Transfusion and Apheresis Science 50 (2014) 26–31
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Armentarium of topical hemostatic products in cardiovascular surgery: An update Jessica Forcillo, Louis P. Perrault ⇑ Cardiac Surgery Department, Montreal Heart Institute, Université de Montréal, Canada
a r t i c l e
i n f o
a b s t r a c t Within Canada, 2.6 million in-hospital surgical procedures are completed annually. Significant bleeding following is the most common surgical complication, occurring in up to 25% of all surgeries. Bleeding causes increased mortality and morbidity, by increasing the number of transfusions required, secondary to increased cumulative blood loss, and by causing hemodynamic instability. A solution to this issue encountered during surgery is the use of hemostatic products. The objectives of this manuscript are (1) to review the spectrum of hemostatic products available in cardiovascular surgery and (2) to provide an update on new topical products soon available, or in development, for optimizing hemostasis during surgical procedures. Ó 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Classification, roles and use of hemostatic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Clinical use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Mechanical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Microporous polysaccharide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Chitin and chitosan-based hemostatic agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Flowable. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Fibrin sealant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1. Cyanoacrylate sealant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2. Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Fibrin sealant versus mechanical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Fibrin sealant versus flowable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Composite of collagen and thrombin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Topical antifibrinolytic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Special tips for each category of hemostatic devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.1. Mechanical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.2. Flowable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.3. Fibrin sealant [28] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.4. Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⇑ Corresponding author. Address: Montreal Heart Institute, 5000 Belanger East, Montreal, Quebec H1T 1C8, Canada. E-mail address: [email protected] (L.P. Perrault). 1473-0502/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.12.009
27 27 27 27 27 27 27 27 29 29 29 29 29 29 29 30 30 30 30 30 30 30 30
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
4.
3.13. Cost analysis Conclusion . . . . . . . . Disclosures . . . . . . . . References . . . . . . . .
at the Montreal Heart Institute (MHI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................................................................................... ...................................................................................... ......................................................................................
27
30 30 30 31
1. Introduction
3.1. Classification, roles and use of hemostatic agents
Within Canada, 2.6 million in-hospital surgical procedures are completed annually [1]. Bleeding after surgery is the most common surgical complication, occurring in around 25% of all surgeries [2]. Bleeding causes increased mortality and morbidity, by increasing the number of transfusions required secondary to increased cumulative blood loss, and by causing hemodynamic instability. Bleeding also impairs visualization of the surgical field and prolongs surgical procedures [3]. Increased bleeding could result in acidosis and hypothermia which could lead to coagulopathy (lethal triad) [4]. The operative bleeding challenges, such as friable tissues, reoperative adhesions, diffuse soft tissue and bone bleeding, are considered uncontrollable issues and bleeding secondary to these issues cannot always be avoided. Also, perioperative bleeding complications such as infection, blood transfusions and transfusion-related reactions, occult bleeding, prolonged or multiple procedures, lethal triad, hemodilution and postoperative coagulopathy (disseminated intravascular coagulation (DIC), factor deficiency, impaired fibrinolytic system) cannot always be anticipated. One of the solutions to this problematic situation encountered during surgeries is the hemostatic local topical products. The objectives of this manuscript are to (1) review the spectrum of hemostatic products available in cardiovascular surgery and to (2) provide an update on new products soon available or in development for optimizing hemostasis during surgical procedures.
The classification of those hemostatic agents currently available is described in Table 1. These hemostatic agents are used when ligation, sutures, compression or cautery are not effective. The types of bleeding where topical agents are used include: diffuse raw surface bleeds, oozing venous-type bleeds, bone bleeding and needle-hole bleeding. The desired attributes are safety, reliable efficacy and prompt control of bleeding, ease of storage and preparation and immediate availability, usability and affordability. Also, it could help decrease the time spent in the operating room. Factors that guide selection of these agents include: size of wound and accessibility of bleeding site, severity of bleeding and coagulation status of patient, and reoperation.
3.2. Clinical use Procedures where patients have high risk of bleeding include, for example, aortic valve replacement, surgery for the ascending and descending aorta, alloplastic patch or plasty, carotid endarterectomy, and all patients over 60 years old. To help manage bleeding, some authors have proposed surgical scenarios for use of the products in cardiovascular surgery (shown in Fig. 1). The choice of topical hemostatic agents is dependent on the surgeon’s preference and depends on individual experience rather than strong evidence-based practice.
3.3. Literature 2. Methodology Literature review was made on Pubmed and MEDLINE between January 1974 and 2012 using keywords such as bleeding, hemostatic agents and cardiac surgery. Priority was placed on randomized controlled trials (RCTs). Additional articles were found according to the references in the selected articles.
3. Discussion The expectations for a new optimal topical hemostatic agent should be: (1) good adhesiveness (± the use of gelatin sponge), (2) short compression time, (3) good hemostatic effect, (4) no disintegration during or shortly after surgery, (5) the cost, (6) the preparation time/easy to use, (7) the modality of delivery (e.g. spray) and (8) the immediacy of action of autologous preparation.
Barnard and Millner did a systematic review on topical hemostatic agents for use in cardiac Surgery in 2009 published in Annals of Thoracic Surgery [5]. Table 2 in their article represents the summary of randomized Controlled Trials of Hemostatic Agents in Cardiovascular Surgery.
3.4. Mechanical Surgicel is reported to be bacteriostatic with antimicrobial activity [6]. Collagen is not as good at reducing infection risk as Surgicel and is reported to cause end-organ damage if it migrates to the blood circulation [7]. Surgicel has been compared to collagen during cardiac surgery procedures that necessitate deep hypothermic circulatory arrest and surgical was superior to collagen in terms of reduced bleeding intra-operatively and reduced drainage post-operatively [8].
