Optimizing the Selection and Use Of Topical...

Statement of NeedIntraoperative hemostasis is an important clinical goal; excessive bleeding is associated with prolonged pro-cedures, extended hospitalization, and serious com-plications. Low clinician awareness has been observed around the availability, selection, and use of the array of topical hemostats. Educational and knowledge gaps also are acknowledged by pharmacists with regard to the use of topical hemostats, as these products may enter hospitals via central supply rather than pharmacy ordering. Topical hemostats have diverse clinical and pharmacoeconomic profi les, and a number of direct and non-medication costs (eg, storage, preparation, product waste, potential for uncommon but serious side eff ects) must be considered with their use.

Program GoalTo educate clinicians on the selection and use of topical hemostats in the hospital setting.

Learning ObjectivesAfter completing this activity, participants should be better able to:

1 Appraise the clinical and economic eff ects of excessive intraoperative or postoperative bleeding and common preoperative strategies for minimiz-ing bleeding events.

2 Describe key clinical factors that infl uence the selection and use of topical hemostats as adjuncts for achieving surgical hemostasis.

3 Delineate clinical characteristics and pharmaco-economic (direct and non-medication costs) con-siderations by which topical hemostats should be evaluated, acquired, and used in hospitals.

4 Develop a plan for reconciling cautionary guidance and clinical best practices with regard to the selec-tion and use of the full range of topical hemostats.

Target AudienceTh is activity is designed to meet the educational needs of physicians, pharmacists, nurses, and other health care professionals.

Accreditation StatementsPhysician: Th is activity has been planned and imple-mented in accordance with the Essential Areas and policies of the Accreditation Council for Continu-ing Medical Education (ACCME) through the joint sponsorship of AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continu-ing medical education for physicians. AKH Inc. desig-nates this enduring activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participa-tion in the activity.

Pharmacist: AKH Inc. is accredited by the Accreditation Council for Pharmacy Edu-cation as a provider of continuing pharmacy

education. AKH Inc. approves this application-based activity for 2.0 contact hours (0.2 CEUs). UAN 0077-9999-12-013-H04-P. Initial release date: April 1, 2012.Nurse: AKH Inc. is accredited as a provider of con-tinuing nursing education by the American Nurses Credentialing Center’s COA. AKH Inc. designates this educational activity for 2 contact hours (0.2 CEUs). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.

Confl ict of Interest StatementIt is the policy of AKH Inc. to ensure independence, balance, objectivity, scientifi c rigor, and integrity in all of its continuing education activities. Th e faculty must disclose to the participants any signifi cant relationships with commercial interests whose products or devices may be mentioned in the activity or with the com-mercial supporter of this continuing education activ-ity. Identifi ed confl icts of interest are resolved by AKH prior to accreditation of the activity and may include any of or combination of the following: attestation to non-commercial content; notifi cation of indepen-dent and certifi ed CME/CE expectations; referral to National Faculty Initiative training; restriction of topic area or content; restriction to discussion of science only; amendment of content to eliminate discussion of device or technique; use of other faculty for discussion of rec-ommendations; independent review against criteria ensuring evidence support recommendation; moderator review; and peer review. AKH/Applied clinical Edu-catin (ACE) planners and reviewers have no relevant fi nancial relationships to disclose.

Financial DisclosuresDr. Baker: Consultant to Accredo Health Group, Inc. (advisory board), Medco Health Solutions (Pharmacy & Th erapeutics Committee)Dr. Boucher: Speakers’ bureau for ZymoGeneticsDr. Doria: Nothing to discloseMary Culpepper (medical writer): Nothing to disclose

Disclosure of Unlabeled UseTh is educational activity may contain discussion of some agents that have been studied but are not FDA-approved for use as hemostatics. Refer to offi cial pre-scribing information for all products for discussion of approved indications, contraindications, and warnings.

Estimated Time of Completion: 120 minutes.Method of ParticipationTh ere are no fees for participating in and receiving credit for this activity. Read the objectives and mono-graph, complete the post-test and evaluation, and mail

to: AKH Inc., PO Box 2187, Orange Park, FL 32067-0534; or fax to (904) 683-3803. Statements of participa-tion will be mailed/emailed approximately 6 to 8 weeks after receipt of mailed or faxed submissions. Online participation is available at topical-hemostats.com. A score of at least 70% is required for successful comple-tion, and one retake is allowed. Th e corrected answer sheet will be provided. Credit is available through April 1, 2013. If you have questions about this CME/CE activity, please contact AKH Inc. at [email protected]

DisclaimerTh is course is designed solely to provide the health care professional with information to assist in his or her practice and professional development and is not a diag-nostic tool to replace professional advice or treatment. Th e course serves as a general guide to the health care professional, and therefore cannot be considered as giv-ing legal, nursing, medical, or other professional advice in specifi c cases. AKH Inc., ACE, and the faculty spe-cifi cally disclaim responsibility for any adverse conse-quences resulting directly or indirectly from information in the course, for undetected error, or through readers’ misunderstanding of the content.

Copyright InformationCopyright © 2012 AKH Inc. and ACE. No part of this syllabus may be used or reproduced in any man-ner whatsoever without written permission except in the case of brief quotations included in articles or reviews.

Chair

Cataldo Doria, MD, PhD, FACSNicoletti Family Professor of Transplant Surgery Director, Division of Transplantation Co-Director, Jefferson Kimmel Cancer Center - Liver Tumor Center Thomas Jefferson University HospitalPhiladelphia, Pennsylvania

Faculty

Danial E. Baker, PharmDProfessor of PharmacotherapyAssociate Dean for Clinical ProgramsDirector, Drug Information CenterCollege of PharmacyWashington State UniversitySpokane, Washington

Bradley A. Boucher, PharmD, FCCP, FCCMProfessor, Vice-Chair for Institutional ProgramsDepartment of Clinical PharmacyAssociate ProfessorDepartment of NeurosurgeryUniversity of Tennessee Health Science CenterMemphis, Tennessee

Medical Writer

Mary Culpepper

Sponsored by Distributed via

Release Date: April 1, 2012 Expiration Date: April 1, 2013

Optimizing the Selection and Use Of Topical HemostatsThis monograph is based on a symposium held in Boston on November 12, 2011.

Participate online at topical-hemostats.com

Supported by an educational grant from

A Bristol-Myers Squibb Company

2

IntroductionDespite advances in surgical techniques and operative hemosta-

sis management, excessive bleeding remains a major surgical compli-cation that contributes to poor clinical outcomes.1 Excessive blood loss has been reported in 3% to 14% of cardiovascular surgeries,2-5 and re-exploration for microvascular bleeding after cardiac surgery is an important source of morbidity and mortality.6 In one study, mortality rates increased from 8% in patients who lost less than 500 mL of blood during surgery to 42.9% for those who lost more than 2,000 mL.1,7 In addition to its clinical consequences, excessive perioperative bleeding leads to increased economic costs related to extended procedure times, transfusion of blood products, prolonged hospital length of stay (LOS), intensive care unit stay, and significant use of clinical and staff resources.1,8,9 Across surgery types, bleeding-related complications or transfusions extended incremental LOS by 6 days in a recent retrospective analysis.8

A key responsibility of the surgeon is to reduce blood loss via hemostasis (ie, arrest bleeding).10 This requires maintenance of a fine balance between bleeding and clotting risks,11 a challenge that is intensified by the increasing use of potent antithrombotic drugs.12 These risks extend beyond surgery; although the hemostatic pen-dulum swings toward bleeding intraoperatively, it moves toward clotting immediately postoperatively and back toward bleeding in recovery.11 Surgeons must anticipate and manage bleeding.

Adjuncts to intraoperative hemostasis such as hemostats, seal-ants, and adhesives represent an increasingly important approach to controlling perioperative bleeding, particularly for minimally invasive operations in which bleeding may not be amenable to conventional methods of hemostasis (ie, suture, ligature, cautery). Optimal selection and use of these agents requires surgical team members—surgeons, anesthesiologists, hematologists, pharmacists, and nurses—to understand the available materials and products

in order to arrest bleeding intraoperatively and minimize risk for adverse events (AEs) postoperatively.

Among adjunct products are topical thrombins, which have been used successfully as hemostats since the 1940s and currently are used in more than 1 million US surgeries annually.10,13 However, bovine-derived topical thrombin preparations occasionally have been asso-ciated with hemostatic abnormalities ranging from asymptomatic to mild or severe bleeding or thrombosis, which rarely have been fatal.14 Believed to be uncommon, immune-mediated coagulopathies (IMCs) result from the development of antibodies that cross-react with human coagulation factors and disrupt inherent clotting mech-anisms. Topical thrombins of 3 biologic origins are available, with 2 introduced since 2007. Clinical concerns associated with each are appropriate for review, given their prevalence as standalone hemo-stats and in combination with other adjuncts to surgical hemostasis.

Minimizing Perioperative Bleeding

Strategies for reducing excessive bleeding are multimodal and can be initiated before, during, and after surgery (Table 1).1,15 Among others, medications that irreversibly inhibit the P2Y12 platelet receptor should be discontinued16; the potentially lethal triad of coagulopathy, hypothermia, and acidosis should be cor-rected17,18; and minimally invasive techniques used. When conven-tional methods are inadequate to control mild to moderate bleeding, or for bleeding that may not be amenable to those approaches (eg, diffuse raw surface bleeding, friable tissue, bone bleeding), topical hemostats represent a reasonable adjunct approach. They are not substitutes for meticulous surgical technique, and their effectiveness depends on appropriate selection and application.

