Variance estimation for the Kappa statistic in the presence of clustered data and heterogeneous observations.

We present a methodology motivated by a controlled trial designed to validate SPOT GRADE, a novel surgical bleeding severity scale. Briefly, the study was designed to quantify inter- and intra-surgeon agreement for characterizing the severity of surgical bleeds via a Kappa statistic. Multiple surgeons were presented with a randomized sequence of controlled bleeding videos and asked to apply the rating system to characterize each wound. Each video was shown multiple times to quantify intra-surgeon reliability, creating clustered data. In addition, videos within the same category may have had different classification probabilities due to changes in blood flow rates and wound sizes. In this work, we propose a new variance estimator for the Kappa statistic, for use in clustered data as well as heterogeneity among items within the same classification category. We then apply this methodology to data from the SPOT GRADE trial.

Prospective, multicenter, randomized, controlled trial evaluating the performance of a novel combination powder vs hemostatic matrix in cardiothoracic operations.

AIM: This trial compared the hemostatic performance of a novel combination powder (CP) to a control hemostatic matrix (HM) in cardiothoracic operations. METHODS: Patients meeting eligibility criteria were enrolled after providing informed consent. Subjects were randomized intraoperatively to receive CP (HEMOBLAST Bellows; Biom'up, France) or HM (FLOSEAL Hemostatic Matrix; Baxter Healthcare Corporation, Hayward, CA). Bleeding was assessed using a clinically validated, quantitative bleeding severity scale. The primary endpoint was total time to hemostasis (TTTH), from the start of device preparation, as an indicator of when a surgeon asks for a surgical hemostat until hemostasis was achieved. TTTH at 3 minutes was utilized for the primary analysis, while TTTH at 5 minutes was considered as a secondary endpoint. RESULTS: A total of 105 subjects were enrolled across four institutions. The primary efficacy endpoint for the superiority of CP relative to HM for success at achieving hemostasis within 3 minutes was met, with 64.2% of the CP group achieving hemostasis compared with 9.6% of the HM group, a difference of 54.54% (37.4%-71.6%; P < .001 for superiority). The secondary efficacy endpoint was also met, with 92.5% of the CP group achieving hemostasis at 5 minutes versus 44.2% in the HM group, a difference of 48.2% (31.1%-65.4%; P < .001 for noninferiority). There were no device-related adverse events. CONCLUSIONS: In this multicenter, randomized, controlled trial, comparison of CP to HM revealed CP superiority and noninferiority for TTTH at 3 and 5 minutes, respectively.

Evaluation of the safety and efficacy of a new hemostatic powder using a quantitative surface bleeding severity scale.

AIMS OF THE STUDY: The safety and efficacy of a hemostatic powder (HP) versus a control agent, absorbable gelatin sponge and thrombin (G + T), were assessed, using a validated, quantitative bleeding severity scale. METHODS: Subjects were randomized to receive HP (256 subjects) or G + T (132 subjects) for treatment of minimal, mild, or moderate bleeding at 20 investigational sites. The primary efficacy endpoint was non-inferiority of HP relative to G + T for success at achieving hemostasis within 6 minutes. Secondary endpoints in rank order included: superiority of HP relative to G + T in mean preparation time; non-inferiority of HP relative to G + T for achieving hemostasis within 3 min; superiority of HP relative to G + T for achieving hemostasis within 6 min; and superiority of HP relative to G + T for success for achieving hemostasis within 3 min. RESULTS: A total of 388 subjects were included in the primary efficacy analysis. At 6 min, hemostasis was achieved in 93.0% (238/256) of the HP group compared to 77.3% (102/132) of the G + T group (non-inferiority P < 0.0001, superiority P < 0.0001). All secondary endpoints were met. Complications were comparable between treatment groups. CONCLUSIONS: HP had superior rates of hemostasis, shorter preparation time, and a similar safety profile compared to G + T in this prospective, randomized trial using quantitative bleeding severity criteria.

Hemostats, sealants, and adhesives III: a new update as well as cost and regulatory considerations for components of the surgical toolbox.