28
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
Table 1 Topical hemostats classification. Mechanical
Flowable
Fibrin/Synthetic Sealants
Active
Gelatin sponge (may be used with thrombin) Porcine gelatin Gelfoam (Pfizer Pharmacia), Surgifoam (Ethicon J&J,) Gelfoam plus (Baxter Healtcare Corp.)
Gelatin
Fibrinogen + thrombin
Bovine thrombin
Collagen
Gelatin matrix + thrombin
Bovine Avitene Sheets (non woven web) (Davol) Ultrafoam Collagen Sponge (Davol)
Tisseel (Baxter) (Human pooled plasma thrombin, human pooled fibrinogen, synthetic aprotinin) Evicel (J&J) (Human pooled plasma thrombin, human pooled fibrinogen, human albumin)
Surgiflo (J&J)* (Porcine gelatin) FloSeal (Baxter) (Bovine gelatin and human pooled plasma thrombin
Synthetic
CoSeal (Baxter Bioglue (Cryolife)
Cellulose Surgicel (J&J) Surgicel Nu-Knit (J&J) Chitin and Chitosan-Based Hemostatic Agents
Human pooled plasma thrombin Evithrom (Omrix Biopharmaceuticals)
Recombinant thrombin Recothrom (ZymoGenetics)
Celox (SAM Medical Products) HemCon (HemCon Medical Technologies Inc) QuickClot(Z-Medical Corp) Polysaccharide spheres Arista (Medafor) *
Thrombin-JMI (King)
J&J: Johnson and Johnson.
Fig. 1. Surgical scenarios in cardiovascular surgery.
29
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31 Table 2 Montreal Heart Institute summary cost of blood products in 2011. Blood products
Cost per unit
Number of units
Annual cost
Globular sediment Cryoprecipitate Regular fresh frozen plasma Apheresis fresh frozen plasma Regular platelet pack Apheresis platelet pack Stable product transfused Labile products loss Total
345,27$ 36,81$ 235,11$ 470,22$ 132,58$ 662,88$
5426 2568 2994 4 3255 715
1,873,435$ 94,500$ 703,919$ 1881$ 431,548$ 473,959$ 428,433$ 155,987$ 4,163,690 $
3.4.1. Microporous polysaccharide Those agents create scaffolding for the formation of a fibrin clot within minutes of application; however there are no trials published in the literature up to now. 3.4.2. Chitin and chitosan-based hemostatic agents Celox is a granular hemostatic agent that interacts directly with red blood cells and platelets to form a clot independently of native factors. A randomized controlled trial (RCT) was published using a porcine model of arterial and venous hemorrhage that compared Celox, HemCon, QuickClot and standard gauze dressings. Celox reduced bleeding to 0%, HemCon to 33% and QuickClot by 8%. Celox improved survival to 100% compared to HemCon 67% and QuickClot 92% [9]. In the United States the military are treated with hemostatic dressings, HemCon and it is coated with Chitosan [10]. 3.5. Flowable In an RCT by Oz, patients undergoing cardiac surgery were randomized into the FloSeal and the control groups in order to control bleeding. After 10 min, bleeding was stopped with the FloSeal in 94% of patient versus 60% with the control group who received Gel foam with thrombin. At 3 min, hemostasis was achieved in 72% of patients in the FloSeal group compared with 23% in the Gel foam and thrombin group. Success rate was significantly different before reversal of heparin with protamine in favor of Floseal, but did not reach a statistical difference after heparin reversal [11]. In a study by Nasso et al. in 2009, Floseal was compared to Gelfoam and Surgicel Nu-Knit to control bleeding in elective primary cardiac surgery: statistically higher rates of successful hemostasis and shorter timeto-hemostasis were observed in the Floseal group (p < 0.001) [12].
was achieved in 54.5% of patients who received the sealant compared to 10% in the control group [13]. Another study, done by Brunkwall et al., showed that, in patient who underwent vascular reconstruction or access below the diaphragm, the use of a cyanoacrylate sealant procured immediate hemostasis in 71.3% and 93.6%, 96.8% and 100% at 1, 5 and 10 min respectively [14]. 3.6.2. Glues There are 24 trials reported by Kjaergard and Fairbrother about the use of fibrin glues in cardiac surgery. Four studies reported no difference and 20 trials reported positive results in term of decreased bleeding [15]. Lamm et al. have, however, reported several cases of acute occlusion of bypass when the fibrin sealant Tissucol fibrin was used in proximity to the anastomoses: a word of caution about special care when using this product was reported [16]. Another RCT compared the use of Bioglue versus control during repair of anastomotic bleeding in patients during cardiac and vascular surgery. Anastomotic bleeding was significantly reduced in the group using Bioglue (19% of anastomoses) versus in the control group (43% of anastomoses) [17]. Adverse effects have however been reported with the use of Bioglue, such as leaking of Bioglue through needle holes, and it may spread away from the site of application and it can cause nerve tissue injury as well as impair normal healing [17–19]. 3.7. Fibrin sealant versus mechanical A study by Rousou et al. tested the efficacy and safety of fibrin sealant as a topical hemostatic agent in patients undergoing either reoperative cardiac surgery or emergency resternotomy. Tisseel was used as the fibrin sealant agent versus Avitene or Surgicel as controls. They obtained 92.6% control of bleeding with Tisseel versus 12.4% with control agents at 5 min (p < 0.001) [20].