Despite the improved safety of the blood supply, the importance of limiting transfusion is recognized (sidebar, Rationale for Restric-tive Transfusion Strategies).19-25

Coagulation and Hemostasis

Coagulation is a physiologic defense mechanism that maintains circulatory integrity and limits blood loss after a vascular insult.10,11,26 The generation of thrombin from its precursor, prothrombin, is the central event of coagulation—a process that is central to physiologic hemostasis, implicated in thrombosis,27 and dependent on a complex sequence of self-activating biochemical reactions among circulating coagulation factors.1 Traditionally, hemostasis has been described as a cascade of enzymatic reactions occurring on cell surfaces contain-ing exposed tissue factor and phospholipids resulting in the forma-tion of thrombin (IIa), a serine protease. The process of coagulation itself is one of vasoconstriction, platelet plug formation, cross-linking of fibrin, and fibrinolysis (ie, clot dissolution).10

Thrombin controls the final step of the coagulation cascade by catalyzing the conversion of soluble fibrinogen to fibrin to form the basis of a blood clot11; inducing cross-linking of the fibrin clot through factor XIII activation; and activating platelets—ultimately forming a stable, cross-linked, fibrin-platelet clot.1 In addition, coagulation activity is amplified via platelet-mediated thrombin generation (ie, thrombin bursts) and activation of factors V, VIII, and XI.2,10,11,28 Thrombin, which also binds to specific receptors, enhanc-ing platelet aggregation, is a multifaceted biological mediator with both procoagulant and anticoagulant functions, among others.11,29 In surgery, thrombin products are used as biologically active hemo-stats to convert fibrinogen to fibrin at the site of active bleeding.30

Table 1. Interventions To Minimize Bleeding1

Preoperative Administer erythropoiesis-stimulating agentsConduct autologous blood donationConsider individualized risk–benefit ratio for proceeding with surgeryDiscontinue medications•Anticoagulants•NSAIDs•Antiplatelet drugs (clopidogrel, prasugrel)•Herbals (ginseng, gingko biloba)Establish evidence-based institution-wide guidelines for lower RBC transfusion thresholds Minimize blood sampling

Intraopera tive Postoperative

Correct coagulopathy, hypothermia, acidosisCorrect hypocalcemiaAdminister systemic (ε-aminocaproic acid, tranexamic acid), topical hemostatic agentsTransfuse blood products, avoid hemodilutionUse blood recovery systems (“cell savers”)

Surgical Use minimally invasive techniques (endoscopic, laparoscopic, robotic)Apply direct pressureUse mechanical devices•Endostaplers•Hemoclips• Intracorporeal devicesUse suture ligation (larger vessels), electrocau-tery (smaller vessels)

NSAID, nonsteroidal anti-inflammitory drug; RBC, red blood cell

Why wait? Access this program and post-test at topical-hemostats.com

3

In the coagulation cascade, circulating prothrombin is con-verted to active thrombin by activated factors X and V.13 Th e con-ventional model (Figure 1)1 is represented as 2 somewhat independent pathways (ie, extrinsic, intrinsic) that converge at the point in which factor V is situated; thrombin generation can be disrupted profoundly by any substance or event that inhibits fac-tor V.1,28 Because some components of physiologic hemostasis were not represented fully by the cascade, a cell-based model has been developed. In these models, coagulation properties are local-ized to specifi c cell surfaces, and thrombin plays central roles in 3 overlapping phases: initiation, amplifi cation (ie, activation of factors V and XI, cleavage of factor XIII); and propagation that ultimately results in clot formation.31

The cascade model has proven useful in characterizing pathways that refl ect the processes measured in the clinical coagulation laboratory.28 When possible, patients should be risk-stratifi ed preoperatively for bleeding or thrombosis,11 with care-ful attention given to history of previous bleeding and use of medications that aff ect that clotting (Table 2). Based on levels of concern, screening laboratory tests of coagulation (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT]) may be ordered.11 Surgical teams also can use point-of-care tests for the measurement of activated clotting time (ACT), aPTT, and PT to guide anticoagulation therapy intraoperatively11; one such test, thromboelastography, evaluates a broad spectrum of the coagulation cascade.32

Rationale for Restrictive Transfusion Strategies

A s a result of screening improvements, the safety of the US blood supply has increased dramatically; rates of trans-

fusion-transmitted HIV and hepatitis C and B viruses are 1 in 2,135,000; 1 in 1,935,000, and 1 in 205,000 transfusions, respec-tively.19 Th e majority of transfusion-related morbidity and mor-tality now is caused by noninfectious complications, such as transfusion-associated acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and hemolytic transfu-sion reactions (associated with ABO or non-ABO alloantibodies) resulting from incorrect blood component transfusion (ie, mis-transfusion).19-21 Blood transfusions also have been associated with dose-responsive increases in multiorgan failure in trauma patients22

and increased mortality in critically ill patients.23 Although the blood supply is the safest it has ever been,20,21 there is a growing appreciation that unnecessary transfusions are not prudent in view of the potential harm from a variety of serious complications24 and that the safest transfusion is no transfusion.19

In the absence of randomized controlled trials (RCTs) dem-onstrating improved outcomes after red blood cell (RBC) transfusion, investigators have sought to determine the thresh-old at which the benefits outweigh the risks.19 For adult trauma and critical care patients, evidence-based recommen-dations developed by a joint task force of the Eastern Asso-ciation for Surgery of Trauma and the American College of Critical Care Medicine of the Society of Critical Care Medi-cine suggest transfusion at hemoglobin [Hb] levels lower than 7 g/dL.25 Th is group cautions, however, that Hb level should not be the sole determinant or “trigger” for transfusion. A task force of the Society of Th oracic Surgeons (STS) and the Soci-ety of Cardiovascular Anesthesiologists (SCA) also recom-mends transfusion as a reasonable strategy when Hb is less than 7 g/dL in patients undergoing thoracic surgery, in which multimodal interventions to preserve RBC volume off er the best chance of maintaining hemostasis.16

Figure 1. Simplifi ed coagulation cascade.1

Common pathway

Prothrombin

Factor Va

Stable fibrin matrix(Blood clot)

Solublefibrinogen

Loose fibrin clot

Simplifi ed coagulation cascade.1

Prothrombin

Solublefibrinogen

Loosefibrin clot

ThrombinFactor XIIIa

Intrinsicpathway

Extrinsicpathway

4

Bleeding in the Surgical Patient

Bleeding is expected in most surgical procedures and may be anticipated in some that are considered nonsurgical (eg, percu-taneous coronary intervention).33 Multiple factors may account for blood loss in procedures with particularly high bleeding risks, such as cardiopulmonary bypass (CPB), and joint or spine orthopedic surgery; a constellation or series of events or “mul-tiple hits” may be responsible, in conjunction with isolated or multiple hemostatic defects.26 For example, surgery induces a hyperadrenergic state, causing the release of tissue plasminogen activator (TPA) and consumption of coagulation factors, plate-lets, and physiologic anticoagulants secondary to bleeding and hemodilution.11

In cardiac and liver surgeries, approximately 75% to 90% of bleeding is caused by local surgical interruption or vessel inter-ruption, with 10% to 25% resulting from acquired or congeni-tal coagulopathy.33 CPB with extracorporeal circulation disrupts hemostasis in several ways: hemodilution, activation of tissue fac-tor and fibrinolysis, consumption of thrombin and plasmin, the release of other inflammatory-mediated factors, and consump-tion of clotting factors.1,31 Also contributing to bleeding in CPB are patient factors (eg, advanced age, emergency surgery, long

duration of extracorporeal circulation). Spinal orthopedic surger-ies may be associated with major and prolonged bleeding as well, a consequence of long surgery duration, muscle dissection, bone excision, and disruption of internal vertebral vessels.31 Other sur-gical procedures with high bleeding risks include joint orthope-dic surgery (eg, hip or knee arthroplasty), hysterectomy, vascular grafting, colorectal surgery, and craniotomy.31 Different surgery types have different effects on the coagulation system, necessitat-ing individualized treatment strategies.11

The volume of intraoperative blood loss varies widely by proce-dure and institution and may be affected by the type and delivery of anesthesia and degree of hypotension. Severe bleeding often is defined as greater than 2 L of blood loss within the first 24 hours postoperatively,9 representing approximately 40% of circulating blood volume in an adult of average size. Although overall mor-tality in elective and urgent surgery is very low (0.1%),33 it can be much higher in specific subcategories, reaching 20% in elective vas-cular surgery with severe bleeding34 and 40% in cases of major organ damage (eg, liver rupture).33

Spectrum of Agents To Aid Hemostasis

Functional characteristics, mechanisms, and materials are important considerations in the selection of an adjunct to hemo-stasis, as are patient factors, surgery type, and the characteristics of the bleeding encountered. Three main groups of agents are FDA-approved to aid in topical hemostasis.

