|
1
|
Wahba A, Kunst G, De Somer F, Kildahl HA, Milne B, Kjellberg G, Bauer A, Beyersdorf F, Ravn HB, Debeuckelaere G, Erdoes G, Haumann RG, Gudbjartsson T, Merkle F, Pacini D, Paternoster G, Onorati F, Ranucci M, Ristic N, Vives M, Milojevic M. 2024 EACTS/EACTAIC/EBCP Guidelines on cardiopulmonary bypass in adult cardiac surgery. Br J Anaesth 2025; 134:917-1008. [PMID: 39955230 PMCID: PMC11947607 DOI: 10.1016/j.bja.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025] Open
Abstract
Clinical practice guidelines consolidate and evaluate all pertinent evidence on a specific topic available at the time of their formulation. The goal is to assist physicians in determining the most effective management strategies for patients with a particular condition. These guidelines assess the impact on patient outcomes and weigh the risk-benefit ratio of various diagnostic or therapeutic approaches. While not a replacement for textbooks, they provide supplementary information on topics relevant to current clinical practice and become an essential tool to support the decisions made by specialists in daily practice. Nonetheless, it is crucial to understand that these recommendations are intended to guide, not dictate, clinical practice, and should be adapted to each patient's unique needs. Clinical situations vary, presenting a diverse array of variables and circumstances. Thus, the guidelines are meant to inform, not replace, the clinical judgement of healthcare professionals, grounded in their professional knowledge, experience and comprehension of each patient's specific context. Moreover, these guidelines are not considered legally binding; the legal duties of healthcare professionals are defined by prevailing laws and regulations, and adherence to these guidelines does not modify such responsibilities. The European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) and the European Board of Cardiovascular Perfusion (EBCP) constituted a task force of professionals specializing in cardiopulmonary bypass (CPB) management. To ensure transparency and integrity, all task force members involved in the development and review of these guidelines submitted conflict of interest declarations, which were compiled into a single document available on the EACTS website (https://www.eacts.org/resources/clinical-guidelines). Any alterations to these declarations during the development process were promptly reported to the EACTS, EACTAIC and EBCP. Funding for this task force was provided exclusively by the EACTS, EACTAIC and EBCP, without involvement from the healthcare industry or other entities. Following this collaborative endeavour, the governing bodies of EACTS, EACTAIC and EBCP oversaw the formulation, refinement, and endorsement of these extensively revised guidelines. An external panel of experts thoroughly reviewed the initial draft, and their input guided subsequent amendments. After this detailed revision process, the final document was ratified by all task force experts and the leadership of the EACTS, EACTAIC and EBCP, enabling its publication in the European Journal of Cardio-Thoracic Surgery, the British Journal of Anaesthesia and Interdisciplinary CardioVascular and Thoracic Surgery. Endorsed by the EACTS, EACTAIC and EBCP, these guidelines represent the official standpoint on this subject. They demonstrate a dedication to continual enhancement, with routine updates planned to ensure that the guidelines remain current and valuable in the ever-progressing arena of clinical practice.
Collapse
Affiliation(s)
- Alexander Wahba
- Department of Cardio-Thoracic Surgery, St. Olavs University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
| | - Gudrun Kunst
- Department of Anaesthetics and Pain Therapy King's College Hospital NHS Foundation Trust, London, United Kingdom; School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
| | | | - Henrik Agerup Kildahl
- Department of Cardio-Thoracic Surgery, St. Olavs University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Benjamin Milne
- Department of Anaesthesia, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Gunilla Kjellberg
- Department of Thoracic Surgery and Anaesthesiology, Uppsala University Hospital, Uppsala, Sweden
| | - Adrian Bauer
- Department of Perfusiology, Evangelic Heart Center, Coswig, Germany
| | - Friedhelm Beyersdorf
- Department of Cardiovascular Surgery, University Hospital Freiburg, Germany; Medical Faculty of the Albert-Ludwigs-University Freiburg, Germany
| | - Hanne Berg Ravn
- Department of Anaesthesia, Odense University Hospital and Institute of Clinical Medicine, Southern Denmark University, Denmark
| | | | - Gabor Erdoes
- University Department of Anesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Renard Gerhardus Haumann
- Department of Cardio-Thoracic Surgery, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, The Netherlands; Department of Biomechanical Engineering, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Tomas Gudbjartsson
- Department of Cardiothoracic Surgery, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Frank Merkle
- Foundation Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Davide Pacini
- Division of Cardiac Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; University of Bologna, Bologna, Italy
| | - Gianluca Paternoster
- Cardiovascular Anesthesia and Intensive Care San Carlo Hospital, Potenza, Italy; Department of Health Science Anesthesia and ICU School of Medicine, University of Basilicata San Carlo Hospital, Potenza, Italy
| | - Francesco Onorati
- Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy
| | - Marco Ranucci
- Department of Cardiovascular Anesthesia and ICU, IRCCS Policlinico San Donato, Milan, Italy
| | - Nemanja Ristic
- Department of Cardiac Surgery, Dedinje Cardiovascular Institute, Belgrade, Serbia
| | - Marc Vives
- Department of Anesthesia & Critical Care, Clínica Universidad de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Milan Milojevic
- Department of Cardiac Surgery and Cardiovascular Research, Dedinje Cardiovascular Institute, Belgrade, Serbia
| |
Collapse
|
|
2
|
Wahba A, Kunst G, De Somer F, Agerup Kildahl H, Milne B, Kjellberg G, Bauer A, Beyersdorf F, Berg Ravn H, Debeuckelaere G, Erdoes G, Haumann RG, Gudbjartsson T, Merkle F, Pacini D, Paternoster G, Onorati F, Ranucci M, Ristic N, Vives M, Milojevic M. 2024 EACTS/EACTAIC/EBCP Guidelines on cardiopulmonary bypass in adult cardiac surgery. Eur J Cardiothorac Surg 2025; 67:ezae354. [PMID: 39949326 PMCID: PMC11826095 DOI: 10.1093/ejcts/ezae354] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/01/2024] [Indexed: 02/17/2025] Open
Affiliation(s)
- Alexander Wahba
- Department of Cardio-Thoracic Surgery, St. Olavs University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Gudrun Kunst
- Department of Anaesthetics and Pain Therapy King’s College Hospital NHS Foundation Trust, London, United Kingdom
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | | | - Henrik Agerup Kildahl
- Department of Cardio-Thoracic Surgery, St. Olavs University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Benjamin Milne
- Department of Anaesthesia, Guy’s & St Thomas’ NHS Foundation Trust, London, United Kingdom
| | - Gunilla Kjellberg
- Department of Thoracic Surgery and Anaesthesiology, Uppsala University Hospital, Uppsala, Sweden
| | - Adrian Bauer
- Department of Perfusiology, Evangelic Heart Center, Coswig, Germany
| | - Friedhelm Beyersdorf
- Department of Cardiovascular Surgery, University Hospital Freiburg, Germany
- Medical Faculty of the Albert-Ludwigs-University Freiburg, Germany
| | - Hanne Berg Ravn
- Department of Anaesthesia, Odense University Hospital and Institute of Clinical Medicine, Southern Denmark University, Denmark
| | | | - Gabor Erdoes
- University Department of Anesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Renard Gerhardus Haumann
- Department of Cardio-Thoracic surgery, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, The Netherlands
- Department Of Biomechanical Engineering, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Tomas Gudbjartsson
- Department of Cardiothoracic Surgery, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Frank Merkle
- Foundation Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Davide Pacini
- Division of Cardiac Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- University of Bologna, Bologna, Italy
| | - Gianluca Paternoster
- Cardiovascular Anesthesia and Intensive Care San Carlo Hospital, Potenza, Italy
- Department of Health Science Anesthesia and ICU School of Medicine, University of Basilicata San Carlo Hospital, Potenza, Italy
| | - Francesco Onorati
- Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy
| | - Marco Ranucci
- Department of Cardiovascular Anesthesia and ICU, IRCCS Policlinico San Donato, Milan, Italy
| | - Nemanja Ristic
- Department of Cardiac Surgery, Dedinje Cardiovascular Institute, Belgrade, Serbia
| | - Marc Vives
- Department of Anesthesia & Critical Care, Clínica Universidad de Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Milan Milojevic
- Department of Cardiac Surgery and Cardiovascular Research, Dedinje Cardiovascular Institute, Belgrade, Serbia
| |
Collapse
|
|
3
|
Goldberger MI, Mamoun N, Fitch Z, Bonadonna D, Schroder J, Welsby I. A Novel Configuration of Venovenous Modified Ultrafiltration for Bivalirudin Removal After HeartMate3 Insertion. J Cardiothorac Vasc Anesth 2025; 39:494-496. [PMID: 39721921 DOI: 10.1053/j.jvca.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/22/2024] [Accepted: 12/01/2024] [Indexed: 12/28/2024]
Affiliation(s)
- Madison I Goldberger
- Division of Cardiothoracic Anesthesiology, Duke University Medical Center, Durham, NC.
| | - Negmeldeen Mamoun
- Division of Cardiothoracic Anesthesiology, Duke University Medical Center, Durham, NC
| | - Zachary Fitch
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
| | - Desiree Bonadonna
- Division of Perfusion Services, Duke University Medical Center, Durham, NC
| | - Jacob Schroder
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
| | - Ian Welsby
- Division of Cardiothoracic Anesthesiology, Duke University Medical Center, Durham, NC
| |
Collapse
|
|
4
|
Chabata CV, Yu H, Ke L, Frederiksen JW, Patel PA, Sullenger BA, Thalji NK. Andexanet Alfa-Associated Heparin Resistance in Cardiac Surgery: Mechanism and In Vitro Perspectives. Arterioscler Thromb Vasc Biol 2025; 45:144-156. [PMID: 39569519 DOI: 10.1161/atvbaha.124.321650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND Andexanet alfa (andexanet) is the only Food and Drug Administration-approved antidote for direct FXa (factor Xa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass. The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown. METHODS The effect of andexanet in vitro was determined using activated clotting times and thromboelastography. Ex vivo cardiopulmonary bypass circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of AT (antithrombin) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance. RESULTS Andexanet prevented UFH-mediated prolongation of activated clotting times and thromboelastography times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and thrombin generation assay validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient cardiopulmonary bypass heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require high UFH doses and potentially AT supplementation. CONCLUSIONS Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided before heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy before AT supplementation.