3.6. Fibrin sealant 3.8. Fibrin sealant versus flowable 3.6.1. Cyanoacrylate sealant Omnex is a synthetic tissue adhesive consisting of a blend of two monomers. One prospective RCT has assessed its efficiency in establishing hemostasis on arterial vascular anastomosis in 151 patients. Mean time to obtain hemostasis from the time that the clamp is released was 119.3 s with the sealant compared to 403.8 s with the control (oxidized cellulose) (p < 0.001). Immediate hemostasis
RCT trials were done comparing CoSeal to Gelfoam and thrombin. In the first trial, using the fibrin sealants during reconstruction for nonruptured aneurysms, more immediate sealing of the suture line sites was observed with CoSeal after return of blood flow than with the other 2 agents [21]. Another RCT showed that overall 10 min sealing success was equivalent for all three sealants, however
30
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
patients where CoSeal was used to control bleeding after placement of a prosthetic vascular grafts demonstrated that with CoSeal immediate anastomotic sealing was achieved at more than twice the rate than with the other two agents [22]. 3.9. Composite of collagen and thrombin
600 000 $
533 062 $
554 538 $
500 000 $ 398 470 $
400 000 $ 300 000 $
271 047 $ 216 491 $
219 662 $
200 000 $
CoStasis is a composite of collagen and bovine thrombin and was compared to collagen and gauze to achieve hemostasis during cardiac surgery. After 3 min, CoStasis achieved hemostasis in 76% of cases compared to 46% in the controls. Details were not given in this study about timing and site of application [23].
100 000 $ 0$ 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012
Fig. 2. Total cost per year of hemostatic and biological products purchased at the Montreal Heart Institute.
3.10. Active Recombinant human thrombin (Recothrom) gained popularity because compared to human and bovine thrombin, it reduces formation of patient thrombin antibodies and diminishes risk of transmission of infection [24]. 3.11. Topical antifibrinolytic agents There are controversies concerning the systemic use of antifibrinolytics agents, especially of aprotinin that was withdrawn from the market due to its marked adverse effects [25]. Tranexamic acid (TA) on the other hand is still used for certain indications during cardiac surgery. However, those agents were successful at reducing bleeding after cardiac surgery. Studies were then done to evaluate if topical use of these very potent agents could reduce bleeding. Fawzy et al. used 1 g of TA diluted in 100 ml of normal saline (NS) versus only NS that were spilled in the pericardial and mediastinal cavities. During the first 24 h post-operatively, cumulative blood loss was significantly less in the TA group (626 ml) versus placebo group (1040 ml) (p = 0.04) [26]. Another study by Baric et al. randomized patients to the use of topical aprotinin, TA or placebo spurred in the pericardial cavities and mediastinal tissues before sternal closure. Topical use of both TA and aprotinin reduced post-operative bleeding (391 ml and 433 ml respectively) compared with 613 ml with placebo (p < 0.001) [27]. 3.12. Special tips for each category of hemostatic devices 3.12.1. Mechanical Avoid using irrigating stream of saline at clot interface to avoid dislodgement of coagulum and resumption of bleeding.
as a sealant between flaps, pre-place lattice work of closing sutures of flaps while product is still polymerizing and avoid later disruption of the adhesive bond between the flaps. When using as a skin graft adhesive avoid too thick a layer that can prevent diffusion of nutrients to graft from underlying muscle.
3.12.4. Active Deliver with absorbable gelatin sponge, operating room gauze or laparotomy pad to facilitate off pressure. Squeeze excess thrombin from sponge prior to application. May be applied with absorbable gelatin powder to create puttylike caulking effect. Avoid prolonged exposure to oxidized regenerated cellulose.
3.13. Cost analysis at the Montreal Heart Institute (MHI) The total costs per year of hemostatic and biological products purchased at the Montreal Heart Institute are shown in Fig. 2. Indeed, the more complex the procedure the more it is costly, because of greater bleeding tendency. In 2011–2012 the total cost spent on hemostatic products was estimated at $554,538 (Fig. 2). On the other side, the total money spent on blood products in 2011 was $4,163,690 (Table 2). Moreover, a cost analysis of re-exploration for bleeding after cardiac surgery demonstrated that the resource utilization costs were substantially higher in patients requiring re-exploration for bleeding and that included prolonged stays in the intensive care unit and blood transfusions [29].
4. Conclusion 3.12.2. Flowable Apply into depths of wound to maximize matrix location at sites of active bleeding. Avoid blood on any sponges or pads used to apply pressure to matrix. Reapply additional material to bleeding site of origin. 3.12.3. Fibrin sealant [28] When using as a hemostat, apply with absorbable gelatin sponge to facilitate application of pressure. When using
In conclusion, topical hemostats are used when conventional hemostatic approaches are inappropriate or ineffective. There are 4 main categories of topical hemostats: Mechanicals, Flowables, Fibrin Sealants and Actives (Thrombins). The choice of topical hemostatic agents is dependent of the surgeon’s preference and depends on individual experience rather than on strong evidencebased practice.
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
Disclosures Dr. L.P. Perrault receives grants from Bayer Inc., Pluromed, Applied Medical, Baxter, St-Jude Medical and Johnson and Johnson.