Sealants polymerize, activate, and form a mechanical barrier to leakage, with or without the presence of blood. They can prevent the leakage of blood (ie, vascular sealing) as well as nonclotting flu-ids (eg, dural sealing to prevent cerebrospinal fluid loss).30

Adhesives fully polymerize, activate, and join tissues and are used externally in combination with deep dermal sutures to facil-itate skin closure. They function without need for an intact clot-ting mechanism; some cyanoacrylate-based adhesives act as barriers against bacteria l penetration as well.30,35

Topical hemostats, which promote blood clot formation directly, are among the most widely used intraoperative bleeding interven-tions. Because of their effectiveness and ease of use, topical hemo-stats often are surgeons’ first choices for controlling bleeding. Also, although direct acquisition costs vary by hospital, topical hemo-stats are relatively inexpensive compared with sealants and adhe-sives. Some are more difficult than others to store, prepare, and use, and these considerations may have clinical and pharmacoeconomic

Table 3. Topical Hemostats30

Use Ease of Preparation, Use Cost Examples

Mechanical Minimal bleeding

Relatively easy Relatively inexpensive GelatinCollagenOxidized regenerated cellulosePolysaccharide spheres

Active Localized, diffuse bleeding

Relatively easy More expensive than mechanical; less expen-sive than flowable, fibrin sealant

Topical thrombins of 3 biologic origins•Bovine•Pooled human plasma•Recombinant

Flowable Localized bleeding

Relatively easy More expensive than mechanical, active

Gelatin granules + thrombin

Fibrin sealant Localized, diffuse bleeding

Relatively more complex More expensive than mechanical, active, flowable

Fibrinogen + thrombin

Table 2. Prepoperative Hemostatic Evaluation11

Risk Level History/Physical Tests

Level 1 Negative history, physical examinationMinor procedure

None required

Level 2 Negative history, physical examinationMajor procedure

aPTT, platelet count

Level 3 Suspicious historyProcedure with high risk for bleeding

aPTT, platelet count, PT, BT

Level 4 History strongly sugges-tive of major hemostatic defect

BT after aspirin to rule out vWD; specific assays for factors VIII and IX; thrombin time

aPTT, activated partial thromboplastin time; BT, bleeding time; PT, prothrombin time; vWD, von Willebrand disease

Reprinted with permission.


5

implications affecting which are purchased by a hospital. Topical hemostats are subcategorized as mechanical, active, flow-

able, and fibrin sealants (fibrin sealant is unique in that it has sepa-rate FDA approvals as a hemostat, sealant, and adhesive) (Table 3).30

Mechanical hemostats (Table 4)36-48 promote clotting by acting as a barrier to blood flow and creating a scaffolding on which clotting can occur.16,30 They can be used immediately out of the package, are applied to a bleeding site using direct pressure, and are most useful

Table 4. Mechanical Agents36-48

Clinical Considerations Risks, Precautions

Porcine gelatin •Gelfoam absorbable gelatina sponge,36 compressed sponge,37

powder38

•Surgifoam absorbable gelatinb sponge,40 powder40

Sponge and powderStore at RTImmediately available for useNot resterilizableUse alone or + saline/topical thrombinWhen possible, remove after hemostasis

Swelling; infection (relatively safe)

Bovine collagen •Avitene Ultrafoam collagen sponge,41 flour,41 sheets41

•Helistat,42 Helitene43

• Instat,44 Instat MCH44

Single or multiple sheetsStore at RTImmediately available for useNot resterilizableUse dry (not + thrombin)Remove excess When possible, remove after hemostasis

Oxidized regenerated cellulose•Surgicel,45 Surgicel Fibrillar,45 Surgicel Nu-Knit,45 Surgicel Snow45

Sheets, flours, spongesStore at RTImmediately available for useNot resterilizableUse dry (not + saline/thrombin)Remove excess

Polysaccharide spheres •Arista AH46

•Hemostase MPH47

•Vitasure48

Powder in bellows applicatorAvoid extreme temperatures (<–40ºF and >140ºF)Immediately available for useNot resterilizableRemove excess

RT, room temperaturea A kit (Gelfoam Plus)39 also is available: porcine gelatin sponge + 125 IU/mL lyophilized human pooled thrombin; does not require refrigeration.b A kit also is available: Surgifoam absorbable gelatin powder for use with thrombin or saline.

Table 5. Active Hemostats (Topical Thrombin)14,49,50

Biologic Origin How Supplied Storage Risks, Precautions

Bovine•Thrombin-JMI14

Powder for solution• 5,000-IU vial + 5-mL diluent; 20,000-IU vial

+ 20-mL diluent• 20,000-IU vial + spray pump, actuator (pump

spray kit) • 5,000- or 20,000-IU vial + 5- or 20-mL

diluent, spray tip, syringe (syringe spray kit)• 5,000-IU vial + 5-mL diluent, nasal drug

delivery device, syringe (epistaxis kit)

2°C-25°C unopened2°C-8°C for ≤24 h after reconstitutionRT for ≤8 h after reconstitution

Black box warningDo not injectDo not use for massive or brisk arterial bleedingAntibody formation, hemostatic abnormalitiesHypersensitivity to material of bovine origin

Human•Evithrom49

Frozen solution• 2-, 5-, 20-mL vials (800-1,200 units/mL)• Device kit containing lyophilized powder for

reconstitution, use with gelatin sponge

Frozen (≤–18°C) for ≤2 y2°C-8°C for ≤30 d unopenedRT for ≤24 h

Do not injectDo not use for massive or brisk arterial bleedingRisk for plasma-derived infectious disease Anaphylactic or severe systemic reaction to human blood products

Recombinant•Recothrom50

Powder for solution• 5,000-IU vial + 5-mL prefilled diluent syringe

with sterile needle-free transfer device, 5-mL empty syringe, preprinted label

• 20,000-IU vial + 20-mL diluent syringe with 2 sterile needle-free transfer devices, 20-mL empty syringe, preprinted label

• 20,000-IU applicator kit with spray pump, spray bottle, syringe spray tip, syringe, bowl, 2 blank labels

2°C-25°C unopened2°C-25°C for ≤24 h after reconstitution

Do not injectDo not use for massive or brisk arterial bleedingHypersensitivity to hamster or snake proteins

RT, room temperature

6

for controlling minimal bleeding. Bovine collagen and polysaccha-ride spheres are considered most effective, and the efficacy of porcine gelatins may be improved when used with topical thrombin.30

Active hemostats (Table 5)14,49,50 promote clotting by converting fibrinogen to fibrin, with the rate of clot formation proportional to the concentration of both thrombin and fibrinogen.51 Topical throm-bins are approved for broad surgical use, and standalone thrombin products can be combined with absorbable gelatin sponges. Because topical thrombins are supplied in a number of formulations there are some differences in their requirements for storage and prep-aration. They are useful for a variety of bleeding scenarios and can be applied locally, with a syringe when bleeding may be difficult to reach, or sprayed over a large area for rapid coverage. Thrombins of all 3 biologic origins are equally effective at controlling local or diffuse bleeding and only slightly more costly than mechanical hemostats.30 Topical thrombins will not work unless bleeding is present. Intravas-cular injection is contraindicated, and thrombin products must not be permitted to enter devices dependent on heparin anticoagulation (eg, blood salvage systems).35

Flowable hemostats (Table 6)30,35,52,53 combine both active and mechanical hemostat components—and some of the most favor-able characteristics of both—to promote clot formation and wound healing. They control bleeding mechanically by obstructing blood flow and, because thrombin is a component, via the rapid conver-sion of fibrinogen into fibrin. Preparation involves reconstituting thrombin and mixing it with absorbable gelatin particles,52,53 a pro-cess that may take operating room (OR) staff several minutes but can allow for customized consistency, thorough coverage of a local wound,30 and accurate administration (eg, spreading) compared with a liquid thrombin. The FDA also has approved a kit con-taining porcine gelatin absorbable powder matrix and lyophilized pooled human thrombin, which can be stored at room temperature and prepared quickly. Swelling is a concern with flowable hemo-stats; excess product should be removed because of this possibility.

