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Tigano S, Casolaro G, Bianchini A, Bernardi E, Laici C, Ramahi L, Vitale G, Siniscalchi A. Hemodynamic Monitoring During Liver Transplantation for Patients on Perioperative Extracorporeal Membrane Oxygenation (ECMO) Support: A Narrative Review. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:768. [PMID: 40283059 PMCID: PMC12028808 DOI: 10.3390/medicina61040768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/04/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Indications for liver transplants are increasing worldwide due to the growing number of transplants performed on patients with significant cardiovascular and respiratory risk factors. Additional support for this trend comes from the growing use of marginal organs, which is made possible by donations made after circulatory death (DCD). Liver transplantation (LT) in such high-risk patients may be challenging and may require perioperative Extracorporeal Membrane Oxygenation (ECMO). There is a lack of evidence on the best hemodynamic monitoring techniques for patients undergoing ECMO support during the perioperative period of LT. This review aims to provide a comprehensive overview of the hemodynamic monitoring standards of patients supported by ECMO before, during, and after LT. Materials and Methods: Comprehensive research was conducted through the PubMed database, and 153 articles regarding patients who needed perioperative ECMO support were found. Among these, 18 articles were finally included in our analysis as the authors specified hemodynamic monitoring techniques and data. The articles included case reports, letters to the editor, and correspondence. Results: We identified 20 cases of patients supported by ECMO as a planned preoperative strategy (9 patients), as a rescue therapy during surgery (7 patients), and as a postoperative support (4 patients). Cardiac catheterism and echocardiography (transthoracic and transesophageal) were the authors' most cited hemodynamic monitoring techniques. Conclusions: Data on hemodynamic monitoring methods used to manage patients supported by ECMO during the whole perioperative period of LT are poor and derived from descriptive low-quality studies. However, a multimodal approach that includes continuous monitoring of pulmonary pressures and echocardiography can increase diagnostic accuracy and improve the decision-making process to manage this complex patient population.
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Affiliation(s)
- Stefano Tigano
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
| | - Giulio Casolaro
- Dipartimento di Scienze Mediche e Chirurgiche, Anesthesia and Intensive Care Medicine, Università di Bologna, 40126 Bologna, Italy;
| | - Amedeo Bianchini
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
| | - Enrico Bernardi
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
| | - Cristiana Laici
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
| | - Linda Ramahi
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
| | - Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Antonio Siniscalchi
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.T.); (A.B.); (E.B.); (C.L.); (L.R.); (A.S.)
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2
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Sánchez Pérez B, Pérez Reyes M, Aranda Narvaez J, Santoyo Villalba J, Perez Daga JA, Sanchez-Gonzalez C, Santoyo-Santoyo J. New therapeutic strategy with extracorporeal membrane oxygenation for refractory hepatopulmonary syndrome after liver transplant: A case report. World J Transplant 2024; 14:89223. [PMID: 38576766 PMCID: PMC10989480 DOI: 10.5500/wjt.v14.i1.89223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/24/2023] [Accepted: 12/22/2023] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Due to the lack of published literature about treatment of refractory hepatopulmonary syndrome (HPS) after liver transplant (LT), this case adds information and experience on this issue along with a treatment with positive outcomes. HPS is a complication of end-stage liver disease, with a 10%-30% incidence in cirrhotic patients. LT can reverse the physiopathology of this process and restore normal oxygenation. However, in some cases, refractory hypoxemia persists, and extracorporeal membrane oxygenation (ECMO) can be used as a rescue therapy with good results. CASE SUMMARY A 59-year-old patient with alcohol-related liver cirrhosis and portal hypertension was included in the LT waiting list for HPS. He had good liver function (Model for End-Stage Liver Disease score 12, Child-Pugh class B7). He had pulmonary fibrosis and a mild restrictive respiratory pattern with a basal oxygen saturation of 82%. The macroaggregated albumin test result was > 30. Spirometry demon strated a forced expiratory volume in one second (FEV1) of 78%, forced vital capacity (FVC) of 74%, FEV1/FVC ratio of 81%, diffusion capacity for carbon monoxide of 42%, and carbon monoxide transfer coefficient of 57%. He required domiciliary oxygen at 2 L/min (16 h/d). The patient was admitted to the intensive care unit (ICU) and extubated in the first 24 h, needing high-flow therapy and non-invasive ventilation and inhaled nitric oxide afterwards. Reintubation was needed after 72 h. Due to the non-response to supportive therapies, installation of ECMO was decided with progressive recovery after 9 d. Extubation was possible on the tenth day, maintaining a high-flow nasal cannula and de-escalating to conventional oxygen therapy after 48 h. He was discharged from ICU on postoperative day (POD) 20 with a 90%-92% oxygen saturation. Steroid recycling was needed twice for acute rejection. The patient was discharged from hospital on POD 27 with no symptoms, with an 89%-90% oxygen saturation. CONCLUSION Due to the favorable results observed, ECMO could become the central axis of treatment of HPS and refractory hypoxemia after LT.
