

SURGICELSURGICEL• Conforms to wound site, minimal sticking to Conforms to wound site, minimal sticking to

gloves or instrumentsgloves or instruments• Effective hemostasis for classic 6-8 minutes, Effective hemostasis for classic 6-8 minutes,

Nu-knit 3-5 minutes, fibrillar 3-4 minutesNu-knit 3-5 minutes, fibrillar 3-4 minutes• No immunogenicity potential, bactericidalNo immunogenicity potential, bactericidal• Absorption within 7-14 days (depending on Absorption within 7-14 days (depending on

amount used, degree of saturation with blood)amount used, degree of saturation with blood)

SURGICELSURGICEL

• Can be passed down endoscopic instrumentsCan be passed down endoscopic instruments

SURGICELSURGICEL

SURGICEL Mesh SURGICEL Mesh adherent to area adherent to area of bleedingof bleeding

SURGICEL Nu-SURGICEL Nu-Knit used to make Knit used to make bolsters for bolsters for partial partial nephrectomynephrectomy

SURGICEL FibrillarSURGICEL Fibrillar

Can be shredded, compacted, or moistened and

molded to various shapes

GELFOAM/SURGIFOAM GELFOAM/SURGIFOAM Absorbable GelatinAbsorbable Gelatin

SURGIFOAM Absorbable Gelatin PowderSURGIFOAM Absorbable Gelatin Powder

GELFOAM Absorbable Gelatin SpongeGELFOAM Absorbable Gelatin Sponge

SURGIFOAM Absorbable Gelatin SpongeSURGIFOAM Absorbable Gelatin Sponge

GELFOAM/SURGIFOAMGELFOAM/SURGIFOAM

• Addition of thrombin or Addition of thrombin or saline allows molding to saline allows molding to specific areasspecific areas

• Doesn’t stick to gloves, Doesn’t stick to gloves, instruments, can be passed instruments, can be passed down endoscopic down endoscopic instrumentsinstruments

• Fast hemostasisFast hemostasis• Minimal foreign body Minimal foreign body

reactionreaction• Absorbs in 4-6 weeksAbsorbs in 4-6 weeks

Flowable GelatinFlowable Gelatin

CompositionComposition

• Animal-derived gelatin Animal-derived gelatin mixed with thrombin (or mixed with thrombin (or saline) in a flowable saline) in a flowable consistencyconsistency

Mode of actionMode of action

• Gelatin provides a Gelatin provides a matrix for platelet matrix for platelet adhesion and adhesion and aggregationaggregation

• Thrombin aids in fibrin Thrombin aids in fibrin clot formationclot formation

• Will not work if the area Will not work if the area is not actively bleedingis not actively bleeding

Flowable Mechanism of ActionFlowable Mechanism of Action• Applied to the tissue surface at the Applied to the tissue surface at the

base of the lesion. Its granules fill the base of the lesion. Its granules fill the wound and conform to its shape.wound and conform to its shape.

• Granules expand approximately 20% Granules expand approximately 20% within about 10 min and restrict the within about 10 min and restrict the flow of blood. Blood that percolates flow of blood. Blood that percolates through the spaces is exposed to high through the spaces is exposed to high concentrations of thrombin.concentrations of thrombin.

• A clot forms around the matrix A clot forms around the matrix provided by the granules and remains provided by the granules and remains in place at the tissue surface.in place at the tissue surface.