Fibrin sealants (Table 7)54-57 function by increasing the rate of blood clot formation via fibrinogen and thrombin concentrations that are higher at the bleeding site than would normally occur in blood.30 These products can be applied locally with a syringe

Table 6. Flowable Agents30,35,52,53


Porcine gelatin ± thrombin•Surgiflo52

Powder, syringe + flexible applicator tipStore at controlled RT (2°C-25°C)Preparation involves mixing (do not use immediately out of package)Remove excess Swelling; viral/prion disease

transmissionRisks associated with particular standalone thrombin that is chosenDo not inject or use intravascularly

Bovine gelatin + pooled human thrombin•FloSeal53

GranularStore at RT3-min reconstitution, mixing30; use mixed product within 2 hApply as paste, gentle pressureMay be reapplied with blunt applicator tip35

Remove excess


Table 7. Fibrin Sealants54-57


Viral/prion disease transmission (with pooled human plasma derivatives)Antibody formation (with bovine thrombin)Swelling (with bovine collagen)May require intact coagulationAir/gas embolism has occurred with fibrin sealant administered using pressurized gasTisseel contains aprotinin, a protein associated with anaphylactic reactions

Pooled human plasma•Tisseel54

Freeze-dried: store at 2°C-25°C; do not refrigerate/freeze reconstituted solutionFrozen: store at ≤–20°C; thaw 5-105 min (water bath/incubator); do not refrigerate/refreeze after thawingUse within 4 h after reconstitution/thawingBest applied to as dry a field as possible

Pooled human plasma •Evicel55

1 vial each of fibrinogen and thrombin frozen solutions + spray applicator Frozen: store at ≤–18°C for ≤2 y; must be thawed; temerature must be ≤37°CAfter thawing, use within 24 h if stored at RT, 30 d if stored refrigerated

Individual human plasma with bovine collagen and bovine thrombin•Vitagel56

Single-use 5 mL treatment syringe + sterile delivery components, transfer syringeCombine with an equal volume of patient plasmaStore at 2°C-8°C; do not freeze

Individual human plasma•Cryoseal57

Single-use unit produces 4 sterile sets of 2 syringes (total volume, 6-16 mL; conditions may affect harvest volume)Store at ≤–18°C for ≤1 yUse within 6 h (at 34°C-37°C)



7

or sprayed over a large area, a feature that makes them beneficial in local and diffuse bleeding. Their use is appropriate in patients with coagulopathy who do not have sufficient fibrinogen to form a clot; however, intact coagulation may be required. Safety concerns include viral or prion disease transmission associated with human plasma derivatives; antibody formation with bovine thrombin; and swelling with bovine collagen.30 Although a ready-to-use, absorb-able patch was FDA-approved for cardiovascular surgery in 2010,58 a key concern with fibrin sealants generally is the need for surgeons to master skillful application techniques.30 Another concern is the complexity of coordinating the reconstitution and preparation of these 2-component products by hospital staff.

In some clinical scenarios, non-fibrin sealants (Table 8)30,59-67 or adhesives may be more appropriate. As noted, adhesives are fast-setting agents that join tissues without need for an intact clotting mechanism and polymerize within approximately 30 seconds. For example, albumin plus glutaraldehyde—a polymer with sealant and adhesive properties—is used for vascular sealing of large blood ves-sels, often in cardiovascular surgeries; it should be used sparingly and applied carefully because of its strong adhesiveness. The surgi-cal team should be familiar with labeling and the clinical particu-lars associated with each agent, such as coordination of preparation time and application techniques.30,35,62

Surgeon Perspectives on Topical Hemostats, Sealants, and Adhesives

The surgeon’s approach to hemostasis is influenced by train-ing, judgment, technical skill, and area of expertise and is viewed through a prism of clinical experience. Clinician choice may be influenced heavily by product availability within the hospital. In different surgical scenarios, the type of bleeding encountered will dictate selection of a topical hemostat. For example, in minimal or mild bleeding proximal to an anastomosis (ie, connection of 2 cut ends of a structure to form a continuous channel) after coronary artery bypass graft, surgeons often will select the least expensive type of hemostat (eg, mechanical). Topical thrombin use is appro-priate for bleeding from needle holes after suture; cauterization in this scenario would compromise the integrity of the anastomosis.

Compression hemostatic agents (eg, oxidized regenerated cel-lulose and microfibrillar collagen) are the most commonly used adjuncts for anastomotic hemostasis.16 These agents also are use-ful in highly vascularized liver surgery, in which diffuse bleeding can be significant and coagulopathy present11 and the use of com-pression in combination with application of a mechanical hemo-stat is a common initial approach. Oxidized regenerated cellulose is bacteriostatic, and there is some evidence—and widespread clinical acceptance—of its effectiveness for suture line bleeding.16 Oxidized cellulose requires a normal clotting system, and its mechanism appears to be a physical effect rather than via alteration of intrinsic clotting. In contrast, microfibrillar collagen provides some hemo-static effect by initiating of platelet activation and aggregation.16 Surgeons may favor specific attributes of products in this class. For example, absence of bulkiness and the degree to which a material will conform to anastomosis may be important at the conclusion of hepatectomy, which is likely to be associated with substantial bleeding in the retroperitoneum “bare area.” Similarly, microfibril-lar collagen—which is available in many forms—conforms well to bleeding surfaces of the type encountered in a broad spectrum of vascular surgeries.

In the presence of localized or diffuse bleeding, topical throm-bin may represent a reasonable approach because of its versatility in preparation and application. Localized bleeding may be controlled with topical thrombin applied using a sponge, porcine gelatin sponge, or absorbable porcine gelatin powder to create a putty- or caulk-like consistency; diffuse bleeding may be controlled with the use of topi-cal thrombin applied by spraying to ensure coverage of large, raw, dif-fuse surface areas (eg, vascular suture lines, adhesions, burn wounds, muscle bleeding, organ parenchyma). In the event of arterial or venous bleeding from adhesions following repair of acute abdomi-nal aneurysm, spray application of thrombin or fibrin sealant may be appropriate so that the product can be applied quickly to a large area. A fibrin sealant also might be used over sutures in neurologic tumor resection to seal the dura and prevent cerebrospinal fluid loss.

Clinical Experience With Topical Thrombins

Topical thrombins have well-recognized clinical utility. Since the first of these—derived from bovine origins—was introduced in the 1940s, the have continued to increase in prevalence and now are used in more than 1 million patients annually in the United States at a cost of $250 million.13,68 The currently available bovine thrombin prod-uct was approved in 1995.14 Compared with earlier versions that con-tained 20% to 30% thrombin, it is purified chromatographically and processed by ultrafiltration to contain fewer protein contaminants and has been shown to be 96% thrombin.14,69 In the past 5 years, throm-bins of human49 and recombinant50 origins have become available.

In 2007, pooled human plasma-derived thrombin became the second topical thrombin product approved in the United States. It is manufactured using pooled human source and recovered plasma obtained from US-licensed plasmapheresis centers and has a potential risk for viral or prion disease transmission, despite manu-facturing steps designed to reduce this risk.49

Recombinant thrombin was FDA-approved in 2008. Derived from a genetically modified Chinese hamster ovary cell line, it has a molecular structure very similar to that of human throm-bin. Allergic reactions to hamster or snake proteins also used in

Table 8. Non-Fibrin Sealants and Adhesives30,59-67

Clinical Considerations

Risks, Precautions

PEG Polymers•Coseal59

•DuraSeal60

•ProGel61

Apply to as dry a field as possibleAvoid dripping to undesired locations

Swelling

Cyanoacrylates •Dermabond62

•Omnex63

• Histoacryl/ Histoacryl Blue64

• Indermil65

•SurgiSeal66

Use to avoid wound dehiscence associated with deep dermal suturesKeep skin edges exposed for ≥20 secAvoid dripping to undesired locationsExternal use only; with deep dermal sutures

Strong adhesiveness

Bovine serum albumin + glutaraldehyde•BioGlue67

Use carefully, sparingly Wall off critical zones of surgical field with sponges/pads to avoid nerve/vessel injury

Potential for tissue necrosis, adhesive embolism30

8

manufacturing are potential risks associated with its use50; genetic engineering reduces the risks for antibody formation and elimi-nates the risk for pathogen transmission.

All 3 thrombin types have similar efficacy,70,71 are labeled as aids to hemostasis whenever oozing blood and minor bleeding from capil-laries and small venules is accessible, and are indicated for use with an absorbable gelatin sponge.14,49,50 Thrombin concentration correlates with reaction rate—the speed at which thrombin causes clot forma-tion30,51; thrombins of all 3 biologic origins are available in concen-trations of 1,000 units/mL. As noted, thrombins often are combined with other hemostats or materials and administered in a variety of ways (eg, dripped, sprayed, moistened on gauze, used with gelatin sponge or powder, or combined with gelatin matrix or fibrinogen). Systemic injection is contraindicated for all topical thrombins and can result in extensive clotting, hypotension, and even death.14,49,50

Surgeons should note the labeled contraindications to use for all hemostatic agents; the boxed warning on bovine thrombin states that patients with known antibodies to bovine thrombin prepara-tions should not be re-exposed to these products.14 A heightened awareness of previous thrombin exposure may be of particular con-cern in types of surgery in which subsequent operations may be anticipated (eg, pediatric heart surgery). Concerns about the poten-tial of relatively higher risks for antibody production with the use of bovine thrombin, compared with recombinant thrombin, are noted in guidelines issued in 2011 by the STS Blood Conservation Guideline Task Force.16 Conclusions regarding the clinical signifi-cance of differences in antibody formation cannot be drawn.