Collapse
Affiliation(s)
- Charlene V Chabata
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
| | - Haixiang Yu
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
- Surgery (H.Y., J.W.F., B.A.S.), Duke University, Durham, NC
| | - Lei Ke
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.K., N.K.T.)
| | | | - Prakash A Patel
- Department of Anesthesiology, Jefferson Abington Hospital, PA (P.A.P.)
| | - Bruce A Sullenger
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
- Surgery (H.Y., J.W.F., B.A.S.), Duke University, Durham, NC
| | - Nabil K Thalji
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.K., N.K.T.)
| |
Collapse
|
|
5
|
Meshulami N, Murthy R, Meyer M, Meyer AD, Kaushik S. Bivalirudin anticoagulation for cardiopulmonary bypass during cardiac surgery. Perfusion 2025; 40:7-19. [PMID: 38084653 DOI: 10.1177/02676591231221708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Abstract
INTRODUCTION Heparin is the primary anticoagulant for cardiopulmonary bypass (CPB) support during cardiac surgery. While widely used, ∼2% of cardiac surgery patients develop heparin-induced thrombocytopenia (HIT) and 4-26% develop heparin resistance. Bivalirudin is an alternative anticoagulant mainly used for percutaneous coronary interventions. Given the challenges associated with heparin anticoagulation, we conducted a review to explore the use of bivalirudin for CPB surgery. METHODS PubMed and Embase scoping review included 2 randomized controlled trials, a retrospective comparison study, 3 pilot studies, and 30 case reports. To provide a contemporary series, we searched for articles published from 2010 to 2023. Our review included studies from both adult and pediatric populations. RESULTS While data is limited, bivalirudin seems to supply similar effectiveness and safety as heparin for CPB anticoagulation. Across the three comparative studies, the heparin cohorts had a 0-9% mortality rate and 0-27% rate of major bleeding/reoperation compared to a 0-3% mortality and 0-6% major bleeding/reoperation rate for the bivalirudin cohorts. Bivalirudin was successfully used as an anticoagulant in a wide range of CPB surgeries (e.g., heart transplants, ventricular assisted device placements, and valve repairs). Successful patient outcomes were reported with bivalirudin infusion of ∼2 mg/kg/hour, activated clotting time monitoring (target >400 s or 2.5× baseline), use of cardiotomy suctions, minimization of stagnant blood, and post-bypass modified ultrafiltration. CONCLUSION Bivalirudin is a safe and effective anticoagulant for CPB, especially for patients with HIT or heparin resistance. Further comparative research is called for to optimize bivalirudin utilization for CPB during cardiac surgery.
Collapse
Affiliation(s)
- Noy Meshulami
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raghav Murthy
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Pediatric Cardiac Surgery, Department of Cardiovascular Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maisy Meyer
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrew D Meyer
- Division of Critical Care, Department of Pediatrics, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
| | - Shubhi Kaushik
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Pediatric Critical Care, Department of Pediatrics, Kravis Children's Hospital at Mount Sinai, Icahn School of Medicine, New York, NY, USA
| |
Collapse
|
|
6
|
Adeoye O, Zheng G, Onwuemene OA. Approaches to management of HIT in complex scenarios, including cardiac surgery. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:396-402. [PMID: 39644041 DOI: 10.1182/hematology.2024000564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Although heparin-induced thrombocytopenia (HIT) presents management challenges for any population, it adds complexity to the management of certain patient populations, including those undergoing cardiac surgery and those with refractory HIT and/or acute bleeding. For each of these scenarios, we review alternative management strategies when standard therapies-heparin cessation and the initiation of a nonheparin anticoagulant-are either insufficient or not practicable. In patients with HIT undergoing cardiac surgery, we review the clinical experience for heparin reexposure using therapeutic plasma exchange (TPE) or antiplatelet therapy. In patients with refractory HIT despite adequate nonheparin anticoagulation, we address the use of intravenous immune globulin, TPE, and rituximab. Finally, in patients with active bleeding, we discuss bleeding management and the risks associated with platelet transfusion. Although they may facilitate a patient-centered approach, most of these strategies are supported by limited evidence.
Collapse
Affiliation(s)
- Oluwatayo Adeoye
- Department of Medicine, St Elizabeth's Medical Center, Boston, MA
| | - Guoliang Zheng
- Division of Hematology, Department of Medicine, Virginia Commonwealth University Health, Richmond, VA
| | | |
Collapse
|
|
7
|
Del Vecchio A, Pham LP, McNeil J, Singh K, Tanaka K, Eaton M, Mazzeffi M. Efficacy of Therapeutic Plasma Exchange or Cangrelor as an Adjunctive Strategy to Facilitate Cardiopulmonary Bypass in Patients with Heparin-Induced Thrombocytopenia: A Systematic Review and Meta-Analysis. J Cardiothorac Vasc Anesth 2024; 38:2915-2924. [PMID: 39353821 DOI: 10.1053/j.jvca.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/01/2024] [Accepted: 09/09/2024] [Indexed: 10/04/2024]
Abstract
OBJECTIVE Conduct a systematic review and meta-analysis of the efficacy of therapeutic plasma exchange (TPE) or intravenous cangrelor to prevent thromboembolism in patients with heparin-induced thrombocytopenia (HIT) who undergo cardiopulmonary bypass (CPB) with heparin. DESIGN Systematic review and meta-analysis. SETTING N/A. PARTICIPANTS Adults having cardiac surgery with a history of HIT who received preoperative or intraoperative TPE or intravenous cangrelor as an adjunct to CPB with heparin. INTERVENTIONS None MEASUREMENTS AND MAIN RESULTS: A systematic review was performed using MEDLINE, PubMed, and Google Scholar. The primary outcome was avoidance of thromboembolism (venous or arterial) during or after CPB. Proportional meta-analysis with a random effects model was used to calculate a weighted-pooled proportion/efficacy for the study's primary outcome. Fifty-seven patients in 17 reports received TPE as an adjunctive treatment to prevent HIT-related thrombosis related to heparinization during CPB and 3 (5.3%) experienced thrombosis. Proportional meta-analysis suggested a weighted-pooled freedom from perioperative thromboembolism rate of 91.0% (95% CI 82.6%-96.9%). Fifteen patients in 6 reports received intravenous cangrelor as an adjunctive treatment to prevent HIT-related thrombosis related to heparinization during CPB and 2 (13.3%) experienced thrombosis. Proportional meta-analysis suggested a weighted-pooled freedom from perioperative thromboembolism rate of 83.0% (95% CI 61.2%- 97.6%). CONCLUSIONS TPE and cangrelor are feasible strategies to prevent thromboembolism in adults with HIT who require CPB with heparin. Given the relatively small number of cases in the published literature and a high likelihood for publication and detection biases, prudence remains warranted when using these strategies.
Collapse
Affiliation(s)
| | - Lam-Phong Pham
- University of Virginia School of Medicine, Charlottesville, VA
| | - John McNeil
- University of Virginia School of Medicine, Department of Anesthesiology, Charlottesville, VA
| | - Karen Singh
- University of Virginia School of Medicine, Department of Anesthesiology, Charlottesville, VA
| | - Kenichi Tanaka
- Oklahoma University College of Medicine, Department of Anesthesiology, Oklahoma City, OK
| | - Michael Eaton
- University of Rochester School of Medicine, Department of Anesthesiology, Rochester, NY
| | - Michael Mazzeffi
- University of Virginia School of Medicine, Department of Anesthesiology, Charlottesville, VA.
| |
Collapse
|
|
8
|
Chabata CV, Yu H, Ke L, Frederiksen JW, Patel PA, Sullenger BA, Thalji NK. Andexanet alfa-associated heparin resistance in cardiac surgery: mechanism and in vitro perspectives. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.09.612152. [PMID: 39314402 PMCID: PMC11419022 DOI: 10.1101/2024.09.09.612152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background Andexanet alfa (andexanet) is the only FDA-approved antidote for direct factor Xa (FXa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass (CPB). The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown. Methods The effect of andexanet in vitro was determined using activated clotting times (ACT) and thromboelastography (TEG). Ex vivo CPB circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of antithrombin (AT) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay (TGA) validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance. Results Andexanet prevented UFH-mediated prolongation of ACT and TEG times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and TGA validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient CPB heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require both AT supplementation and very high UFH doses. Conclusions Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided prior to heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy prior to AT supplementation. Highlights Andexanet alfa causes heparin resistance not by depleting antithrombin, but rather by sequestering heparin-bound antithrombin such that it cannot act as an anticoagulant.Heparin responsiveness in the presence of Andexanet alfa is triphasic such that the effect of a dose of heparin can now be predicted in vitro based on the relative concentrations of andexanet, heparin, and antithrombin.The in vitro insights provided by this work provide a rational starting point for further clinical elucidation of the problem and management of andexanet-associated heparin resistance.
Collapse
|
|
9
|
Abraham AS, Wakefield BJ. Pro: Hemostasis Management of Patients on Extracorporeal Membrane Oxygenation Is Different Than Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth 2024:S1053-0770(24)00437-3. [PMID: 39068101 DOI: 10.1053/j.jvca.2024.06.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/12/2024] [Accepted: 06/30/2024] [Indexed: 07/30/2024]
Abstract
Cardiopulmonary bypass and extracorporeal membrane oxygenation have many similarities, but there are significant differences in managing hemostasis. Cardiopulmonary bypass includes shorter mechanical circulatory support times, blood stasis, higher flows, and an increased blood-air interface. These factors cause differences in the risk of coagulopathy, management of anticoagulation, monitoring of the hemostatic system, and management of coagulopathy. This article aims to identify these key differences in the hemostatic system between patients on cardiopulmonary bypass and those on extracorporeal membrane oxygenation.
