Journal of the Association of PAs in Cardiothoracic and Vascular Surgery
Editor-in-Chief
Aaron R. Morton, DMSc, MMSc, PA-C, ATC, FAPACVS Emory University, Atlanta, GA
Associate Editor—International Vicky Vink PA Switzerland
Associate Editor Writer Development
Edward A. Ranzenbach, PA-C, MPAS, CAQ-CVTS, FAPACVS, DFAAPA Misenheimer, NC
Editorial Board
Cardiac Section Editor
Michael Lalonde, MHA, PA-C Branford, CT
Thoracic Section Editor
Matthew Vercauteren MPAS, PA-C, FAPACVS Pittsburgh, PA
Vascular Section Editor
Daniel Geersen MPAP, PA-C Morrisville, NC
Editorial Member at Large
Hantz B. Fontaine PA-C New York, NY
Publisher
David E. Lizotte, Jr. MPAS, PA-C, FAPACVS
Executive Director APACVS Festus, MO
EDITORIAL MISSION:
The JAPACVS is the official clinical journal of the Association of PAs in Cardiothoracic and Vascular Surgery. The mission of the JAPACVS is to improve Cardiac, Vascular and Thoracic Surgical and CVT Critical Care patient care by publishing the most innovative, timely, practice-proven educational information available for the physician assistant profession.
PUBLISHED CONTENT IN THE JAPACVS: Statements and opinions expressed in the articles and communications herein are those of the authors and not necessarily those of the Publisher or the Association of PAS in Cardiothoracic and Vascular Surgery (APACVS). The Publisher and the APACVS disclaim any responsibility or liability for such material, including but not limited to any losses or other damage incurred by readers in reliance on such content. Neither Publisher nor APACVS verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damage incurred by readers in reliance on thereon. Neither Publisher nor APACVS guarantees, warrants, or endorses any product or service advertised in this publication, nor do they guaranty any claim made by the manufacturer of such product or service.
APACVS
1208 Victoria Crossing Festus, MO 63028 Phone (502) 321-6155 admin@apacvs.org
JAPACVS/Journal of the Association of PAs in Cardiothoracic and Vascular Surgery is published quarterly (4 issues per volume, one volume per year) by APACVS 1208 Victoria Crossing, Festus, MO 63028. Volume 5, Number 1, Winter 2023. One year subscription rates: $40 in the United States and Possessions. Single copies (prepaid only): $20 in the United States
© 2024 APACVS, INC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including by photocopy, recording, or information storage and retrieval system, without permission in writing from the publisher.
Editorial
4 From the Editor’s Desk
Aaron R. Morton, DMSc, MMSc, PA-C, ATC, FAPACVS— Editor
-In-Chief
Peer Reviewed Content
8 Reduction of AKI in Adult Cardiothoracic Surgery
Dylan Ryan DMSc, PA-C
17 The Role of fibrin hemostatic sealants in cardiac surgery
Emily Mulee PA-C
APACVS is the only association representing Cardiac, Thoracic and Vascular Surgery and CTV Critical Care PAs. By PAs, For PAs!
Aaron R. Morton, DMSc, MMSc, PA-C, ATC, FAPACVS Editor-in-Chief
Welcome to the next instalment in my From the Editor’s Desk series on the benefit of membership with professional organizations. I sincerely hope the first installment was insightful and enlightening on the foundational benefits of education by a professional organization like the APACVS. Having a strong history of innovative educational offerings and supporting lifelong learning is the backbone of the APACVS. However, it is far from the only way the APACVS serves its members.
An effective professional organization provides not only sound and plentiful educational opportunities but also advocates for its members. The Merriam-Webster Dictionary defines advocate as “one who supports or promotes the interest of a cause or group.” The APACVS is the ONLY organization that advocates for our specialty and sub-specialty fields and has done so for over 40 years. During this time, we have had the opportunity to support many members and our specialty at large on a host of issues. Most often this advocacy is assisting with a local
or practice issue, as was the case when a hospital attempted to require PAs to have surgical technologist certification to operate in an OR. Other examples include pushing back against a state attempting to restrict PA surgical practice as well as ongoing efforts to modernize a decades old health code that specifies type participants in cardiac surgery as is the case with California Title 22. At times, it also includes working with federal governmental committees on CTV PA practice and billing issues or collaboration with other national organizations to advance our PA specialty practice.