[17]
[18]
References [1] CIHR. Hospital discharge data. 2007. [2] C.L. Pharmacy practice news. Special report. Topical thrombins. 2008. [3] Marietta M, Facchini L, Pedrazzi P, Busani S, Torelli G. Pathophysiology of bleeding in surgery. Transplantation Proc 2006;38:812–4. [4] Schreiber MA. Damage control surgery. Crit Care Clin 2004;20:101–18. [5] Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thoracic Surgery 2009;88:1377–83. [6] Scher KS, Coil Jr JA. Effects of oxidized cellulose and microfibrillar collagen on infection. Surgery 1982;91:301–4. [7] Robicsek F. Microfibrillar collagen hemostat in cardiac surgery. J Thoracic Cardiovascular Surgery 2004;127:1228 [author reply 1228]. [8] Sirlak M, Eryilmaz S, Yazicioglu L, Kiziltepe U, Eyileten Z, Durdu MS, et al. Comparative study of microfibrillar collagen hemostat (colgel) and oxidized cellulose (surgicel) in high transfusion-risk cardiac surgery. J Thoracic Cardiovascular Surgery 2003;126:666–70. [9] Millner RW, Lockhart AS, Bird H, Alexiou C. A new hemostatic agent: initial life-saving experience with celox (chitosan) in cardiothoracic surgery. Ann Thoracic Surgery 2009;87:e13–14. [10] Rao SB, Sharma CP. Use of chitosan as a biomaterial: studies on its safety and hemostatic potential. J Biomed Mater Res 1997;34:21–8. [11] Oz MC, Cosgrove 3rd DM, Badduke BR, Hill JD, Flannery MR, Palumbo R, et al. Controlled clinical trial of a novel hemostatic agent in cardiac surgery. The fusion matrix study group. Ann Thoracic Surgery 2000;69:1376–82. [12] Nasso G, Piancone F, Bonifazi R, Romano V, Visicchio G, De Filippo CM, et al. Prospective, randomized clinical trial of the floseal matrix sealant in cardiac surgery. Annals Thoracic Surgery 2009;88:1520–6. [13] Lumsden AB, Heyman ER. Prospective randomized study evaluating an absorbable cyanoacrylate for use in vascular reconstructions. J Vascular Surgery 2006;44:1002–9 [discussion 1009]. [14] Brunkwall J, Ruemenapf G, Florek HJ, Lang W, Schmitz-Rixen T. A single arm, prospective study of an absorbable cyanoacrylate surgical sealant for use in vascular reconstructions as an adjunct to conventional techniques to achieve hemostasis. J Cardiovascular Surgery 2007;48:471–6. [15] Kjaergard HK, Fairbrother JE. Controlled clinical studies of fibrin sealant in cardiothoracic surgery–a review. Eur J Cardio-Thoracic Surgery: Official J Eur Assoc Cardio-Thoracic Surgery 1996;10:727–33. [16] Lamm P, Adelhard K, Juchem G, Weitkunat R, Milz S, Kilger E, et al. Fibrin glue in coronary artery bypass grafting operations: Casting
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
[29]
31
out the devil with beelzebub? Eur J Cardio-Thoracic Surgery: Official J Eur Assoc Cardio-Thoracic Surgery 2007;32:567–72. Coselli JS, Bavaria JE, Fehrenbacher J, Stowe CL, Macheers SK, Gundry SR. Prospective randomized study of a protein-based tissue adhesive used as a hemostatic and structural adjunct in cardiac and vascular anastomotic repair procedures. J Am Coll Surgeons 2003;197:243–52 [discussion 252–243]. LeMaire SA, Carter SA, Won T, Wang X, Conklin LD, Coselli JS. The threat of adhesive embolization: bioglue leaks through needle holes in aortic tissue and prosthetic grafts. Ann Thoracic Surgery 2005;80:106–10 [discussion 110–101]. LeMaire SA, Schmittling ZC, Coselli JS, Undar A, Deady BA, Clubb Jr FJ, et al. Bioglue surgical adhesive impairs aortic growth and causes anastomotic strictures. Ann Thoracic Surgery 2002;73:1500–5 [discussion 1506]. Rousou J, Levitsky S, Gonzalez-Lavin L, Cosgrove D, Magilligan D, Weldon C, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study. J Thoracic Cardiovascular Surgery 1989;97:194–203. Hagberg RC, Safi HJ, Sabik J, Conte J, Block JE. Improved intraoperative management of anastomotic bleeding during aortic reconstruction: results of a randomized controlled trial. Am Surgeon 2004;70:307–11. Glickman M, Gheissari A, Money S, Martin J, Ballard JL. A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than gelfoam/thrombin: Results of a randomized controlled trial. Arch Surg 2002;137:326–31 [discussion 332]. A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial. Surgery. 2001;129:445–450. Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens Jr KL, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am College Surgeons 2007;205:256–65. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. New Engl J Med 2006;354:353–65. Fawzy H, Elmistekawy E, Bonneau D, Latter D, Errett L. Can local application of tranexamic acid reduce post-coronary bypass surgery blood loss? A randomized controlled trial. J Cardiothoracic Surgery 2009;4:25. Baric D, Biocina B, Unic D, Sutlic Z, Rudez I, Vrca VB, et al. Topical use of antifibrinolytic agents reduces postoperative bleeding: A doubleblind, prospective, randomized study. Eur J Cardio-Thoracic Surgery: Off J Eur Assoc Cardio-Thoracic Surgery 2007;31:366–71 [discussion 371]. 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 Thrombosis/ Hemostasis: Official J Int Acad Clin Appl Thrombosis/Hemostasis 2010;16:497–514. Alstrom U, Levin LA, Stahle E, Svedjeholm R, Friberg O. Cost analysis of re-exploration for bleeding after coronary artery bypass graft surgery. Br J Anaesthesia 2012;108:216–22.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Armentarium of topical hemostatic products in cardiovascular surgery: An update Jessica Forcillo, Louis P. Perrault ⇑ Cardiac Surgery Department, Montreal Heart Institute, Université de Montréal, Canada
a r t i c l e
i n f o
