Comparison of hemostatic agents used in vascular surgery

2.1.1 Gelatin

Gelatin is a hydrocolloid made from acid partial hydrolysis of porcine-derived collagen that is whipped into foam and then dried. It is available in sponge and powder forms, and may be used as a stand alone or in combination with topical thrombin. Gelatin absorbs the blood up to 40 times its weight and expands to 200% of its initial dimensions. The dry sponge form can be cut to any size and shape. It can be applied dry, or directly to the bleeding surface with pressure applied once in place, to achieve hemostasis. After deployment, it can be left in place and is absorbed after 4 – 6 weeks. Two well-known gelatins are Surgifoam and Gelfoam. Benefits of gelatin are as follows: It is relatively low cost, it may be stored at room temperature, and it can be used off the shelf in the ORC. However, some safety issues exist, including the potential for ‘overswelling’ when used within small spaces, potentially causing damage. For this reason, it is not used intravascularly.

2.1.2 Collagen

Collagen hemostats are derived from bovine skin. They bind tightly to blood surfaces to provide a matrix for clot formation and strengthening, as well as enhancement of platelet aggregation, degranulation and release of clotting factors, thus further promoting clot formation. They have been found to be effective in controlling arterial bleeding and in patients with low platelet counts. They are available in sheets and flours, conform and adhere to irregular surfaces and are ready to use out of the box. Although more expensive than porcine gelatin, hemostasis can generally be achieved in a shorter amount of time (1 – 5 min). It can be easily removed with irrigation and suction, reducing rebleeding and the need for multiple applications. Left in place, it is absorbed in 8 – 10 weeks. Problems that have been associated with bovine collage include swelling and allergic reaction. Therefore, collagen hemostats should not be used in any area where they may exert pressure on adjacent structures or for skin closure as it may interfere with healing of the skin edges, as well as not in patients with known allergies or sensitivities to materials of bovine origin. Popular collagen hemostats are Avitene, Helistat-Instat and Ultrafoam.

2.1.3 Oxidized regenerated cellulose

ORC products are derived from plant-based alpha-cellulose. They are available in an absorbable knitted fabric, in single or multiple sheets, and can be either low or high density. ORC products are stored at room temperature, can be used immediately, and absorb 7 – 10 times its own weight. They act in the intrinsic pathway causing contact activation and platelet activation and, as absorbed, a gelatinous mass is formed, aiding in clot formation. These products are used to control capillary, venous and small arterial bleeding, and can be cut into strips or smaller pieces for placement. They need to be applied dry and are absorbed within 4 – 8 weeks. ORC products should not be used in closed spaces due to potential swelling or for control of bleeding from large arteries. Three commercial forms are Surgicel, Oxycel and Surgicel Nu-Knit. Surgicel and Surgicel Nu-Knit come in knit, solid fiber form, whereas Oxycel comes in knit, hollow fiber form; however, they work essentially the same way.

2.3.1 SurgiFlo

SurgiFlo is a sterile and absorbable hemostatic porcine gelatin matrix that is mixed with Thrombin JMI (a protein substance produced through the interaction of thrombin of bovine origin and calcium chloride) applied directly to the bleeding sites to impart hemostasis.

Woodworth et al. assessed the clinical efficacy of SurgiFlo subsequent to endoscopic sinus surgery in 30 patients. It was found that SurgiFlo was clinically effective in the cessation of bleeding in 96.7% of patients within 10 min of administration, with no complications observed (e.g., infection, adhesion or synechiae) [8]. SurgiFlo is used during cardiovascular surgery for anastomotic sealing.

2.3.2 FloSeal

FloSeal is comprised of a gelatin matrix, calcium chloride and plasma derived human thrombin. When it is applied to a superficial wound or surgical site, the gelatin granules absorb the blood and swells (20% within 10 min) to form a tamponade, which conforms well to the geometries of wounds. High concentrations of thrombin serve to rapidly react with the patient’s fibrinogen in the formation of a ‘mechanically stable clot,’ which is reabsorbed within 6 – 8 weeks. A unique characteristic of Floseal is its requirement for the presence of blood for activation [9]. In addition, it may hypothetically initiate thromboembolic events if injected directly into medium to large vessels [10].