National and local governmental and specialty group advocacy is foundational and often runs arm and arm with educational objections in professional organizations, however effective professional organizations lead progressive efforts to support members. Many are unaware of the APACVS’s strong history of progressively advocating for our members and specialty. Years before the current AAPA and NP public advertisements promoting the respective professions, the APACVS placed adds in multiple surgical journals advocating for the benefit of PA utilization. One such advertisement is attached within this issue of the JAPACVS. Some of our more senior readers will probably recognize it as it was run in multiple journals including the Annals of Thoracic Surgery. Please take a look at it and consider the messaging and its meaning. Does this still ring true today? Is this public effort of advocacy something that is still needed in our contemporary practice of medicine? Please reach out and let me know your thoughts.
-AM Aaron Morton DMSc, MMSc, PA-C, ATC, FAPACVS Editor-in-Chief
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* Thermal spread is de fi ned as the extent (length) of thermal injury of the vessel extending laterally outward from the edge of the Hemopro 2 jaws at the location of the interaction between the jaws and the vessel. 1. Lombardi P, Lau L. Measurement of Thermal Spread from Use of Vasoview Hemopro: Study Demonstrates Minimal Thermal Injury to Endothelium. White Paper. Maquet Cardiovascular. July, 2008. LT7900184.Abstract
In adults over the age of 18, acute kidney injury (AKI) is a common preventable complication in the postoperative phase following cardiac surgery. Traditional open heart surgery requires cardiopulmonary bypass, which leads to the risk of reduced blood flow to vital organs. Particularly the renal system is at elevated risk for ischemia if not optimally perfused. This article serves as a data analysis identifying biomarkers representative of AKI and methods to reduce the incidence of AKI. Optimal fluid management in the postoperative period is essential to further avoiding AKI. Prevention and early detection are vital in mitigating the risk of AKI. Strict fluid replacement is assessed upon reviewing hemodynamics, and set parameters of serum creatinine, NephroCheck® (Biomerieux, Lyon, France), and urine output. AKI not only causes acute renal issues but can also have lasting negative impacts on renal function. On the hospital end, AKI leads to increased length of stay (LOS) and poor outcomes, thereby causing reduced quality of care based on data collected by the Society of Thoracic Surgery (STS). Hospitals practicing cardiac surgery review quarterly or yearly AKI rates, making it one of the most prominent discussed complications in this field. Further research is continuously needed to improve guidelines surrounding optimal fluid management. However, enough research exists proving that properly monitored renal function with preventative measures in place leads to improved patient and hospital outcomes.
Keywords: cardiac surgery, AKI, fluid resuscitation, NephroCheck, serum creatinine, ERAS
Introduction
Acute kidney injury (AKI) in the postoperative cardiac surgery setting is a prevalent complication that is not only treatable but preventable. Patients undergoing cardiac surgery are placed
on cardiopulmonary bypass and are at risk for extended periods of hypotension leading to malperfusion of the kidneys. This ultimately results in elevated levels of serum creatinine, known as AKI. An estimated 3.5-31.0% of patients undergoing cardiac surgery develop AKI postoperatively.1 Risk factors predisposing patients to AKI include obesity, female gender, blood transfusions, COPD, and the requirement of inotropic or vasoconstrictor medications postoperatively.2 AKI leads to prolonged intensive care unit (ICU) length of stay, increased hospital costs, and overall mortality.2 Hospitals performing cardiac surgery collect data on all AKI incidences, as it pertains to one of the main elements comparing them to other institutions. The Society of Thoracic Surgery establishes endpoints, complications, and goals for the standard of care within the specialty of cardiothoracic surgery. Elevated AKI rates can cause hospital systems to be ranked lower and thus lead to decreased surgeries and overall compensation.