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Affiliation(s)
- Belinda Sánchez Pérez
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
| | - María Pérez Reyes
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
| | - Jose Aranda Narvaez
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
| | - Julio Santoyo Villalba
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
| | - Jose Antonio Perez Daga
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
| | - Claudia Sanchez-Gonzalez
- Department of General and Digestive Surgery, Regional University Hospital of Malaga, Malaga 29010, Spain
| | - Julio Santoyo-Santoyo
- Hepatobiliary and Trasplantation Unit, General and Digestive Surgery Department, University Regional Hospital, Malaga 29010, Spain
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3
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Qiu Y, Hilmi I. The applications of ECMO in liver transplant recipients. Transplant Rev (Orlando) 2024; 38:100816. [PMID: 38104398 DOI: 10.1016/j.trre.2023.100816] [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: 09/21/2023] [Revised: 11/23/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023]
Abstract
Extracorporeal membrane oxygenation (ECMO) has emerged as a vital instrument for sustaining respiratory and cardiac functions when traditional methods have failed. Its function in managing acute pulmonary and cardiac challenges during liver transplantation (LT) has expanded significantly. While ECMO was initially viewed as a rescue strategy for acute intraoperative or posttransplant complications, its application now also encompasses the pretransplant stage of LT. Our review aims to thoroughly summarize both research and specific cases where ECMO has been utilized across pre- and perioperative phases in liver transplant recipients. By assessing the published literature, we discuss specific indications, the types of ECMO employed, their outcomes, and the unique challenges of applying ECMO during LT. In particular, the pretransplant use of ECMO is increasing, and its prudent introduction prior to LT, supported by meticulous planning, has the potential to optimize patient outcomes. It is challenging to manage liver transplant patients on ECMO. More research and experience are needed to refine the techniques and improve patient outcomes. Furthermore, decision-making must be tailored to each patient's unique circumstances, and a clear, practical, and well-defined plan for subsequent steps is essential.
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Affiliation(s)
- Yue Qiu
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Department of Anesthesiology and Perioperative Medicine Education Office, Liliane S. Kaufmann Building, 3471 Fifth AVE, Suite 402, Pittsburgh, PA 15213, USA.
| | - Ibtesam Hilmi
- Anesthesiology and Perioperative Medicine, Clinical and Translational Science Institute, University of Pittsburgh, School of Medicine, Montefiore Anesthesiology Office 200 Lothrop St, Pittsburgh, PA 15213, USA.
