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Ann Thorac Surg 1998;66:482-486
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Vivostat system autologous fibrin sealant: preliminary study in elective coronary bypass grafting

^a Department of Cardiothoracic Surgery, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

Accepted for publication March 27, 1998.

Address reprint requests to Dr Kjaergard, Department of Cardiothoracic Surgery, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark

	Abstract

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Background. The Vivostat System is a medical device for the preparation of an autologous fibrin sealant from 120 mL of the patient’s blood in the operating room. The system is fully automated and microprocessor controlled and is made up of three components: an automated processor unit, an automated applicator unit, and a disposable, single-patient–use unit, which includes a preparation set and a Spraypen applicator. The biochemical process is initiated by batroxobin, which acts upon the fibrinogen in the patient’s plasma. The completion of the process depends entirely on endogenous thrombin in producing the sealant.

Methods. Twenty-four volunteer patients undergoing elective primary coronary artery bypass grafting were randomized to either conventional hemostasis (control group) or the use of Vivostat fibrin sealant as an adjunct to conventional hemostasis. The patients were followed up at 1 month and 1 year.

Results. The preparation process was completed in 30 minutes. No safety issues associated with the use of the sealant were identified. From 120 mL of the patient’s blood the yield of fibrin sealant was 4.5 mL (range, 3.9 to 4.8 mL). There was a favorable trend toward lower amounts of chest tube drainage in the Vivostat group. In the Vivostat group, 1 of 11 patients (9%) required a perioperative transfusion and in the control group 3 of 12 patients (25%) required a perioperative transfusion.

Conclusions. It is possible to prepare autologous fibrin sealant with the Vivostat system in 30 minutes. No exogenous thrombin is required. The sealant has no known adverse effects and may prove to be a useful adjunct to hemostasis in cardiothoracic surgery.

	Introduction

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Since the early days of surgery there has been interest in using various forms of sealants as adjuncts to conventional means of achieving hemostasis. Many synthetic materials and biological glues have been developed. Synthetic fabrics can produce significant foreign body reactions in tissue, and the biological glues prepared from pooled human donor plasma have an inherent risk of transmission of blood-borne disease [1]. They have the additional disadvantage of requiring the local administration of high-dose exogenous thrombin of either bovine or human origin. The Vivostat System is a medical device for the preparation of an autologous fibrin sealant in the operating room. This system is being developed by ConvaTec of Skillman, New Jersey (a Bristol-Myers Squibb Company). The purpose of this study is to report a study of the Vivostat System done in patients undergoing primary elective coronary artery bypass grafting (CABG).

	Patients and methods

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
This was a prospective, randomized, single-blind, parallel group study evaluating the use of the Vivostat System-produced fibrin sealant as an adjunct to hemostasis versus the use of traditional methods of hemostasis alone (sutures, clips, and electrocautery) in patients undergoing primary elective CABG. The Scientific Ethical Committee of Copenhagen County approved this study on May 14, 1996.

Twenty-four volunteer patients were admitted for elective CABG. The mean age of the patients was 62.4 years (range, 44 to 77 years). Mean weight was 84.6 kg, mean height was 175 cm, and 91% of the patients were male. After providing informed consent, patients were enrolled and randomized to one of two groups. Group I received Vivostat-derived autologous fibrin sealant as an adjunct to conventional hemostasis. Group II, the control group, received conventional hemostasis alone. Patient characteristics were noted and are reported in the Results section.

Inclusion criteria
The following inclusion criteria were considered:

Age between 18 and 80 years

Coronary artery disease demonstrated by arterio gram

Suitable candidate for CABG with a maximum of five distal anastomoses

Cleveland Clinic Severity Score of 3 or less

Preoperative plasma fibrinogen level of greater than 2 mg/mL

Having a cardiac operation for the first time

Harvesting of the left internal mammary artery re quired

Clotting studies within the normal range

Written informed consent provided

Exclusion criteria
The following were the exclusion criteria used:

Severe diffuse left ventricular impairment with con gestive heart failure

Platelet count less than 125,000/µL

Previous heart operation

Previous intracoronary interventional therapy such as angioplasty or placement of a stent