Early detection of AKI is crucial and several tests exist to diagnose AKI including serum creatinine and NephroCheck. Fluid replacement therapy early in the postoperative phase can reduce the risk of AKI. Additionally, optimal fluid and blood pressure management in the preoperative and intraoperative phases will further reduce the incidence of AKI and improve patient outcomes. With adequate maintenance of blood pressure, oncotic pressure, and the presence of adequate vascular fluid in all phases of surgery, patients have more reserve for hypotensive events and a diminished risk of developing AKI.
AKI can be defined as acute reduction of kidney function, including structural injury, often secondary to inter- and post-operative malperfusion.3 Criteria to meet the definition of AKI include a serum creatinine greater than or equal to 1.5 times the baseline, an increase in serum creatinine by greater than or equal to 0.3 mg/dL within 48 hours, or urine output less than 0.5mL/kg/hr for 6 hours or more.3 Multiple tests are used to identify AKI, consisting of serum creatinine, NephroCheck, glomerular filtration rate (GFR), and urine output. When considering a patient who is developing AKI or currently meets the criteria, healthcare providers must determine whether injury to the kidneys is occurring prerenal, intrinsic, or postrenal. Prerenal injury is associated with hypovolemia, reduced cardiac function, vasodilation, and
increased vascular afterload. Intrinsic injury causes include shock, hemorrhage from surgery or trauma, infection, and nephrotoxic medications. Postrenal injury is associated with post-kidney obstruction or clot within the tubule.3 Risk factors leading to AKI include age, obesity, valve replacement surgery, myocardial infarction, reduced ejection fraction (EF), the requirement of vasopressor or inotropic medications, transfusion of blood products, intra-aortic balloon pump (IABP) use, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD).1 Valve replacement can be associated with increased requirement of blood transfusions, which can cause inflammatory reactions leading to AKI.4 IABP use can lead to AKI due to malpositioning in the descending aorta and because it is often used for a extended perior of time, altering perfusion of the kidneys.5
AKI is a prevalent topic as it is closely monitored by all institutions practicing the cardiac surgery specialty. To further identify the significance AKI can have on a patient, evidence shows that AKI is a signal for multi-organ system failure; and not simply single-organ dysfunction.3 In the cardiac surgery population, roughly 40% of patients develop AKI in the postoperative period, and it is likely that other organs are experiencing injury simultaneously once AKI occurs.6 AKI can cost hospitals anywhere from $38,000 - $80,000 when it occurs, and it is oft times preventable and treatable.7 Reducing AKI improves a patient’s hospital course by limiting time in the intensive care unit (ICU), providing the chance for earlier beta-blocker start time leading to a reduced chance of developing arrhythmias such as atrial fibrillation, and limiting the chance of chronic renal complications.1 This benefits the patient, surgical team, and hospital by decreasing the ICU length of stay, hospital length of stay, and lowering overall costs.
AKI’s prevalent negative impacts on the patient and hospital demonstrates the need for establishing early detection as the standard of care. Early intervention in AKI in the pre-, inter, and post-op phase provides better outcomes for the patient with reduced cost to the hospital.
Adequate fluid balance is critical within the first 48-hour period post-cardiac surgery.8 Some institutions propose the idea to reduce AKI by setting new parameters for hemodynamic goals once certain biomarker thresholds are met. Examples of AKI warning signs include an increase of serum
creatinine of >0.2 within a 24-hour period or reduced urine output of <1mL/kg/hr for 3 hours. When these events take place, evidence shows that a mean arterial pressure goal of >75mmHg, as opposed to the standard 65mmHg, will reduce the risk of AKI.8 Additional methods to reduce AKI, once it is recognized, include establishing a goal fluid balance, increased cardiac index goal of 2.5 instead of the standard 2.2, and maintaining increased stroke volume. Using a Swan-Ganz catheter or modern hemodynamic monitors to represent a clear picture of the patient’s fluid status can reduce AKI as well. Modern hemodynamic monitors provide evidence of left-sided heart function. These monitors provide access to additional parameters such as stroke volume variation (SVV), dynamic arterial elastance (Eadyn), and pressure reached over certain increments of time (dP/dT). Assessing these indicators can trigger further fluid analysis. Decisions can be made to administer fluid replacement, make no intervention, or to administer a trial of diuresis. Proper hemodynamic monitoring leads to early detection of AKI and identifies the need for possible interventions, thereby reducing AKI.