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4
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Qiu Y, Hilmi I. The applications of ECMO in liver transplant recipients. Transplant Rev (Orlando) 2024; 38:100816. [DOI: https:/doi.org/10.1016/j.trre.2023.100816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2024]
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5
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Lee J, Allen WL, Scott CL, Aniskevich S, Pai SL. Preemptive Venoarterial Extracorporeal Membrane Oxygenation for Liver Transplantation-Judicious Candidate Selection. J Clin Med 2023; 12:4965. [PMID: 37568367 PMCID: PMC10419537 DOI: 10.3390/jcm12154965] [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: 05/31/2023] [Revised: 06/26/2023] [Accepted: 07/20/2023] [Indexed: 08/13/2023] Open
Abstract
Portopulmonary hypertension is a relatively common pathologic condition in patients with end-stage liver disease. Traditionally, severe pulmonary hypertension is regarded as a contraindication to liver transplantation (LT) due to a high perioperative mortality rate. Recently, extracorporeal membrane oxygenation (ECMO) has been utilized for intraoperative management of LT. As venoarterial (VA) ECMO may benefit certain high-risk LT patients by reducing the ventricular workload by the equivalent of the programmed flow rate, its usage requires multidisciplinary planning with considerations of the associated complications. We highlighted two cases at our single-center institution as examples of high-risk pulmonary hypertension patients undergoing LT on planned VA ECMO. These patients both survived the intraoperative period; however, they had drastically different postoperative outcomes, generating discussions on the importance of judicious patient selection. Since ECMO has removed the barrier of intraoperative survivability, the patient selection process may need to put weight on the patient's potential for postoperative recovery and rehabilitation. Considerations on LT recipients undergoing preemptive ECMO need to expand from the ability of the patients to withstand the demands of the surgery during the immediate perioperative period to the long-term postoperative recovery course.
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Affiliation(s)
| | - Wesley L. Allen
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA; (J.L.); (C.L.S.); (S.A.); (S.-L.P.)
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Laici C, Bianchini A, Miglionico N, Bambagiotti N, Vitale G, Fallani G, Ravaioli M, Siniscalchi A. Planned Extracorporeal Life Support Employment during Liver Transplantation: The Potential of ECMO and CRRT as Preventive Therapies-Case Reports and Literature Review. J Clin Med 2023; 12:jcm12031239. [PMID: 36769889 PMCID: PMC9953574 DOI: 10.3390/jcm12031239] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
Liver Transplantation (LT) has become the gold standard treatment for End-Stage Liver Disease (ESLD). One of the main strategies to manage life-threatening complications, such as cardio-respiratory failure, is Extracorporeal Membrane Oxygenation (ECMO) in the peri-transplantation period, with different configurations of the technique and in combination with other extracorporeal care devices such as Continuous Renal Replacement Therapy (CRRT). This retrospective study includes three clinical cases of planned ECMO support strategies in LT and evaluates their application compared with current literature exploring PubMed/Medline. The three LT supported with ECMO and CRRT were performed at IRCCS Polyclinic S. Orsola-Malpighi, Bologna. All three cases of patients with compromised organ function analysed produced positive outcomes. The planned use of ECMO and CRRT support in peri-transplantation has allowed the patients to overcome contraindications and successfully undergo LT. In recent years, only a few reports have documented successful LT outcomes performed with intraoperative ECMO in critically ESLD patients. However, the management of LT with ECMO and/or CRRT assistance is an emerging challenge, with the need for more published evidence on this topic to guide treatment choices in patients with severe, acute and reversible respiratory and cardiovascular failure after LT.
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Affiliation(s)
- Cristiana Laici
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Amedeo Bianchini
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Noemi Miglionico
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Niccolò Bambagiotti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Correspondence:
| | - Guido Fallani
- Hepatobiliary and Transplant Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Matteo Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
- Hepatobiliary and Transplant Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Antonio Siniscalchi
- Postoperative and Abdominal Organ Transplant Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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7
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Yoon YI, Lim JH, Lee SG, Kang PJ, Hwang GS, Ha SM, Do HY, Hong SK, Huh JW. Role of extracorporeal membrane oxygenation as a salvage therapy for liver transplantation recipients in a high-volume transplant center. Liver Transpl 2023; 29:67-79. [PMID: 36030502 DOI: 10.1002/lt.26567] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/08/2022] [Accepted: 07/20/2022] [Indexed: 01/14/2023]
Abstract
Extracorporeal membrane oxygenation (ECMO) has been used sporadically in adult orthotopic liver transplantation (OLT) recipients for the treatment of acute cardiopulmonary failure. This retrospective study aimed to identify OLT patients who would benefit from ECMO support. We reviewed 109 OLT patients who received ECMO support for more than 24 h from January 2007 to December 2020. Among the enrolled patients, 15 (13.8%) experienced 18 ECMO-related complications and 12 (11.0%) experienced ECMO reapplication after weaning during the same hospitalization period. The successful weaning rates were 50.98% in patients who received ECMO support during the peritransplantation period (0-30 days from transplantation) and 51.72% in patients who received ECMO support in the post-OLT period (more than 30 days after OLT); 24 (47.1%) and 23 (39.7%) patients survived until hospital discharge, respectively. The 109 enrolled OLT recipients who received ECMO support during the perioperative period had a 1-year survival rate of 42.6%. Multivariate analyses identified the following as significant and independent risk factors for in-hospital mortality: ECMO treatment prior to 2011 ( p = 0.04), septic shock as the indication for ECMO treatment ( p = 0.001), and a total bilirubin level of ≥5.0 mg/dl ( p = 0.02). The outcomes of adult OLT recipients with ECMO treatment were acceptable in terms of weaning success and survival until hospital discharge. This study confirmed that ECMO treatment for OLT recipients with septic shock and elevated bilirubin levels might be associated with a higher in-hospital mortality and demonstrated the importance of a multidisciplinary ECMO team approach.