Studies have been conducted to assess the efficacy of Flo-Seal in comparison with other hemostatic agents. In a Swiss study undertaken in 2000, FloSeal was used in 17 patients who required peripheral vascular intervention. The efficacy of FloSeal was quantified by the profusion of bleeding prior to and following the time to complete hemostasis, the amount of FloSeal that was required to achieve hemostasis and the requirement for subsequent operations in order to control bleeding. Fifteen of the 17 patients had complete hemostasis over a brief timeline and 2 patients required further treatment. There were no local or systemic complications indicated as a result of the use of FloSeal [10].

A prospective randomized trial performed in Italy in 2009 involved 415 patients who were undergoing either elective thoracic, coronary or valvular procedures. FloSeal was utilized for 209 of the patients, whereas the remaining 206 received Surgicel Nu-Knit or Gelfoam-12, contingent on the preference of the surgeon. The analysis of the study was somewhat complicated, since some of the patients were given heparin, while others were subjected to hypothermia, both of which may impair the normal clotting cascade. However, there were statistically higher hemostatic rates and more rapid hemostasis times for the FloSeal group, in addition to lower morbidity. The cost-effectiveness of FloSeal was not addressed [11].

An additional study was conducted to contrast the effectiveness of FloSeal with Gelfoam–thrombin. Three hundred and nine patients with cardiac or spinal problems were specifically selected, as their bleeding sites would not be readily accessible to other hemostatic agents. There were 93 cardiac patients in the study, and 48 were treated with FloSeal (some patients had multiple bleeding sites). The onset of hemostasis within 10 min was shown to be significantly better in the FloSeal group: 92/104 (88%) compared to 35/61 (57%) in the Gelfoam–thrombin group. At heavy bleeding sites, FloSeal demonstrated improved performance over Gelfoam. Complete hemostasis was indicated to be 94% for the FloSeal group in contrast to 66% for the Gelfoam group. The surgeon made an assessment as per the ease of use of both products and found that application to the bleeding sites was easier and conformation to the tissue was improved with FloSeal [12].

3.1.1 Evicel

Evicel is a fibrin sealant derived from pooled human plasma supplied as a package containing two separate vials of fibrinogen and human thrombin, respectively. The active ingredients are fractionated from pooled human plasma. The two deep frozen solutions must be defrosted prior to use. After thawing and warming to 20 – 30°C, the two solutions are mixed. In 2007, the FDA expanded the use of Evicel (formerly Crosseal) for use in vascular surgery.

3.1.2 Tisseel

Tisseel is perhaps one of the best known of the fibrin sealants. It is composed of human fibrinogen and thrombin combined with aprotinin and calcium chloride. Aprotinin is a serine oxidase inhibitor that prevents the degradation of fibrinogen and stabilizes the fibrin clot that is formed. However, it is also a potential allergen as it is a foreign protein that is derived from bovine lung tissue. Although there have been reports of allergic reactions, and a rare instance of an immediate and severe anaphylactic reaction approaching lethality, reactions were primarily associated with multiple exposures [17].

Tisseel is primarily used in cardiopulmonary situations, such as emergency ascending aorta, ascending–hemiarch replacement [18], cardiopulmonary bypass [19] and ascending aorta replacement [20]. Tisseel does not work in a bleeding (wet) wound. The bleeding must be stopped by clamping the vessel proximately, the blood removed and the tissue (blood vessel) cleaned, and dried before applying the Tisseel. Two to three minutes should be allowed for drying and polymerization to occur and the vessel to reflow.

Lowe et al. treated 317 patients who were engaged in a Phase III, prospective, randomized, double–blind, multicenter study and undergoing cardiac surgery. Tisseel VH or Tisseel VH solvent/detergent (S/D) was applied at surgeon-determined bleeding sites and compared. Tisseel VH S/D was developed as a next-generation fibrin sealant in frozen, ready-to-use form with an added virus inactivation step (S/D treatment) to provide added safety and convenience to Tisseel VH. It was found that the newer generation Tisseel VH S/D was at least as efficacious as Tisseel VH; the percentage of patients who successfully attained and sustained hemostasis at the primary treatment site (designated as medium bleeding sites) until surgical closure was 89.6% with Tisseel VH and 88.2% with Tisseel VH S/D. The Tisseel VH S/D, however, had a slightly higher rate of success for mild or minimal bleeding sites compared to the Tisseel VH, with hemostatic success at 95.1 versus 94.4%, respectively [19].

In a group of 38 children with congenital heart defects, Tisseel gave excellent hemostasis in 31 patients, good hemostasis in 6 and poor in only 1 patient [21]. In a nationwide study of 140 patients requiring arterioarterial bypasses or arteriovenous shunts, the Tisseel group had 62.9% hemostasis compared to manual compression, which had only 31.4% efficacy. There were no adverse effects noted from use of the Tisseel [22].