Once AKI is diagnosed, an optimal fluid balance must be targeted and tailored to the individual patient. Fluid overload can cause heart failure and pulmonary edema, whereas too little fluid can lead to reduced cardiac output associated with constriction of the vasculature, and may further exacerbate the AKI. Within the first 24 hours of surgery, the utilization of diuretics predisposes patients to develop AKI and has led to recommendations to hold administration until closer to the 48-hour window post-cardiac surgery.8 Additionally, hesitancy in fluid resuscitation, due to elevated central venous pressure or reduced cardiac function, can lead to hypovolemia, vasoconstriction, and reduced renal perfusion associated with AKI. Fluid resuscitation instead of diuresis has been marked as the initial intervention in the setting of hypotension, tachycardia, and possible organ malperfusion.8 Studies show that a goal fluid balance protocol window should be kept between -5% and 3%, in regards to overall input/outputs during the hospital course.8 This narrow window recommendation provides evidence of the difficulty of fluid management but also emphasizes the need for further research on how to best manage fluid in patients on an individual basis.
Intraoperative and preoperative fluid balance considerations must be considered as well.
Studies have shown an intraoperative decrease in volume due to aggressive ultrafiltration, while on cardiopulmonary bypass (CPB), leads to elevated risks of AKI.8 Additionally, the nonpulsatile flow maintained on CPB disrupts the balance between cortical and medullary perfusion leading to altered renal function.9
Patients undergoing CPB are predisposed to an inflammatory reaction, which negatively affects the kidneys. A reaction occurs when contact is made between plasma proteases, within the lining of the CPB circuit, and the patient’s blood. Coagulation pathways are activated by factor XII. Factor XII causes the generation of bradykinin leading to the activation of the intrinsic coagulation pathway.10 Due to the insertion of cannulas into the vasculature, the extrinsic coagulation pathway is activated. Together, these cause a systemic inflammatory response, which is presented as vasodilation, increase in microvascular permeability, and expanding interstitial edema. During CPB ischemia occurs and when oxygen is reintroduced an ischemia-reperfusion injury can occur. This causes the release of inflammatory markers such as cytokines, interluekin IL-6, IL-8, and tumor necrosis factor (TNF), all of which leading to possible kidney injury.10
Efforts have been made to reduce this inflammatory reaction from both a pharmacologic and non-pharmacologic standpoint. Some studies have found use with peroxynitrite, which activates glutamine reducing the adherence of neutrophils.11 Rolipram, a phosphodiesterase 4 inhibitor has also been found to assist in lessening the inflammatory reaction by decrease plasma elastase, TNF, interluekins, and fluid into the extracellular space, while still maintaining adequate oxygenation.11 From a nonpharmacologic standpoint, different filters have been studied to reduce the inflammatory reaction including the zero balance ultrafiltration (by regulating water distribution through appropriate infusion of saline while filtering, which decreases tissue edema and increases perfusion of organs) and leukocyte filters (reducing the number of leukocytes to prevent inflammation).11
In the preoperative phase, patients who present for surgery who are malnourished
or dehydrated are predisposed to reduced cardiac output and increased rates of AKI. Enhanced recovery after surgery (ERAS) are surgical programs aimed to establish improved perioperative management. ERAS is applicable to various types of surgery, especially cardiac surgery. ERAS recommends that instead of keeping patients nil per os (NPO) at midnight the day of surgery, regardless of the scheduled time for surgery, patients should be placed NPO within 6-8 hours prior to surgery.12 This allows for increased hydration and nutrition leading to an increased reserve for recovery. An additional test that ERAS emphasizes in the setting of post-operative cardiac surgery is NephroCheck.12 NephroCheck is a urine test used for the early identification of AKI. To complete this test, a sample of fresh urine is placed into an incubator. It uses a single-use cartridge that detects biomarkers of acute kidney injury (TIMP-2 and IGFBP-7). With these two biomarkers detected, kidney injury can be identified/predicted. The turn around time for results on this test are about 20 minutes. NephroCheck is usually obtained within the first 24 hours post surgery and then subsequently 12 hours after the first test if it was initially positive. This second test ensures a trend in the correct direction and that appropriate interventions have been made to prevent AKI. If a positive NephroCheck is identified, changes in hemodynamic goals can be adjusted for more optimal perfusion to the kidneys.13 There is still more data required to confidently say whether NephroCheck will have an impact on reduction of overall cost to the hospital, reduced AKI, and decreased LOS.