The hemostat, sealant, and adhesive components of the surgical toolbox continue to evolve and enter clinical practice at a rapid rate. The goal of this comprehensive, sequential review is to update these components to include those now available (February 2012) as well as to explore cost and regulatory factors that impact the development and use of these materials. A unique system of definitions for organizing these components based on group, category, and class is used as a means of improving the understanding and appropriate use of these materials. The system will be used here to present the most recent additions to the toolbox, which are evaluated based on safety, efficacy, usability, and cost. These new additions include pooled human plasma fibrinogen and thrombin embedded in an equine collagen patch for cardiac surgical hemostasis, polyethylene glycol (PEG) and human serum albumin for lung surgical pneumostasis, modified PEG and trilysine amine for spinal sealing, octyl and butyl lactoyl cyanoacrylate for vascular sealing, and a variety of octyl and butyl cyanoacrylates with or without dyes and/or polyester mesh for skin closure with the creation of a bacterial barrier. The system of definitions will also be used to clarify key strategies in the current health care environment for reducing costs and for increasing understanding of Food and Drug Administration regulatory decisions for these materials.

Evaluation of the Safety and Efficacy of a Novel Thrombin Containing Combination Hemostatic Powder Using a Historical Control.

This clinical study compares 2 hemostatic agents, a novel combination powder (CP) (HEMOBLAST™ Bellows) and an established polysaccharide starch powder (PP) (Arista™ AH) to assess the usefulness of CP. Retrospective comparative analysis of CP (July 2018 to July 2019, 68 patients) to PP (January 2011 to January 2013, 94 patients) in cardiothoracic patients was performed using linear regression models adjusting for age, sex, and procedure type for the endpoints: blood loss; protamine to skin closure time (hemostasis time); chest tube output and blood products required 48 hours postoperatively; ICU stay; postoperative comorbidities; and 30 day mortality. 162 patients (108 M: 54 F) underwent 162 cardiothoracic surgical procedures including: transplantation (n = 44), placement of ventricular assist device (n = 87), and others (n = 31). Use of CP compared to PP (Estimated Mean Difference [95% CI], P-value) produced significant reductions: blood loss (mL) (-886.51 [-1457.76, -312.26], P = 0.003); protamine to skin closure time (min) (-16.81 [-28.03, -5.59], P = 0.004); chest tube output (48 hrs, mL) (-445.76 [-669.38, -222.14], P < 0.001); packed red blood cell transfusions (units) (-0.98 [-1.56, -0.4], P = 0.001); and postoperative comorbidities (-0.31 [-0.55, -0.07], P = 0.012). There were no differences in the ICU stay (4.07 [-2.01, 10.15], P = 0.188) or 30-day mortality (0.57 [0.20, 1.63], P = 0.291). The use of CP in complex cardiothoracic operations resulted in improved hemostasis and significant clinical benefits in blood loss, transfusion requirements, morbidity, and time in operating room.

Fibrin sealant: past, present, and future: a brief review.

BACKGROUND: Fibrin sealant is a two-component topical hemostat, sealant, and tissue adhesive consisting of fibrinogen and thrombin that has been used in the United States as a blood bank- or laboratory-derived product since the 1980s and has been commercially available since 1998. METHODS/RESULTS: Initially, surgeons employed hospital-based materials because of the lack of availability of a commercially produced agent. At present, there are five U.S. Food and Drug Administration (FDA)-approved forms including products derived from pooled or autologous human plasma as well as bovine plasma. On-label indications include hemostasis, colonic sealing, and skin graft attachment. Recent clinical and experimental uses include tissue or mesh attachment, fistula closure, lymphatic sealing, adhesion prevention, drug delivery, and tissue engineering. CONCLUSIONS: The modern literature on fibrin sealant now exceeds 3000 articles and continues to expand. This brief review presents the history of this material, its present clinical use, and its future applications.

SPOT GRADE II: Clinical Validation of a New Method for Reproducibly Quantifying Surgical Wound Bleeding: Prospective, Multicenter, Multispecialty, Single-Arm Study.

The SPOT GRADE (SG), a Surface Bleeding Severity Scale, is a unique visual method for assessing bleeding severity based on quantitative determinations of blood flow. This study assessed the reliability of the SG scale in a clinical setting and collected initial data on the safety and efficacy of HEMOBLAST Bellows (HB), a hemostatic agent, in abdominal and orthopedic operations. Twenty-seven patients were enrolled across 3 centers and received the investigational device. Bleeding severity and hemostasis were independently assessed by 2 surgical investigators at baseline and at 3, 6, and 10 minutes after application of HB and compared for agreement. The mean paired κ statistic for assignment of SG scores was .7754. The mean paired κ statistics for determining eligibility for participation in the trial based on bleeding severity and the mean paired κ statistics determining the presence of hemostasis were .9301 and .9301, respectively. The proportion of patients achieving hemostasis within 3, 6, and 10 minutes of HB application were 50.0%, 79.2%, and 91.7%, respectively. There were no unanticipated adverse device effects and one possible serious adverse device effect, as determined by the Independent Data Monitoring Committee (IDMC). The reliability of the SG scale was validated in a clinical setting. Initial data on the safety and efficacy of HB in abdominal and orthopedic operations were collected, and there were no concerns raised by the investigators or the IDMC.