Rousou undertook a detailed survey of the literature on fibrin sealants spanning the years 1979 – 2012 and found Tisseel to be the most prevalently examined. It was demonstrated that Tisseel as well as other fibrin sealants were well tolerated and efficacious in providing hemostasis for a range of cardiac and aortic surgeries (e.g., coronary artery bypass graft [CABG], valve replacement, ventricular septal defect repair, infective endocarditis management, aortic surgery). Highlighted advantages included rapid achievement of hemostasis, reduction in blood loss and number of repeat procedures [16].

3.1.3 Vitagel

Vitagel combines microfibrillar collagen with thrombin, fibrinogen and platelets. Vitagel uses the patient’s own plasma, eliminating the risk of viral transmission associated with products containing pooled human donor components. Vitagel is formulated to produce a safe and effective hemostat by forming a 3-D scaffold of collagen and fibrin enhanced with activated platelets.

3.1.4 TachoSil

TachoSil was approved for use in adults only in 2010 [23]. TachoSil is a two-layer patch/sponge material with one side comprised of equine collagen and the other of human fibrinogen and thrombin. The collagen is seated on the wound, whereas the fibrinogen and thrombin serve to complete the normal coagulation cascade [24].

In a comparative study involving TachoSil and the standard hemostatic fleece, TachoSil performed favorably. In a study of 119 patients who had bleeding from aorta (56%), right ventricle (16%), right atrium (13%) and arterial blood vessel (74%), 59 of the patients were treated with TachoSil, whereas the remainder was treated with the hemostatic fleece. Tacho-Sil was observed to achieve complete hemostasis within 3 min in 75% of the patients compared to 33% for the control group. Three patients in the control group required TachoSil to initiate the cessation of bleeding. Side effects were similar for both treatment groups [25]. TachoSil fibrin glue has also been shown to be effective in patients with acute myocardial infarction involving pulmonary bypass [26].

Compared to Gore-Tex, a nonadhesive and nonthrombogenic substance, significantly fewer macroscopic adhesions were found in the TachoSil group at all sites except at the coronary arteries where there were no significant differences. Additionally, TachoSil prevented the formation of retrosternal adhesions, unlike Gore-Tex and the untreated control group. There was no significant difference in the adhesion level between the Gore-Tex and the no-treatment control group [27].

3.1.5 Bolheal

Bolheal is a dual solution fibrin sealant that comprises two solutions (A and B) stored separately as frozen liquid or can be refrigerated in a liquid form, thereby avoiding waste of unused product, for up to 30 days after thawing. Solution A consists of 80 mg/ml human fibrinogen, 75 IU/ml of human plasma-derived coagulation factor XIII and 1000 KIE of bovine aprotinin, whereas solution B consists of 250 IU/ml of human thrombin and 5.9 mg/ml of calcium chloride. In clinical practices, Solution A and B are mixed in the ratio of 1:1 in volume. When mixed together, these agents mimic the last stages of the clotting cascade to form a fibrin clot. Twenty patients who underwent emergency ascending aorta or ascending–hemiarch replacement were divided into two groups in a randomized comparative study. Ten patients (group G) were treated with a rub-and-spray technique, whereas the remaining 10 patients (group C) received none. The rub-and-spray method involved the use of a finger to rub a fibrinogen solution over needle holes, followed by spraying of the Bolheal fibrin sealant over the sites. The rub-and-spray method using Bolheal for the group G patients exhibited significant hemostatic efficacy over group C patients. Of an overall ~ 55 needle holes, the proportion of those that were bleeding was ~ 4.8% for group G in contrast to ~ 72.8% for group C, blood loss during hemostasis was ~ 99 ml for group G compared to ~ 257 ml for group C and postoperative blood loss over 12 h was ~ 268 for group G and ~ 526 ml for group C [6]. Although commercially available in Japan, Bolheal has not been approved by the FDA for use in the United States.

3.1.6 Grifols

The fibrin sealant Grifols (FS Grifols) is composed of frozen solutions of human fibrinogen and human thrombin combined with calcium chloride. This investigative product is currently in clinical trials and patients are actively being recruited. The estimated study completion date is slated for December 2013 [28].

