Use Of Tissue Sealants And Hemostatic Agents

Use of Tissue Sealants and Hemostatic Agents in Surgery Martha K. Terris, M.D. Medical College of Georgia

Hemostasis “life in the balance” CVA MI DVT PE Trauma Surgery Anticoagulation Hemophilia Bleeding to Death Clotting to Death

Why Use Hemostatic Agents Minimize blood loss Improve visualization Save operative time Reduce or avoid transfusion Manage anticoagulated patient Avoid conversion of lap procedures Prevent leakage of non-bloody fluids Decrease post-op drainage and infection Decrease hospital length of stay

A Century of Hemostasis Surgeons today have an impressive set of tools to manage intra-operative bleeding. But how do you know what to use? 1900 1950 2000 Clamps Clips Sutures Direct Compression Bone wax Electrocautery Laser Argon beam ORC Gelatin Thrombin Flowable gelatin Fibrin Sealants Synthetic Sealants

History of Hemostasis Prior to 1900 Prior to 1950

Factors in Choosing a Hemostatic Agent Product cost Availability Storage Procedural applicability Format (sponge, fabric, powder, paste, liquid) Preparation Delivery Speed to hemostasis Durability of hemostasis Source (bovine, porcine, human, plant) Immunogenicity Impact on infection/healing Absorption rate Swelling

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)

Materials Properties/Handling Mechanism of action Passive (aides platelet plug formation) Active (aides fibrin clot formation) Application format Fabric Woven (suturable vs see-through) Non-woven (layers vs peanuts vs cigars) Flowable Paste (spread with fingers) Slurry (apply with syringe) Liquid Drip (controlled delivery) Spray (broad coverage)

Site Characterization Area: large vs small Intensity: light vs heavy Accessibility: open vs confined Surface type: raw vs smooth

Bleed Collagen, ORC Flowable Gelatin Thrombin Fibrin Sealant

Bleed Platelet inhibitors, NSAIDS, ASA, Clopidogrel Thrombin inhibitors, Heparin, Warfarin tPA, uPA Trauma, Time, Us!

INSTAT Instat Collagen (Absorbable Hemostat Sponge) Instat MCH (Microfibrillar Collagen Hemostat Powder)

AVITENE Avitene Collagen Sponge (Absorbable Hemostat Sponge) Avitene MCH Flour (Microfibrillar Collagen Hemostat Powder)

Collagen INSTAT (J&J) and Avitene (Davol) Not widely used in urologic surgery Plant-derived Available as sponge or powder Can be used dry or wet, cut, sutured, wrapped Won’t adhere to wet instruments or gloves Hemostasis in 3-5 minutes

Avitene Applicators Extended applicators available for deeper open or laparoscopic application of Avitene Use a syringe of air to clear any product still in applicator

Oxidized Regenerated Cellulose (ORC) Advantages Multiple application formats (mesh, knit, fibrillar) Plant-derived Minimal tissue reaction Bactericidal Disadvantages Swelling can cause pressure on adjacent structures Impairs bone healing Absorbs Fluids Causes platelet plug formation

SURGICEL Conforms to wound site, minimal sticking to gloves or instruments Effective hemostasis for classic 6-8 minutes, Nu-knit 3-5 minutes, fibrillar 3-4 minutes No immunogenicity potential, bactericidal Absorption within 7-14 days (depending on amount used, degree of saturation with blood)

SURGICEL Can be passed down endoscopic instruments

SURGICEL SURGICEL Mesh adherent to area of bleeding SURGICEL Nu-Knit used to make bolsters for partial nephrectomy

SURGICEL Fibrillar Can be shredded, compacted, or moistened and molded to various shapes

GELFOAM/SURGIFOAM Absorbable Gelatin SURGIFOAM Absorbable Gelatin Powder GELFOAM Absorbable Gelatin Sponge SURGIFOAM Absorbable Gelatin Sponge

GELFOAM/SURGIFOAM Addition of thrombin or saline allows molding to specific areas Doesn’t stick to gloves, instruments, can be passed down endoscopic instruments Fast hemostasis Minimal foreign body reaction Absorbs in 4-6 weeks

Flowable Gelatin Composition Animal-derived gelatin mixed with thrombin (or saline) in a flowable consistency Mode of action Gelatin provides a matrix for platelet adhesion and aggregation Thrombin aids in fibrin clot formation Will not work if the area is not actively bleeding

Flowable Mechanism of Action Applied to the tissue surface at the base of the lesion. Its granules fill the wound and conform to its shape. Granules expand approximately 20% within about 10 min and restrict the flow of blood. Blood that percolates through the spaces is exposed to high concentrations of thrombin. A clot forms around the matrix provided by the granules and remains in place at the tissue surface.