Infusion of thrombolytic agent

Use of artificial conduits or radial or epigastric artery

Significant concurrent renal, hepatic, or pulmonary disease

History of psychiatric disease

Requirement of intraaortic balloon pump or assist device

Coronary endarterectomy

Associated surgical procedure such as valve replace ment

Ingestion of aspirin, warfarin, or other vitamin K antagonists or low-dose heparin within 1 week

Intraoperative infusion of aprotinin

Prior treatment with fibrin sealant or batroxobin

Pregnancy or lactation

High risk for human immunodeficiency virus or hepatitis

The Vivostat System
The system is fully automated and microprocessor controlled and comprises three components. The first is the automated processor unit (Fig 1), a nonsterile, reusable, fully automated, microprocessor-controlled electromechanical device that drives and controls the biochemical process that takes place within the disposable preparation unit (Prep Unit). It is that biochemical process that prepares a concentrated fibrin I solution from whole blood. The second element is the automated applicator unit, a nonsterile, reusable, microprocessor-controlled electromechanical device, which houses the fibrin I and buffer cartridges and feeds those solutions into the application pen through a multilumen catheter. The third component is a disposable single-patient–use unit, a disposable single-use patient kit, which contains everything needed to prepare and apply the Vivostat sealant. This includes a preparation set into which blood is collected and in which the biochemical process that produces the fibrin I solution takes place, and an application pen (Fig 2) through which the fibrin sealant is dispensed onto the tissues being treated.

View larger version (101K): [in this window] [in a new window]   Fig 1. The Vivostat System for the automated preparation of autologous fibrin sealant in the operating room in 30 minutes.

View larger version (95K): [in this window] [in a new window]   Fig 2. The Spraypen system in use in cardiac operations. It allows the surgeon to spray the solution evenly over the target tissue in a controlled fashion. The sealant polymerizes immediately upon application and crosslinks over several minutes.

First, 120 mL of the patient’s blood is drawn and mixed with 17 mL of 4% trisodium citrate USP for anticoagulation. Blood is collected by gravity drainage directly into the Prep Unit, either by direct venipuncture or through an existing intravenous line. The Prep Unit is then placed into the processor and the automated processing begun. Rapid Cycle Centrifugation results in the isolation of about 60 mL of platelet-poor plasma, which is reacted with biotin-batroxobin for 10 minutes at 37°C. The biotin-batroxobin catalyzes the release of fibrinopeptide A only from fibrinogen and does not activate factor XIII. This results in the formation of a fibrin I polymer that is acid soluble. The fibrin I polymer is isolated by further centrifugation and dissolved in 3.5 mL 0.2 mol/L sodium acetate buffer (pH4). Avidin, covalently bound to argarose, is added to the solution, which complexes with the biotin-batroxobin, and the biotin-batroxobin:avidin-agarose complexes are then separated from the fibrin I solution by filtration. By this process, greater than 99% of the complexed biotin-batroxobin:avidin-agarose is removed.

A vial containing the purified concentrated fibrin I solution is then transferred to the applicator unit. A syringe within the applicator unit contains 1.0 mL of 0.75 mol/L carbonate/bicarbonate buffer (pH10). The two solutions are administered simultaneously and intimately mixed during the application process in a 7:1 ratio (fibrin I:pH10 buffer). At the resulting neutral pH, in the presence of calcium ions, endogenous prothrombin is converted to thrombin, and the endogenous thrombin causes fibrinopeptide B to be cleaved from fibrin I to form fibrin II. Thrombin also activates endogenous Factor XIII, which acts upon the acid-soluble fibrin II polymer to form a chemically stable cross-linked fibrin II polymer that is a clinically useful fibrin sealant. The Spraypen applicator allows the solution to be spread evenly over the target tissue. Small amounts of sealant can thus be accurately delivered in small increments. The sealant polymerizes on contact and sets over several minutes.

As the system is presently designed, no components of the collected 120 mL of blood can be returned to the patient. A future design of the system is planned that will make it possible to salvage the collected red blood cells and return them to the patient. Other planned modifications of the system may make it possible to collect a platelet-rich, rather than a platelet-poor, plasma.