Collapse
Affiliation(s)
- Abey S Abraham
- Department of Cardiothoracic Anesthesiology, Department of Intensive Care and Resuscitation, Cleveland Clinic, Cleveland, OH
| | - Brett J Wakefield
- Department of Cardiothoracic Anesthesiology, Department of Intensive Care and Resuscitation, Cleveland Clinic, Cleveland, OH.
| |
Collapse
|
|
10
|
Huang X, Du P, Jia H, Wang A, Hua Y, Liu X, Wu K, Li B, Zhao H. Methodologic Quality and Pharmacotherapy Recommendations for Patient Blood Management Guidelines for Cardiac Surgery on Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth 2024; 38:1569-1576. [PMID: 38594156 DOI: 10.1053/j.jvca.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/04/2024] [Accepted: 03/08/2024] [Indexed: 04/11/2024]
Abstract
Patient blood management (PBM) guidelines for patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) have increased during the past decade, and pharmacotherapy plays an important role in PBM. In the face of the undefined consistency in the methodologic quality and pharmacotherapy recommendations across multiple guidelines, this study exclusively evaluated methodologies of the related guideline development process, and compiled medication recommendations of PBM for cardiac surgery patients. PBM guidelines for cardiac surgery under CPB were searched through some mainstream literature and guideline databases from database establishment to May 15, 2023. Nine guidelines meeting inclusion criteria were included in this study. The quality of the guidelines was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. "Stakeholder involvement" received the lowest mean score of 49.38% in the AGREE II scoring among the guidelines. PBM for cardiac surgery patients spans the perioperative phase. Drug therapy strategies of PBM for cardiac surgery patients involve anemia therapy, perioperative administration of antithrombotic drugs, intraoperative anticoagulation, and the use of hemostatic drugs. Unlike for adults, there is less evidence about the management of antithrombotic drugs and hemostatic drugs for pediatric cardiac surgery patients. Recombinant activated factor VII (rFVIIa) and desmopressin (DDAVP) are not recommended after pediatric cardiac surgery, whereas prothrombin complex concentrate could be considered in clinical trials. As for the controversies regarding the administration of rFVIIa and DDAVP after adult cardiac surgery by different societies, clinicians should exercise their clinical judgment based on individual patient features.
Collapse
Affiliation(s)
- Xiaojing Huang
- Department of Pharmacy, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Pengqiang Du
- Department of Pharmacy, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Haipan Jia
- Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou, China
| | - Aifeng Wang
- Department of Pharmacy, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Ying Hua
- Children's Heart Center Intensive Care Unit, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Xuelan Liu
- Children's Heart Center Intensive Care Unit, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Kaiyuan Wu
- Children's Heart Center Intensive Care Unit, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Bin Li
- Children's Heart Center Intensive Care Unit, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Hongwei Zhao
- Department of Pharmacy, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
| |
Collapse
|
|
11
|
Mishima Y, Butt AL, Vandyck KB, Levy JH, Stewart KE, Tanaka KA. Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro. Br J Anaesth 2024; 132:1204-1210. [PMID: 38594117 DOI: 10.1016/j.bja.2024.02.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/06/2024] [Accepted: 02/03/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. METHODS Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 μM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin-antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. RESULTS In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml-1) and supplementing antithrombin (1.5-4.5 μM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml-1) and antithrombin (3 μM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin-antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. CONCLUSIONS Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.
Collapse
Affiliation(s)
- Yuko Mishima
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Amir L Butt
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kofi B Vandyck
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jerrold H Levy
- Duke University Medical Center, Department of Anesthesiology, Critical Care, and Surgery (Cardiothoracic), Durham, NC, USA
| | - Kenneth E Stewart
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kenichi A Tanaka
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| |
Collapse
|
|
12
|
Nadtochiy SM, Stefanos T, Wissler R, Gu Y, Feng C, Lebedko N, Eaton MP. Effect of bivalirudin on coagulation in neonatal (cord) and adult human blood in vitro. Paediatr Anaesth 2024; 34:415-421. [PMID: 38055634 DOI: 10.1111/pan.14814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Bivalirudin is recommended as an alternative to heparin in cardiac surgery with cardiopulmonary bypass. Although it has been used in infants and children for this indication, there is a paucity of data on the pharmacologic effects of bivalirudin in neonates. Given the immaturity of the hemostatic system in neonates, we hypothesized that coagulation responses to bivalirudin in this population would be different than in adults. METHODS Blood samples were drawn from placenta-cord units and from healthy adult donors. The study was carried out in two steps. First, bivalirudin was added to cord and adult blood samples at concentrations of 0, 5, 10, 15, and 20 μg/mL. Activated clotting time and thromboelastographic variables were recorded. Next, we used a Chandler loop system to assess the efficacy of bivalirudin in a simple model of cardiopulmonary bypass. The loops were primed with cord or adult blood and were run until thrombus was detected. Plasma bivalirudin concentrations were measured at 1, 15, 30, 45, 60, and 75 min after initiating rotation of the loops using liquid chromatography/mass spectrometry. RESULTS Bivalirudin elicited a dose-dependent prolongation inhibition of coagulation in both cord and adult blood samples with greater potency in cord blood in comparison to adult blood (activated clotting time: 627 ± 50 vs. 452 ± 22 s at 15 μg/mL bivalirudin, p < .0001). This relative potency was also demonstrated in the Chandler loop system, but interestingly, cord blood appeared to inactivate bivalirudin more rapidly than adult blood with earlier clotting in loops containing cord blood. CONCLUSIONS This study demonstrates that bivalirudin has greater potency in cord blood in vitro than in adult blood. Plasma degradation appears to proceed more rapidly in cord blood than in adults. Both of these findings should be considered when planning dosing regimens in neonatal patients.
Collapse
Affiliation(s)
- Sergiy M Nadtochiy
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Tatsiana Stefanos
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Richard Wissler
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Yang Gu
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Changyong Feng
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Natalie Lebedko
- School of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Michael P Eaton
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| |
Collapse
|
|
13
|
Peña-Blanco L, Gutiérrez-Soriano L, Montes FR, Barragán-Méndez A, Beltrán-Villegas S, López-Reyes JJ, Villa-Hincapié CA, Umaña JP. Heparin-induced DRESS syndrome in a paediatric patient and successful anaesthetic management in cardiovascular bypass surgery: case report. J Cardiothorac Surg 2024; 19:242. [PMID: 38632589 PMCID: PMC11022424 DOI: 10.1186/s13019-024-02722-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/29/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin. CASE PRESENTATION We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia. CONCLUSION The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.
Collapse
Affiliation(s)
- Laura Peña-Blanco
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia.
| | - Laura Gutiérrez-Soriano
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
| | - Félix Ramón Montes
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
| | - Andrea Barragán-Méndez
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
- Universidad del Rosario, Bogotá, Colombia
| | - Susana Beltrán-Villegas
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
- Universidad del Rosario, Bogotá, Colombia
| | - Juan José López-Reyes
- Anesthesiology Department, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
- Universidad del Rosario, Bogotá, Colombia
| | - Carlos A Villa-Hincapié
- Department of Cardiovascular Surgery, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
| | - Juan Pablo Umaña
- Department of Cardiovascular Surgery, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
| |
Collapse
|
|
14
|
Kido K, Kabulski GM, Szymanski TW, Shiga T, Shimizu M, Hashiguchi M. Meta-Analysis Comparing Bivalirudin Versus. Unfractionated Heparin in Adult Patients With Extracorporeal Membrane Oxygenation. J Pharm Pract 2024; 37:429-434. [PMID: 36449392 DOI: 10.1177/08971900221143406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Introduction: Unfractionated heparin (UFH) has traditionally been the agent of choice in patients on extracorporeal membrane oxygenation (ECMO). However, direct thrombin inhibitors (DTI) have recently garnered more attention in ECMO because of their advantages over UFH. Given the heterogeneous results of multiple recent published studies, we performed a meta-analysis to describe pooled outcomes between bivalirudin and UFH anticoagulation in patients on ECMO. Methods: Relevant studies were identified from MEDLINE and Google Scholar database searches through April 23, 2022. The primary efficacy outcome was thromboembolism (TE), and secondary efficacy outcomes included all-cause mortality and circuit thrombosis. The primary safety outcome was major bleeding. Results: A total of 6 studies were included in the meta-analysis. Bivalirudin use was associated with significantly lower risk of TE (OR 0.61; 95% CI 0.38-.99; P = .05; I2 = 0%) and circuit thrombosis (OR 0.51; 95% CI .32-.80; P = .004; I2 = 0%) compared with UFH. There was no significant difference in all-cause mortality risk (OR 0.75; 95% CI .52-1.09; P = .13; I2 = 30%) between the bivalirudin and UFH groups. No significant difference in the risk of major bleeding between 2 groups was found (OR 0.67; 95% CI 0.25-1.81; P = .43; I2 = 80%). Conclusion: These data support that bivalirudin is a reasonable alternative to UFH in patients on ECMO. Randomized controlled trials are needed to confirm bivalirudin's efficacy and safety results compared with UFH.
Collapse
Affiliation(s)
- Kazuhiko Kido
- Department of Clinical Pharmacy, West Virginia University School of Pharmacy, Morgantown, WV, USA
| | - Galen M Kabulski
- Department of Pharmacy, Ruby Memorial Hospital, Morgantown, WV, USA
| | | | - Tsuyoshi Shiga
- Department of Clinical Pharmacology and Therapeutics, The Tokyo Jikei University School of Medicine, Tokyo, Japan
| | - Mikiko Shimizu
- Department of Pharmaceutics and Pharmacometrics, School of Pharmacy, Shujitsu University, Okayama, Japan
| | | |
Collapse
|
|
15
|
Fong KY, Yeo S, Luo H, Kofidis T, Teoh KLK, Kang GS. Stroke prevention strategies for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials. ANZ J Surg 2024; 94:522-535. [PMID: 38529814 DOI: 10.1111/ans.18947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/15/2023] [Accepted: 03/04/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND Stroke is a much-feared complication of cardiac surgery, but existing literature on preventive strategies is fragmented. Hence, a systematic review and meta-analysis of stroke prevention strategies for cardiac surgery was conducted. METHODS An electronic literature search was conducted to retrieve randomized controlled trials (RCTs) investigating perioperative interventions for cardiac surgery, with stroke as an outcome. Random-effects meta-analyses were conducted to generate risk ratios (RRs), 95% confidence intervals (95% CI), and forest plots. Descriptive analysis and synthesis of literature was conducted for interventions not amenable to meta-analysis, focusing on risks of stroke, myocardial infarction and study-defined major adverse cardiovascular events (MACE). RESULTS Fifty-six RCTs (61 894 patients) were retrieved. Many included trials were underpowered to detect differences in stroke risk. Among pharmacological therapies, only preoperative amiodarone was shown to reduce stroke risk in one trial. Concomitant left atrial appendage closure (LAAC) significantly reduced stroke risk (RR = 0.55, 95% CI = 0.36-0.84, P = 0.006) in patients with preoperative atrial fibrillation, and there was no difference in on-pump versus off-pump coronary artery bypass grafting (CABG) (RR = 0.94, 95% CI = 0.64-1.37, P = 0.735). Much controversy exists in literature on the timing of carotid endarterectomy relative to CABG in patients with severe carotid stenosis. The use of preoperative remote ischemic preconditioning was not found to reduce rates of stroke or MACE. CONCLUSION This review presents a comprehensive synthesis of existing interventions for stroke prevention in cardiac surgery, and identifies gaps in research which may benefit from future, large-scale RCTs. LAAC should be considered to reduce stroke incidence in patients with preoperative atrial fibrillation.