There exist numerous tools and methods to reduce AKI and further research is needed to pinpoint exactly how to use all of the tools at hand in conjunction with one another for the most effective management and outcome. For now, with the concomitant use of all biomarkers and hemodynamic monitoring accessible, along with established protocols to identify/treat AKI, the greatest chance to prevent AKI can be achieved.
Conclusion
AKI is a mostly preventable complication of cardiac surgery. Healthcare providers treating AKI must first identify the cause, whether it is a prerenal, intrinsic, or postrenal issue. Once this problem is identified, strict hemodynamic parameter goals can be established to prevent, treat,
and lessen the severity of AKI. Each patient undergoing cardiac surgery requires a specifically optimized balance of fluid. Determining correct fluid resuscitation versus diuresis is imperative to cardiac output and renal perfusion. Utilization of implemented protocols recommended by ERAS and team-based approaches can effectively execute treatment plans for AKI. The goal of reducing AKI is imperative to all institutions practicing cardiac surgery, and with the right system in place, AKI can be minimized and both patients and the hospital will strongly benefit.
References
1. Ramos K, Dias C. Acute kidney injury after cardiac surgery in patients without chronic kidney disease. Braz J Cardiovasc Surg. 2018;33(5):454-461. doi:10.21470/1678-9741-20180084
2. Yuan S. Acute kidney injury after cardiac surgery: risk factors and novel biomarkers. Braz J Cardiovasc Surg. 2019;34(3):352-360. Published 2019 Jun 1. doi:10.21470/1678-9741-20180212
3. Makris K, Spanou L. Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin Biochem Rev. 2016;37(2):85-98.
4. Carrascal Y, Laguna G, Blanco M, Pañeda L, Segura B. Acute Kidney Injury after Heart Valve Surgery in Elderly Patients: any Risk Factors to Modify?. Braz J Cardiovasc Surg. 2021;36(1):19. Published 2021 Feb 1. doi:10.21470/1678-9741-2019-0483
5. Zhang XY, Fan ZG, Xu HM, Xu K, Tian NL. Clinical Outcomes for Acute Kidney Injury in Acute Myocardial Infarction Patients after Intra-Aortic Balloon Pump Implantation: A SingleCenter Observational Study. Rev Cardiovasc Med. 2023;24(6):172. doi:10.31083/j.rcm2406172
6. Massoth C, Zarbock A, Meersch M. Acute kidney injury in cardiac surgery. Crit Care Clin. 2021;37(2):267-278. doi:10.1016/j.ccc.2020.11.009
7. Silver SA, Long J, Zheng Y, Chertow GM. Cost of acute kidney injury in hospitalized patients. J Hosp Med. 2017;12(2):70-76. doi:10.12788/jhm.2683
8. Chen X, Xu J, Li Y, et al. The effect of postoperative fluid balance on the occurrence and progression of acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth. 2021;35 (9):2700-2706. doi:10.1053/j.jvca.2020.10.007
9. O’Neal JB, Shaw AD, Billings FT. Acute kidney injury following cardiac surgery: current understanding and future directions. Crit Care. 2016;20(1):187. doi:10.1186/s13054-016-1352-z
10.Bronicki RA, Hall M. Cardiopulmonary Bypass-Induced Inflammatory Response: Pathophysiology and Treatment. Pediatr Crit Care Med. 2016;17(8 Suppl 1):S272-S278. doi:10.1097/ PCC.0000000000000759
11.Liguori GR, Kanas AF, Moreira LF. Managing the inflammatory response after cardiopulmonary bypass: review of the studies in animal models. Rev Bras Cir Cardiovasc. 2014;29(1):93102. doi:10.5935/1678-9741.20140017
12.Melnyk M, Casey RG, Black P, Koupparis AJ. Enhanced recovery after surgery (ERAS) protocols: time to change practice?. Can Urol Assoc J. 2011;5(5):342-348. doi:10.5489/cuaj.11002
13. L'Acqua C, Sisillo E, Salvi L, Introcaso G, Biondi ML. NephroCheck after cardiac surgery: does it play a role in daily practice? A sequel of "NephroCheck results should be corrected for dilution". Int J Artif Organs. 2019;42(11):665-667. doi:10.1177/0391398819852958
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University of Utah Hospital
ABSTRACT
