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Original Articles: Adult Cardiac

Prospective, Randomized Clinical Trial of the FloSeal Matrix Sealant in Cardiac Surgery

^a Cardiac Surgery Department, GVM Hospitals of Care and Research, Bari, Italy
^b Division of Cardiac Surgery, Centro di Ricerca e Formazione ad Alta Tecnologia nelle Scienze Biomediche, Catholic University of the Sacred Heart, Campobasso, Italy

Accepted for publication July 10, 2009.

^_* Address correspondence to Dr Nasso, Division of Cardiac Surgery, Anthea Hospital, Via Camillo Rosalba, 35-37, Bari, 70124, Italy (Email: gnasso{at}libero.it).

Dr Nasso discloses that he has a financial relationship with Baxter Biosurgery, Inc.

 

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background: Topical hemostatic agents composed of a gelatin-based matrix and thrombin have been reported to be effective, in addition to traditional means, in terminating bleeding during cardiac operations. We compared a hemostatic matrix sealant agent (FloSeal; Baxter Inc, Deerfield, IL) with alternative topical hemostatic agents in a mixed cohort of elective cardiac and thoracic aortic operations.

Methods: Following sample size calculation, in a prospective randomized study design, 209 patients were treated with FloSeal matrix sealant (FloSeal group) and 206 patients received alternative agents as topical hemostatic materials (comparison group). FloSeal is composed of a self-expandable gelatin matrix component and purified bovine thrombin. Comparisons included hemostatic patches or sponges composed of either oxidized regenerated cellulose or purified porcine skin gelatin. Study endpoints were the following: rate of successful intraoperative hemostasis (identified by cessation of bleeding) and time required for hemostasis; overall postoperative bleeding; rate of transfusion of blood products; rate of surgical revision for bleeding; postoperative morbidity; and intensive care unit stay.

Results: Statistically higher rates of successful hemostasis and shorter time-to-hemostasis were observed in the FloSeal group (p < 0.001 both). Time-to-event analysis confirmed this finding (p = 0.0025). Postoperative bleeding and rate of transfusion of blood products were statistically decreased in the FloSeal group (p < 0.001 both). Rates of revision for bleeding and of minor complications were not statistically different among groups in the overall cohort, but were significantly lesser in the FloSeal group if only patients with overt intraoperative bleeding are considered (p = 0.04 both). The advantages observed in the FloSeal group were not offset in patients undergoing systemic hypothermia.

Conclusions: The topical hemostatic agent used in the FloSeal group is effective in terminating intraoperative bleeding as an adjunct to traditional surgical methods for stopping bleeding. Its judicious use is associated with lesser need for transfusion of blood products and rate of revision for bleeding. Its cost-utility profile should be addressed in dedicated trials.

Hemostasis, a key tenet of any surgical procedure, is even more crucial in the cardiac surgery practice. High-pressure anastomoses and (or) suture lines within the cardiac chambers or the great vessels are created during virtually all cardiac surgical procedures. This renders the use of topical hemostatic agents, together with a meticulous operative technique, one major contributor to the safety of routine operations. In addition, heparinization for cardiopulmonary bypass, contact of blood with extracorporeal circulation tubing-oxygenator and systemic hypothermia in selected cases, contribute to a various degree of coagulopathy in most cardiac surgical patients [1]. Postoperative bleeding is a feared complication associated with transfusion of blood products, prolonged intensive care unit stay, need for surgical revision of hemostasis, and even increased mortality.

It has already been suggested in controlled trials that a topical hemostatic matrix surgical sealant (FloSeal; Baxter Biosurgery, Deerfield, IL), composed by a self-expandable gelatin-based matrix and purified bovine thrombin solution obtained from bovine plasma (product currently available in the European Union), is effective in stopping bleeding in patients subjected to cardiac operations [2]. It is versatile and can be adapted to various surfaces, including actively bleeding vascular anastomoses. FloSeal is reportedly useful even in other surgical specialties, including spinal surgery (98% of bleeding sites controlled within 10 minutes [3]), control of spontaneous supratentorial and intracerebral hemorrhages [4], control of bleeding in renal trauma and nephrectomy (enhanced renal parenchymal hemostasis [5, 6] and management of major collecting-system injury [7]), 100% hemostasis rate and excellent clot integration into the surrounding tissues in a swine model of liver and spleen rupture [8], 98% rate of successful hemostasis in a series of liver resection operations even in the setting of cirrhotic liver [9], and successful laparoscopic application after stripping of ovarian cyst [10]. Other studies have noticed no significant differences in the clinical results of gelatin matrix sealants with or without thrombin in the setting of partial nephrectomy [11]. Nonetheless, the previous investigations focused on cardiac surgery could not associate the use of topical surgical sealant with a significant decrease in the rate of postoperative bleeding-related complications, possibly due to insufficient sample size. The present prospective, controlled study was conducted with the aim to clarify the following: (1) whether FloSeal surgical sealant is effective in obtaining hemostasis in a cohort of mixed cardiac-thoracic aortic procedures versus control topical hemostatic agents; and (2) whether the routine use of FloSeal surgical sealant is associated with a decreased rate of postoperative bleeding-related complications within a sample size-controlled trial.