Collapse
Affiliation(s)
- Khi Yung Fong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Selvie Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Haidong Luo
- Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Singapore
| | - Theodoros Kofidis
- Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Singapore
| | - Kristine L K Teoh
- Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Singapore
| | - Giap Swee Kang
- Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Singapore
| |
Collapse
|
|
16
|
Yang J, Xie X, Li J, Li Y, Li B, Wang C, Jiang P. Which strategy is better for lung transplantation: Cardiopulmonary bypass or extracorporeal membrane oxygenation? Perfusion 2024:2676591241242018. [PMID: 38557237 DOI: 10.1177/02676591241242018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Background: In lung transplantation surgery, extracorporeal life support (ECLS) is essential for safety. Various support methods, including cardiopulmonary bypass (CPB) and off-pump techniques, are used, with extracorporeal membrane oxygenation (ECMO) gaining prominence. However, consensus on the best support strategy is lacking.Purpose: This article reviews risks, benefits, and outcomes of different support strategies in lung transplantation. By consolidating knowledge, it aims to clarify selecting the most appropriate ECLS modality.Research Design: A comprehensive literature review examined CPB, off-pump techniques, and ECMO outcomes in lung transplantation, including surgical results and complications.Study Sample: Studies, including clinical trials and observational research, focused on ECLS in lung transplantation, both retrospective and prospective, providing a broad evidence base.Data Collection and/or Analysis: Selected studies were analyzed for surgical outcomes, complications, and survival rates associated with CPB, off-pump techniques, and ECMO to assess safety and effectiveness.Results: Off-pump techniques are preferred, with ECMO increasingly vital as a bridge to transplant, overshadowing CPB. However, ECMO entails hidden risks and higher costs. While safer than CPB, optimizing ECMO postoperative use and monitoring is crucial for success.Conclusions: Off-pump techniques are standard, but ECMO's role is expanding. Despite advantages, careful ECMO management is crucial due to hidden risks and costs. Future research should focus on refining ECMO use and monitoring to improve outcomes, emphasizing individualized approaches for LT recipients.
Collapse
Affiliation(s)
- Jianbao Yang
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xinling Xie
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Jian Li
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Yongnan Li
- Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Bin Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Cheng Wang
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Peng Jiang
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| |
Collapse
|
|
17
|
Haffler ZJ, Hughes TG, Yeager LS. Intraoperative Bivalirudin Use in Patient Undergoing Femoral Endarterectomy with Heparin-Induced Thrombocytopenia: Case Report and Review of the Literature. Vasc Endovascular Surg 2024; 58:452-456. [PMID: 38016142 DOI: 10.1177/15385744231216034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2023]
Abstract
PURPOSE To describe the intraoperative use of bivalirudin during lower extremity revascularization in the setting of heparin-induced thrombocytopenia (HIT). CASE SUMMARY A 65 year-old man presented with left common iliac, external iliac, and femoral artery occlusion necessitating revascularization with left femoral endarterectomy and common and external iliac stent angioplasty. Three months before the femoral endarterectomy, the patient was hospitalized for a coronary artery bypass procedure. During this admission, the patient tested positive for the presence of heparin-PF4 antibody complexes. With the patient's recent history of HIT, bivalirudin was selected as the optimal agent for intraoperative anticoagulation. Bivalirudin was administered as a 50 mg bolus, followed by a continuous infusion initiated at 1.75 mg/kg/hr. Repeated bivalirudin boluses were necessary to maintain an activated clotting time (ACT) necessary for the revascularization procedures and recurrent subacute thrombi despite appropriate ACT values. DISCUSSION Bivalirudin has been utilized for cardiopulmonary bypass and carotid endarterectomy (CEA), but data for dosing in lower extremity revascularization are lacking. As the risk for thrombosis with HIT continues for months after diagnosis, it is important to elucidate optimal dosing of non-heparin anticoagulant options, such as the direct thrombin inhibitor, bivalirudin. The absence of validated dosing strategies for bivalirudin can result in prolonged operative times, increased risk of bleeding, and inadequate anticoagulation. CONCLUSION Bivalirudin is an appropriate agent for intraoperative anticoagulation in lower extremity revascularization. However, further investigation into the optimal intraoperative bivalirudin dosing regimen is necessary.
Collapse
Affiliation(s)
- Zachary J Haffler
- Department of Pharmacy, UK HealthCare, Lexington, KY, USA
- Department of Pharmacy, Pharmacy Practice and Science Department, UK College of Pharmacy, UK HealthCare, Lexington, KY, USA
| | - Travis G Hughes
- Division of Vascular and Endovascular Surgery, UK HealthCare, Lexington, KY, USA
| | | |
Collapse
|
|
18
|
Laskey D, Housman B, Dawodu G, Scheinin S. Intraoperative Extracorporeal Support during Lung Transplantation: Not Just for the High-Risk Patient. J Clin Med 2023; 13:192. [PMID: 38202198 PMCID: PMC10779858 DOI: 10.3390/jcm13010192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The use of intraoperative mechanical support during lung transplantation has traditionally been a controversial topic. Trends for intraoperative mechanical support strategies swing like a pendulum. Historically, cardiopulmonary bypass (CPB) was the modality of choice during transplantation. It provides full hemodynamic support including oxygenation and decarboxylation. Surgical exposure is improved by permitting the drainage of the heart and provides more permissive retraction. CPBs contain drainage reservoirs with hand-held pump suction catheters promoting blood conservation through collection and re-circulation. But CPB has its disadvantages. It is known to cause systemic inflammation and coagulopathy. CPB requires high doses of heparinization, which increases bleeding risks. As transplantation progressed, off-pump transplantation began to trend as a preferable option. ECMO, however, has many of the benefits of CPB with less of the risk. Outcomes were improved with ECMO compared to CPB. CPB has a higher blood transfusion requirement, a higher need for post-operative ECMO support, a higher re-intubation rate, high rates of kidney injury and need for hemodialysis, longer ICU stays, higher incidences of PGD grade 3, as well as overall in-hospital mortality when compared with ECMO use. The focus now shifts to using intraoperative mechanical support to protect the graft, helping to reduce ischemia-reperfusion injury and allowing for lung protective ventilator settings. Studies show that the routine use of ECMO during transplantation decreases the rate of primary graft dysfunction and many adverse outcomes including ventilator time, need for tracheostomy, renal failure, post-operative ECMO requirements, and others. As intraoperative planned ECMO is considered a safe and effective approach, with improved survival and better overall outcomes compared to both unplanned ECMO implementation and off-pump transplantation, its routine use should be taken into consideration as standard protocol.
Collapse
Affiliation(s)
- Daniel Laskey
- Thoracic Surgery Department, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, One Gustave L. Levy Place, Box 1023, New York, NY 10029, USA; (B.H.); (G.D.); (S.S.)
| | | | | | | |
Collapse
|
|
19
|
Eaton MP, Nadtochiy SM, Angona RE. Dabigatran in Rabbit Cardiopulmonary Bypass: Reply. Anesthesiology 2023; 139:909-910. [PMID: 37721862 DOI: 10.1097/aln.0000000000004701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Affiliation(s)
- Michael P Eaton
- University of Rochester School of Medicine and Dentistry, Rochester, New York (M.P.E.).
| | | | | |
Collapse
|
|
20
|
Boysan E, Circi R, Beyazal OF, Şener E. Bivalirudin for cardiopulmonary bypass in a patient with heparin allergy. J Cardiothorac Surg 2023; 18:258. [PMID: 37697290 PMCID: PMC10496239 DOI: 10.1186/s13019-023-02359-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 08/29/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Hypersensitivity reactions to heparin are uncommon conditions but pose a serious clinical problem for patients requiring cardiopulmonary bypass. Bivalirudin is a reversible direct thrombin inhibitor that can be used instead of heparin. CASE REPORT A 49-year-old male patient was admitted to our hospital for coronary artery bypass graft operation with mitral insufficiency and tricuspid valve insufficiency. Heparin allergy was confirmed by skin biopsy and skin tests. Due to this allergy, we used bivalirudin (Bivacard VEM drug, Turkey) during the surgery. A loading dose of 1.0 mg/kg (100 mg) bivalirudin was administered through the central line and a continuous infusion of 2.5 mg/kg/h of the anticoagulant was initiated following the approved protocol. Serial ACTs were obtained at 15-minute intervals during the procedure and the measurements were 330s, 320s, 350s, 360s, and 340s consecutively. Additional boluses of 0.5 mg/kg (50 mg) were administered for each measurement. Left anterior descending, obtuse marginal arteries and the right coronary artery were grafted with the left internal mammary and saphenous veins. Also, mitral valve replacement with St Jude mechanical heart valve and tricuspid ring annuloplasty was performed with Medtronic Duran ring. After the surgery, the patient had an uneventful period in the postoperative intensive care unit with a total of 600ml and 300ml chest tube drainage for two days and was discharged on the 7th day. CONCLUSION Alternative anticoagulation strategies are needed for cardiopulmonary bypass in patients unable to use heparin. Bivalirudin may be recommended as a viable alternative anticoagulant in patients with heparin allergy during cardiopulmonary bypass. However, each patient should be evaluated individually and it should not be forgotten that more than recommended doses may be needed.
Collapse
Affiliation(s)
- Emre Boysan
- Department of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, Turkey
| | - Renda Circi
- Department of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, Turkey
| | - Osman Fehmi Beyazal
- Department of Cardiovascular Surgery, Başakşehir Çam and Sakura City Hospital, İstanbul, Turkey.