a b s t r a c t Within Canada, 2.6 million in-hospital surgical procedures are completed annually. Significant bleeding following is the most common surgical complication, occurring in up to 25% of all surgeries. Bleeding causes increased mortality and morbidity, by increasing the number of transfusions required, secondary to increased cumulative blood loss, and by causing hemodynamic instability. A solution to this issue encountered during surgery is the use of hemostatic products. The objectives of this manuscript are (1) to review the spectrum of hemostatic products available in cardiovascular surgery and (2) to provide an update on new topical products soon available, or in development, for optimizing hemostasis during surgical procedures. Ó 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Classification, roles and use of hemostatic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Clinical use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Mechanical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Microporous polysaccharide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Chitin and chitosan-based hemostatic agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Flowable. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Fibrin sealant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1. Cyanoacrylate sealant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2. Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Fibrin sealant versus mechanical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Fibrin sealant versus flowable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Composite of collagen and thrombin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Topical antifibrinolytic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Special tips for each category of hemostatic devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.1. Mechanical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.2. Flowable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.3. Fibrin sealant [28] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12.4. Active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⇑ Corresponding author. Address: Montreal Heart Institute, 5000 Belanger East, Montreal, Quebec H1T 1C8, Canada. E-mail address: [email protected] (L.P. Perrault). 1473-0502/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.12.009
27 27 27 27 27 27 27 27 29 29 29 29 29 29 29 30 30 30 30 30 30 30 30
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
4.
3.13. Cost analysis Conclusion . . . . . . . . Disclosures . . . . . . . . References . . . . . . . .
at the Montreal Heart Institute (MHI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................................................................................... ...................................................................................... ......................................................................................
27
30 30 30 31
1. Introduction
3.1. Classification, roles and use of hemostatic agents
Within Canada, 2.6 million in-hospital surgical procedures are completed annually [1]. Bleeding after surgery is the most common surgical complication, occurring in around 25% of all surgeries [2]. Bleeding causes increased mortality and morbidity, by increasing the number of transfusions required secondary to increased cumulative blood loss, and by causing hemodynamic instability. Bleeding also impairs visualization of the surgical field and prolongs surgical procedures [3]. Increased bleeding could result in acidosis and hypothermia which could lead to coagulopathy (lethal triad) [4]. The operative bleeding challenges, such as friable tissues, reoperative adhesions, diffuse soft tissue and bone bleeding, are considered uncontrollable issues and bleeding secondary to these issues cannot always be avoided. Also, perioperative bleeding complications such as infection, blood transfusions and transfusion-related reactions, occult bleeding, prolonged or multiple procedures, lethal triad, hemodilution and postoperative coagulopathy (disseminated intravascular coagulation (DIC), factor deficiency, impaired fibrinolytic system) cannot always be anticipated. One of the solutions to this problematic situation encountered during surgeries is the hemostatic local topical products. The objectives of this manuscript are to (1) review the spectrum of hemostatic products available in cardiovascular surgery and to (2) provide an update on new products soon available or in development for optimizing hemostasis during surgical procedures.
The classification of those hemostatic agents currently available is described in Table 1. These hemostatic agents are used when ligation, sutures, compression or cautery are not effective. The types of bleeding where topical agents are used include: diffuse raw surface bleeds, oozing venous-type bleeds, bone bleeding and needle-hole bleeding. The desired attributes are safety, reliable efficacy and prompt control of bleeding, ease of storage and preparation and immediate availability, usability and affordability. Also, it could help decrease the time spent in the operating room. Factors that guide selection of these agents include: size of wound and accessibility of bleeding site, severity of bleeding and coagulation status of patient, and reoperation.
3.2. Clinical use Procedures where patients have high risk of bleeding include, for example, aortic valve replacement, surgery for the ascending and descending aorta, alloplastic patch or plasty, carotid endarterectomy, and all patients over 60 years old. To help manage bleeding, some authors have proposed surgical scenarios for use of the products in cardiovascular surgery (shown in Fig. 1). The choice of topical hemostatic agents is dependent on the surgeon’s preference and depends on individual experience rather than strong evidence-based practice.
3.3. Literature 2. Methodology Literature review was made on Pubmed and MEDLINE between January 1974 and 2012 using keywords such as bleeding, hemostatic agents and cardiac surgery. Priority was placed on randomized controlled trials (RCTs). Additional articles were found according to the references in the selected articles.
3. Discussion The expectations for a new optimal topical hemostatic agent should be: (1) good adhesiveness (± the use of gelatin sponge), (2) short compression time, (3) good hemostatic effect, (4) no disintegration during or shortly after surgery, (5) the cost, (6) the preparation time/easy to use, (7) the modality of delivery (e.g. spray) and (8) the immediacy of action of autologous preparation.
Barnard and Millner did a systematic review on topical hemostatic agents for use in cardiac Surgery in 2009 published in Annals of Thoracic Surgery [5]. Table 2 in their article represents the summary of randomized Controlled Trials of Hemostatic Agents in Cardiovascular Surgery.
3.4. Mechanical Surgicel is reported to be bacteriostatic with antimicrobial activity [6]. Collagen is not as good at reducing infection risk as Surgicel and is reported to cause end-organ damage if it migrates to the blood circulation [7]. Surgicel has been compared to collagen during cardiac surgery procedures that necessitate deep hypothermic circulatory arrest and surgical was superior to collagen in terms of reduced bleeding intra-operatively and reduced drainage post-operatively [8].