Efficacy and Effectiveness of Topical Thrombin

Bovine thrombin—the oldest form of topical thrombin prod-uct—has been used effectively in an array of surgical settings. Its efficacy also has been validated in RCTs in which it has been the active comparator in studies evaluating the newer topical thrombins.70,71

Human plasma-derived thrombin was compared with bovine thrombin in a prospective, double-blind, multicenter Phase III RCT of 305 patients.71 Doria and colleagues randomized patients under-going cardiovascular, neurologic, or general surgeries to receive either bovine (n=152) or human (n=153) thrombin administered with a gelatin sponge. Individuals with known antibodies to bovine throm-bin were excluded. In both groups, 97.4% of patients achieved the primary end point of hemostasis at 10 minutes. Equivalency in the human and bovine thrombin treatment groups also was demon-strated for hemostasis at 6 minutes (94.8% vs 92.8%, respectively) and 3 minutes (73.2% vs 72.4%, respectively). AEs in both groups were similar and as expected for the procedures, with pruritus being the most common. No patients in the human thrombin group sero-converted for anti-human thrombin or anti-human factor V/Va anti-bodies, compared with 2.38% (3 of 126) in the bovine thrombin group who developed seroconversion for anti-human thrombin and 7.94% (10 of 126) who developed anti-bovine thrombin antibodies (P=0.0015). No significant differences were noted in need for trans-fusions, duration of surgery, or hospital LOS.71

Recombinant thrombin was evaluated for relative efficacy com-pared with bovine thrombin in a study of 411 patients under-going spinal surgery, hepatic surgery, peripheral arterial bypass, or placement of an arteriovenous graft.70 In this double-blind, multicenter Phase III RCT by Chapman and colleagues, sub-jects were randomized to receive either recombinant (n=205) or

bovine thrombin (n=206), at a concentration of 1,000 U/mL, with an absorbable gelatin sponge; 401 patients completed the study. In both treatment groups, 95% of patients achieved the primary efficacy end point of hemostasis at 10 minutes (bovine thrombin group, 95.1%; recombinant thrombin group, 95.4%), demonstrat-ing comparable efficacy (Figure 2). However, in a post hoc analysis by Weaver and colleagues of patients undergoing peripheral arte-rial bypass surgery (n=88), hemostasis at 3 minutes was achieved in a significantly greater proportion of subjects receiving recom-binant thrombin (55%) than those receiving bovine thrombin (39%).72 Incidence of AEs in the Chapman study was similar for the 2 groups; most AEs were as expected for the surgery type and moderate in severity.70 Antiproduct antibody development was reported in 1.5% (3 of 198) of the recombinant group, compared with 21.5% (43 of 200) of the bovine group (P=0.0001) (Fig-ure 3).70 There was no causal association between antibody devel-opment and any AEs in either treatment group. Pooled safety data from 8 clinical trials also have shown that recombinant thrombin is well tolerated with a low rate of antibody formation.73

The clinical effects of immunogenic response to topical bovine thrombin also have been evaluated. An open-label, prospective, observational case cohort study by Paterson et al assessed the effect on clinical hemostasis of human antibodies to bovine thrombin or factor V/Va in response to topical bovine thrombin in patients with and without preexisting anti-bovine antibodies.74 The study enrolled 550 patients who underwent surgery with bovine throm-bin administered at surgeon’s discretion. Patients were assigned to 1 of 4 cohorts based on presurgery presence or absence of antibody to bovine thrombin (aBT), and use or nonuse of bovine thrombin during study surgery; 481 patients assigned to cohorts completed the study. The hypothesis was that patients with presurgery aBT administered the bovine thrombin during surgery would experience postsurgical changes from baseline aPTT that were not clinically different (ie, were noninferior) to those in patients without pre-surgery aBT and who did not receive bovine thrombin in surgery. Based on adjusted mean change in aPTT values at 48 hours post-surgery, the study failed to establish noninferiority between primary cohorts (noninferiority was defined as 15% shift from baseline; reference value, 30 seconds).

In secondary end point analyses, the number of bovine thrombin-treated patients with human anti-bovine factor V/Va antibodies (aBV/Va) increased at weeks 4 and 8 postsurgery com-pared with 48 hours. At 4 weeks postsurgery, 70% of evaluable patients (n=50) in the cohort of patients with (+)presurgery aBT/(+)bovine thrombin exposure had cross-reacting antibodies to factor V, compared with 52% (n=39) at 48 hours; in the cohort with (-)presurgery aBT/(-)bovine thrombin exposure during sur-gery, 12% of patients (n=14) had cross-reacting antibodies to fac-tor V at week 4, compared with 8% (n=10) at 48 hours. However, no immunologic markers at 48 hours or weeks 4 or 8 were related to changes in coagulation parameters. The study’s major limita-tion was its observational design, which precluded drawing con-clusions about causality.

Recognition and Management of IMC

Distinctions are recognized between technical causes of surgical bleeding (eg, inadequate repair of vessels, intraoperative injury, or damage to organs) and coagulopathy, or disorders of hemostasis.15,75 These can result from therapeutic coagulation, acidosis, enzymatic


9

dissolution of fibrin related to CPB, heparin-induced thrombocy-topenia, liver dysfunction, disseminated intravascular coagulation, inaction or dissolution of fibrinogen in the blood (fibrinogenoly-sis), consumptive loss of coagulation factors, hypothermia, or other mechanical and metabolic derangements.76 Postsurgical coagulopa-thies may be hemorrhagic or thrombotic; inherited (eg, hemophilia, von Willebrand disease); or acquired (vitamin K deficiency, liver disease). IMCs are caused by an autoimmune reaction or cross-reacting antibodies in the coagulation system.

Despite the fact that bovine thrombin is highly purified, its use can result in the development of these antibodies to endoge-nous human coagulation factors, notably factor V and thrombin.77 Although rare, acquired factor V deficiency can induce coagulation defects and severe bleeding complications.68,78-80

Although its precise incidence is not known, bovine thrombin-associated IMC has been recognized for more than 20 years as a distinct type of acquired coagulopathy, and identified by the Joint Commission as an iatrogenic and preventable complication that poses a threat to patient safety and warrants increased attention.81 Its recognition poses clinical challenges, partly because clinician aware-ness of IMC is believed to be low—particularly among surgeons—and its incidence may be underreported.76 Manifestations of bovine thrombin-associated IMC may be subtle, ranging from asymptom-atic coagulation laboratory changes with bleeding risk, or minor bleeding (eg, epistaxis or hematuria), to major bleeding events or per-sistent, uncontrolled, life-threatening bleeding. Late-onset bleeding that develops after a patient has been discharged from the hospital can further complicate clinical recognition of IMC82; inhibitors typ-ically develop 7 to 10 days after a primary exposure during surgery, and the inhibitors can last for several weeks to months.76,83

Prior exposure to bovine thrombin has been identified as the most common causal factor in the development of IMC.72,84-90 However, documentation of such exposure is not routinely avail-able in patient medical records; even when it is, records may not be seen by the surgeon. Thus, a patient’s history of conditions for which multiple surgeries are likely (ie, pediatric congenital cardiac disease) or history of previous surgery in which bovine thrombin use was likely (eg, multiple cardiac, pediatric, neurologic, or vascu-lar surgeries or wound debridement) may provide the best clues to

detection.76,79,89,91 Clinicians should exercise vigilance in obtaining and reviewing such history, including any documentation. Because thrombin products enter hospitals via central surgical supply rather than being purchased through the pharmacy department, however, such documentation often is not available.

Coagulation factor inhibitors should be suspected in patients with unexplained postoperative bleeding in the presence of prolonged PT and aPTT; if a mixing study (1:1 mix of patient plasma with normal pooled plasma) fails to correct, an inhibitor may be considered the presumptive cause, and a hematology consult should be requested. Specific quantitative assays of factor V and factor V inhibitor may be conducted (factor V assays are available readily in most laboratories, but specific factor V antibody assays generally are not).76

The challenges of managing an acquired factor inhibitor are for-midable. One reason for this is the lack of a predictable pattern of antibody response or coagulopathy development.83 A consensus pan-el’s review of 64 case reports in which exposure to bovine thrombin was known or presumed found near-equal representation of bleed-ing and nonbleeding presentations.76 There is incomplete evidence to guide the management of IMC, particularly when it is accompanied by clinically significant bleeding. Platelet therapy may be reason-able because of the store of factor V on platelet surfaces,76 although treatment approaches are speculative, and supportive care is patient-specific. Corticosteroids, IV immunoglobulin therapies, and plasma-pheresis have been used with varying degrees of success.76

A bleeding IMC may increase hospital LOS by a factor of 2 to 2.5 if transfusion of blood products is required.33,92 However, the clinical and economic consequences of IMC can be severe even if bleeding is not present; coagulation studies are costly and time-consuming, and prolonged clotting time may delay therapeutic procedures. Other direct costs associated with IMC management include specialist consults, and coagulation monitoring (sidebar, An IMC Case Report).

Roles for the Hospital Pharmacist and Nurse In Optimizing Topical Hemostasis

Together with medical staff, the hospital pharmaceuti-cal service shares responsibility for formulary selections and the development of policies that minimize drug errors and assure

Figure 3. Antibody production in thrombin Phase III study.70

Figure 2. Cumulative incidence of hemostasis over time.50,70

Bovine thrombin

Recombinant thrombin

Baseline Day 29

5.0(10/200)

1.5(3/198)

21.5 (43/200)

1.5 (3/198)

0

5

10

15

20

25

100

Patie

nts

With

An

ti-Th

rom

bin

An

tibod

ies,

%

Recombinant thrombin (n=198)Bovine thrombin (n=203)

95(193)92

(183)81(160)

48(95)

95(189)88

(178)72

(146)

46(93)

0

100

1.5 3 6 10

20

60

80

40

Time, min

Patie

nts

Ach

ievi

ng

H

emost

atis

, %

10

medication safety.92,94 Surgical hemostasis is an area that presents many opportunities for multidisciplinary collaboration by phar-macists, surgeons, anesthesiologists, hematologists, nurses, and others—particularly in the setting of the Pharmacy & Therapeu-tics (P&T) Committee.