The SPOT GRADE: A New Method for Reproducibly Quantifying Surgical Wound Bleeding.

STUDY DESIGN: Benchtop model with prospective surgeon video testing. OBJECTIVE: To create a surface bleeding severity scale, the SPOT GRADE (SG), for quantitative assessment of target bleeding site (TBS) blood loss. This is of particular interest for spinal surgery due to epidural bleeding and an inability to use diathermy and radiofrequency cautery close to nerve roots. SUMMARY OF BACKGROUND DATA: A novel apparatus perfusable at known flow rates and simulating different sized wounds was used to create movies to educate surgeons on specific degrees of bleeding. METHODS: Training (36) and testing (108) videos were created using a benchtop apparatus employing different bleeding severities based on the six-level SG (none, minimal, mild, moderate, severe, and extreme) and TBS sizes (1, 10, and 50 cm). Fourteen surgeons in four specialties (cardiothoracic, abdominal, spine, and orthopedic lower extremity) were trained and tested to evaluate SG characteristics including inter-rater and intrarater reliability. RESULTS: The interclass correlation coefficient was estimated to be 0.89840 (95% confidence interval [CI]: 0.85771, 1), whereas the intraclass correlation coefficient was estimated to be 0.93673 (95% CI: 0.89603, 1). In 98% of cases (95% CI: 0.9736, 0.9927), surgeons correctly identified eligible bleeds for a future clinical trial (scores = 1, 2, or 3) and in 91% of cases (95% CI: 0.8895, 0.9344), surgeons correctly identified noneligible bleeds (scores = 4 or 5). In 98.6% of cases (95% CI: 0.9777, 0.9945), physicians correctly identified true hemostasis (score = 0). Based upon these data the probability of a physician rating a bleed incorrectly as hemostasis (score = 0) is estimated to be 1.51% (95% CI: 0.0061, 0.0363). CONCLUSION: This SG is reproducible and reliable providing a basis for educating surgeons on TBS blood loss. It appears to be a new standard for evaluating wound blood loss. LEVEL OF EVIDENCE: 2.

Active and mechanical hemostatic agents.

Mechanical and active topical sealant and hemostatic agents are now available in several different forms. These agents have utility in a variety of settings as adjuncts to the control of surgical bleeding. As an example, they have been very important in improving the treatment of one of the most difficult of cardiovascular procedures, repair of acute aortic dissection. Research and development continues on potential new products. Improvements in the efficacy of these products as well as delivery systems and product safety will make these agents even better and more widely accepted.

Absorbable cyanoacrylate as a vascular hemostatic sealant: a preliminary trial.

No absorbable cyanoacrylate tissue adhesive for safe internal surgical use is available. This prospective multicenter preliminary study was designed to evaluate the safety and effectiveness of an investigational absorbable cyanoacrylate (IAC) as an adjunct to hemostasis in arteriovenous shunt (AVS) procedures for dialysis access. Consenting adults (10) underwent placement of expanded polytetrafluoroethylene (ePTFE) upper extremity vascular grafts for AVS access using continuous 5-0 or 6-0 polypropylene after heparinization (> or =3000 units i.v.). Arterial anastomoses were evaluated after sealing with IAC followed by 120 seconds of polymerization time. After vascular clamp removal, the mean time to hemostasis was 9.1 +/- 28.8 seconds. Additionally, 90 per cent (9/10) and 100 per cent (10/10) achieved hemostasis by 1 and 5 minutes, respectively. No patients required further adjunctive hemostatic measures. Adverse event safety data analysis through 12 weeks revealed occlusion of graft or vessel in four patients and graft thrombosis in one patient, all thought unrelated to sealant use. Other unrelated adverse events (bleeding, death, deep venous thrombosis, edema, erythema, hematoma, infection, and rash) occurred in single patients. Thus, IAC could be a useful sealant for vascular procedures with a potentially satisfactory safety profile. Larger, randomized, multicenter, prospective trials to further evaluate the use of this material are indicated and appropriate.