All required biocompatibility and bioburden tests have been done on the system, and no safety issues were discovered.

Operation
Doctor Kjaergard operated on all patients. A pulmonary artery catheter (Swan-Ganz) was inserted before the operation. The operative technique was the same in all cases, a standard CABG using the left internal mammary artery and greater saphenous vein grafts. Before cardiopulmonary bypass was initiated the patients were given 3 mg/kg heparin, which was reversed with protamine at the end of the operation. During the operation, additional heparin was administered when the activated clotting time fell to less than 480 seconds. The patients were cooled systemically to 32°C. The left internal mammary artery was harvested using electrocautery and all side branches were clipped. The left pleura were opened. Three drains were inserted: a pericardial drain, a retrosternal drain, and a left pleural drain. A system for autotransfusion of shed mediastinal and pleural blood was used postoperatively [3].

Application of fibrin sealant
The total produced volume of fibrin sealant was applied with a spray system at the end of the operation, after reversal of heparin with protamine. The sealant was applied at any bleeding sites after conventional hemostasis was performed. Additionally, it was applied at the anastomoses, the mammary artery pedicle, the mediastinum, and the sternal marrow.

	Results

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Baseline patient characteristics
The majority of patients had three-vessel coronary artery disease (73% in group I and 92% in group II). Both groups included subjects who had suffered previous myocardial infarctions (36% in group I and 33% in group II). The highest Cleveland Clinic severity score was 1 in group I (45% of patients) and 2 in group II (17% of patients). The baseline laboratory data were similar in both groups. The majority of patients (92%) in the groups were being treated with medications before the day of the operation.

Survival and adverse events
None of the patients died. A total of 47 adverse events were recorded, 20 in group I and 27 in group II. The most frequent adverse event was atrial fibrillation (11 incidents, five in group I and six in group II). Five occurrences of anemia (two in group I and three in group II) followed this. Five patients had pleural effusions (2 in group I and 3 in group II). Three patients had pneumothoraces (2 in group I and 1 in group II). Other adverse events were mild and recorded only once or twice. Only one event was deemed to be serious, a case of pulmonary edema in a patient in group II.

Follow-up at 1 month
All patients were relieved of angina pectoris and were without any permanent injuries 1 month after the operation.

Follow-up at 1 year
All patients were alive and had resumed normal activity. One patient in group I had a recurrence of angina pectoris. A coronary angiogram revealed that two of five grafts were occluded. The patient refused reoperation and was doing well with medical treatment.

Transfusions
A total of 4 patients had postoperative blood transfusions, 1 in group I (9%) and 3 in group II (25%). A transfusion was administered if the hematocrit fell to less than 25%.

Chest tube drainage
Total chest tube drainage was recorded from the time of chest tube placement until the chest tubes were removed. Chest tubes were removed after the measured output was less than 30 mL/h for 3 hours. The volume of drainage ranged from 420 to 1,765 mL in group I and 200 to 3,200 mL in group II (mean, 887 mL in group I and 1,089 mL in group II; median 720 mL in group I and 733 mL in group II). These differences were not statistically significant (p > 0.4).

Reoperations
No patients were reoperated on for bleeding. One patient in group II underwent two reoperations, the first for a repair of a defect in the thoracic fascia, followed 2 days later by open insertion of a pericardial drain for a pericardial effusion.

Withdrawals
One subject in group I was withdrawn. Although the fibrin sealant was successfully prepared, it was not applied because of accidental spillage.

Volume of fibrin sealant
The mean volume of fibrin sealant produced from 120 mL of the patient’s blood was 4.5 mL (n = 11; range, 3.9 to 4.8 mL).