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Affiliation(s)
- Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Jung-Hyeon Lim
- Department of Thoracic and Cardiovascular Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Pil-Je Kang
- Department of Thoracic and Cardiovascular Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Gyu-Sam Hwang
- Department of Anesthesiology and Pain Medicine , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Su-Min Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Ha-Yeon Do
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Suk-Kyung Hong
- Division of Acute Care Surgery, Department of Surgery , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
| | - Jin-Won Huh
- Department of Pulmonary and Critical Care Medicine , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea
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8
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Shimura K, Matsumoto S, Ide K, Baba C, Nakagawa S, Shoji K, Uchida H, Fukuda A, Sakamoto S, Kasahara M. Rescue venovenous extracorporeal membrane oxygenation for the deterioration of acute respiratory distress syndrome in pediatric liver transplantation. Pediatr Transplant 2022; 26:e14305. [PMID: 35567762 DOI: 10.1111/petr.14305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/24/2022] [Accepted: 04/24/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Twenty percent of pediatric patients with BA develop ACLF with increased mortality while awaiting LT. Respiratory complications are common in pediatric ACLF and are associated with increased morbidity and mortality. ARDS is the most severe manifestation of acute respiratory failure with considerable risk of mortality. METHODS A 5-month-old girl with post-Kasai BA preoperatively experienced ARDS from RSV infection while awaiting LT. She developed decompensated liver failure with shock, acute kidney injury, coagulopathy, and pulmonary hemorrhage after several episodes of sepsis over the course of 1 month in the PICU. At this stage, RSV was not detected in the patient's tracheal aspirate by real-time polymerase chain reaction. She underwent living donor LT to manage her pre-existing critical state. Following reperfusion during LT, her pre-existing ARDS rapidly deteriorated, which was alleviated by intraoperative VV ECMO. RESULTS Severe respiratory acidosis improved rapidly following ECMO, and LT was completed uneventfully. The patient was successfully weaned off ECMO on POD 3. CONCLUSIONS This is the first pediatric case rescued by the intraoperative application of ECMO during LT. Our case and cumulative evidence suggest that VV ECMO can serve as rescue therapy for perioperative refractory respiratory failure in pediatric LT.