Fibrin sealant tissue adhesive--review and update.

The field of surgical tissue adhesives is rapidly developing, with multiple products now available. Fibrin sealant, the first widely available tissue adhesive, continues to be used in traditional as well as in new and creative ways. The product is now fully mature as a hemostatic agent in cardiac, liver, and spleen surgery. It is also useful as a sealant in a variety of clinical applications, including procedures such as colonic anastomosis, as well as in seroma prevention following soft tissue dissection. Newer uses such as reduced suture vascular and intestinal anastomosis, fistula closure, surgery in patients with hemophilia, and laparoscopic/endoscopic procedures are being studied in both laboratory and clinical settings. The most recent additions to the capabilities of fibrin sealant include the use of this tissue adhesive as a slow-release drug delivery system and as a substrate for cellular growth and tissue engineering. This article will review the basis of fibrin sealant effectiveness and will also cover the recent developments in the rapidly evolving employment of this material.

Left ventricular dysfunction after pericardiectomy for constrictive pericarditis.

A 56-year-old man was admitted to our hospital with a diagnosis of suspected constrictive pericarditis. After the diagnosis was confirmed by cardiac catheterization, an elective pericardiectomy was performed without complication. Four days after surgery dyspnea developed in the patient, and he was found to have an acute decrease in left ventricular ejection fraction (LVEF) by echocardiography. The patient's symptoms and the LVEF improved over time and returned to normal 4 weeks after surgery. Transient hemodynamic dysfunction of the left ventricle has previously been reported after pericardiectomy or pericardiocentesis; however, we know of no reports in the literature that confirm an acute reduction in LVEF by echocardiography after pericardiectomy for constrictive pericarditis.

Fibrin sealant facilitates hemostasis in arteriovenous polytetrafluoroethylene grafts for renal dialysis access.

A prospective randomized study was performed to evaluate the efficacy of fibrin sealant (FS) in patients undergoing upper-extremity polytetrafluoroethylene (PTFE) graft placement for dialysis. This procedure appears to be a reproducible and clinically relevant model for evaluating FS in vascular surgery. Consenting adult patients (n = 28) undergoing placement of a PTFE graft (6 mm) were randomized to either the treatment group using FS (Hemaseel APR, Haemacure Corp., Sarasota, FL) or control comparator groups (four) of bovine thrombin (T) (Thrombogen, GenTrac Inc., Middleton, WI), pressure (P), bovine thrombin (Thrombogen, GenTrac Inc.) -soaked cellulose sponges (TG) (Gelfoam, Upjohn Co., Kalamazoo, MI), or oxidized regenerated cellulose (S) (Surgicel, Johnson & Johnson, New Brunswick, NJ). All patients received heparin (3000 IU intravenous push) before placement of vascular clamps. The mean time to hemostasis was 29.3 seconds for FS, 147.4 seconds for T, 872.2 seconds for P, 346 seconds for TG, and 1044.5 seconds for S. There were no significant adverse events. FS appeared to be a superior hemostatic agent in these vascular procedures. No complications from FS were noted.

Experience improves successful use of fibrin sealant in total knee arthroplasty: implications for surgical education.

This study evaluating fibrin sealant application in total knee arthroplasty (TKA) found significant differences in the decline in adjusted hemoglobin loss at 48 hours postoperatively in the treatment group (FS) relative to the control group (C) when the groups were segregated into early and late subgroups. The decline between the late C, 3.53 +/- 0.22 g/dL, and the late FS, 3.01 +/- 0.20 g/dL, was 0.52 g/dL (p = 0.04). The decline between the early C, 3.51 +/- 0.21 g/dL, and the early FS, 3.25 +/- 0.22 g/dL, was 0.26 g/dL (p = 0.34). This study demonstrates the importance of experience and education in successful application of tissue adhesives.

Fibrin sealant reduces perioperative blood loss in total hip replacement.

Patients (n = 81) undergoing total hip replacement (THR) were randomized to receive either standard of care plus fibrin sealant (FS) (10 mL total) or standard of care alone to evaluate the efficacy of FS for reducing blood loss in THR. Considering the 81 intent-to-treat patients, adjusted perioperative blood loss was reduced significantly in the FS group, by 197 mL [95% CI: 45 mL, 319 mL] or 23.5% [95% CI: 5.4%, 38.1%] (p = 0.014). When protocol violators were eliminated, leaving 73 patients, the adjusted FS group perioperative bleeding was reduced by 221 mL [95% CI: 63 mL, 351 mL] or 27.1% [95% CI: 7.6%, 42.5%] (p = 0.0098).