The primary responsibility of the P&T committee is formulary management via the clinical judgment of a range of professionals in the diagnosis, prevention, or treatment of disease and promo-tion of health.94 The formulary itself represents the ongoing selec-tion of the most medically appropriate and cost-effective products and therapies to serve the health interests of a given patient popu-lation.94,95 This process is informed primarily by published reports (eg, RCTs, reviews, drug monographs, addenda), which provide new evidence concerning drug efficacy, stability, tolerability, meth-ods of administration, cost, and pharmacoeconomics and may war-rant reevaluation of agents used, dosage strengths, or formulations stocked by a hospital or health system.94 Information for appraisal in P&T also comes from practice guidelines, labeling revisions, AE updates, FDA announcements, expert opinion, and internal data. These sources may be particularly important in therapeutic areas for which there is a limited evidence base to guide clinical deci-sion making. For example, a 2010 Joint Commission newsletter reported that bovine thrombin-associated IMC may occur days to weeks after surgery and should be considered in the differential diagnosis in cases of unexplained postoperative bleeding or unex-plained PT, aPTT, or thrombin time in the absence of bleeding.81

Although the perception among medical staff may be that the P&T committee is an entity best left alone to do its work, the lit-erature shows that safety is best evaluated by an interdisciplinary group of health care providers who may uncover potential hazards of use before an agent is introduced to the formulary.95 In fact, adherence to department “silo” mentalities or budgets may suggest an unwillingness to take into account available evidence reflecting improved patient outcomes or decreased total costs.24 A physician who deals with acute or surgical bleeding can contribute to for-mulary decision making by sharing clinical, safety, and availability concerns about drug classes or specific agents, especially if scien-tific evidence or direct comparisons of various agents are lacking.

All P&T members should be involved in disseminating infor-mation on the decisions made and the rationales thereof. For phar-macists, a primary responsibility is the effective communication of actions related to the medication use evaluation process to ensure

that policy is integrated into therapeutic decision making.94 Spe-cifically, in-service education, grand rounds, interaction with other clinicians at the time of dispensing, staff meetings, email, newslet-ters, mailings, prescriber detailing, and pharmacy or institutional Web sites offer opportunities for targeted communication.94 These and other methods can be used by pharmacists to help establish and support a culture of medication safety.

In the setting of surgical hemostasis and acute bleeding, phar-macists may participate in a range of efforts to reduce transfusion rates or enhance the safety of topical hemostat use. One example pertains to minimizing the risk for accidental intravascular admin-istration, a danger addressed in warnings from both the FDA and the Institute for Safe Medication Practices.96,97 Despite cautionary labeling on all topical thrombin products, instances of inadvertent injection are documented, and one such event was fatal.97 Similar-ities in packaging for topical thrombin and parenteral products (ie, vial and syringe) may contribute to the potential for misadminis-tration. This suggests opportunities for pharmacist involvement in communicating with clinicians who make therapeutic decisions at the point of care; for example, auxiliary “Do Not Inject” labeling of syringes used in thrombin reconstitution may help reduce the risk for misadministration.

Nurses are on the front lines of safety in the OR and periop-erative setting as well and should be involved in safe-use initia-tives, such as safety checklists (Figure 4).97 Nurses are responsible for communicating the presence of topical thrombin in the ster-ile field and are expected to try to delay introducing it until after all parenteral products have been administered. Manufacturers of top-ical hemostats recognize this and include OR nurses as a key tar-get audience for instructional information. Similarly, some fibrin sealant product labeling specifically addresses scrub and circulat-ing nurses, providing detailed information on safe transfer of the fibrinogen component to the sterile field.

Pharmacoeconomic review is another important element in the review of all products. Generally done by pharmacists work-ing with other health care professionals and the purchasing depart-ment, this evaluation considers acquisition price as well as indirect costs related to storage, preparation, management of complica-tions associated with use and effect on patient care. Among aver-age wholesale prices for topical hemostats, topical thrombins generally are less costly than flowables and somewhat more costly than mechanical hemostats, with fibrin sealants generally the most

An IMC Case Report

The significant consumption of blood and blood products, LOS, and use of other resources are incremental cost drivers

in the management of IMC, as illustrated in a recent case report of a 76-year-old woman who developed severe hemorrhagic com-plications after surgical exposure to bovine thrombin.93 Initially she was diagnosed with disseminated intravascular coagulation but continued to experience episodic bleeding. Eventually, mix-ing studies and clotting factor assays revealed significantly reduced factor V activity (<5% of normal) and an ongoing IMC, and inhibitor titer assay confirmed the presence of a factor V inhib-itor. The patient’s critical care hospitalization lasted 64 days and required 282 units of blood products and 2 reoperations in addi-tion to other resources (Table 9)93 for a total cost of $444,996.

Table 9. Costs Associated With IMC Case93

Resource Cost/Unit, $

Units Total Cost, $

ICU LOS (no ventilator)

4,022/d 64 d 257,408

Blood productsPacked RBCsFFPPlatelets

1,45972

656

78129

62

113,8029,288

40,672

IVIG 181 132 23,826

Total estimated cost 444,996

FFP, fresh frozen plasma; ICU, intensive care unit; IVIG, intravenous immunoglobulin; LOS, length of stay; RBC, red blood cell


11

expensive topical hemostats. Pricing for thrombins of all 3 biologic origins is competitive, with human thrombin products incremen-tally—although not excessively—more costly than bovine throm-bin; acquisition costs vary by institution based on contract pricing, purchasing group criteria, and volume usage.

Waste reduction is a key consideration in the pharmacoeco-nomics review process. In a 9-month university hospital study that evaluated a switch from the formulary thrombin (bovine-derived, 20,000-IU vials with spray applicators) to recombinant thrombin (5,000-IU vials with or without a spray kit), the switch yielded a savings of $92,396 (38%), an apparent consequence of reducing product waste and mixing smaller quantities of thrombin for use with a sponge or sprayer.98

Making Sense of the Science: Understanding Clinical Research

As noted, formulary decisions are based in part on a critical eval-uation of the literature. With the dynamic flow of research and increasing demands on health care providers, many clinicians report that they cannot always read the medical literature critically.99 Thus, a review of concepts is appropriate.

Studies must be evaluated and understood in the context of the research hierarchy. Often, this is represented as a pyramid with sys-tematic reviews and meta-analyses at the top, followed by evidence guidelines and summaries; RCTs, case cohorts and nonrandom-ized controlled studies; clinical research critiques; literature reviews; case reports, case series, and practice guidelines; and clinical refer-ence texts. Because meta-analyses and systematic review are only as strong as the quality of research being reviewed, it is important to understand the additional elements of study design and appraise commonly used measures.

Most clinical research can be categorized broadly as experimen-tal (randomized or nonrandomized) or observational (analytical or

descriptive). The experimental RCT represents the gold standard of investigations designed to evaluate an intervention because the assignment of a subject to an exposure is done purely by chance rather than by the investigator.99 A good RCT also minimizes selection and confounding biases in the determining outcomes.99 One limitation is the potential for an RCT to lack external valid-ity—the extent to which results can be generalized to the broader community as opposed to a more homogenous trial population. Observational studies track subjects forward in time from exposure or nonexposure to outcome (or involve control subjects who are identified retrospectively). Finally, case–control studies trace back-ward from outcome to exposure (eg, epidemiologic studies to track outbreaks of food-borne illness), and descriptive studies (eg, case series reports) do not have a comparison group; thus investigators cannot examine associations.

Insightful review of design and methodology, including dropout rate, patient demographics, interventions, and power, can shed light on the complexities of any study and determine the applicability of that work to the practice changes. In meta-analyses, attention to study selection is key. The authors of the 2007 STS/SCA practice guideline for blood transfusion and conservation used a systemic, comprehensive literature search to make their recommendations.100 In so doing, they searched MEDLINE, EMBASE, CINAHL, and the Cochrane Collaboration. Had they used only used one database, MEDLINE, for example, their results would have been skewed; MEDLINE only contains approximately one-third of the world’s medical literature, with poor representation in such subspe-cialties as cardiothoracic surgery.

It is also important to understand the various parameters that are to report study results. Commonly used are relative risk, the probability of the event occurring in the exposed group versus a non-exposed group, and absolute risk reduction, the amount by which therapy reduces the risk for an undesirable outcome. These and other measures of association express results of dichotomous

Have pharmacy prepare label, dispense drug, including doses for operating room ✓

Never leave vial/syringe at patient’s bedside where it could be confused with parenteral product ✓

Apply auxiliary warning labels to syringes containing thrombin: “For topical use only— do not inject” ✓

Communicate presence of product in sterile field, delay doing so until all parenteral products have been administered ✓

Differentiate parenteral, topical products by using absorbable gelatin sponge or dry form when possible ✓

Consider using spray kits to differentiate thrombin from parenteral products; never leave syringe unlabeled before applying spray mechanism ✓

Figure 4. Thrombin safety checklist.97

12

outcomes (eg, sick vs healthy). Studies also often use P-value and/or confidence interval to report statistical data. Confidence interval may be particularly useful because it indicates strength, direction, and a plausible range of effect, as well as the likelihood of chance occurrence. Finally, another useful tool is the number needed to treat (NNT), defined as the number of patients who must be treated to prevent one additional undesirable outcome (Figure 5). The result is useful in determining how much of an effect a study outcome will have on the care of a patient population and how many patients might benefit versus the number exposed to the treatment.