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Affiliation(s)
- Kisho Shimura
- Division of Critical Care Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Shotaro Matsumoto
- Division of Critical Care Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Kentaro Ide
- Division of Critical Care Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Chiaki Baba
- Division of Anesthesia, National Center for Child Health and Development, Tokyo, Japan
| | - Satoshi Nakagawa
- Division of Critical Care Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Kensuke Shoji
- Division of Infectious Diseases, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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9
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Park J, Lin MY, Wray CL, Kaldas FM, Benharash P, Gudzenko V. Applications and Outcomes of Extracorporeal Life Support Use in Adult Liver Transplantation: A Case Series and Review of Literature. ASAIO J 2022; 68:683-690. [PMID: 34506329 DOI: 10.1097/mat.0000000000001562] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The use of extracorporeal life support (ECLS) is increasingly reported in adult liver transplantation (LT). However, neither the role of ECLS in the perioperative setting for LT nor its outcomes has been well defined. We performed a retrospective chart review of all adult LT patients at our institution who received ECLS from 2004 to 2021. We also conducted a comprehensive literature search for adult LT cases that involved perioperative ECLS for respiratory or cardiac failure. Over the study period, 11 LT patients required ECLS at our institution, two for respiratory and nine for cardiac failure. Both patients with respiratory failure received ECLS as a bridge to LT and survived to discharge. Nine patients required ECLS for acute cardiac failure either intraoperatively or postoperatively, and two survived to discharge. In the literature, we identified 35 cases of respiratory failure in LT patients requiring perioperative ECLS. Applications included preoperative bridge to LT (n = 6) and postoperative rescue (n = 29), for which overall survival was 44%. We identified 31 cases of cardiac failure in LT patients requiring either ECLS or cardiopulmonary bypass for cardiac support or rescue for intraoperative or postoperative cardiac failure (n = 30). There is evidence for consideration of ECLS as a bridge to LT in patients with potentially reversible respiratory failure or as rescue therapy for respiratory failure in posttransplant patients. ECLS has a prohibitively high risk of futility in pretransplant patients with cardiac failure but may have a role in LT patients with a functioning graft and potentially reversible cardiac failure.
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Affiliation(s)
- Jeieung Park
- From the Department of Anesthesiology and Perioperative Care, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael Y Lin
- Division of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, California, Los Angeles
| | - Christopher L Wray
- Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, California, Los Angeles
| | - Fady M Kaldas
- Dumont-UCLA Transplant and Liver Cancer Center, Department of Surgery, David Geffen School of Medicine, University of California, California, Los Angeles
| | - Peyman Benharash
- Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine, University of California, California, Los Angeles
| | - Vadim Gudzenko
- Division of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, California, Los Angeles
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10
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Reid TD, Kratzke IM, Dayal D, Raff L, Serrano P, Kumar A, Zendel A, Herdman V, Gallaher J, Carlson R, Charles AG, Desai CS. The role of extracorporeal membrane oxygenation in adult liver transplant patients: A qualitative systematic review of literature. Artif Organs 2021; 46:578-596. [PMID: 34816462 DOI: 10.1111/aor.14120] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/05/2021] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND A paucity of evidence exists regarding risks and benefits of extracorporeal membrane oxygenation (ECMO) in adult liver transplantation. METHODS This was a systematic review conducted from January 1, 2000 to April 24, 2020 of adult liver transplant recipients (pre- or post-transplant) and donors who underwent Veno-arterial or Veno-venous ECMO cannulation. Death was the primary outcome, with graft function and complications as secondary outcomes. RESULTS Forty-one articles were identified that fit criteria. A total of 183 donors were placed on ECMO, with recipient complication profiles and mortality that mirrored rates from standard criteria donors. Sixty-one recipients were placed on ECMO intraoperatively or postoperatively. Most patients experienced at least one complication with infections as the most common cause and minimal complications specifically related to ECMO use. Multisystem organ failure (MSOF) and infections were more common among liver recipients who died compared to those who survived. Overall mortality at 90 days was 45.9%. Causes of death were most commonly MSOF and infections. CONCLUSIONS ECMO use in adult liver transplantation is a useful adjunct. Recipient morbidity and mortality from donors placed on ECMO parallel that of recipients from standard criteria donors, and morbidity and mortality of recipients placed on ECMO are similar to other ECMO populations.
