Extracorporeal life support 9811992746, 9789811992742

Table of contents :
Preface
Introduction of Chief Editor, Feilong Hei
The Main Academic Title
Scientific Research and Clinical Achievements
Introduction of Chief Editor, Yulong Guan
The Main Academic Title
Scientific Research and Clinical Achievements
Scientific Achievements
Scientific Training
Scientific Monographs
Scientific Papers
Introduction of Chief Editor, Kun Yu
The Main Academic Title
Scientific Research and Clinical Achievements
Contents
1: Physiology of Extracorporeal Life Support
Cardiovascular Physiology
Heart
Vasculature
Blood
Blood Composition
Transportation of O2 in Blood
Transportation of CO2 in Blood
Cardiovascular Pathophysiology
ECMO Circuit and Circuit Physiology
Blood Pumps
Roller Pumps
Rotary Pumps
Interaction Between Centrifugal Pump and Patient
Gas Exchange Device: Artificial Oxygenator
Blood Oxygenation in Oxygenator
CO2 Removal in Oxygenator
Other Functions of Oxygenator
Cannulas
Tubing and Connectors
Mechanism of Cardiorespiratory Support
Physiology of VA-ECMO
Hemodynamic Effects of VA-ECMO
Gas Exchange in VA-ECMO
Advantages and Disadvantages of VA-ECMO
Physiology of VV-ECMO
Hemodynamic Effects of VV-ECMO
Oxygenation in VV-ECMO
CO2 Removal in VV-ECMO
Recirculation During VV-ECMO
Advantages and Disadvantages of VV-ECMO
VA-ECMO vs. VV-ECMO
Pharmacokinetics During ECMO
Pumpless Extracorporeal Lung Assist (pECLA)
Summary
References
2: Equipment and Devices of Extracorporeal Life Support
Blood Pump
Centrifugal Pump Physics
Components of a Centrifugal Pump
Commercial Centrifugal Pumps
Membrane Oxygenator
Commercial Gas Exchange Devices
ECLS Tubing
General Principles of Circuit Design
Surface Coating Technology
Heat Exchanger/Heater-Cooler Device
Medicare Monitoring During ECLS
Hemoglobin Saturation Measurement
Anticoagulation Monitoring
Circuit Pressures
Colloid Osmotic Pressure
Plasma Free Hemoglobin
Temperature Monitoring
References
3: Types of Extracorporeal Life Support and Evolution of Extracorporeal Oxygenators
The Retrospective Glance on the Historical Development of ECLS/ECMO and Extracorporeal Oxygenators
Evolution of Extracorporeal Oxygenator and Its Use in Extracorporeal Life Support
Development of High-Performance Extracorporeal Oxygenators for ECMO Use—High Gas Exchange Efficiency, Low Flow Resistance, and Plasma Leak-Tight Oxygenator
Extracorporeal Membrane Oxygenation (ECMO)
Veno-Venous Extracorporeal Membrane Oxygenation (VV ECMO) Mode
VV Configurations and Cannulation Strategies
Special Consideration: Right Ventricular Failure During ARDS and VV ECMO
Veno-Arterial Extracorporeal Membrane Oxygenation (VA ECMO) Mode
VA Configuration and Cannulation Strategies
Venovenous-Arterial (VV-A) ECMO, Alternative Configuration of Peripheral VA Mode and Cannulation Strategies
Veno-Veno-Arterial (V-VA) ECMO, a “Hybrid” Mode Configuration in North-South or Harlequin Syndrome or Differential Hypoxia
Conclusion
References
4: Cannulation and Decannulation of Extracorporeal Life Support
Cannulation Sites
Femoral Artery
Axillary Artery
Carotid Artery
Ascending Aorta
Femoral Vein
Right Internal Jugular Vein
Subclavian Vein
Right Atrium
Cannula Selection
Single-Lumen Cannula
Dual-Lumen Cannula
Methods and Techniques of Cannulation
Surgical Cannulation
Femoral Vessel Cannulation
Neck Vessel Cannulation
Axillary Artery Cannulation
Central-VA ECMO Cannulation
Percutaneous Cannulation
Pre-Procedure Preparation
Peri-Procedure
Post-Procedure
Semi-Percutaneous Cannulation
Decannulation
Decannulation of Arterial Cannula
Decannulation of Venous Cannula
Left Ventricular Venting
Surgical Venting
Sternotomy
Mini-Thoracotomy
Percutaneous Venting
Transseptal Venting
Transpulmonary Venting
Transaortic Venting
References