Surgical bleeding is expected during any cardiac surgery; if not well controlled, it can affect overall patient outcomes. Mechanical hemostatic agents - such as sutures, the use of surgical clippers, or the application of direct pressure - are the standard of care in any surgical procedure. Adjunct hemostatic agents are used in conjunction with these to achieve hemostasis. The purpose of this article is to review the role of fibrin hemostatic agents as adjuncts in achieving hemostasis, specifically in cardiac surgery, and the associated impacts on patient outcomes.
INTRODUCTION
Intraoperative bleeding during cardiac surgery is a common occurrence; achieving hemostasis is critical to overall patient outcomes and is an essential part of a successful procedure. It has been estimated that up to 15% of all open cardiac cases experience major intra or postoperative bleeding.1 This can lead to increased mortality, prolonged time on cardiopulmonary bypass, and the need for transfusions of blood products.1 Patients who experience bleedingrelated complications and/or require blood product transfusions tend to experience an extended period of hospitalization and increased stay duration in the ICU in comparison to patients without such events leading to higher healthcare costs.1 Therefore, it is important to use all resources available to reduce the incidence and/or severity of bleeding complications. By doing so, we can subsequently improve overall health outcomes and reduce the cost of the patient’s hospital stay.
There are two forms of hemostatic agents. Mechanical hemostatic agents and adjunct hemostasis agents. Mechanical hemostatic agents, include sutures, surgical clips, and the application of direct pressure.2 These are standard hemostatic practices during any surgical procedure. Adjunct hemostatic agents are used when mechanical techniques alone do not suffice, and additional tools are needed to help control bleeding.2,3
Adjunct hemostatic agents were developed in the early 20th century to reduce bleeding on the battlefield.2 Adjunct hemostatic agents can be divided into four broad categories: inorganic agents derived from natural minerals, polysaccharide hemostatic agents, biological hemostatic agents, and synthetic hemostatic agents. Each of these agents have been shown to be highly effective in controlling bleeding compared to mechanical agents alone.2
Hemostasis is a physiological process that immediately activates upon vascular injury to prevent excessive bleeding.4 It involves a series of complex mechanisms that work together to form a blood clot, which maintains blood fluidity.4 Hemostasis can be divided into two main stages: primary hemostasis and secondary hemostasis.5 Primary hemostasis involves vasoconstriction and the aggregation of platelets at the site of injury, forming a platelet plug (Figure 1)5,6. The recruitment of platelets to the injured vessel is due to a protein molecule known as von Willebrand factor (vWF) that is present within the sub endothelium and plasma.5 Secondary hemostasis mainly involves the initiation of the coagulation cascade resulting in the formation of a stable fibrin clot.5
The coagulation cascade consists of three pathways: the intrinsic pathway, the extrinsic pathway, and the common pathway (Figure 1).6 The extrinsic and intrinsic pathways occur simultaneously and converge at the common pathway, where the final steps of clot formation occur.6
The extrinsic pathway comprises factor III (tissue factor) and plasma factor VII (proconvention).4,6 This pathway is activated when injured cells release factor III, which binds
with calcium and triggers the activation of factor VII to factor VIIa.4,6 Activation of factor VII requires the presence of vitamin K.6 Factor VIIa catalyzes the conversion of factor X into factor Xa, which is the starting point for the common pathway.6