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Affiliation(s)
- Trista D Reid
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Trauma and Acute Care Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ian M Kratzke
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Diana Dayal
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lauren Raff
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Trauma and Acute Care Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Pablo Serrano
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Transplant Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Aman Kumar
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Transplant Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Alex Zendel
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Transplant Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Victoria Herdman
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jared Gallaher
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Trauma and Acute Care Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Rebecca Carlson
- Health Sciences Library, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Anthony G Charles
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Trauma and Acute Care Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Chirag S Desai
- Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Division of Transplant Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Management of severe idiopathic pulmonary hypertension in a patient with acute liver failure treated with liver transplantation. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Bezinover D, Mukhtar A, Wagener G, Wray C, Blasi A, Kronish K, Zerillo J, Tomescu D, Pustavoitau A, Gitman M, Singh A, Saner FH. Hemodynamic Instability During Liver Transplantation in Patients With End-stage Liver Disease: A Consensus Document from ILTS, LICAGE, and SATA. Transplantation 2021; 105:2184-2200. [PMID: 33534523 DOI: 10.1097/tp.0000000000003642] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Hemodynamic instability (HDI) during liver transplantation (LT) can be difficult to manage and increases postoperative morbidity and mortality. In addition to surgical causes of HDI, patient- and graft-related factors are also important. Nitric oxide-mediated vasodilatation is a common denominator associated with end-stage liver disease related to HDI. Despite intense investigation, optimal management strategies remain elusive. In this consensus article, experts from the International Liver Transplantation Society, the Liver Intensive Care Group of Europe, and the Society for the Advancement of Transplant Anesthesia performed a rigorous review of the most current literature regarding the epidemiology, causes, and management of HDI during LT. Special attention has been paid to unique LT-associated conditions including the causes and management of vasoplegic syndrome, cardiomyopathies, LT-related arrhythmias, right and left ventricular dysfunction, and the specifics of medical and fluid management in end-stage liver disease as well as problems specifically related to portal circulation. When possible, management recommendations are made.
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Affiliation(s)
- Dmitri Bezinover
- Department of Anesthesiology and Perioperative Medicine, Pennsylvania State University, Penn State Health, Milton S. Hershey Medical Center, Hershey, PA. Represents ILTS and LICAGE
| | - Ahmed Mukhtar
- Department of Anesthesia and Surgical Intensive Care, Cairo University, Almanyal, Cairo, Egypt. Represents LICAGE
| | - Gebhard Wagener
- Department of Anesthesiology, Columbia University Medical Center, New York, NY. Represents SATA and ILTS
| | - Christopher Wray
- Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Ronald Reagan Medical Center, Los Angeles, CA. Represents SATA
| | - Annabel Blasi
- Department of Anesthesia, IDIBAPS (Institut d´investigació biomèdica Agustí Pi i Sunyé) Hospital Clinic, Villaroel, Barcelona, Spain. Represents LICAGE and ILTS
| | - Kate Kronish
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA. Represents SATA
| | - Jeron Zerillo
- Department of Anesthesiology, Perioperative and Pain Medicine, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, NY. Represents SATA and ILTS
| | - Dana Tomescu
- Department of Anesthesiology and Intensive Care, Carol Davila University of Medicine and Pharmacy, Fundeni Clinical Institute, Bucharest, Romania. Represents LICAGE
| | - Aliaksei Pustavoitau
- Department of Anesthesia and Critical Care Medicine, Johns Hopkins Hospital, Johns Hopkins School of Medicine, Baltimore, MD. Represents ILTS
| | - Marina Gitman
- Department of Anesthesiology, University of Illinois Hospital, Chicago, IL. Represents SATA and ILTS
| | - Anil Singh
- Department of Liver Transplant and GI Critical Care, Sir HN Reliance Foundation Hospital, Cirgaon, Mumbai, India. Represents ILTS
| | - Fuat H Saner
- Department of General, Visceral and Transplant Surgery, Essen University Medical Center, Essen, Germany. Represents LICAGE
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Hildreth BA, Panarello G, Martucci G, Tuzzolino F, Piacentini A, Occhipinti G, Giunta A, Genco F, Raffa GM, Pilato M, Capitanio G, Arcadipane A. ECMO Retrieval over the Mediterranean Sea: Extending Hospital Arms. MEMBRANES 2021; 11:210. [PMID: 33802762 PMCID: PMC8002579 DOI: 10.3390/membranes11030210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/07/2021] [Accepted: 03/12/2021] [Indexed: 01/19/2023]
Abstract