28
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
Table 1 Topical hemostats classification. Mechanical
Flowable
Fibrin/Synthetic Sealants
Active
Gelatin sponge (may be used with thrombin) Porcine gelatin Gelfoam (Pfizer Pharmacia), Surgifoam (Ethicon J&J,) Gelfoam plus (Baxter Healtcare Corp.)
Gelatin
Fibrinogen + thrombin
Bovine thrombin
Collagen
Gelatin matrix + thrombin
Bovine Avitene Sheets (non woven web) (Davol) Ultrafoam Collagen Sponge (Davol)
Tisseel (Baxter) (Human pooled plasma thrombin, human pooled fibrinogen, synthetic aprotinin) Evicel (J&J) (Human pooled plasma thrombin, human pooled fibrinogen, human albumin)
Surgiflo (J&J)* (Porcine gelatin) FloSeal (Baxter) (Bovine gelatin and human pooled plasma thrombin
Synthetic
CoSeal (Baxter Bioglue (Cryolife)
Cellulose Surgicel (J&J) Surgicel Nu-Knit (J&J) Chitin and Chitosan-Based Hemostatic Agents
Human pooled plasma thrombin Evithrom (Omrix Biopharmaceuticals)
Recombinant thrombin Recothrom (ZymoGenetics)
Celox (SAM Medical Products) HemCon (HemCon Medical Technologies Inc) QuickClot(Z-Medical Corp) Polysaccharide spheres Arista (Medafor) *
Thrombin-JMI (King)
J&J: Johnson and Johnson.
Fig. 1. Surgical scenarios in cardiovascular surgery.
29
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31 Table 2 Montreal Heart Institute summary cost of blood products in 2011. Blood products
Cost per unit
Number of units
Annual cost
Globular sediment Cryoprecipitate Regular fresh frozen plasma Apheresis fresh frozen plasma Regular platelet pack Apheresis platelet pack Stable product transfused Labile products loss Total
345,27$ 36,81$ 235,11$ 470,22$ 132,58$ 662,88$
5426 2568 2994 4 3255 715
1,873,435$ 94,500$ 703,919$ 1881$ 431,548$ 473,959$ 428,433$ 155,987$ 4,163,690 $
3.4.1. Microporous polysaccharide Those agents create scaffolding for the formation of a fibrin clot within minutes of application; however there are no trials published in the literature up to now. 3.4.2. Chitin and chitosan-based hemostatic agents Celox is a granular hemostatic agent that interacts directly with red blood cells and platelets to form a clot independently of native factors. A randomized controlled trial (RCT) was published using a porcine model of arterial and venous hemorrhage that compared Celox, HemCon, QuickClot and standard gauze dressings. Celox reduced bleeding to 0%, HemCon to 33% and QuickClot by 8%. Celox improved survival to 100% compared to HemCon 67% and QuickClot 92% [9]. In the United States the military are treated with hemostatic dressings, HemCon and it is coated with Chitosan [10]. 3.5. Flowable In an RCT by Oz, patients undergoing cardiac surgery were randomized into the FloSeal and the control groups in order to control bleeding. After 10 min, bleeding was stopped with the FloSeal in 94% of patient versus 60% with the control group who received Gel foam with thrombin. At 3 min, hemostasis was achieved in 72% of patients in the FloSeal group compared with 23% in the Gel foam and thrombin group. Success rate was significantly different before reversal of heparin with protamine in favor of Floseal, but did not reach a statistical difference after heparin reversal [11]. In a study by Nasso et al. in 2009, Floseal was compared to Gelfoam and Surgicel Nu-Knit to control bleeding in elective primary cardiac surgery: statistically higher rates of successful hemostasis and shorter timeto-hemostasis were observed in the Floseal group (p < 0.001) [12].
was achieved in 54.5% of patients who received the sealant compared to 10% in the control group [13]. Another study, done by Brunkwall et al., showed that, in patient who underwent vascular reconstruction or access below the diaphragm, the use of a cyanoacrylate sealant procured immediate hemostasis in 71.3% and 93.6%, 96.8% and 100% at 1, 5 and 10 min respectively [14]. 3.6.2. Glues There are 24 trials reported by Kjaergard and Fairbrother about the use of fibrin glues in cardiac surgery. Four studies reported no difference and 20 trials reported positive results in term of decreased bleeding [15]. Lamm et al. have, however, reported several cases of acute occlusion of bypass when the fibrin sealant Tissucol fibrin was used in proximity to the anastomoses: a word of caution about special care when using this product was reported [16]. Another RCT compared the use of Bioglue versus control during repair of anastomotic bleeding in patients during cardiac and vascular surgery. Anastomotic bleeding was significantly reduced in the group using Bioglue (19% of anastomoses) versus in the control group (43% of anastomoses) [17]. Adverse effects have however been reported with the use of Bioglue, such as leaking of Bioglue through needle holes, and it may spread away from the site of application and it can cause nerve tissue injury as well as impair normal healing [17–19]. 3.7. Fibrin sealant versus mechanical A study by Rousou et al. tested the efficacy and safety of fibrin sealant as a topical hemostatic agent in patients undergoing either reoperative cardiac surgery or emergency resternotomy. Tisseel was used as the fibrin sealant agent versus Avitene or Surgicel as controls. They obtained 92.6% control of bleeding with Tisseel versus 12.4% with control agents at 5 min (p < 0.001) [20].