Flowable Mechanism of ActionFlowable Mechanism of Action

• Granules not incorporated in the clot Granules not incorporated in the clot can and should be removed with can and should be removed with gentle irrigationgentle irrigation

• Absorbed within 6-8 weeksAbsorbed within 6-8 weeks

Flowable GelatinFlowable Gelatin

AdvantagesAdvantages

• Rapid hemostasisRapid hemostasis• Precise applicationPrecise application• 75% more tissue 75% more tissue

contact than traditional contact than traditional gelatin spongegelatin sponge

• FlowableFlowable• Absorbable in 4-8 Absorbable in 4-8

weeksweeks

DisadvantagesDisadvantages

• Allergic potential (when Allergic potential (when bovine thrombin is bovine thrombin is used)used)

• Swells 20% as it Swells 20% as it absorbs fluidabsorbs fluid

• Preparation timePreparation time• CostCost

SURGIFLO

• Uses human thrombin• Low risk of immune

reaction• Prep time: 30 minutes

FLOSEAL

• Uses bovine thrombin• Higher risk of immune

reaction• Prep time: 60 minutes

Flowable Gelatin

Flowable Gelatins

Surgiflo

Endoscopic Applicator for Flowable Endoscopic Applicator for Flowable GelatinsGelatins

• Indicated for the endoscopic Indicated for the endoscopic delivery of hemostatic agentsdelivery of hemostatic agents

• Narrow cannula allows precise Narrow cannula allows precise application of more productapplication of more product

• Use stylet or syringe with air to Use stylet or syringe with air to express any remaining product express any remaining product out of applicatorout of applicator

• $1500, reusable$1500, reusable

BleedBleed



ThrombinThrombin


ThrombinThrombin• Bovine-derived or human thrombin (equivalent time to Bovine-derived or human thrombin (equivalent time to

hemostasis): Thrombin, Evithrom, Recothromhemostasis): Thrombin, Evithrom, Recothrom• Converts patient fibrinogen to fibrinConverts patient fibrinogen to fibrin• Available in a freeze-dried lyophilized powder that can Available in a freeze-dried lyophilized powder that can

be stored at room temperature but must be mixed be stored at room temperature but must be mixed • Liquid versions must be refrigeratedLiquid versions must be refrigerated• Multiple application techniques available (soaked in Multiple application techniques available (soaked in

other products, spray)other products, spray)• ExpensiveExpensive

ThrombinThrombin• BovineBovine

• Purified from pooled bovine plasmaPurified from pooled bovine plasma

• Not 100% homologous with human thrombinNot 100% homologous with human thrombin

• Bovine thrombin & factor V contain carbohydrate groups that are Bovine thrombin & factor V contain carbohydrate groups that are inherently immunogenic in humansinherently immunogenic in humans

• Recombinant HumanRecombinant Human

• Human prothrombin gene is spliced into Chinese hamster ovary (CHO) Human prothrombin gene is spliced into Chinese hamster ovary (CHO) cellscells

• CHO cells make human prothrombin CHO cells make human prothrombin

• Prothrombin activated with snake venom enzyme (cleaves prothrombin Prothrombin activated with snake venom enzyme (cleaves prothrombin to thrombin)to thrombin)

• Human Human

• Purified from pooled human plasmaPurified from pooled human plasma

• Viral transmission riskViral transmission risk

Bovine ThrombinBovine Thrombin

• Used in a wide variety of surgical procedures, Used in a wide variety of surgical procedures, estimated >500,000 Americans exposed each yearestimated >500,000 Americans exposed each year

• Anaphylactic deaths reported from use in vascular Anaphylactic deaths reported from use in vascular surgery resulting in black box warning from FDAsurgery resulting in black box warning from FDA

Isolation of anti-Bovine Thrombin AntibodiesIsolation of anti-Bovine Thrombin Antibodies

1989 90 91 92 93 94 95 96 97 98 99 00 01

Clinical Reports of Patients with Major Clinical Reports of Patients with Major Complications from AntibodiesComplications from Antibodies

Prospective Analysis of Prospective Analysis of Thrombin Exposure in Surgical Thrombin Exposure in Surgical PatientsPatients

Autoimmune Autoimmune Processes Processes Linked with Linked with Use of Bovine Use of Bovine ThrombinThrombin

Pooled Human Plasma Products• Primary risk is pathogen transmission

• In 1977, FDA banned all commercially prepared human fibrinogen preparations because of the high rate of disease transmission (HBV)