3.1.7 CryoSeal

CryoSeal, manufactured by ThermoGenesis, was the first sealant to be produced from single units of human plasma, thus eliminating the risks that are associated with pooled plasma products. CryoSeal components are 100% human (cryoprecipitate and thrombin), which contain no animal products or synthetics. It is produced from single-donor, fresh-frozen quarantine apheresis plasma units that are obtained from healthy, voluntary, nonremunerated donors. A recent report by Hazelaar et al. concluded that the single-donor origin and the absence of fibrinolytic inhibitors make CryoSeal a good alternative to multidonor and autologous fibrin sealants [29].

In a multicenter, randomized clinical trial involving 153 patients who underwent elective hepatectomy, the efficacy of CryoSeal in establishing hemostasis was confirmed. In these cases, the CryoSeal fibrinolytic factor plasminogen, which has been reported to reduce the potential for viral transmission compared to pooled products [30], was observed to be threefold higher than Tisseel, at 360 mg/ml versus 20 – 120 mg/ml, respectively.

Cryoseal contains a higher level of plasminogen (107 mg/ ml) than does Tisseel (40 – 120 mg/ml) [30]. This higher plasminogen content in CryoSeal allows clots to degrade sooner than Tisseel when the plasminogen is converted to plasmin, to unfold potent clot dissolving enzymes. This has the advantage of limiting the spread of a clot, which may cause damage or blockage should it become too large.

3.2.1 CoSeal

CoSeal Surgical Sealant is devoid of any human or animal materials. CoSeal comprises entirely two PEGs: a dilute hydrogen chloride solution and a sodium phosphate/ carbonate solution [31]. PEG is available in a wide range of molecular weights (e.g., 300 – 10,000,000 g/mol) contingent upon the polymerization of ethylene oxide. When administered, the combination of these solutions results in the formation of a hydrogel, which cross-links with proteins to initiate spontaneous bonding with tissues. The sealant is completely absorbed by the body within 30 days of application [32].

A study conducted with 12 dogs that were undergoing iliac polytetrafluoroethylene (PTFE) grafts to test the efficacy of CoSeal as a hemostatic agent demonstrated clear benefits. One end of the graft was treated with CoSeal, whereas the other end (control) was treated with gauze and manual pressure. There was a distinct benefit for the use of CoSeal; time to hemostasis was 5 versus 15 min for the control. Blood loss was lower at the Coseal-treated end (19 gm compared to 284 gm from the control end). The CoSeal was still visible 7 days postoperatively and moderate inflammation was seen on days 7, 30 and 60 [33].

In Germany, 124 patients underwent aortic procedures that were performed by six surgeons. Three of the surgeons utilized CoSeal, whereas the other three did not. The aortic procedures included full aortic root replacement, reconstruction or full replacement of the ascending aorta and aortic arch procedures. CoSeal was sprayed on the suture lines and allowed to dry. It was demonstrated that the CoSeal group required fewer transfusions (e.g., RBCs: CoSeal 761 compared to 1248 in the control group; fresh frozen plasma: 413 vs 779 in the control group; and reduced postoperative drainage loss: 985 ml in the CoSeal-treated group compared to 1709 ml in the control group). In addition, fewer CoSeal-treated patients required re-sternotomies (1 of 48 CoSeal vs 6 of 54 in control) and less time in the intensive care unit. The authors concluded that CoSeal was a very good hemostatic agent that saved 1943 Euros per patient [34].

3.2.2 DuraSeal

DuraSeal is a sealant system consisting of PEG ester solution, antrilysine amine solution and FD&C blue #1 colorant. It is a patented synthetic, absorbable hydrogel delivered by a dual syringe applicator and can be stored at room temperature and prepared in < 2 min. When mixed together by spraying, the precursors cross-link immediately to form hydrogel sealant. The blue colorant in DuraSeal provides the surgeons with excellent visualization of coverage and thickness of the material upon application. Postoperatively, DuraSeal continues to seal the suture line as healing progresses under the gel. After several weeks, the hydrogel breaks down into water-soluble molecules that are absorbed and cleared through the kidneys.

Its original use was in neurosurgery and when sprayed on the dura, it has sufficient tissue adherence and cohesive strength to withstand cerebrospinal fluid pressures. In a study reported by Nishimura et al. in 2012, DuraSeal was analyzed to test its feasibility for use in superficial temporal artery-middle cerebral artery anastomosis, a common procedure for the treatment of cerebral ischemia, cerebral aneurysms and tumors. In a cohort of 42 patients, DuraSeal obtained a water-tight dural closure easily and safely, even in bypass surgery [35].