The retrieval and transport of patients from peripheral hospitals to high volume extracorporeal membrane oxygenation (ECMO) centers aims to reduce complications and improve survival. In Sicily (Italy), our institute houses a mobile ECMO team that serves a population of around 10 million people for a vast area in southern Italy and Malta. This observational, descriptive study includes all patients that required veno-venous (V-V) ECMO and transport by a mobile team between October 2009 and May 2020. Linear and multiple logistic regressions were applied to explore the risk factors for mortality in the ICU. Kaplan-Meier estimates were generated to predict the survival in patients transported by helicopter or ambulance, and the two cohorts were compared according to their baseline characteristics. Of 122 patients transported, 89 (73%) survived to ICU discharge (50 (41%) patients were transported by ambulance, and 72 (59%) were transported by helicopter). Independent predictive factors associated with mortality in a stepwise multiple regression model were prone positioning, acute kidney injury, and the number of days spent on mechanical ventilation (MV). Kaplan-Meier estimates for survival favored the helicopter cohort (79%) rather than the ambulance cohort (64%). Patients transported by helicopter had better pre-ECMO profiles, with shorter hospital and ICU stays, a shorter duration of MV use, and higher RESP scores, which indicate better survival probabilities. ECMO transport can be carried out safely over long distances; in rural areas with underdeveloped roads, transportation via helicopter or ambulance can extend the arm of the hospital to remote areas. Early ECMO initiation can be crucial in improving survival outcomes, and when transportation is the limiting factor to starting ECMO support, it should be attempted at the earliest logistical stage possible.
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Affiliation(s)
| | - Giovanna Panarello
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
| | - Gennaro Martucci
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
| | - Fabio Tuzzolino
- Research Office, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy;
| | - Alberto Piacentini
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
| | - Giovanna Occhipinti
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
| | - Andrea Giunta
- Perfusion Service, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy;
| | - Fabio Genco
- Emergency Rescue Service, 118 Service—Region of Sicily, 91021 Sicily, Italy;
| | - Giuseppe M. Raffa
- Cardiac Surgery Unit, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.M.R.); (M.P.)
| | - Michele Pilato
- Cardiac Surgery Unit, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.M.R.); (M.P.)
| | - Guido Capitanio
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
| | - Antonio Arcadipane
- Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy; (G.P.); (A.P.); (G.O.); (G.C.); (A.A.)
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15
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The Utility of ECMO After Liver Transplantation: Experience at a High-volume Transplant Center and Review of the Literature. Transplantation 2019; 103:1568-1573. [DOI: 10.1097/tp.0000000000002716] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Intraoperative anesthetic management of the liver transplant recipient with portopulmonary hypertension. Curr Opin Organ Transplant 2019; 24:121-130. [DOI: 10.1097/mot.0000000000000613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Martucci G, Panarello G, Occhipinti G, Raffa G, Tuzzolino F, Capitanio G, Carollo T, Lino G, Bertani A, Vitulo P, Pilato M, Lorusso R, Arcadipane A. Impact of cannula design on packed red blood cell transfusions: technical advancement to improve outcomes in extracorporeal membrane oxygenation. J Thorac Dis 2018; 10:5813-5821. [PMID: 30505489 DOI: 10.21037/jtd.2018.09.119] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Technological improvement has contributed to making veno-venous extracorporeal membrane oxygenation (VV-ECMO) safer and easier, spreading its use in acute respiratory failure (ARF). Methods This is a retrospective observational study carried out in the ECMO center at IRCCS-ISMETT, a medical center focused on end-stage organ failure treatment in Italy. We investigated the effect of different cannula designs on the amount of blood product transfused. Eighty-nine consecutive patients affected with ARF on VV-ECMO from 2008 to 2016 were compared according to type of cannulation: older percutaneous cannula (Standard group, 52 patients) and HLS© BIOLINE-coated, but with shorter drainage cannula (BIOLINE group, 37 patients). Results The two study groups were comparable in terms of baseline characteristics [age, body mass index (BMI), Simplified Acute Physiology Score (SAPS-II), Sequential Organ Failure Assessment (SOFA), Predicting Death For Severe ARDS on VV-ECMO (PRESERVE) score] and ECMO management [median hematocrit (Htc), platelet nadir, antithrombin III (AT III), heparin, activated partial thromboplastin time (APTT)]. In the BIOLINE group, a lower amount of packed red blood cells (pRBC) was transfused considering both total number [4 units, interquartile range (IQR) 1-9 vs. 12 units, IQR 5.5-21; P<0.01] and mL of pRBC/day of ECMO support (91, IQR 21-158 vs. 193.5, IQR 140.5-254; P<0.01). In the BIOLINE group, a trend in reduction of ECMO days (P=0.05) and length of intensive care unit (ICU) stay was found (P=0.06), but no differences in rates of ECMO weaning and ICU discharge were evidenced. The BIOLINE group constituted a saving of €1,295.20 per patient/treatment, counting the costs for cannulation and pRBC administration. Conclusions More biocompatible and shorter drainage cannula may represent one of the contributing factors to a reduction in transfusions and costs of VV-ECMO in the current ongoing technological improvement in ECMO.