- Cardiovascular Surgery Department, Başakşehir G-434 Street No: 2L, 34480, Başakşehir, İstanbul, Turkey.
| | - Erol Şener
- Department of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, Turkey
| |
Collapse
|
|
21
|
Cartwright B, Mundell N. Anticoagulation for cardiopulmonary bypass, Part 2: alternatives and pathological states. BJA Educ 2023; 23:256-263. [PMID: 37389280 PMCID: PMC10300449 DOI: 10.1016/j.bjae.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/28/2023] [Indexed: 07/01/2023] Open
Affiliation(s)
- B. Cartwright
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia
- University of Sydney, Sydney, NSW, Australia
| | - N. Mundell
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| |
Collapse
|
|
22
|
Revelly E, Scala E, Rosner L, Rancati V, Gunga Z, Kirsch M, Ltaief Z, Rusca M, Bechtold X, Alberio L, Marcucci C. How to Solve the Conundrum of Heparin-Induced Thrombocytopenia during Cardiopulmonary Bypass. J Clin Med 2023; 12:jcm12030786. [PMID: 36769435 PMCID: PMC9918281 DOI: 10.3390/jcm12030786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a major issue in cardiac surgery requiring cardiopulmonary bypass (CPB). HIT represents a severe adverse drug reaction after heparin administration. It consists of immune-mediated thrombocytopenia paradoxically leading to thrombotic events. Detection of antibodies against platelets factor 4/heparin (anti-PF4/H) and aggregation of platelets in the presence of heparin in functional in vitro tests confirm the diagnosis. Patients suffering from HIT and requiring cardiac surgery are at high risk of lethal complications and present specific challenges. Four distinct phases are described in the usual HIT timeline, and the anticoagulation strategy chosen for CPB depends on the phase in which the patient is categorized. In this sense, we developed an institutional protocol covering each phase. It consisted of the use of a non-heparin anticoagulant such as bivalirudin, or the association of unfractionated heparin (UFH) with a potent antiplatelet drug such as tirofiban or cangrelor. Temporary reduction of anti-PF4 with intravenous immunoglobulins (IvIg) has recently been described as a complementary strategy. In this article, we briefly described the pathophysiology of HIT and focused on the various strategies that can be applied to safely manage CPB in these patients.
Collapse
Affiliation(s)
- Etienne Revelly
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Correspondence:
| | - Emmanuelle Scala
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
| | - Lorenzo Rosner
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Valentina Rancati
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Ziyad Gunga
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Matthias Kirsch
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Zied Ltaief
- Department of Intensive Care Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Marco Rusca
- Department of Intensive Care Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Xavier Bechtold
- Department of Cardiac Surgery, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Lorenzo Alberio
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
| | - Carlo Marcucci
- Department of Anesthesiology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne (UNIL), Rue du Bugnon 21, 1011 Lausanne, Switzerland
| |
Collapse
|
|
23
|
Davidson S. Assays to Monitor Bivalirudin. Methods Mol Biol 2023; 2663:369-380. [PMID: 37204724 DOI: 10.1007/978-1-0716-3175-1_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Bivalirudin (Angiomax, Angiox) is a parenteral direct thrombin inhibitor (DTI) that is used for patients with heparin-induced thrombocytopenia (HIT), where heparin cannot be used due to the risk of thrombosis. Bivalirudin is also licensed for use in cardiology procedures (e.g., percutaneous transluminal coronary angioplasty; PTCA). Bivalirudin is a synthetic analogue of hirudin found in the saliva of the medicinal leech and has a relatively short half-life of ~25 min. Several assays can be used to monitor bivalirudin; these include the activated partial thromboplastin time (APTT), activated clotting time (ACT), ecarin clotting time (ECT), an ecarin-based chromogenic assay, thrombin time (TT), the dilute TT, and the prothrombinase-induced clotting time (PiCT). Drug concentrations can also be measured using liquid chromatography tandem mass spectrometry (LC/MS) and clotting or chromogenic-based assays with specific drug calibrators and controls.
Collapse
Affiliation(s)
- Simon Davidson
- Division of Medicine, University College London, London, UK
| |
Collapse
|
|
24
|
Waterford SD, Ad N. Reply: Nonvitamin K oral anticoagulants in cardiac surgery: New avenues. J Thorac Cardiovasc Surg 2022:S0022-5223(22)01271-5. [PMID: 36564323 DOI: 10.1016/j.jtcvs.2022.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Stephen D Waterford
- Division of Cardiac Surgery, White Oak Medical Center, Adventist HealthCare, University of Maryland, Takoma Park, Md
| | - Niv Ad
- Division of Cardiac Surgery, White Oak Medical Center, Adventist HealthCare, University of Maryland, Takoma Park, Md
| |
Collapse
|
|
25
|
Chen Y, Phoon PHY, Hwang NC. Heparin Resistance During Cardiopulmonary Bypass in Adult Cardiac Surgery. J Cardiothorac Vasc Anesth 2022; 36:4150-4160. [PMID: 35927191 PMCID: PMC9225936 DOI: 10.1053/j.jvca.2022.06.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/09/2022] [Accepted: 06/17/2022] [Indexed: 12/15/2022]
Abstract
The use of heparin for anticoagulation has changed the face of cardiac surgery by allowing a bloodless and motionless surgical field throughout the introduction of cardiopulmonary bypass (CPB). However, heparin is a drug with complex pharmacologic properties that can cause significant interpatient differences in terms of responsiveness. Heparin resistance during CPB is a weighty issue due to the catastrophic consequences stemming from inadequate anticoagulation, and the treatment of it necessitates a rationalized stepwise approach due to the multifactorial contributions toward this entity. The widespread use of activated clotting time (ACT) as a measurement of anticoagulation during CPB is examined, as it may be a false indicator of heparin resistance. Heparin resistance also has been repeatedly reported in patients infected with COVID-19, which deserves further exploration in this pandemic era. This review aims to examine the variability in heparin potency, underlying mechanisms, and limitations of using ACT for monitoring, as well as provide a framework towards the current management of heparin resistance.
Collapse
Affiliation(s)
- Yufan Chen
- Department of Anaesthesiology, Singapore General Hospital, Singapore,Department of Cardiothoracic Anesthesia, National Heart Centre, Singapore
| | - Priscilla Hui Yi Phoon
- Department of Anaesthesiology, Singapore General Hospital, Singapore,Department of Cardiothoracic Anesthesia, National Heart Centre, Singapore
| | - Nian Chih Hwang
- Department of Anaesthesiology, Singapore General Hospital, Singapore; Department of Cardiothoracic Anesthesia, National Heart Centre, Singapore.
| |
Collapse
|
|
26
|
Neunert C, Chitlur M, van Ommen CH. The Changing Landscape of Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation: Use of the Direct Thrombin Inhibitors. Front Med (Lausanne) 2022; 9:887199. [PMID: 35872781 PMCID: PMC9299072 DOI: 10.3389/fmed.2022.887199] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredictable response, challenging monitoring, development of heparin resistance, and risk of heparin-induced thrombocytopenia (HIT). Direct thrombin inhibitors (DTIs), such as bivalirudin and argatroban, might be a good alternative. This review will discuss the use of both UFH and DTIs in pediatric patients with ECMO therapy.
Collapse
Affiliation(s)
- Cindy Neunert
- Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
| | - Meera Chitlur
- Division of Hematology, Oncology, Carmen and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Central Michigan University, Detroit, MI, United States
- *Correspondence: Cornelia Heleen van Ommen,
| | - Cornelia Heleen van Ommen
- Department of Pediatric Hematology and Oncology, Erasmus Medical Center University Medical Center Sophia Children’s Hospital, Rotterdam, Netherlands
| |
Collapse
|
|
27
|
Nadtochiy SM, Stefanos T, Angona RE, Lebedko N, Baldzizhar A, Feng C, Eaton MP. Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass. Anesth Analg 2022; 135:52-59. [PMID: 35389372 DOI: 10.1213/ane.0000000000006019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB. METHODS The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition. RESULTS In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban. CONCLUSIONS The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.
Collapse
Affiliation(s)
- Sergiy M Nadtochiy
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Tatsiana Stefanos
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Ronald E Angona
- Cardiovascular Perfusion, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, New York
| | - Natalie Lebedko
- SUNY Upstate Medical University, School of Medicine, Syracuse, New York
| | - Aksana Baldzizhar
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Changyong Feng
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Michael P Eaton
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| |
Collapse
|
|
28
|
A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation. Transplantation 2022; 106:2143-2154. [PMID: 35642975 DOI: 10.1097/tp.0000000000004195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Direct-acting oral anticoagulant (DOAC) use has increased dramatically since their introduction because of the growing evidence of proven efficacy and enhanced safety compared with warfarin and the low-molecular-weight heparins in the general population. Unfortunately, there is a dearth of quality data regarding the safety and efficacy of the DOACs in patients awaiting organ transplant and those who received a solid organ transplant. This review aims to evaluate the available literature and considerations regarding anticoagulation use in transplant recipients, focusing on preoperative, perioperative, and postoperative DOAC use.
Collapse
|
|
29
|
Sharma G, Hasija S, Kapoor PM. Perfusion Strategies for Bivalirudin Anticoagulation: AIIMS Protocol. JOURNAL OF CARDIAC CRITICAL CARE TSS 2022. [DOI: 10.1055/s-0042-1750011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
AbstractAnticoagulation strategies for cardiac surgery are witnessing a change with the identification of serious limitations of heparin, including development of resistance in 3 to 13% of patients undergoing cardiac surgery and heparin-induced thrombocytopenia/thrombosis syndrome in 1 to 5.5% of patients. Heparin alternatives have a potential role in these scenarios. Bivalirudin, a reversible direct thrombin inhibitor, has an onset time of 2 to 4 minutes and half-life of 25 minutes, is eliminated mainly by a proteolytic mechanism, does not require antithrombin III for effect, and is nonimmunogenic. The considerations for extracorporeal circulation are peculiar with its use, and this article outlines the aspects of initiating, maintaining, and terminating cardiopulmonary bypass and extracorporeal membrane oxygenation with bivalirudin as the anticoagulant.