3.6. Fibrin sealant 3.8. Fibrin sealant versus flowable 3.6.1. Cyanoacrylate sealant Omnex is a synthetic tissue adhesive consisting of a blend of two monomers. One prospective RCT has assessed its efficiency in establishing hemostasis on arterial vascular anastomosis in 151 patients. Mean time to obtain hemostasis from the time that the clamp is released was 119.3 s with the sealant compared to 403.8 s with the control (oxidized cellulose) (p < 0.001). Immediate hemostasis
RCT trials were done comparing CoSeal to Gelfoam and thrombin. In the first trial, using the fibrin sealants during reconstruction for nonruptured aneurysms, more immediate sealing of the suture line sites was observed with CoSeal after return of blood flow than with the other 2 agents [21]. Another RCT showed that overall 10 min sealing success was equivalent for all three sealants, however
30
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
patients where CoSeal was used to control bleeding after placement of a prosthetic vascular grafts demonstrated that with CoSeal immediate anastomotic sealing was achieved at more than twice the rate than with the other two agents [22]. 3.9. Composite of collagen and thrombin
600 000 $
533 062 $
554 538 $
500 000 $ 398 470 $
400 000 $ 300 000 $
271 047 $ 216 491 $
219 662 $
200 000 $
CoStasis is a composite of collagen and bovine thrombin and was compared to collagen and gauze to achieve hemostasis during cardiac surgery. After 3 min, CoStasis achieved hemostasis in 76% of cases compared to 46% in the controls. Details were not given in this study about timing and site of application [23].
100 000 $ 0$ 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012
Fig. 2. Total cost per year of hemostatic and biological products purchased at the Montreal Heart Institute.
3.10. Active Recombinant human thrombin (Recothrom) gained popularity because compared to human and bovine thrombin, it reduces formation of patient thrombin antibodies and diminishes risk of transmission of infection [24]. 3.11. Topical antifibrinolytic agents There are controversies concerning the systemic use of antifibrinolytics agents, especially of aprotinin that was withdrawn from the market due to its marked adverse effects [25]. Tranexamic acid (TA) on the other hand is still used for certain indications during cardiac surgery. However, those agents were successful at reducing bleeding after cardiac surgery. Studies were then done to evaluate if topical use of these very potent agents could reduce bleeding. Fawzy et al. used 1 g of TA diluted in 100 ml of normal saline (NS) versus only NS that were spilled in the pericardial and mediastinal cavities. During the first 24 h post-operatively, cumulative blood loss was significantly less in the TA group (626 ml) versus placebo group (1040 ml) (p = 0.04) [26]. Another study by Baric et al. randomized patients to the use of topical aprotinin, TA or placebo spurred in the pericardial cavities and mediastinal tissues before sternal closure. Topical use of both TA and aprotinin reduced post-operative bleeding (391 ml and 433 ml respectively) compared with 613 ml with placebo (p < 0.001) [27]. 3.12. Special tips for each category of hemostatic devices 3.12.1. Mechanical Avoid using irrigating stream of saline at clot interface to avoid dislodgement of coagulum and resumption of bleeding.
as a sealant between flaps, pre-place lattice work of closing sutures of flaps while product is still polymerizing and avoid later disruption of the adhesive bond between the flaps. When using as a skin graft adhesive avoid too thick a layer that can prevent diffusion of nutrients to graft from underlying muscle.
3.12.4. Active Deliver with absorbable gelatin sponge, operating room gauze or laparotomy pad to facilitate off pressure. Squeeze excess thrombin from sponge prior to application. May be applied with absorbable gelatin powder to create puttylike caulking effect. Avoid prolonged exposure to oxidized regenerated cellulose.
3.13. Cost analysis at the Montreal Heart Institute (MHI) The total costs per year of hemostatic and biological products purchased at the Montreal Heart Institute are shown in Fig. 2. Indeed, the more complex the procedure the more it is costly, because of greater bleeding tendency. In 2011–2012 the total cost spent on hemostatic products was estimated at $554,538 (Fig. 2). On the other side, the total money spent on blood products in 2011 was $4,163,690 (Table 2). Moreover, a cost analysis of re-exploration for bleeding after cardiac surgery demonstrated that the resource utilization costs were substantially higher in patients requiring re-exploration for bleeding and that included prolonged stays in the intensive care unit and blood transfusions [29].
4. Conclusion 3.12.2. Flowable Apply into depths of wound to maximize matrix location at sites of active bleeding. Avoid blood on any sponges or pads used to apply pressure to matrix. Reapply additional material to bleeding site of origin. 3.12.3. Fibrin sealant [28] When using as a hemostat, apply with absorbable gelatin sponge to facilitate application of pressure. When using
In conclusion, topical hemostats are used when conventional hemostatic approaches are inappropriate or ineffective. There are 4 main categories of topical hemostats: Mechanicals, Flowables, Fibrin Sealants and Actives (Thrombins). The choice of topical hemostatic agents is dependent of the surgeon’s preference and depends on individual experience rather than on strong evidencebased practice.
J. Forcillo, L.P. Perrault / Transfusion and Apheresis Science 50 (2014) 26–31
Disclosures Dr. L.P. Perrault receives grants from Bayer Inc., Pluromed, Applied Medical, Baxter, St-Jude Medical and Johnson and Johnson.