• In 1998, FDA lifted this ban due to improved methods for plasma protein purification

Hemostasis and Sealing Market• Collagen

• INSTAT MCH (Microfibrillar Collagen Hemostat) - J&J

• Avitene MCH – Davol (Bard)

• ORC (Oxidized Regenerated Cellulose)• Surgicel – J&J/Ethicon

• Gelatin• Gelfoam – Pfizer/Baxter• Surgifoam – J&J

• Flowable Gelatins• Floseal - Baxter

• Surgiflow - J&J

• Thrombin• Thrombin – King Pharma

• Evithrom – J&J

• Recothrom – Zymogenetics

• Fibrin Sealants• Tisseel – Baxter

• Evicel – J&J

• Synthetic Sealants• Bioglue – Cryolife

• Duraseal – Tyco

• CoSeal – Baxter

• Omnex – J&J/Ethicon (Europe only)

• LifeBond – (FDA approval pending)

History of Fibrin SealantsHistory of Fibrin Sealants• 1909 – The use of fibrin to facilitate hemostasis was 1909 – The use of fibrin to facilitate hemostasis was

reported for the first timereported for the first time• 1944 – Plasma derived fibrinogen and thrombin were 1944 – Plasma derived fibrinogen and thrombin were

used to enhance adherence of skin graftsused to enhance adherence of skin grafts• 1972 – Highly concentrated fibrinogen made from 1972 – Highly concentrated fibrinogen made from

frozen plasma used to perform nerve anastomosisfrozen plasma used to perform nerve anastomosis• 1975 – First clinical reports of autologous fibrin 1975 – First clinical reports of autologous fibrin

sealant published in Europesealant published in Europe• 1981 – Fibrin sealant consisting of human thrombin, 1981 – Fibrin sealant consisting of human thrombin,

highly stabilized human fibrinogen with enriched highly stabilized human fibrinogen with enriched factor XIII introducedfactor XIII introduced

Fibrin Sealants Target the Final Fibrin Sealants Target the Final Steps of the Coagulation CascadeSteps of the Coagulation Cascade

Thrombin and FibrinogenThrombin and Fibrinogen• Can be stored in separate vials at -18Can be stored in separate vials at -18ooC for 2 C for 2

years or refrigerated at 4years or refrigerated at 4ooC for 30 daysC for 30 days• Can be thawed at room temperature or in 37Can be thawed at room temperature or in 37ooC C

water bathwater bath• Dual delivery systems design to prevent mixing Dual delivery systems design to prevent mixing

of the two until contact with the target tissueof the two until contact with the target tissue

Anti-FibrinolyticsAnti-Fibrinolytics

• Anti-fibrinolytics inhibit the formation of Anti-fibrinolytics inhibit the formation of plasmin from plasminogenplasmin from plasminogen

• Plasmin breaks down the fibrin clotPlasmin breaks down the fibrin clot• Tisseel contains aprotinin, an antifibrinolyticTisseel contains aprotinin, an antifibrinolytic• Plasminogen has been removed from Evicel Plasminogen has been removed from Evicel

through an extra step in the manufacturing through an extra step in the manufacturing process and therefore does not need an process and therefore does not need an antifibrinolytic agent to prevent the formation antifibrinolytic agent to prevent the formation of plasmin and subsequent breakdown of the of plasmin and subsequent breakdown of the fibrin clot.fibrin clot.

BleedBleed



ThrombinThrombin


US Indications by BrandUS Indications by Brand• Evicel – Adjunct to hemostasis for use in patients Evicel – Adjunct to hemostasis for use in patients

undergoing surgery when control of bleeding by undergoing surgery when control of bleeding by standard surgical techniques is ineffective or standard surgical techniques is ineffective or impractical.impractical.