	Comment

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
The use of fibrin sealant in cardiothoracic surgery was pioneered in the mid-1970s. Today, fibrin sealant is used primarily as a hemostatic and adhesive agent, and as a sealant of pulmonary air leaks. An initial concern with fibrin sealant was that it might lead to dense adhesions; however, it may in fact decrease them [4, 5]. The number of controlled clinical studies of fibrin sealant is increasing, with the majority of the reports showing a beneficial effect of fibrin sealant [6]. In the United States fibrin sealants were briefly available commercially, but were withdrawn from the market after the Food and Drug Administration ruling in 1978 banning products derived from pooled human fibrinogen [7]. Although the risk is small, there is a potential for transmission of infectious agents, especially viruses. The use of exogenous thrombin, especially of bovine origin, in high doses is also associated with a risk, as some of the products may contain factor V or other impurities. In a number of patients, antibodies to both human and bovine factor V have developed, which may result in a severe bleeding diathesis if exogenous thrombin is used a second time [8–10]. An additional adverse reaction that has been observed when fibrin sealant (composed of bovine thrombin and cryoprecipitate) is injected into the bleeding parenchymal tissue of trauma victims is immediate severe hypotension [11]. This may be due in part to various impurities in some thrombin preparations and to the high concentrations that are often administered to patients in the United States, where this type of fibrin sealant is widely used [9]. In addition, cryoprecipitate is not virally inactivated and has a variable fibrinogen concentration. The concentration of fibrinogen in these preparations also varies widely because of the preparation procedures employed and variable plasma fibrinogen levels in the donated blood, which can vary both physiologically and pathologically (a typical range is 2 to 6 mg/mL) [12]. Such differences directly affect the properties and performance of the resultant homemade fibrin sealant. The Vivostat System overcomes the potential infective and antigenic risks associated with the use of currently available fibrin sealant. The system relies only upon endogenous thrombin for polymerization of the final sealant, as no exogenous thrombin is added.

This study using Vivostat in humans was performed in volunteer CABG patients, because first-time CABG is a safe procedure with a mortality in this institution of less than 1%. Also, the patients are observed for at least 18 hours in an intensive care unit, where eventual serious adverse events may be detected [3].

The results of this study using a Vivostat prototype demonstrate that an autologous fibrin sealant can be prepared in the operating room in 30 minutes with a stable concentration (about 20 mg/mL) and volume of sealant. The acidified fibrin I solution may be kept at room temperature for up to 8 hours before application without a loss of sealant effectiveness (unpublished data, ConvaTec).

The results also indicate that the sealant is without risk to the patient. None of the patients died, and the adverse events noted were similar in both groups and were of the type expected after conventional CABG. One patient in the control group who was readmitted with pulmonary edema went on to make a full recovery after resumption of administration of diuretic agents.

The number of patients included in this pilot and safety study is too small to make a valid conclusion regarding the efficacy of autologous fibrin sealant in first-time CABG patients; however, there was a trend towards reduction of the volume of drainage and the number of transfusions, favoring the fibrin sealant group. We would not suggest that chest tube drainage is equivalent to blood loss. Furthermore, if one adds the 120 mL of blood withdrawn for the preparation of fibrin sealant to total fluid loss in group I, the mean fluid loss for that group would be 1,007 mL, very similar to the mean fluid loss in group II (1,089 mL). Other investigators who have performed controlled studies by anterior mediastinal spray application of fibrin sealant in patients undergoing first-time CABG found a reduction in postoperative drainage [13, 14]. The reduction in bleeding did not exceed 300 mL, however, which is most often not clinically significant, as this amount may not increase the requirement for blood transfusions. Also, the use of autotransfusion systems may halve the need for blood transfusions [3]. In patients reoperated for CABG, on the other hand, fibrin sealant may reduce postoperative blood loss and decrease the incidence of emergency resternotomy [15]. This very small study was designed to be a safety study, and not intended to assess effectiveness end points. We did note, however, that only 1 of 11 Vivostat patients required a transfusion whereas 3 of 12 control patients required a transfusion. Although we would not contend that this observation could be regarded as anything more than anecdotal, it did encourage us to evaluate this endpoint in a subsequent appropriately designed and sized study. The planned study will be a multicenter study and will include reoperative coronary bypass patients as well as patients having a primary operation.

In this study patients taking aspirin, heparin, and warfarin-type drugs were excluded. Since this study was done, other studies have shown that the Vivostat System produced fibrin sealant that can be successfully prepared from donors who are taking aspirin or heparin (unpublished data, ConvaTec). A study is currently being conducted to evaluate the use of the Vivostat System in patients taking warfarin-type drugs.