Collapse
Affiliation(s)
- Gaurav Sharma
- Department of Perfusion Technology, All India Institute of Medical Sciences, New Delhi, India
| | - Suruchi Hasija
- Department of Cardiac Anaesthesia and Critical Care, All India Institute of Medical Sciences, New Delhi, India
| | - Poonam Malhotra Kapoor
- Department of Cardiac Anaesthesia and Critical Care, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
30
|
Management of Heparin-Induced Thrombocytopenia Using Plasmapharesis in Patients Undergoing HeartMate 3 Left Ventricular Assist Device. ASAIO J 2021; 68:e152-e155. [PMID: 34967780 DOI: 10.1097/mat.0000000000001631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) type-2 is a rare, but life-threatening complication that presents a unique challenge in patients undergoing cardiac surgery. Patients that require cardiac surgery with HIT present a dilemma between intraoperative anticoagulation, perioperative bleeding risk, and perioperative thrombotic events. We describe a case series of four patients who developed HIT in their hospital course before HeartMate 3 (HM3) left ventricular assist device implantation. Following a multidisciplinary approach, all patients did well intraoperatively with an approach of preoperative plasmapheresis, intraoperative unfractionated heparin (UFH), and postoperative conversion to bivalirudin with a bridge to warfarin. However, two patients had postoperative bleeding complications on bivalirudin. This case series details the therapeutic challenges encountered for HM3 implantation in patients with HIT and offers a therapeutic alternative to intraoperative bivalirudin in the effort to decrease perioperative complications in this challenging patient population.
Collapse
|
|
31
|
Ito Y, Saito A, Shirai Y, Motomura N. Off-pump coronary artery bypass with heparin in a patient with a history of heparin-induced thrombocytopenia: a case report. Surg Case Rep 2021; 7:265. [PMID: 34928442 PMCID: PMC8688592 DOI: 10.1186/s40792-021-01339-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/03/2021] [Indexed: 12/04/2022] Open
Abstract
Background Cardiovascular surgery for patients with a history of heparin-induced thrombocytopenia (HIT) with thrombosis requires careful perioperative anticoagulation therapy. When cardiovascular surgery is required for patients having ‘remote’ HIT, such as those who had a history of HIT and platelet factor-4/heparin antibodies turned out to be negative, it is recommended that re-exposure to heparin should be limited only to the intraoperative phase. However, few case reports have described detailed strategies for perioperative anticoagulation regimens. Case presentation We present the case of a 76-year-old woman, presenting with unstable angina pectoris and requiring coronary artery bypass grafting. She had a history of cardiac resuscitation and percutaneous coronary intervention for unstable angina pectoris with ventricular tachycardia 7 years prior, which caused HIT with thrombosis resulting in amputation of four fingers. On admission, platelet factor-4/heparin antibodies, biomarkers for HIT were not detected; the platelet count was 18.0 × 104/µl. Off-pump coronary artery bypass grafting was performed using heparin; argatroban infusion was continued until 9 h prior to the operation and restarted 3 h postoperatively, bridged with regular warfarin from 4 days to 3 months postoperatively. Platelet factor-4 /heparin antibodies were detected on postoperative day 8 without any clinical symptoms and became negative by day 91. Conclusion We consider this anticoagulation strategy is effective especially in countries, where bivalirudin is not available. Re-exposure to heparin in cardiovascular surgery for patients with a history of ‘remote HIT’ is reasonable, and appropriate anticoagulation is important for an uneventful postoperative course.
Collapse
Affiliation(s)
- Yuya Ito
- Department of Cardiovascular Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan
| | - Aya Saito
- Department of Cardiovascular Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan.
| | - Yuki Shirai
- Department of Cardiovascular Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan
| | - Noboru Motomura
- Department of Cardiovascular Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan
| |
Collapse
|
|
32
|
Pishko AM. Heparin-induced thrombocytopenia and cardiovascular surgery. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2021; 2021:536-544. [PMID: 34889428 PMCID: PMC8791147 DOI: 10.1182/hematology.2021000289] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Clinicians generally counsel patients with a history of heparin-induced thrombocytopenia (HIT) to avoid heparin products lifelong. Although there are now many alternative (nonheparin) anticoagulants available, heparin avoidance remains challenging for cardiac surgery. Heparin is often preferred in the cardiac surgery setting based on the vast experience with the agent, ease of monitoring, and reversibility. To "clear" a patient with a history of HIT for cardiac surgery, hematologists must first confirm the diagnosis of HIT, which can be challenging due to the ubiquity of heparin exposure and frequency of thrombocytopenia in patients in the cardiac intensive care unit. Next, the "phase of HIT" (acute HIT, subacute HIT A/B, or remote HIT) should be established based on platelet count, immunoassay for antibodies to platelet factor 4/heparin complexes, and a functional assay (eg, serotonin release assay). As long as the HIT functional assay remains positive (acute HIT or subacute HIT A), cardiac surgery should be delayed if possible. If surgery cannot be delayed, an alternative anticoagulant (preferably bivalirudin) may be used. Alternatively, heparin may be used with either preoperative/intraoperative plasma exchange or together with a potent antiplatelet agent. The optimal strategy among these options is not known, and the choice depends on institutional experience and availability of alternative anticoagulants. In the later phases of HIT (subacute HIT B or remote HIT), brief intraoperative exposure to heparin followed by an alternative anticoagulant as needed in the postoperative setting is recommended.
Collapse
Affiliation(s)
- Allyson M. Pishko
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Correspondence Allyson M. Pishko, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, 3rd Floor Dulles, Philadelphia, PA 19104; e-mail:
| |
Collapse
|
|
33
|
Wanat-Hawthorne A, Tanaka K, Angona R, Feng C, Eaton M. Survey of Practice Pattern in Patients With Heparin-Induced Thrombocytopenia Requiring Cardiopulmonary Bypass. Anesth Analg 2021; 133:1180-1186. [PMID: 34415867 DOI: 10.1213/ane.0000000000005721] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are routinely anticoagulated with heparin before the initiation of bypass. Heparin is contraindicated, however, in patients with acute HIT, and alternatives to routine practice are often used. While guidelines have recently been published addressing this topic 10, there remains variance between institutions in how these cases are treated. Our goal was to better delineate practice trends in the diagnosis and management of HIT patients requiring CPB. METHODS We surveyed members of the Society of Cardiovascular Anesthesiologists (SCA) and the American Society for Extracorporeal Technology (AmSECT) using an online survey tool. RESULTS We received 304 completed surveys (5.8% response rate), 75% completed by an anesthesiologist, and 24% by a perfusionist. The majority of respondents used clinical history and/or antibody testing (71% and 63%, respectively) to diagnose HIT. Seventy-five percent of respondents reported using an institutional protocol for HIT-CPB cases. Most respondents (89%) reported having at least 1 case in the last 3 years, with a total case experience of at least 785 cases (785 = the minimum number of cases in each case volume category × the number of respondents choosing that category). The strategy recommended in published guidelines, bivalirudin, was the most commonly reported alternative anticoagulation strategy (75%) used by respondents in HIT cases, with most (83%) using the activated clotting time (ACT) to monitor anticoagulation. CONCLUSIONS Most responding SCA and AmSECT members reported that their institution used a protocol or guideline for HIT/CPB cases, and most guidelines directed the use of bivalirudin as an alternative anticoagulant. Various other methods such as plasmapheresis are also being used with success in this patient population. Further research, including comparison studies of alternative anticoagulant strategies, is required to elucidate the best approach to these difficult cases.
Collapse
Affiliation(s)
- Alycia Wanat-Hawthorne
- From the Department of Anesthesiology and Pain Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kenichi Tanaka
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ronald Angona
- Department of Cardiovascular Perfusion, University of Rochester Medical Center, Rochester, New York
| | | | - Michael Eaton
- Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| |
Collapse
|
|
34
|
Abstract
From preoperative medications to intraoperative needs to postoperative thromboprophylaxis, anticoagulants are encountered throughout the perioperative period. This review focuses on coagulation testing clinicians utilize to monitor the effects of these medications.
Collapse
|
|
35
|
Extracorporeal Membrane Oxygenation Complications in Heparin- and Bivalirudin-Treated Patients. Crit Care Explor 2021; 3:e0485. [PMID: 34278315 PMCID: PMC8280085 DOI: 10.1097/cce.0000000000000485] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Supplemental Digital Content is available in the text. OBJECTIVES: Extracorporeal membrane oxygenation is a potentially life-saving intervention in refractory cardiopulmonary failure, but it requires anticoagulation to prevent circuit thromboses, which exposes the patient to hemorrhagic complications. Heparin has traditionally been the anticoagulant of choice, but the direct thrombin inhibitor bivalirudin is routinely used in cases of heparin-induced thrombocytopenia and has been suggested as a superior choice. We sought to examine the timing of hemorrhagic and thrombotic complications after extracorporeal membrane oxygenation cannulation and to compare the rates of such complications between patients anticoagulated with heparin versus bivalirudin. DESIGN: Retrospective cohort study. SETTING: Johns Hopkins Hospital patients between January 2016 and July 2019. PATIENTS: Adult (> 18 yr) extracorporeal membrane oxygenation patients. INTERVENTIONS: Patients were anticoagulated either with heparin or bivalirudin. MEASUREMENTS AND MAIN RESULTS: We compared rates of hemorrhagic and thrombotic complications by time on heparin versus bivalirudin and characterized the average time to each complication. Of 144 extracorporeal membrane oxygenation patients (mean age 55.3 yr; 58% male), 41% were on central venoarterial extracorporeal membrane oxygenation, 40% on peripheral venoarterial extracorporeal membrane oxygenation, and 19% on venovenous extracorporeal membrane oxygenation. Thirteen patients (9%) received bivalirudin during their extracorporeal membrane oxygenation run, due to concern for (n = 8) or diagnosis of (n = 4) heparin-induced thrombocytopenia or for heparin resistance (n = 1). The rate of hemorrhagic or thrombotic complications did not differ between heparin (0.13/d) and bivalirudin (0.06/d; p = 0.633), but patients on bivalirudin received significantly fewer blood transfusions (1.0 U of RBCs/d vs 2.9/d on heparin; p < 0.001). CONCLUSIONS: Our results confirm the safety and efficacy of bivalirudin as an alternative anticoagulant in extracorporeal membrane oxygenation and suggest a potential benefit in less blood product transfusion, although prospective studies are needed to evaluate the true effect of bivalirudin versus the disease processes that prompted its use in our study population.