Clinical Application of RCT Data

Both the Chapman and Doria investigations are of good qual-ity and highlight the application of some of the principles dis-cussed above. One notable aspect of the Chapman study is its group sequential design with a flexible sample size; investi-gators sought to enroll 400 to 600 patients to provide an ade-quate safety evaluation and expose a minimum of approximately 200 patients to recombinant thrombin.70 This design allowed as many as 3 interim analyses (2 were conducted), and the maxi-mum number of patients was computed to maintain 99.5% power to declare comparable efficacy when the 2 treatments were equiv-alent. At the second interim analysis, available data were deemed sufficient, and the independent data monitoring committee rec-ommended that the study continue as planned until 400 patients with evaluable efficacy data were enrolled. On the primary end point of hemostasis at 10 minutes, the study showed no difference between the 2 thrombin products. A limitation of the work is that no placebo group was included.

In the Doria RCT, a sample size of 278 was selected based on the assumption that the success rate in the control group would be 77%.71 This allowed investigators to ascertain equivalence with 95% confidence and 90% power; the sample size was increased to 304 to allow for potential dropouts. Efficacy and safety analyses were

performed using an intent-to-treat population. Hemostasis equiv-alency was demonstrated in both treatment groups. Limitations included no placebo-control group, potential intersurgeon variabil-ity in application technique and hemostasis assessment, and antibody assessment not evaluable for all patients.

In both the Chapman and Doria studies, the surrogate marker of hemostasis at 10 minutes was the primary efficacy end point—a very practical measurement of the desired clinical effect, absence of bleeding from the surgical site. There was no difference in the pri-mary outcome, so a NNT could not be calculated.

Conclusion

Excess bleeding is associated with a continuum of clinical and economic outcomes. A multimodal approach to perioperative hemostasis requires familiarity with hemostat characteristics and limitations. Topical hemostats are integral elements of the surgeon’s tool kit, and all members of the multidisciplinary care team must be knowledgeable about these important adjuncts to hemostasis. Among the most widely used topical hemostats are thrombins, which are available for use as standalone products or in conjunc-tion with other agents. Topical thrombins have demonstrated sim-ilar efficacy in a limited number of studies; however, the risks for viral or disease transmission or development of cross-reacting anti-bodies against endogenous coagulation factors may be higher with human- and bovine plasma-derived products, respectively. Cross-reacting antibodies have been implicated, although rarely, with IMC and carry the potential for clinically severe bleeding events. As such, clinicians would be prudent to remain vigilant about the issues with use and documentation of thrombin products in the surgical setting, whether as standalone or combination products, as well as the diagnosis and management of IMC.

Surgeons, pharmacists, and perioperative nurses share in the responsibilities—in the OR and beyond—of achieving intraoper-ative hemostasis through the optimal selection and use of available hemostatic agents.

Is this a meaningful parameter?

Cannot be calculated

YES NO Can this end point be phrased as a “yes/no” question?

YES NO Is there a statistical difference between the 2 groups?

YES NO Calculation1 / (pB – pA)

• pA, probability of desired outcome in intervention group

• pB, probability of desired outcome in control group

Interpretation• Ideal NNT = 1, indicating that all

subjects improve with treatment and none improves with control

• Increasing NNT = less effective treatment

Figure 5. Number needed to treat.NNT, number needed to treat


13

References1. Boucher BA, Traub O. Achieving hemostasis in the surgical field. Pharmacotherapy.

2009;29(7 Pt 2):2S-7S.

2. Dunn B, Uber W, Ikonomidis J. Topical thrombin preparations and their use in cardiac surgery. Open-Access Surgery. 2009;2:15-34.

3. Dacey L, Munoz J, Baribeau Y, et al. Re-exploration for hemorrhage following coro-nary artery bypass grafting: incidence and risk factors. Northern New England Car-diovascular Disease Study Group. Arch Surg. 1998;133:442-447.

4. Despotis G, Avidan M, Lublin DM. Off-label use of recombinant factor VIIA con-centrates after cardiac surgery. Ann Thorac Surg. 2005;80(1):3-5.

5. Karkouti K, Yau TM, Riazi S, et al. Determinants of complications with recom-binant factor VIIa for refractory blood loss in cardiac surgery. Can J Anaesth. 2006;53(8):802-809.

6. Karthik S, Grayson AD, McCarron EE, Pullan DM, Desmond MJ. Reexploration for bleeding after coronary artery bypass surgery: risk factors, outcomes, and the effect of time delay. Ann Thorac Surg. 2004;78(2):527-534; discussion 534.

7. Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet. 1988;1(8588):727-729.

8. Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11:135.

9. Despotis GJ, Goodnough LT. Management approaches to platelet-related microvas-cular bleeding in cardiothoracic surgery. Ann Thorac Surg. 2000;70(2 suppl):S20-32.

10. Kessler CM, Ortel TL. Recent developments in topical thrombins. Thromb Haemost. 2009;102(1):15-24.

11. Adams GL, Manson RJ, Turner I, Sindram D, Lawson JH. The balance of thrombosis and hemorrhage in surgery. Hematol Oncol Clin North Am. 2007;21(1):13-24.

12. Tanaka KA, Key NS, Levy JH. Blood coagulation: hemostasis and thrombin regula-tion. Anesth Analg. 2009;108(5):1433-1446.

13. Lawson JH. The clinical use and immunologic impact of thrombin in surgery. Semin Thromb Hemost. 2006;32(suppl 1):98-110.

14. Thrombin, topical USP (bovine origin). Thrombin-JMI [package insert]. Bristol, Ten-nessee: King Pharmaceuticals, Inc; 2011.

15. Dagi TF. The management of postoperative bleeding. Surg Clin North Am. 2005;85(6):1191-1213.

16. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91(3):944-982.

17. Johnson JL, Moore EE, Kashuk JL, et al. Effect of blood products transfusion on the development of postinjury multiple organ failure. Arch Surg. 2010;145(10):973-977.

18. Sihler KC, Napolitano LM. Complications of massive transfusion. Chest. 2010;137(1):209-220.

19. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood trans-fusion. Anesthesiology. 2011;115(3):635-649.

20. FDA Consumer Affairs Branch (CBER). Fatalities reported to FDA following blood collection and transfusion. Annual summary for fiscal year 2010. 2011.

21. Vamvakas E, Blajchman M. Transfusion-related mortality: the ongoing risks of allogenic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406-3417.

22. Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132(6):620-624; discussion 624-625.

23. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288(12):1499-1507.

24. Boucher BA, Hannon TJ. Blood management: a primer for clinicians. Pharmacother-apy. 2007;27(10):1394-1411.

25. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157.

26. Despotis G, Avidan M, Eby C. Prediction and management of bleeding in cardiac surgery. J Thromb Haemost. 2009;7(suppl 1):111-117.

27. Mann KG. Thrombin formation. Chest. 2003;124(3 suppl):4S-10S.

28. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterio-scler Thromb Vasc Biol. 2002;22(9):1381-1389.

29. Mann KG. Thrombin: can’t live without it; probably die from it. Chest. 2003;124(3 suppl):1S-3S.

30. Spotnitz WD, Burks S. State-of-the-art review: Hemostats, sealants, and adhesives II: update as well as how and when to use the components of the surgical toolbox. Clin Appl Thromb Hemost. 2010;16(5):497-514.

31. Zimmerman LH. Causes and consequences of critical bleeding and mechanisms of blood coagulation. Pharmacotherapy. 2007;27(9 Pt 2):45S-56S.

32. Klein SM, Slaughter TF, Vail PT, et al. Thromboelastography as a perioperative mea-sure of anticoagulation resulting from low molecular weight heparin: a comparison with anti-Xa concentrations. Anesth Analg. 2000;91(5):1091-1095.

33. Shander A. Financial and clinical outcomes associated with surgical bleeding compli-cations. Surgery. 2007;142 (4 suppl):S20-S25.

34. Porte RJ, Leebeek FW. Pharmacological strategies to decrease transfusion require-ments in patients undergoing surgery. Drugs. 2002;62(15):2193-2211.

35. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: components of the surgi-cal toolbox. Transfusion. 2008;48:1502-1516.

36. Gelfoam Absorbable Gelatin Sterile Sponge [package insert]. New York, NY: Phar-macia & Upjohn Co, a division of Pfizer, Inc; 2008.

37. Gelfoam Absorbable Gelatin Sterile Compressed Sponge [package insert]. New York, NY: Pharmacia & Upjohn Co, a division of Pfizer, Inc; 2008.

38. Gelfoam Absorbable Gelatin Sterile Powder [package insert]. New York, NY: Phar-macia & Upjohn Co, a division of Pfizer, Inc; 2008.

39. Gelfoam Plus Hemostasis Kit [package insert]. Hayward, CA: Baxter Healthcare Corp; 2010.

40. Surgifoam Absorbable Gelatin Sponge [package insert]. Somerville, NJ: Johnson & Johnson Wound Management, a division of Ethicon, Inc; 2008.