One randomized controlled trial has previously addressed the intraoperative efficacy of the FloSeal matrix sealant in stopping bleeding [2]. The present manuscript takes into analysis the perioperative and postoperative clinical outcome of patients treated with topical hemostatic agents.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
The local Ethical Committee approved the study protocol and the patients enrolled in the study received full information, were willing to enter the trial, and provided written informed consent.

Study outcome measures included the following: rate of successful intraoperative hemostasis and time required for hemostasis; overall postoperative bleeding (as measured by chest tube output and indexed for body surface area); rate of transfusion of blood products both intraoperatively and in the postoperative; rate of surgical revision for bleeding after initial transferal to the intensive care unit (ICU); and rate of postoperative morbidity and total length of ICU stay.

Patients Selection and Study Design
The clinical trial presented herein was designed in December 2005. On the basis of historic institutional data, sample size calculation indicated that a total of 356 study cases were required to detect with a 0.80 power a statistically significant difference between the treatment and the control group with respect to endpoint: overall postoperative bleeding; 381 study cases with respect to endpoint: rate of transfusion of blood products; and 363 cases with respect to endpoint: rate of surgical revision for bleeding (alpha level: 0.05).

Therefore, starting in January 2005 all patients undergoing cardiac surgery were screened at the time of hospital admission and enrolled according to the following inclusion criteria.

1 Scheduled for elective primary cardiac (coronary, valvular, or combined) and (or) thoracic aortic surgery. Patients undergoing cardiac reoperation were excluded.

2 Patients with known or suspected hypersensitivity reaction to any component of study products or to bovine-derived material, and patients undergoing repair of acute thoracic aortic dissection were excluded. Patients with known or suspected preoperative coagulation disorder were excluded.

After inclusion in the study, patients were randomized with the aid of a computerized algorithm to either the FloSeal group (use of FloSeal) or to the comparator group (control group, other topical hemostatic agents employed according to the surgeon's preference, among the following: Surgicel Nu-Knit absorbable hemostat [Ethicon Inc, Somerville, NJ] and Gelfoam 12 (Upjohn and Pharmacia, Kalamazoo, MI). The above were used as control topical hemostatic agents because they were already available in hospital formulary. Additionally, both Surgicel Nu-Knit and Gelfoam represent hemostatic patches-sponges that provide a mesh to support the patient's activated coagulation factors. Conversely, last-generation FloSeal contains human thrombin derived from pooled human plasma, and combines its biologic activity (activation of fibrinogen) with the mechanical support of a self-expanding granule matrix. Thus, this investigation essentially addresses the usefulness of combined biologic and mechanical activity versus mechanical activity alone of topical hemostatic agents. The study was performed under an "intention-to-treat" protocol.

The investigation was conducted within the Cardiac Surgery Division, Catholic University, Sede di Campobasso, Italy (University, multispeciality hospital setting) until December 2006 and afterward within the Cardiac Surgery Division, Anthea Hospital, Bari, Italy (Territorial, multispeciality hospital). One-way analysis of variance (ANOVA) was employed to disclose significant differences among baseline variables (as listed in Table 1) with respect to subgroups of patients obtained from each Institution. Clustering of data by site did not occur. Enrollment into the study was terminated in September 2008. The local Ethical Committees gave approval to the study protocol.

1 To any bleeding site (graft anastomosis edge, suture lines at the sites of atriotomy-aortotomy, thoracic aortic-vascular prosthesis anastomosis, muscular diffuse bleeding, undersurface of the sternum during the final hemostasis phase) regardless that bleeding was stopped or not by conventional means (electrocautery, direct pressure, suture ligation, stitch placement).

2 To any of the above sites (graft anastomosis edge, suture lines at the sites of atriotomy-aortotomy, thoracic aortic-vascular prosthesis anastomosis, muscular diffuse bleeding) even in the absence of active bleeding.