Fibrin Sealant: The Only Approved Hemostat, Sealant, and Adhesive-a Laboratory and Clinical Perspective.

Background. Fibrin sealant became the first modern era material approved as a hemostat in the United States in 1998. It is the only agent presently approved as a hemostat, sealant, and adhesive by the Food and Drug Administration (FDA). The product is now supplied as patches in addition to the original liquid formulations. Both laboratory and clinical uses of fibrin sealant continue to grow. The new literature on this material also continues to proliferate rapidly (approximately 200 papers/year). Methods. An overview of current fibrin sealant products and their approved uses and a comprehensive PubMed based review of the recent literature (February 2012, through March 2013) on the laboratory and clinical use of fibrin sealant are provided. Product information is organized into sections based on a classification system for commercially available materials. Publications are presented in sections based on both laboratory research and clinical topics are listed in order of decreasing frequency. Results. Fibrin sealant remains useful hemostat, sealant, and adhesive. New formulations and applications continue to be developed. Conclusions. This agent remains clinically important with the recent introduction of new commercially available products. Fibrin sealant has multiple new uses that should result in further improvements in patient care.

Hemostats, sealants, and adhesives: a practical guide for the surgeon.

Hemostats, sealants, and adhesives are useful adjuncts to modern surgical procedures. To maximize their benefit, a surgeon needs to understand the safety, efficacy, usability, and cost of these agents. To be truly added to a surgeon's own toolbox, the operator must also have knowledge of when and how to best use these materials. This commentary is designed to succinctly facilitate this understanding and knowledge. A nomenclature and classification system based on group, category, and class has been created to help with this process and is provided here. By using this system, materials consisting of similar design and for common indications can be compared. For example, in this system, the three functional groups are hemostats, sealants, and adhesives. The hemostats may be divided into four categories: mechanical, active, flowable, and fibrin sealant. These hemostat categories are further subdivided into generic classes based on the composition of the approved materials. Similarly, categories and classes are provided for sealants and adhesives. In this commentary, the salient points with respect to the characteristics of these agents are presented. A discussion of when these agents can be used in specific indications and how they may be applied to achieve the best results is also provided.

Efficacy and safety of fibrin sealant for tissue adherence in facial rhytidectomy.

The purpose of this review is to clarify the present use of fibrin sealant in rhyditectomy procedures and help maximize the appropriate and safe application of this material. A set of terms and definitions for hemostats, sealants, and adhesives based on group, category, and class will be employed to highlight the specific capabilities of fibrin sealant. Fibrin sealant has now emerged as an example of maximizing the usefulness of a surgical agent and is the only product with Food and Drug Administration approval in all three groupings: hemostats; sealants; and adhesives. A variety of manufacturers' fibrin sealant products are available including multiple liquids and one patch. A single liquid product is now specifically indicated for skin flap adherence during rhytidectomy. The unique characteristic of this particular two component fibrin sealant adhesive agent is its slower polymerization rate as a result of a low thrombin concentration which when combined with fibrinogen permits adequate time for manipulation of flaps and tissues prior to final fixation. In addition to its flap adherence and potential space elimination capability, fibrin sealant is also an excellent blood clotting agent and can seal tissues to prevent lymphatic leak or serous fluid accumulation. Thus, it is almost ideally suited to reduce the occurrence of fluid accumulation, hematomas, ecchymoses, and swelling, as well as to possibly eliminate the need for drains following rhytidectomy. A literature review of fibrin sealant in rhytidectomy is included to help define the current state of its clinical use. The author's recommendations for the best use of this material during facial procedures are also provided.

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.

The goal of this submission is to describe how and when to best use hemostats, sealants, and adhesives as well as to compare their characteristics and to update the surgical toolbox with respect to any new products approved by the Food and Drug Administration (FDA) as of this date (November 2009). The materials will be presented in 3 major groups each containing specific categories: (1) hemostats; mechanical, active, flowable, and fibrin sealant, (2) sealants; fibrin sealant, polyethylene glycol polymer, and albumin and glutaraldehyde, (3) adhesives; cyanoacrylate, albumin and glutaraldehyde, and fibrin sealant. The categories will be used for comparisons based on safety, efficacy, usability, and cost. Recommendations with respect to how and when to best use these materials will be presented. A review of the recent literature is also provided with respect to the most recent uses of these materials in specific surgical specialties.