[17]
[18]
References [1] CIHR. Hospital discharge data. 2007. [2] C.L. Pharmacy practice news. Special report. Topical thrombins. 2008. [3] Marietta M, Facchini L, Pedrazzi P, Busani S, Torelli G. Pathophysiology of bleeding in surgery. Transplantation Proc 2006;38:812–4. [4] Schreiber MA. Damage control surgery. Crit Care Clin 2004;20:101–18. [5] Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thoracic Surgery 2009;88:1377–83. [6] Scher KS, Coil Jr JA. Effects of oxidized cellulose and microfibrillar collagen on infection. Surgery 1982;91:301–4. [7] Robicsek F. Microfibrillar collagen hemostat in cardiac surgery. J Thoracic Cardiovascular Surgery 2004;127:1228 [author reply 1228]. [8] Sirlak M, Eryilmaz S, Yazicioglu L, Kiziltepe U, Eyileten Z, Durdu MS, et al. Comparative study of microfibrillar collagen hemostat (colgel) and oxidized cellulose (surgicel) in high transfusion-risk cardiac surgery. J Thoracic Cardiovascular Surgery 2003;126:666–70. [9] Millner RW, Lockhart AS, Bird H, Alexiou C. A new hemostatic agent: initial life-saving experience with celox (chitosan) in cardiothoracic surgery. Ann Thoracic Surgery 2009;87:e13–14. [10] Rao SB, Sharma CP. Use of chitosan as a biomaterial: studies on its safety and hemostatic potential. J Biomed Mater Res 1997;34:21–8. [11] Oz MC, Cosgrove 3rd DM, Badduke BR, Hill JD, Flannery MR, Palumbo R, et al. Controlled clinical trial of a novel hemostatic agent in cardiac surgery. The fusion matrix study group. Ann Thoracic Surgery 2000;69:1376–82. [12] Nasso G, Piancone F, Bonifazi R, Romano V, Visicchio G, De Filippo CM, et al. Prospective, randomized clinical trial of the floseal matrix sealant in cardiac surgery. Annals Thoracic Surgery 2009;88:1520–6. [13] Lumsden AB, Heyman ER. Prospective randomized study evaluating an absorbable cyanoacrylate for use in vascular reconstructions. J Vascular Surgery 2006;44:1002–9 [discussion 1009]. [14] Brunkwall J, Ruemenapf G, Florek HJ, Lang W, Schmitz-Rixen T. A single arm, prospective study of an absorbable cyanoacrylate surgical sealant for use in vascular reconstructions as an adjunct to conventional techniques to achieve hemostasis. J Cardiovascular Surgery 2007;48:471–6. [15] Kjaergard HK, Fairbrother JE. Controlled clinical studies of fibrin sealant in cardiothoracic surgery–a review. Eur J Cardio-Thoracic Surgery: Official J Eur Assoc Cardio-Thoracic Surgery 1996;10:727–33. [16] Lamm P, Adelhard K, Juchem G, Weitkunat R, Milz S, Kilger E, et al. Fibrin glue in coronary artery bypass grafting operations: Casting
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
[29]
31
out the devil with beelzebub? Eur J Cardio-Thoracic Surgery: Official J Eur Assoc Cardio-Thoracic Surgery 2007;32:567–72. Coselli JS, Bavaria JE, Fehrenbacher J, Stowe CL, Macheers SK, Gundry SR. Prospective randomized study of a protein-based tissue adhesive used as a hemostatic and structural adjunct in cardiac and vascular anastomotic repair procedures. J Am Coll Surgeons 2003;197:243–52 [discussion 252–243]. LeMaire SA, Carter SA, Won T, Wang X, Conklin LD, Coselli JS. The threat of adhesive embolization: bioglue leaks through needle holes in aortic tissue and prosthetic grafts. Ann Thoracic Surgery 2005;80:106–10 [discussion 110–101]. LeMaire SA, Schmittling ZC, Coselli JS, Undar A, Deady BA, Clubb Jr FJ, et al. Bioglue surgical adhesive impairs aortic growth and causes anastomotic strictures. Ann Thoracic Surgery 2002;73:1500–5 [discussion 1506]. Rousou J, Levitsky S, Gonzalez-Lavin L, Cosgrove D, Magilligan D, Weldon C, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study. J Thoracic Cardiovascular Surgery 1989;97:194–203. Hagberg RC, Safi HJ, Sabik J, Conte J, Block JE. Improved intraoperative management of anastomotic bleeding during aortic reconstruction: results of a randomized controlled trial. Am Surgeon 2004;70:307–11. Glickman M, Gheissari A, Money S, Martin J, Ballard JL. A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than gelfoam/thrombin: Results of a randomized controlled trial. Arch Surg 2002;137:326–31 [discussion 332]. A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial. Surgery. 2001;129:445–450. Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens Jr KL, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am College Surgeons 2007;205:256–65. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. New Engl J Med 2006;354:353–65. Fawzy H, Elmistekawy E, Bonneau D, Latter D, Errett L. Can local application of tranexamic acid reduce post-coronary bypass surgery blood loss? A randomized controlled trial. J Cardiothoracic Surgery 2009;4:25. Baric D, Biocina B, Unic D, Sutlic Z, Rudez I, Vrca VB, et al. Topical use of antifibrinolytic agents reduces postoperative bleeding: A doubleblind, prospective, randomized study. Eur J Cardio-Thoracic Surgery: Off J Eur Assoc Cardio-Thoracic Surgery 2007;31:366–71 [discussion 371]. 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 Thrombosis/ Hemostasis: Official J Int Acad Clin Appl Thrombosis/Hemostasis 2010;16:497–514. Alstrom U, Levin LA, Stahle E, Svedjeholm R, Friberg O. Cost analysis of re-exploration for bleeding after coronary artery bypass graft surgery. Br J Anaesthesia 2012;108:216–22.