• Tisseel – Adjunct to hemostasis in surgeries Tisseel – Adjunct to hemostasis in surgeries involving heparinized patients undergoing involving heparinized patients undergoing cardiopulmonary bypass and treatment of splenic cardiopulmonary bypass and treatment of splenic injury due to blunt or penetrating trauma when injury due to blunt or penetrating trauma when control of bleeding by standard surgical control of bleeding by standard surgical techniques is ineffective or impractical. Also an techniques is ineffective or impractical. Also an effective sealant in closure of colostomies.effective sealant in closure of colostomies.

Fibrin Sealants

EVICEL

• Uses human thrombin (all human components)

• Low risk of immune reaction

• No aprotinin or tansexamanic acid

• Prep time <1 minute• Clear clot• Spray or drip

TISSEEL

• Uses bovine thrombin• Higher risk of immune

reaction• Contains aprotinin• Prep time 15 minutes• Cloudy white clot• Spray (syringe or

pressure delivery) or drip

Tisseel

Evicel

Tisseel

Fibrin SealantsFibrin Sealants

• Not indicated for treatment of severe or brisk Not indicated for treatment of severe or brisk bleedingbleeding

• Do not inject directly into vascular structures Do not inject directly into vascular structures or organsor organs

• Can apply in multiple layersCan apply in multiple layers• OK to use cautery or suture through layers of OK to use cautery or suture through layers of

sealantsealant• Clot longevity is comparable for both Tisseel Clot longevity is comparable for both Tisseel

and Eviceland Evicel

Synthetic SealantsSynthetic Sealants• Co-Seal and BioGlue most commonly usedCo-Seal and BioGlue most commonly used• Creates a shell over the area appliedCreates a shell over the area applied• Caution not to cover things that will be removedCaution not to cover things that will be removed

BioGlueBioGlue• Composed of Glutaraldehyde and purified Composed of Glutaraldehyde and purified

bovine serum albumin (BSA)bovine serum albumin (BSA)• Binds covalently to tissue surface proteins Binds covalently to tissue surface proteins

(won’t work if place on non-protein surface)(won’t work if place on non-protein surface)• Supplied with multiple syringe tips as they clot Supplied with multiple syringe tips as they clot

off as soon as there is no active injection.off as soon as there is no active injection.

CoSealCoSeal• Composed of two synthetic Composed of two synthetic

polyethylene glycols (PEGs) in polyethylene glycols (PEGs) in hydrogen chloride and sodium hydrogen chloride and sodium phosphatephosphate

• When mixed the PEGS form a hydrogel When mixed the PEGS form a hydrogel that adheres to tissue and covalently that adheres to tissue and covalently bonds to itselfbonds to itself

• Completely synthetic, no gluteraldehydeCompletely synthetic, no gluteraldehyde• Swells up to 4 times its volume in 24 hrs Swells up to 4 times its volume in 24 hrs

and additional swelling may occur as and additional swelling may occur as the gel resorbsthe gel resorbs

CostCost• Avitene powder $625 (5ml)Avitene powder $625 (5ml)• Avitene sheets $350-550Avitene sheets $350-550• Surgicel $12-20Surgicel $12-20• Gelfoam $80-120Gelfoam $80-120• Floseal $262 (5ml) Floseal $262 (5ml) • Bovine Thrombin $80 (5ml)Bovine Thrombin $80 (5ml)• Evithrom $95 (5ml)Evithrom $95 (5ml)• Recothrom $110 (5ml)Recothrom $110 (5ml)• Tisseel $220 (4ml) Tisseel $220 (4ml) • Evicel $340 (4ml)Evicel $340 (4ml)• BioGlue $325 (5ml)BioGlue $325 (5ml)• CoSeal $630 (4ml)CoSeal $630 (4ml)

““All Bleeding Stops”All Bleeding Stops”

Use Of Tissue Sealants And Hemostatic Agents

Technology

Transcript of Use Of Tissue Sealants And Hemostatic Agents