41. Avitene Ultrafoam Collagen Sponge. Warwick, RI: Davol, Inc. http://www.davol.com/products/surgical-specialties/hemostasis/avitene-ultrafoam-collagen-sponge/. Accessed February 16, 2012.

42. Helistat (absorbable collagen hemostatic sponge) [package insert]. Plainsboro, NJ: Integra LifeSciences (no date given).

43. Helitene (absorbable collagen hemostatic agent) [package insert]. Plainsboro, NJ: Integra NeuroSciences (no date given).

44. InStat MCH (microfibrillar collagen hemostat) [package insert]. Somerville, NJ: Johnson & Johnson Wound Management; 2010.

45. Surgicel Original, Surgicel Nu-Knit, Surgicel Fibrillar Absorbable Hemostats Sur-gicel Snow [package insert]. Somerville, NJ: Johnson & Johnson Wound Manage-ment; 2010.

46. Arista absorbable hemostatic particles (microporous polysaccharide hemosphere technology) [package insert]. Minneapolis, Minnesota: Medafor, Inc; 2007.

47. Hemostase MPH [brochure]. Guildford, Surrey, UK: CryoLife Europa, Ltd; 2008.

48. Vitasure absorbable hemostat (microporous polysaccharide hemosphere technology) [package insert]. Minneapolis, Minnesota: Medafor, Inc; 2008.

49. Evithrom Thrombin, topical (human) [package insert]. Somerville, NJ: Ethicon, Inc; 2011.

50. Recothrom (thrombin, topical [recombinant]) [package insert]. Seattle, Washington: ZymoGenetics Inc; 2009.

51. Cada D, Levien T, Baker D. Thrombin, topical (recombinant). Available at: http://www.factsandcomparisons.com/assets/hpdatenamed/20080701_July2008_form.pdf. Accessed January 19, 2010. Hospital Pharmacy. 2008;43:577-585.

52. Surgiflo Hemostatic Matrix (Made from Absorbable Gelatin Sponge USP) plus FlexTip [package insert]. Somerville, NJ: Ethicon, Inc; 2010.

53. Floseal Hemostatic Matrix [package insert]. Fremont, CA: Baxter Healthcare Corp; 2005.

54. Tisseel [fibrin sealant] [package insert]. Westlake Village, CA: Baxter Healthcare Corp; 2012.

55. Evicel Fibrin Sealant (Human) [package insert]. Somerville, NJ: Ethicon, Inc; 2009.

14

56. Vitagel surgical hemostat [package insert]. Malvern, Pennsylvania: Orthovita, Inc; 2007.

57. CryoSeal (fibrin sealant) [brochure]. Rancho Cordova, California:Thermogenesis Corp; 2006.

58. TachoSil (Absorbable Fibrin Sealant Patch) [package insert].Westlake Village, CA: Baxter Healthcare Corp; 2010.

59. Coseal Surgical Sealant [package insert]. Hayward, CA: Baxter Healthcare Corp; 2009.

60. DuraSeal Dura Sealant System [package insert]. Waltham, MA: Confluent Surgi-cal, Inc; (no year given).

61. ProGel pleural air leak sealant [instructions for use]. Irvine, CA: Neomend, Inc; (no year given).

62. Dermabond Advanced Topical Skin Adhesive [package insert]. San Lorenzo, Puerto Rico; Ethicon, LLC; 2011.

63. Omnex Surgical Sealant [package insert]. Somerville, NJ: Johnson & Johnson Wound Management; 2010.

64. Histoacryl, Histoacryl Blue [Web site]. Ann Arbor, MI: TissueSeal, LLC; 2005. http://www.tissueseal.com/. Accessed February 10, 2012.

65. Indermil tissue adhesive [instructions for use]. Norwalk, CT: United States Surgical, a division of Tyco Healthcare Group LP; (no date given).

66. SurgiSeal Topical Skin Adhesive (2-octyl cyanoacrylate) [package insert]. Wyomissing, PA; Adhezion Biomedical, LLC; 2010.

67. BioGlue Surgical Adhesive [instructions for use]. Kennesaw, GA: CryoLife; 2010.

68. Ham S, Lew E, Weaver F. Thrombin use in surgery: an evidence-based review of its clinical use. J Blood Medicine. 2010;1:135-142.

69. Crean SM, Michels SL, Reynolds MW. Exogenous bovine thrombin as a biomarker of exposure and outcome. Expert Rev Mol Diagn. 2008;8(5):651-661.

70. Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind com-parative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.

71. Doria C, Fischer CP, Wood CG, et al. Phase 3, randomized, double-blind study of plasma-derived human thrombin versus bovine thrombin in achieving hemostasis in patients undergoing surgery. Curr Med Res Opin. 2008;24:785-794.

72. Weaver FA, Lew W, Granke K, et al. A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures. J Vasc Surg. 2008;47:1266-1273.

73. Ballard JL, Weaver FA, Singla NK, Chapman WC, Alexander WA. Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin. J Am Coll Surg. 2010;210(2):199-204.

74. Paterson CA, Pixton GC, Proskin HM, et al. Immune responses associated with peri-operative exposure and reexposure to topical bovine thrombin do not impair hemo-stasis. Clin Appl Thromb Hemost. 2011;17(6):620-632.

75. Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thorac Surg. 2009;88(4):1377-1383.

76. Ness P, Creer M, Rodgers GM, et al. Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety. Patient Saf Surg. 2009;3(1):8.

77. Voils SA. Thrombin products: economic impact of immune-mediated coagulopathies and practical formulary considerations. Pharmacotherapy. 2009;29(7 Pt 2):18S-22S.

78. Lawson JH, Lynn KA, Vanmatre RM, et al. Antihuman factor V antibodies after use of relatively pure bovine thrombin. Ann Thorac Surg. 2005;79(3):1037-1038.

79. Foster KN, Kim H, Potter K, Matthews MR, Pressman M, Caruso DM. Acquired factor V deficiency associated with exposure to bovine thrombin in a burn patient. J Burn Care Res. 2010;31(2):353-360.

80. Sarfati MR, Dilorenzo DJ, Kraiss LW, et al. Severe coagulopathy following intraop-erative use of topical thrombin. Ann Vasc Surg. 2004;18:349-351.

81. Joint Commission Resources. Bovine Thrombin-Associated IMC: A Threat to Patient Safety and the Bottom Line. Joint Commission Perspectives on Patient Safety. 2010;10:5-6.

82. Christie RJ, Carrington L, Alving B. Postoperative bleeding induced by topical bovine thrombin: report of two cases. Surgery. 1997;121:708-710.

83. Savage WJ, Kickler TS, Takemoto CM. Acquired coagulation factor inhibi-tors in children after topical bovine thrombin exposure. Pediatr Blood Cancer. 2007;49:1025-1029.

84. Ortel TL, Mercer MC, Thames EH, et al. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg. 2001;233:88-96.

85. Ortel TL, Moore KD, Quinn-Allen MA, et al. Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations. Blood. 1998;91(11):4188-4196.

86. Zehnder JL, Leung LL. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood. 1990;76(10):2011-2016.

87. Banninger H, Hardegger T, Tobler A, et al. Fibrin glue in surgery: frequent devel-opment of inhibitors of bovine thrombin and human factor V. Br J Haematol. 1993;85(3):528-532.

88. Dorion RP, Hamati HF, Landis B, et al. Risk and clinical significance of develop-ing antibodies induced by topical thrombin preparations. Arch Pathol Lab Med. 1998;122:887-894.

89. Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion. 2002;42:18-26.

90. Chouhan VD, De La Cadena RA, Nagaswami C, et al. Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin, and factor V following exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet function. Thromb Haemost. 1997;77:343-349.

91. Crow SS, Sullivan VV, Aysola AE, et al. Postoperative coagulopathy in a pedi-atric patient after exposure to bovine topical thrombin. Ann Thorac Surg. 2007;83:1547-1549.

92. Lomax C. Safety of topical thrombins: the ongoing debate. Patient Saf Surg. 2009;3(1):21.

93. Rodgers G, Kraiss L. Severe postoperative immune-mediated coagulopathy associ-ated with bovine thrombin exposure. Pharmacotherapy. 2010;30:319e-324e.

94. Tyler LS, Cole SW, May JR, et al. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health Syst Pharm. 2008;65(13):1272-1283.

95. Institute for Safe Medication Practices. The truth about hospital formularies survey. February 10, 2005. http://www.ismp.org/newsletters/acutecare/articles/20050210.asp. Accessed January 19, 2012.

96. FDA. Danger giving topical thrombin intravascularly. August 15, 2008. http://www.youtube.com/watch?v=OopHG7c81rY. Accessed January 19, 2012.

97. Institute for Safe Medication Practices. Danger of giving topical thrombin intravas-cularly. 2008;6:1. Medication Safety Alert.

98. Lyda CM, et al. Presented at: American Society of Health-System Pharmacists Annual Meeting; December 8, 2009; Las Vegas, NV. [Poster 6-088].

99. Grimes DA, Schulz KF. An overview of clinical research: the lay of the land. Lancet. 2002;359(9300):57-61.

100. Ferraris VA, Ferraris SP, Saha SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83 (5 suppl):S27-S86.

Optimizing the Selection and Use Of Topical...

Documents

Transcript of Optimizing the Selection and Use Of Topical...