Collapse
|
|
36
|
Simon ER, Rakholia M, McHenry ML, Mishra PK, Singh R, Javangula K, Minhaj MM, Chaney MA. Cardiac Surgery in a Patient With Antiphospholipid Syndrome and Heparin-Induced Thrombocytopenia. J Cardiothorac Vasc Anesth 2021; 36:1196-1206. [PMID: 34344598 DOI: 10.1053/j.jvca.2021.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 11/11/2022]
Affiliation(s)
- Eric R Simon
- Department of Anesthesiology, Perioperative, and Pain Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Milap Rakholia
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA
| | - Marie LaPenta McHenry
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA
| | - Pankaj Kumar Mishra
- Department of Cardiac Surgery, Yorkshire Heart Centre, Leeds General Infirmary, Leeds, United Kingdom
| | - Rajendra Singh
- Cardiac Anaesthesia and Critical Care, Yorkshire Heart Centre, Leeds General Infirmary, Leeds, United Kingdom
| | - Kalyana Javangula
- Department of Cardiac Surgery, Yorkshire Heart Centre, Leeds General Infirmary, Leeds, United Kingdom
| | - Mohammed M Minhaj
- Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL
| | - Mark A Chaney
- Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL.
| |
Collapse
|
|
37
|
Wahba A, Milojevic M, Boer C, De Somer FMJJ, Gudbjartsson T, van den Goor J, Jones TJ, Lomivorotov V, Merkle F, Ranucci M, Kunst G, Puis L. 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery. Eur J Cardiothorac Surg 2021; 57:210-251. [PMID: 31576396 DOI: 10.1093/ejcts/ezz267] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Alexander Wahba
- Department of Cardio-Thoracic Surgery, St Olav's University Hospital, Trondheim, Norway.,Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Milan Milojevic
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, Dedinje Cardiovascular Institute, Belgrade, Serbia.,Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Christa Boer
- Department of Anaesthesiology, Amsterdam UMC, VU University, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
| | | | - Tomas Gudbjartsson
- Department of Cardiothoracic Surgery, Faculty of Medicine, Landspitali University Hospital, University of Iceland, Reykjavik, Iceland
| | - Jenny van den Goor
- Department of Cardiothoracic Surgery, Academic Medical Centre of the University of Amsterdam, Amsterdam, Netherlands
| | - Timothy J Jones
- Department of Paediatric Cardiac Surgery, Birmingham Women's and Children's Hospital, Birmingham, UK
| | - Vladimir Lomivorotov
- Department of Anesthesiology and Intensive Care, E. Meshalkin National Medical Research Center, Novosibirsk State University, Novosibirsk, Russia
| | - Frank Merkle
- Academy for Perfusion, Deutsches Herzzentrum, Berlin, Germany
| | - Marco Ranucci
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Gudrun Kunst
- Department of Anaesthetics and Pain Medicine, King's College Hospital NHS Foundation Trust and School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Luc Puis
- Department of Perfusion, University Hospital Brussels, Jette, Belgium
| | | |
Collapse
|
|
38
|
Behandlung der heparininduzierten Thrombozytopenie unter extrakorporaler Membranoxygenierung. ZEITSCHRIFT FUR HERZ THORAX UND GEFASSCHIRURGIE 2021. [DOI: 10.1007/s00398-021-00437-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
39
|
Zaleski KL, DiNardo JA, Eaton MP. Bivalirudin: Are kids just adults to the ¾ power? Paediatr Anaesth 2021; 31:628-630. [PMID: 34029430 DOI: 10.1111/pan.14168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/12/2021] [Accepted: 02/28/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Katherine L Zaleski
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | - James A DiNardo
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Michael P Eaton
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| |
Collapse
|
|
40
|
Wolstencroft P, Arnold P, Anderson BJ. Dose estimation for bivalirudin during pediatric cardiopulmonary bypass. Paediatr Anaesth 2021; 31:637-643. [PMID: 33423355 DOI: 10.1111/pan.14125] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/15/2020] [Accepted: 01/05/2021] [Indexed: 01/19/2023]
Abstract
AIM A typical adult-based bivalirudin regimen during cardiopulmonary bypass uses a loading dose of 1 mg kg-1 and a circuit prime (volume L × 13 mg) with a subsequent intravenous infusion 2.5 mg h-1 kg-1 . Dose in children remains unknown. We wished to determine a practical bivalirudin dosing schedule for children undergoing surgery with cardiopulmonary bypass. METHODS Published pharmacokinetic parameters in children who were anticoagulated for cardiac catheterization using bivalirudin were compared to adult by scaling for size using allometry. An infusion regimen suitable for children was determined using a bivalirudin target concentration (13 mg L-1 ) common in adults for effect during cardiopulmonary bypass. Predicted bivalirudin infusion rates in children were compared to regimens published as case reports. RESULTS Current pediatric bivalirudin infusion rates are based on those used in adults with titration during cardiopulmonary bypass to achieve activated clotting times longer than 400 s. Bivalirudin clearance (mL min-1 kg-1 ) can be estimated in children by scaling adult parameters using allometry. Clearance decreases through childhood and higher infusion rates in children would achieve target concentration rapidly without the need to titrate initial infusion rate. An infusion rate of 4.5 mg h-1 kg-1 in a 10 kg infant, 4 mg h-1 kg-1 in a 20 kg child and 3.5 mg h-1 kg-1 in a child 30-40 kg will target an activated clotting time slower than 400 s. Adult regimens could be used in those children heavier than 50 kg. CONCLUSION Bivalirudin infusion in children should be started after loading dose at rates greater than those used in adults. Dose in neonates remains uncertain because neither pharmacokinetics nor coagulation pharmacodynamics have been adequately characterized.
Collapse
Affiliation(s)
- Philip Wolstencroft
- Department of Paediatric Anaesthesia, Starship Children's Hospital, Auckland, New Zealand
| | - Philip Arnold
- Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's Hospital, Liverpool, UK
| | - Brian J Anderson
- Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
41
|
Loyaga-Rendon RY, Kazui T, Acharya D. Antiplatelet and anticoagulation strategies for left ventricular assist devices. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:521. [PMID: 33850918 PMCID: PMC8039667 DOI: 10.21037/atm-20-4849] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Left ventricular assist devices (LVAD) have revolutionized the management of advanced heart failure. However, complications rates remain high, among which hemorrhagic and thrombotic complications are the most important. Antiplatelet and anticoagulation strategies form a cornerstone of LVAD management and may directly affect LVAD complications. Concurrently, LVAD complications influence anticoagulation and anticoagulation management. A thorough understanding of device, patient, and management, including anticoagulation and antiplatelet therapies, are important in optimizing LVAD outcomes. This article provides a comprehensive state of the art review of issues related to antiplatelet and anticoagulation management in LVADs. We start with a historical overview, the epidemiology and pathophysiology of bleeding and thrombotic complications in LVADs. We then discuss platelet and anticoagulation biology followed by considerations prior to, during, and after LVAD implantation. This is followed by discussion of anticoagulation and the management of thrombotic and hemorrhagic complications. Specific problems, including management of heparin-induced thrombocytopenia, anticoagulant reversal, novel oral anticoagulants, artificial heart valves, and noncardiac surgeries are covered in detail.
Collapse
Affiliation(s)
| | - Toshinobu Kazui
- Division of Cardiothoracic Surgery, University of Arizona, Tucson, AZ, USA
| | - Deepak Acharya
- Division of Cardiovascular Diseases, University of Arizona, Tucson, AZ, USA
| |
Collapse
|
|
42
|
Nadtochiy SM, Baldzizhar A, Stefanos T, Feng C, O'Leary KE, Jones-Smith KL, Angona RE, Eaton MP. High-Dose Dabigatran Is an Effective Anticoagulant for Simulated Cardiopulmonary Bypass Using Human Blood. Anesth Analg 2021; 132:566-574. [PMID: 32833714 DOI: 10.1213/ane.0000000000005089] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Currently no ideal alternative exists for heparin for cardiopulmonary bypass (CPB). Dabigatran is a direct thrombin inhibitor for which a reversal agent exists. The primary end point of the study was to explore whether Dabigatran was an effective anticoagulant for 120 minutes of simulated CPB. METHODS The study was designed in 2 sequential steps. Throughout, human blood from healthy donors was used for each experimental step. Initially, increasing concentrations of Dabigatran were added to aliquots of fresh whole blood, and the anticoagulant effect measured using kaolin/tissue factor-activated thromboelastography (rapidTEG). The dynamics of all thromboelastography (TEG) measurements were studied with repeated measures analysis of variance (ANOVA). Based on these data, aliquots of blood were treated with high-concentration Dabigatran and placed in a Chandler loop as a simple ex vivo bypass model to assess whether Dabigatran had sufficient anticoagulant effects to maintain blood fluidity for 2 hours of continuous contact with the artificial surface of the PVC tubing. Idarucizumab, humanized monoclonal antibody fragment, was used to verify the reversibility of Dabigatran effects. Finally, 3 doses of Dabigatran were tested in a simulated CPB setup using a heart-lung machine and a commercially available bypass circuit with an arteriovenous (A-V) loop. The primary outcome was the successful completion of 120 minutes of simulated CPB with dabigatran anticoagulation, defined as lack of visible thrombus. Thromboelastographic reaction (R) time was measured repeatedly in each bypass simulation, and the circuits were continuously observed for clot. Scanning Electron Microscopy (SEM) was used to visualize fibrin formation in the filters meshes during CPB. RESULTS In in vitro blood samples, Dabigatran prolonged R time and reduced the dynamics of clot propagation (as measured by speed of clot formation [Angle], maximum rate of thrombus generation [MRTG], and time to maximum rate of thrombus generation [TMRTG]) in a dose-dependent manner. In the Chandler Loop, high doses of Dabigatran prevented clot formation for 120 minutes, but only at doses higher than expected. Idarucizumab decreased R time and reversed anticoagulation in both in vitro and Chandler Loops settings. In the A-V loop bypass simulation, Dabigatran prevented gross thrombus generation for 120 minutes of simulated CPB. CONCLUSIONS Using sequential experimental approaches, we showed that direct thrombin inhibitor Dabigatran in high doses maintained anticoagulation of blood for simulated CPB. Idarucizumab reduced time for clot formation reversing the anticoagulation action of Dabigatran.