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Affiliation(s)
- Gennaro Martucci
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Giovanna Panarello
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Giovanna Occhipinti
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Giuseppe Raffa
- Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Fabio Tuzzolino
- Statistician, Research Office, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Guido Capitanio
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Tiziana Carollo
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Giovanni Lino
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Alessandro Bertani
- Thoracic Surgery and Lung Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Patrizio Vitulo
- Pneumology Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Michele Pilato
- Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Roberto Lorusso
- Cardio-Thoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Antonio Arcadipane
- Department of Anesthesia and Intensive Care, IRCCS - ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
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Sun X, Qiu W, Chen Y, Lv G, Fan Z. Utilization of extracorporeal membrane oxygenation for a severe cardiocirculatory dysfunction recipient in liver transplantation: A case report. Medicine (Baltimore) 2018; 97:e12407. [PMID: 30213015 PMCID: PMC6155962 DOI: 10.1097/md.0000000000012407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
RATIONALE Severe cardiac dysfunction or severe pulmonary hypertension is a contraindication of liver transplantation (LT). Extracorporeal membrane oxygenation (ECMO) is an advanced therapy for severe lung and/or cardiocirculatory dysfunction or failure. The application of ECMO to patients during the LT perioperative period may help recipients with severe cardiac disease to maintain the heart function and alleviate the reperfusion syndrome. PATIENT CONCERNS A female liver recipient complained about weakness for 6 months. DIAGNOSES The patient was diagnosed as hepatitis B virus (HBV)-related hepatic cirrhosis (MELD 24, Child-Pugh C) with severe mitral regurgitation, severe tricuspid regurgitation, left atrium and left ventricle enlargement, cardiac insufficiency, pulmonary arterial hypertension, and hypoxemia. INTERVENTIONS The patient underwent LT from a cardiac deceased donor. The surgery was completed by venoarterial ECMO. The femoral vessels cannulation was done after the dissection of the patient's liver and before the venous blocking. Venous cannula reached to the position below renal vein, while arterial cannula reached to common iliac artery. We regulated the ECMO index according to the patient's condition. The dosage of heparin was adjusted on the basis of the activated clotting time. Respiratory support, milrinone, furosemide, and mannitol were used to improve the circulation. The bleeding volume of surgery was 1200 mL. The cardiocirculatory function and other vital signs remained good in the perioperative period. In the first 24 hours after surgery, central venous pressure decreased from 17 to 7 cmH2O. Thirty hours after surgery, the ECMO was removed. Eighteen hours later, the recipient did not need respiratory support. OUTCOMES No complications of transplantation or ECMO were found. LESSONS It is feasible to utilize ECMO as a cardiocirculatory function support in the LT. ECMO does not increase the risk of hemorrhage. ECMO can play an important role in ensuring the security of the liver recipients in the surgery and in the postoperative period.
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Monaco F, Belletti A, Bove T, Landoni G, Zangrillo A. Extracorporeal Membrane Oxygenation: Beyond Cardiac Surgery and Intensive Care Unit: Unconventional Uses and Future Perspectives. J Cardiothorac Vasc Anesth 2018; 32:1955-1970. [DOI: 10.1053/j.jvca.2018.03.031] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Indexed: 02/06/2023]
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