For the purpose of this study, we applied the following definitions. Time to hemostasis is the time required to obtain successful hemostasis for a single bleeding site; hemostasis time is the operative time comprised between the removal of cardiopulmonary bypass cannulae and the closure of the sternum.

Time to hemostasis at any bleeding point was measured and recorded by operative room nurses starting from application of FloSeal. Success or failure of hemostasis at any bleeding point was noticed by the operating surgeon and recorded by operative room nurses. According to the published literature, successful hemostasis was defined as hemostasis occurring by 10 minutes after application of the topical hemostatic agent. The operative time comprised between decannulation and the closure of the sternum was noticed also and recorded (defined as hemostasis time).

Comparator group patients were managed according to the same protocol with the use of alternative topical hemostatic agents (Surgicel Nu-Knit absorbable hemostat; Gelfoam 12). Hemostatic agents were applied only after full reversal of heparinization by protamine sulfate. One single reapplication of hemostatic agent was allowed.

Systemic hypothermia was indicated as the following: (1) in the aortic cases involving open distal aortic anastomosis or an arch procedure requiring circulatory arrest (moderate hypothermia: 22°C to 25°C rectal temperature); and (2) as an institutional protocol, in patients with known hemodynamically significant internal carotid artery disease and (or) past history of cerebrovascular accidents (mild hypothermia: 30°C to 32°C rectal temperature).

Collection of Data and Statistical Methods
Details of operation performed, duration of cardiopulmonary bypass, and intraoperative complications were recorded prospectively by the operative room nurses. Patients were followed-up by 96 hours postoperatively to track the following outcome complications: overall bleeding from chest tubes (as indexed per body surface area); need for surgical revision of hemostasis and for transfusion of blood products; amount of blood products transfused; onset of postoperative morbidity (including stroke, shock, sepsis, myocardial infarction, renal failure, respiratory insufficiency, prolonged inotropic support); and length of ICU stay. Data were entered into the database by surgical assistants at the time of discharge of patients from the hospital.

Data were prospectively entered in a computerized database and analyzed through SPSS software version 11.0.1 for Windows (SPSS Inc, Chicago, IL). Sample size calculation was performed through the PS software version 2.1.31 for Windows [13]. Continuous data are presented as mean ± standard deviation and compared through the Student t test. Categoric data are given as percentages and compared through the ² test. Tests were two-tailed and Yates correction was applied. Time-to-event analysis was performed by calculation of Kaplan-Meier estimates. For the purposes of the present investigation, bleeding from a specific site (as the response event) and the time to successful intraoperative hemostasis for the same site were included in the Kaplan-Meier calculations. Actuarial curves were compared with the log-rank test.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Study design is summarized in Figure 1. The two study groups were comparable with respect to baseline characteristics as outlined in Table 1. Isolated coronary surgery was the most frequent category of operation performed, but more complex operations (combined coronary and valvular surgery) associated with prolonged cardiopulmonary bypass time, and aortic operations requiring systemic hypothermia were performed in a substantial amount of cases. Systemic hypothermia was indeed employed in 21% of group 1 patients and in 20% of group 2 patients. Both hypothermia and prolonged cardiopulmonary bypass time have been associated with a variable degree of alteration of the coagulation cascade [14–16]. Study fallout was 5 patients (3 from the FloSeal group and 2 from the comparator group) who deceased within the 96th postoperative hour and hence did not complete the study follow-up.

View larger version (32K): [in this window] [in a new window]   Fig 1. Study design.

View larger version (23K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot: time to successful hemostasis for first bleeding site (entire study cohort). (Control group – –: = control, + = control-censored; FloSeal group —: = FloSeal, + = FloSeal-censored; * = log-rank test.)

View larger version (21K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot: time to successful hemostasis for first bleeding site (patients who underwent systemic hypothermia). (Control group – –: = control, + = control-censored; FloSeal group —: = FloSeal, + = FloSeal-censored; * = log-rank test.)

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

The present investigation indicates that the routine use of FloSeal is associated with a significantly higher rate of successful hemostasis and shorter time for achievement of hemostasis in comparison with control materials (gelatin sponges and oxidized cellulose). Such result is obtained in a global cohort of patients, including those not presenting major sites of intraoperative bleeding during the hemostasis phase. In the latter cases, topical hemostatic agents were applied to all potential sources of bleeding including coronary graft anastomoses and sites of cardiotomy. This policy may be questioned as an overtreatment and economically unjustified. Nonetheless, in the entire study cohort a significantly lower overall postoperative bleeding was observed. More importantly, a significantly lower rate of need for transfusion of blood products was noticed too, even though patients treated with FloSeal sealant in the absence of overt bleeding were included. Bleeding from any target site may indeed develop later during the earliest postoperative hours even though it was not apparent during the surgical hemostasis phase in the operative room.