The intrinsic pathway involves several clotting factors, including factor XII (Hageman factor), factor XI (plasma thromboplastin antecedent), factor IX (Christmas factor), and factor VIII (antihemophilic factor).6 The first step of the intrinsic pathway is the activation of Factor XII to Factor XIIa by exposure to the damaged endothelium or negatively charged surfaces, such as collagen.6 Factor XIIa creates a positive feedback reaction that leads to the conversion of factor XI to factor Xia. Factor XIa activates factor IX to factor IXa, which continues the reaction and activates factor X into factor Xa, leading to the common pathway.6,7
The common pathway starts with the conversion of factor X into factor Xa, which stimulates thrombin formation.6 Upon activation of factor Xa, it catalyzes the activation of II (prothrombin) into factor IIa (thrombin). The presence of factor IIa activates factor I (fibrinogen) into fibrin.6,7 Fibrin is an insoluble protein that is essential in the formation of clots. Multiple fibrin subunits form a fibrin stand, which stabilizes the initially formed platelet plug, leading to the formation of a clot.6 Fibrin also plays a vital role by engaging leukocytes and modifying certain processes of the inflammatory process to repair and remodel the damaged vessel and prevent the invasion of pathogens.8,9 The partial thromboplastin time (PTT) assesses the intrinsic and common pathways, while the prothrombin time (PT) measures the extrinsic and common pathways5 .
Adjunct fibrin hemostasis agents mimic the natural hemostatic cascade and have been shown to be safe for use in many surgical procedures. These agents are produced from human plasma and mimic the final stage of the coagulation process, leading to the formation of stable clots.3
In 1998, the FDA approved fibrin sealants (Figure 2) as a medical product, and they are currently the only agent licensed for use as a hemostat, tissue sealant, and wound adhesive.13
2231. doi:10.1021/ acsbiomaterials.1c01437 Copyright 2022, American Chemical Society13
Some commercially available fibrin hemostatic agents include Tisseel, Tachosil, Evicel, and Vistaseal. These agents all contain three clotting factors at different concentration levels. These factors include factors I (fibrinogen), thrombin, and factor XIII (Table 1).12,13 Once administered to a bleeding or injured site, fibrinogen, and thrombin, which are the key functional components (Table 1), react to form a fibrin clot.12 Due to this key feature, these sealants are commercially available in either a dual-syringe application system or liquid spray form.11
A systematic review by Novotny et al.3 discussed different types of fibrin sealants and their use in cardiac surgery. The types of fibrin sealants discussed in this article included those sold under the brand names Tisseel, BioGlue, and Tachosil. Tisseel was the first fibrin sealant readily available for surgical use and has been shown to be effective in controlling capillary bleeding. BioGlue, another FDA-approved fibrin sealant, is primarily used to repair large vessels like the aorta or pulmonary vein, where bleeding control is critical. These agents are advantageous in surgical procedures like aortic dissection repair, valve repair surgeries, or in older patients with friable tissue. This review further investigated the overall safety of fibrin sealant use. Based on an Italian retroactive clinical study in thoracic surgery, fibrin sealants did not place the patient at an increased risk of surgical complications or pose any advanced side effects. This could be attributed to the fact that they are human derivatives and, therefore, do not cause any increased risk of inflammation or infection. The use of Tachosil, mostly in pediatric cardiac patients requiring reoperation due to bleeding, was also investigated. Most of the bleeding was noted on suture lines or injuries on the epicardial tissue. In over 110 surgeries included in this study, using Tachosil reduced the need for blood transfusions or the use of other hemostatic agents. This reduced the
of the surgeries and, as a result, the cost of hospitalization. The authors noted that fibrin sealants offered benefits to both the surgeon and the patient by reducing overall operative time and surgical complications.