A nurse or perfusionist may readily prepare the autologous fibrin sealant produced by the Vivostat System. We believe it has a large potential in surgery, and applicators for endoscopic surgery are being developed. The prototype used in this study has been improved to increase and stabilize the fibrin concentration in the sealant.

The Vivostat System is not now commercially available. Multicenter pivotal studies are being conducted to support applications for regulatory approval in the United States, Europe, and Japan.

	Footnotes

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Doctor Trumbull is Medical Director, Advanced Technology Development, for ConvaTec, the Bristol-Myers Squibb company developing the Vivostat System. Doctor Kjaergard is an independent investigator who received no personal payment for his participation in this study. Only study-related expenses were paid by ConvaTec.

	References

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 

1. Basu S., Marini C.P., Bauman F.G., et al. Comparative study of biological glues: cryoprecipitate glue, two-component fibrin sealant, and "French" glue. Ann Thorac Surg 1995;60:1255-1262.[Abstract/Free Full Text]
2. Kjaergard H.K., Fairbrother J.E., Cederholm-Williams S.A., Edwardson P.A.D., Hollingsbee D.A., Holm N.E. The Vivostat system for the automated preparation of autologous fibrin sealant. Cardiovasc Eng 1997;2:204-206.
3. Schmidt H., Mortensen P.E., Følsgaard S.L., Jensen E.A. Autotransfusion after coronary artery bypass grafting halves the number of patients needing blood transfusion. Ann Thorac Surg 1996;61:1177-1181.[Abstract/Free Full Text]
4. McCarthy P.M. Fibrin glue in cardiothoracic surgery. Transfus Med Rev 1993;7:173-179.[Medline]
5. Borris W.J., Gu J., McGrath L.B. Effectiveness of fibrin sealant in the reduction of postoperative intrapericardial adhesions. J Invest Surg 1996;9:327-333.[Medline]
6. Kjaergard H.K., Fairbrother J.E. Controlled clinical studies of fibrin sealant in cardiothoracic surgery—a review. Eur J Cardiothorac Surg 1996;10:727-733.[Abstract]
7. Food and Drug Administration. Revocation of fibrinogen licenses. FDA Drug Bulletin 1978;8:15.
8. Berruyer M., Amiral J., French P., et al. Immunization by bovine thrombin used with fibrin glue during cardiovascular operations: development of thrombin and factor V inhibitors. J Thorac Cardiovasc Surg 1993;105:192-197.
9. Jackson M.R., MacPhee M.J., Drohan W.N., Alving B.M. Fibrin sealant: current and potential clinical applications. Blood Coagulation and Fibrinolysis 1996;7:737-746.[Medline]
10. Muntean W., Zenz W., Edlinger G., Beitzke A. Severe bleeding due to factor V inhibitor after repeated operations using fibrin sealant containing bovine thrombin. Throm Haemost 1997;77:1223.[Medline]
11. Ochsner M.G., Maniscalco-Theberge M.E., Champion H.R. Fibrin glue as a hemostatic agent in hepatic and splenic trauma. J Trauma 1990;30:884-887.[Medline]
12. Pisciotto P.T., Anderson K.C., Goodnough L.T., et al. The need for standardization of cryoprecipitate-derived fibrin adhesive. Transfusion Sci 1993;14:291-294.[Medline]
13. Spotnitz W.D., Dalton M.S., Baker J.W., Nolan S.P. Reduction of perioperative hemorrhage by anterior mediastinal spray application of fibrin glue during cardiac operations. Ann Thorac Surg 1987;44:529-553.[Abstract]
14. Tanemoto K., Hata T., Tsushima Y., Konaga E. Use of fibrin glue at the anterior mediastinum to reduce postoperative drainage in cardiac surgery. J Jpn Assoc Thorac Surg 1998;26:942-946.
15. Rousou J., Gonzalez-Lavin L., Cosgrove D., et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. J Thorac Cardiovasc Surg 1989;97:194-203.[Abstract]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Henrik K. Kjaergard Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kjaergard, H. K. Articles by Trumbull, H. R. Search for Related Content PubMed PubMed Citation Articles by Kjaergard, H. K. Articles by Trumbull, H. R.