If the only patients who were recorded to have intraoperative bleeding from any site are taken into analysis, the above intergroup differences become more striking. Additionally, patients in the FloSeal group display a statistically lower incidence of need for surgical revision of hemostasis and, interestingly, a slightly decreased incidence of minor postoperative morbidity. Such finding may be reasonably linked with the following: (1) the lower incidence of surgical reexploration and the decreased need for transfusion, both factors strongly associated with poorer postoperative course and occurrence of morbidity after cardiac surgery [14, 17]; and (2) better end-organ perfusion in the absence of significant early postoperative blood loss. These concepts may be corroborated by the finding that the duration of ICU stay was shorter among the FloSeal group patients who had intraoperative bleeding versus equivalent comparator group patients; although not statistically significant, this finding may have a clinical significance to be further addressed within larger patient series. While our sample size calculation was not tailored on the incidence of postoperative morbidity, the prospective, randomized design of the study renders a selection bias to this point unlikely. To support this idea the calculated European System for Cardiac Operative Risk Evaluation, the most widely adopted cardiac surgery risk stratification system [18], was comparable among the study groups.

Taking into analysis the patients who underwent mild-to-moderate systemic hypothermia for brain protection during cardiac surgery, still the advantages associated with the use of FloSeal are apparent (shorter hemostasis time and lower rate of surgical revision for bleeding). Nonetheless, the rate of transfusion of blood products was not statistically different among groups. Such discrepancy in comparison with the general cohort is probably linked with the different kind of transfusion performed. Packed red blood cells were more frequently transfused in the general cohort and among patients having intraoperative bleeding, on the basis of reduced hemoglobin level due to hemorrhage. Conversely, a substantial number of patients in the hypothermia subgroup received fresh frozen plasma and platelet transfusion on the basis of overt coagulopathy.

Although the present study did not include a formal cost-utility and cost-efficacy analysis, it is accepted that an efficient control of bleeding both intraoperatively and postoperatively contributes to the reduction of hospital costs by decreasing the need for blood transfusion, the requirements for additional treatments, and even the duration of ICU stay. Postoperative morbidity, which was found to be increased among comparator group patients, is associated with the need for additional pharmacologic treatments, employment of nurse time, and prolonged hospital stay. Similarly, revision for bleeding is an extra treatment with additional hospital costs (employment of personnel and operative room time) as far as clinical shortcomings (increased risk of wound infection). Dedicated cost-analysis papers can be devoted to this issue. Additionally, FloSeal does not contain bovine thrombin. This component may elicit immune response with antibody formation and cross-reaction with the host's coagulation factors, leading to rare cases of complex postoperative coagulopathies [12].

In conclusion, the present controlled trial indicates that the routine use of the FloSeal matrix sealant is efficient in terminating bleeding as an adjunct to basilar surgical hemostatic maneuvers in a sample size-controlled cohort of mixed cardiac procedures. Its cautious use may be justified on high-pressure anastomoses and cardiotomy suture lines even in the absence of overt bleeding. In our overall study cohort it is associated with shorter time for hemostasis and decreased need for blood transfusion and of surgical reexploration for bleeding. Such advantages are amplified if only the patients with important intraoperative bleeding are analyzed, and are not offset by the coexistence of factors facilitating bleeding such as the use of systemic hypothermia. No intraoperative or postoperative adverse events were referred to the use of the matrix sealant during the present investigation. This clinical study not only demonstrates the agent under investigation to be effective for hemostasis but translates this benefit to outcomes such as reduction in blood transfusion, revision for bleeding, ICU stay, and minor complications. Hospital decision-makers may be able to leverage these clinical outcomes and translate these benefits to actual cost savings within the context of their own hospital institution.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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): Giuseppe Nasso Felice Piancone Raffaele Bonifazi Vito Romano Giuseppe Visicchio Carlo Maria De Filippo Barbara Impiombato Francesco Alessandrini Giuseppe Speziale Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nasso, G. Articles by Speziale, G. Search for Related Content PubMed PubMed Citation Articles by Nasso, G. Articles by Speziale, G. Related Collections Extracorporeal circulation