Rousou 11 systematically reviewed the efficiency of fibrin sealants in different types of cardiovascular surgery. Overall, this review noted that fibrin sealants improved patient outcomes and reduced bleeding compared to using mechanical techniques alone. In coronary artery bypass grafting surgery (CABG), fibrin sealants were used as an adjunct to sutures in most of the anastomosis and were noted to reduce overall bleeding time. The author reviewed a randomized clinical study on elderly patients undergoing CABG. He noted that patients who received adjunct fibrin sealants lost significantly less blood and therefore, required fewer blood transfusions than those who did not receive any sealants. These patients were also reported to have a shorter hospital stay. The use of Tisseel in these surgeries, compared to other hemostatic agents, was shown to reduce bleeding time and the lower risk of reoperation due to bleeding. This systematic review also showed that in ventricular septal defect (VSD) closure procedures, using a surgical patch with running sutures reinforced with Tisseel reduced the risk of residual VSDs by over 50% and improved short- and long-term results in those patients. In aortic surgeries, the author noted that using Tisseel and Tachosil effectively reduced bleeding from vessel anastomosis. In the repair of abdominal aortic aneurysms (AAA), the use of Tisseel was noted to reduce the risk of an endoleak, a common and sometimes fatal complication of endovascular aortic aneurysm repair where blood leaks around the stent graft creating a larger aneurysm which is prone to rupture if not repaired. This study noted a 2% risk of an endoleak in patients where Tisseel was used compared to a 15% risk in those who did not receive any adjunct sealant.
Daud et.al14 presented a meta-analysis on the use of adjunct fibrin agents in cardiac and vascular surgery and their overall effect on patient outcomes. A total of 7622 patients in twentyone studies were included. These studies included thirteen randomized controlled trials (RTCs), three prospective cohort studies, and five retrospective studies. A meta-analysis of the RTCs on volume of blood lost revealed a mean difference of about 120ml and a 2.5-minute difference on
average in the time to hemostasis in favor of sealant use.14 However, this study was inconclusive on the 30-day mortality risk and post-operative need for blood transfusion in patients who received fibrin sealants compared to those who did not.
In 2019, Nenezić D, Ayguasanosa J, Menyhei G, et al.15 completed a prospective singleblind, randomized, phase III study on the efficacy of Grifol , a fibrin sealant, compared to manual compression. This study revealed that the median time to hemostasis was six minutes faster in patients who received the sealant than those who had manual compression only.
Intraoperative bleeding during cardiac surgery is a common occurrence, and achieving hemostasis is crucial. The standard practice of achieving hemostasis in any surgical procedure includes the use of sutures, surgical clips, or electrocautery. Uncontrolled bleeding in cardiac surgery can increase cardiopulmonary bypass time, the need for transfusion of blood products and, subsequently, the cost of care for the patient. In situations when these mechanical tools are insufficient, adjunct hemostasis agents like fibrin have been proven to help improve hemostasis. These agents are meant to complement standard tools like sutures, not replace them. Several fibrin sealants like Tisseel, Tachosil, and BioGlue are routinely used in cardiac surgery to achieve hemostasis. Overall, from the article review, the consensus is that these agents reduce bleeding time and total blood loss. Additional studies need to be completed to review their role in reducing the 30-day mortality of patients and the risk of infection.
1. Al-Attar N, Johnston S, Jamous N, et al. Impact of bleeding complications on length of stay and critical care utilization in cardiac surgery patients in England. J Cardiothorac Surg. 2019;14 (1):64. Published 2019 Apr 2. doi:10.1186/s13019-019-0881-3
2. Vyas KS, Saha SP. Comparison of hemostatic agents used in vascular surgery. Expert Opin Biol Ther. 2013;13(12):1663-1672. doi:10.1517/14712598.2013.848193
3. Novotny R, Hlubocký J, Mitáš P, Lindner J. Fibrin sealants in cardiac surgery: The last five years of their development and application. Adv Clin Exp Med. 2018;27(6):857-862. doi:https:// doi.org/10.17219/acem/68981
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