Flowable Mechanism of Action Granules not incorporated in the clot can and should be removed with gentle irrigation Absorbed within 6-8 weeks

Flowable Gelatin Advantages Rapid hemostasis Precise application 75% more tissue contact than traditional gelatin sponge Flowable Absorbable in 4-8 weeks Disadvantages Allergic potential (when bovine thrombin is used) Swells 20% as it absorbs fluid Preparation time Cost

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

Endoscopic Applicator for Flowable Gelatins Indicated for the endoscopic delivery of hemostatic agents Narrow cannula allows precise application of more product Use stylet or syringe with air to express any remaining product out of applicator $1500, reusable

Thrombin Bovine-derived or human thrombin (equivalent time to hemostasis): Thrombin, Evithrom, Recothrom Converts patient fibrinogen to fibrin Available in a freeze-dried lyophilized powder that can be stored at room temperature but must be mixed Liquid versions must be refrigerated Multiple application techniques available (soaked in other products, spray) Expensive

Thrombin Bovine Purified from pooled bovine plasma Not 100% homologous with human thrombin Bovine thrombin & factor V contain carbohydrate groups that are inherently immunogenic in humans Recombinant Human Human prothrombin gene is spliced into Chinese hamster ovary (CHO) cells CHO cells make human prothrombin Prothrombin activated with snake venom enzyme (cleaves prothrombin to thrombin) Human Purified from pooled human plasma Viral transmission risk

Bovine Thrombin Used in a wide variety of surgical procedures, estimated >500,000 Americans exposed each year Anaphylactic deaths reported from use in vascular surgery resulting in black box warning from FDA

Isolation of anti-Bovine Thrombin Antibodies 1989 90 91 92 93 94 95 96 97 98 99 00 01 Clinical Reports of Patients with Major Complications from Antibodies Prospective Analysis of Thrombin Exposure in Surgical Patients Autoimmune Processes Linked with Use of Bovine Thrombin

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

History of Fibrin Sealants 1909 – The use of fibrin to facilitate hemostasis was reported for the first time 1944 – Plasma derived fibrinogen and thrombin were used to enhance adherence of skin grafts 1972 – Highly concentrated fibrinogen made from frozen plasma used to perform nerve anastomosis 1975 – First clinical reports of autologous fibrin sealant published in Europe 1981 – Fibrin sealant consisting of human thrombin, highly stabilized human fibrinogen with enriched factor XIII introduced

Fibrin Sealants Target the Final Steps of the Coagulation Cascade

Thrombin and Fibrinogen Can be stored in separate vials at -18 o C for 2 years or refrigerated at 4 o C for 30 days Can be thawed at room temperature or in 37 o C water bath Dual delivery systems design to prevent mixing of the two until contact with the target tissue

Anti-Fibrinolytics Anti-fibrinolytics inhibit the formation of plasmin from plasminogen Plasmin breaks down the fibrin clot Tisseel contains aprotinin, an antifibrinolytic Plasminogen has been removed from Evicel through an extra step in the manufacturing process and therefore does not need an antifibrinolytic agent to prevent the formation of plasmin and subsequent breakdown of the fibrin clot.

US Indications by Brand Evicel – Adjunct to hemostasis for use in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Tisseel – Adjunct to hemostasis in surgeries involving heparinized patients undergoing cardiopulmonary bypass and treatment of splenic injury due to blunt or penetrating trauma when control of bleeding by standard surgical techniques is ineffective or impractical. Also an 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

Fibrin Sealants Not indicated for treatment of severe or brisk bleeding Do not inject directly into vascular structures or organs Can apply in multiple layers OK to use cautery or suture through layers of sealant Clot longevity is comparable for both Tisseel and Evicel

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

BioGlue Composed of Glutaraldehyde and purified bovine serum albumin (BSA) Binds covalently to tissue surface proteins (won’t work if place on non-protein surface) Supplied with multiple syringe tips as they clot off as soon as there is no active injection.

CoSeal Composed of two synthetic polyethylene glycols (PEGs) in hydrogen chloride and sodium phosphate When mixed the PEGS form a hydrogel that adheres to tissue and covalently bonds to itself Completely synthetic, no gluteraldehyde Swells up to 4 times its volume in 24 hrs and additional swelling may occur as the gel resorbs

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

Use Of Tissue Sealants And Hemostatic Agents

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