Collapse
Affiliation(s)
- Sergiy M Nadtochiy
- From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Squiccimarro E, Jiritano F, Serraino GF, ten Cate H, Paparella D, Lorusso R. Quantitative and Qualitative Platelet Derangements in Cardiac Surgery and Extracorporeal Life Support. J Clin Med 2021; 10:jcm10040615. [PMID: 33561947 PMCID: PMC7914426 DOI: 10.3390/jcm10040615] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 01/19/2023] Open
Abstract
Thrombocytopenia and impaired platelet function are known as intrinsic drawbacks of cardiac surgery and extracorporeal life supports (ECLS). A number of different factors influence platelet count and function including the inflammatory response to a cardiopulmonary bypass (CPB) or to ECLS, hemodilution, hypothermia, mechanical damage and preoperative treatment with platelet-inhibiting agents. Moreover, although underestimated, heparin-induced thrombocytopenia is still a hiccup in the perioperative management of cardiac surgical and, above all, ECLS patients. Moreover, recent investigations have highlighted how platelet disorders also affect patients undergoing biological prosthesis implantation. Though many hypotheses have been suggested, the mechanism underlying thrombocytopenia and platelet disorders is still to be cleared. This narrative review aims to offer clinicians a summary of their major causes in the cardiac surgery setting.
Collapse
Affiliation(s)
- Enrico Squiccimarro
- Department of Cardiac Surgery, Mater Dei Hospital, 70125 Bari, Italy;
- Department of Emergency and Organ Transplant (DETO), University of Bari, 70125 Bari, Italy
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands;
| | - Federica Jiritano
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands;
- Cardiac Surgery Unit, Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
- Correspondence:
| | - Giuseppe Filiberto Serraino
- Cardiac Surgery Unit, Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Hugo ten Cate
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, D-55131 Mainz, Germany;
- Thrombosis Center Maastricht, Maastricht University Medical Center (MUMC), 6229HX Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), 6229HX Maastricht, The Netherlands
| | - Domenico Paparella
- Division of Cardiac Surgery, Santa Maria Hospital, GVM Care & Research, 70125 Bari, Italy;
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Roberto Lorusso
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands;
- Cardiovascular Research Institute Maastricht (CARIM), 6229HX Maastricht, The Netherlands
| |
Collapse
|
|
44
|
Moreno-Duarte I, Cooter M, Onwuemene OA, Ghadimi K, Welsby IJ. Clinical outcomes of cardiac surgery patients undergoing therapeutic plasma exchange for heparin-induced thrombocytopenia. Vox Sang 2021; 116:217-224. [PMID: 32965049 PMCID: PMC10308265 DOI: 10.1111/vox.13008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/29/2020] [Accepted: 08/31/2020] [Indexed: 10/14/2023]
Abstract
BACKGROUND AND OBJECTIVES Heparin-induced thrombocytopenia (HIT) is an antibody-mediated condition that leads to thrombocytopenia and possible thrombosis. Patients with HIT who require cardiac surgery pose a challenge as high doses of heparin or heparin alternatives are required to permit cardiopulmonary bypass (CPB). Intraoperative therapeutic plasma exchange (TPE) is a valuable adjunct in the management of antibody-mediated syndromes including HIT. The clinical impact of TPE on thromboembolic events, bleeding and mortality after heparin re-exposure is not well established. We hypothesized that TPE with heparin re-exposure will not lead to HIT-related thromboembolic events, bleeding or increased mortality after cardiac surgery with CPB. MATERIALS AND METHODS We reviewed 330 patients who received perioperative TPE between September 2012 and September 2017. RESULTS Twenty four patients received TPE for HIT before anticipated heparin use for CPB. Most patients were males (79%) scheduled for advanced heart failure therapies. Three patients (12·5%) died within 30 days after surgery but none of the deaths were considered HIT-related. Thromboembolic events (TE) occurred in 3 patients within 7 days of surgery; of those, two were possibly HIT-related. CONCLUSION Therapeutic plasma exchange with heparin re-exposure was not strongly associated with HIT-related thrombosis/death after cardiac surgery with CPB.
Collapse
Affiliation(s)
| | - Mary Cooter
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Oluwatoyosi A Onwuemene
- Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Kamrouz Ghadimi
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ian J Welsby
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| |
Collapse
|
|
45
|
Arepally GM, Padmanabhan A. Heparin-Induced Thrombocytopenia: A Focus on Thrombosis. Arterioscler Thromb Vasc Biol 2021; 41:141-152. [PMID: 33267665 PMCID: PMC7769912 DOI: 10.1161/atvbaha.120.315445] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 11/13/2020] [Indexed: 01/19/2023]
Abstract
Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.
Collapse
Affiliation(s)
| | - Anand Padmanabhan
- Divisions of Hematopathology, Transfusion Medicine, and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (A.P.)
| |
Collapse
|
|
46
|
Weingarten N, Schraufnagel D, Plitt G, Zaki A, Ayyat KS, Elgharably H. Comparison of mechanical cardiopulmonary support strategies during lung transplantation. Expert Rev Med Devices 2020; 17:1075-1093. [PMID: 33090042 DOI: 10.1080/17434440.2020.1841630] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Lung transplantation outcomes are influenced by the intraoperative mechanical cardiopulmonary support strategy used. This surgery was historically done either on cardiopulmonary bypass (CPB) or off pump. Recently, there has been increased interest in intraoperative support with veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO). However, there is a lack of consensus on the relative risks, benefits and indications for each intraoperative support strategy. AREAS COVERED This review includes information from cohort studies, case-control studies, and case series that compare morbidity and/or mortality of two or more intraoperative cardiopulmonary support strategies during lung transplantation. EXPERT OPINION The optimal strategy for intraoperative cardiopulmonary support during lung transplantation remains an area of debate. Current data suggest that off pump is associated with better outcomes and could be considered whenever feasible. ECMO is generally associated with preferable outcomes to CPB, but the data supporting this association is not robust. Interestingly, whether CPB is unplanned or prolonged might influence outcomes more than the use of CPB itself. These observations can help guide surgical teams in their approach for intraoperative mechanical support strategy during lung transplantation and should serve as the basis for further investigations.
Collapse
Affiliation(s)
- Noah Weingarten
- Department of General Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| | - Dean Schraufnagel
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| | - Gilman Plitt
- Department of General Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| | - Anthony Zaki
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| | - Kamal S Ayyat
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| | - Haytham Elgharably
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation , Cleveland, OH, USA
| |
Collapse
|
|
47
|
Abstract
Purpose of Review This review will illustrate the importance of heparin-induced thrombocytopenia in the intraoperative and critical care settings. Recent Findings Heparin-induced thrombocytopenia (HIT) occurs more frequently in surgical patients compared with medical patients due to the inflammatory release of platelet factor 4 and perioperative heparin exposure. Recognition of this disease requires a high index of suspicion. Diagnostic tools and therapeutic strategies have been expanded and refined in recent years. Summary HIT is a condition where antibodies against the heparin/platelet factor 4 complex interact with platelet receptors to promote platelet activation, aggregation, and thrombus formation. Our review will focus on intraoperative and postoperative considerations related to HIT to help the clinician better manage this rare but often devastating hypercoagulable disease process.
Collapse
|
|
48
|
Erdoes G, Ortmann E, Martinez Lopez De Arroyabe B, Reid C, Koster A. Role of Bivalirudin for Anticoagulation in Adult Perioperative Cardiothoracic Practice. J Cardiothorac Vasc Anesth 2020; 34:2207-2214. [DOI: 10.1053/j.jvca.2019.08.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/25/2019] [Accepted: 08/14/2019] [Indexed: 12/11/2022]
|
|
49
|
Rizk J, Mehra MR. Anticoagulation management strategies in heart transplantation. Prog Cardiovasc Dis 2020; 63:210-218. [PMID: 32035125 DOI: 10.1016/j.pcad.2020.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/19/2022]
Abstract
Anticoagulation before, during, and after heart transplantation (HT) presents unique challenges to clinicians. Bleeding and thrombotic morbidity continues to affect this patient population throughout all phases of the HT journey. Reversal is commonly required since patients are commonly bridged to HT with left ventricular assist devices, which require chronic anti platelet and anticoagulation. Caution must be exercised in patients requiring cardiopulmonary bypass during surgery who are at risk of complications from heparin induced thrombocytopenia. The reported incidence of venous thromboembolism following HT is high, particularly during the first post-HT year, most likely due to surgery, biopsies, specific immunosuppression (mTOR inhibitors) and immobilization. It is crucial to maintain long-term oral anticoagulation after the first venous thromboembolism event, especially when risk factors exist. A major issue, and one for which there remains considerable debate, is the optimal treatment of such complications, particularly upper extremity venous thrombosis. For both warfarin and the thrombin inhibitors or Factor Xa inhibitors, the clinician must determine potential drug interactions based on the HT drug regimen, and then develop a patient-specific management strategy.
Collapse
Affiliation(s)
- John Rizk
- Arizona State University, Edson College, Phoenix, AZ, United States of America
| | - Mandeep R Mehra
- Brigham and Women's Heart & Vascular Center and Harvard Medical School, Boston, MA, United States of America.
| |
Collapse
|
|
50
|
Puis L, Milojevic M, Boer C, De Somer FMJJ, Gudbjartsson T, van den Goor J, Jones TJ, Lomivorotov V, Merkle F, Ranucci M, Kunst G, Wahba A. 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery. Interact Cardiovasc Thorac Surg 2020; 30:161-202. [PMID: 31576402 PMCID: PMC10634377 DOI: 10.1093/icvts/ivz251] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Luc Puis
- Department of Perfusion, University Hospital Brussels, Jette, Belgium
| | - Milan Milojevic
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, Dedinje Cardiovascular Institute, Belgrade, Serbia
- Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Christa Boer
- Department of Anaesthesiology, Amsterdam UMC, VU University, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands
| | | | - Tomas Gudbjartsson
- Department of Cardiothoracic Surgery, Faculty of Medicine, Landspitali University Hospital, University of Iceland, Reykjavik, Iceland
| | - Jenny van den Goor
- Department of Cardiothoracic Surgery, Academic Medical Centre of the University of Amsterdam, Amsterdam, Netherlands
| | - Timothy J Jones
- Department of Paediatric Cardiac Surgery, Birmingham Women’s and Children’s Hospital, Birmingham, UK
| | - Vladimir Lomivorotov
- Department of Anesthesiology and Intensive Care, E. Meshalkin National Medical Research Center, Novosibirsk State University, Novosibirsk, Russia
| | - Frank Merkle
- Academy for Perfusion, Deutsches Herzzentrum, Berlin, Germany
| | - Marco Ranucci
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Gudrun Kunst
- Department of Anaesthetics and Pain Medicine, King's College Hospital NHS Foundation Trust and School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Alexander Wahba
- Department of Cardio-Thoracic Surgery, St Olav s University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| |
Collapse
|