Recently, DuraSeal was granted a Conformité Européenne (CE) mark, allowing its use in Europe to seal suture lines as an adjunct to the standard closure techniques during arterial and venous reconstructions in vascular surgery [36] and during elective pulmonary resection for visceral pleural air leaks [37].

3.2.3 ProGel

ProGel is an adhesive that was synthesized in order to seal pleural air leaks subsequent to surgery. It is a spray-on liquid mixture comprised of human serum albumin and PEG. Other pleural sealants have been formulated including a fibrin sealant and two synthetic sealants. Intraoperative air leaks (IOALs) are serious complications that occur following lung surgery and arise in 47 – 75% of patients. IOALs require a chest tube to enable the release of air, which prolongs the time spent in the intensive care unit and increases the chances of infection and length of hospital stay.

In a single-surgeon retrospective study of Progel, it was found that 75 patients out of 121 (57.9%) had an issue with IOAL. Of the 75 with IOAL, 36 were treated with Progel in addition to a standard pleural sealant. Thirty-four patients received only the pleural sealant. Progel was revealed to control air leaks better than the control group. When Progel was utilized, only 11% of the patients continued to have IOAL events, whereas in the control group, 56.8% had persistent leaks. The length of time that a chest tube was required was shorter for the Progel group (1 day compared to 2.5) and the hospital stay was halved; 1.5 days was required for the group treated with Progel versus 3 days for the control group [38].

4.2.1 Bioglue

A 2001 study that compared the hemostatic performance of Bioglue against Surgicel in sheep concluded that Bioglue could be beneficial for coagulopathic patients undergoing vascular procedures. In this study, bypass surgery was conducted on the descending thoracic aorta after all animals had received heparin and aspirin. Bioglue demonstrated an improved performance in the prevention of blood loss over Surgicel when administered immediately postoperatively (470 vs 995 ml) and also reduced total blood loss (668 vs 1497 ml) to a greater extent. After 3 months, the Bioglue-treated sheep exhibited minimal inflammatory response [41].

Free wall rupture (FWR) following myocardial infarction (MI) results in oozing into the pericardial space or acute rupture. One study related the experience of nine patients with MI who presented to the emergency room with pain and cardiac tamponade. The elapsed time between the MI and the FWR was 122 h. In all nine patients, the area of necrosis and pericardial hematoma was easily discernible. All hematomas were located on the left ventricle, albeit at different sites. The surgeon placed a Teflon patch over the affected area, which was then soaked with Bioglue. There were no postoperative deaths within 30 days and all of the patients preserved left ventricular function with no apparent restriction of motion [42].

Passage et al. conducted a very large and complex study in 2002 in which 115 patients with a wide variety of cardiovascular problems were treated and the results analyzed. The most common problems seen were 39 aortic aneurisms and 30 aortic dissections. The repairs included, but were not limited to, aortic root replacements and aortic wall repair. Bioglue was employed to induce hemostasis in 79 cases, tissue adherence in 21 and tissue strengthening in 30. It was concluded that Bioglue was a very effective reagent in these procedures. It was found to be versatile and reliable, with a rapid hemostatic time, and bound solidly to tissues [43].

One of the functions of biological sealants is to facilitate the adherence of separated tissues, as with a dissected aneurysm. In these cases, Bioglue is carefully applied between the two layers and the false lumen is closed [44]. Bioglue may be quite efficacious in the repair of aortic dissections; however, it is not without risks. As reported by Modi et al., a 57-year-old man treated for an aortic dissection with Bioglue appeared to have no immediate problems, but returned to the emergency room 3 months later with unstable angina and angiogram that revealed a severe ostial left coronary stenosis. It was concluded that Bioglue had leaked from the aorta into the ostium, which caused an inflammatory response due to glutaraldehyde, resulting in fibrosis and stenosis [45].

The use of Bioglue is not recommended for pediatric use as the glutaraldehyde that is combined with the bovine serum albumin produces an inelastic seal. Ten 4-week-old piglets underwent primary aortic anastomoses, of which five obtained Bioglue reinforcement, and after 7 weeks, the lumens of the aortas were compared. The animals treated with Bioglue had aorta lumen diameters of 1.5 cm compared to the control group, which had lumen diameters of 2.7 cm (p = 0.054). In addition, all Bioglue-treated animals had fibrosis, whereas none was present for the controls (p = 0.008) [46]. The authors concluded that BioGlue reinforcement impaired vascular growth and caused stricture when applied to aorto-aortic anastomatoses.