5: Anticoagulation During Extracorporeal Life Support
Hemostatic Alterations
Anticoagulation
Unfractionated Heparin
Direct Thrombin Inhibitors
Antiplatelet Agents
Anticoagulation Monitoring
ACT
aPTT
Anti-Factor Xa Assay
Thromboelastography/Thromboelastometry-Guided Algorithm
Anticoagulation Management During ECLS
Bleeding
Thrombosis
Conclusions
References
6: Management of Pediatric Extracorporeal Life Support
Overview and History
Centrifugal Pump Takes the Place of Roller Pump
Hollow Fiber Oxygenator Takes the Place of Silicon Membrane Oxygenator
Cannula
Circuit and Coating Technique
Outcomes
Indications
Respiratory Failure
Cardiac Support
Perioperation Support of Heart
Nonstructural Heart Disease
Cannulation Strategies
VA ECMO
Neck Cannulation
Central Cannulation
Groin Cannulation
VV ECMO
Decannulation
ECMO Circuit Priming
Initiation of ECMO
Selection of Cannula
ECMO Flow
ICU Management and Assessment of Support
Ventilation
Hypoxia
Cardiac Output
Fluid Management and Nutrition
Sedation
Anticoagulation
Key Points in Management
Systemic and Local Hypoxia
Left Heart Decompression
VA ECMO for Single Ventricle
Special Situations
Cannulation Site Care
Hypertension
Infection
Bleeding and Thrombosis
Weaning from ECMO
References
7: Management of Adult Extracorporeal Life Support
Monitoring
Monitoring of ECLS Equipment
Blood Flow Rate and Pump Rotation Speed
Sweep Gas Flow
Gas Exchange of Oxygenator
Pressure Monitoring in the Circuits
Water Tank Temperature
Thrombus in the Circuits
Patient’s Monitoring
Hemodynamic Parameters
Respiratory System
Nervous System
Gastrointestinal System
Renal Function
Blood System
Respiratory and Circulatory Management
VV ECLS
Target Values
Ventilator Management
ECLS Blood Flow and Sweep Gas Flow
Hemodynamics
Patient Position
VA ECLS
Target Values Control
Respiratory Management
Hemodynamics
Blood Management
Hematocrit
Destruction of Red Blood Cells
Anticoagulation During Extracorporeal Life Support
Kidney Function and Electrolytes
Kidney Function
Blood Gas Parameters and Electrolytes
Management of Edema and Fluids
The Mechanisms of Edema During ECLS
Fluid Management During ECLS
Central Nervous System
Assessment of Central Nervous System During ECLS
Central Nervous System Protective Measures During ECLS
Gastrointestinal Tract Management and Nutritional Support
Parenteral Nutrition
Enteral Nutrition
Nutritional Assessment
Analgesia and Sedation
Evaluation and Goals
Commonly Used Drugs
Conscious ECLS
Temperature Management
Vascular Complications
Blood Vessel Damage
Limb Ischemia
Infection and Antibiotics
Urinary Tract Infection
Pulmonary Infections
Intravascular Infection Caused by Indwelling Catheter
Wound Infection
Intestinal Infection
Fungal Infection
Discontinuation of ECLS
Requirements for ECLS Discontinuation
Testing Before Discontinuation
VV ECLS
VA ECLS
Repeat ECLS Assistance
Termination of Ineffective ECLS
References
8: Extracorporeal Life Support During Cardiac Arrest
Selection of ECPR Patients
No Flow Time and Low Flow Time
Age
CPR Quality: EtCO2
Ventilator Setting
Strategies of Cannulation
Management
Complications
Neurological Outcome
References
9: Adverse Events and Complications of Extracorporeal Life Support
Categories of Complications and the Cumulative Incidence
Mechanical Adverse Events
Pump Failure
Symptoms
Causes
Solution
Low Flow/Cutting Off
Symptoms
Causes
Solution
Air in Circuit
Symptoms
Causes
Solution
Oxygenator Failure
Symptoms
Causes
Solution
Thrombosis
Symptoms
Causes
Solution
Tubing Rupture
Symptoms
Causes
Solution
Others
Cannulation-Related Complications
Clinical Manifestations
Causes
Solution
Hematologic Disorders
Thrombosis
Incidence
Clinical Manifestations
Mechanisms
Management of Thrombosis
Bleeding
Definition and Incidence
Clinical Manifestations
Mechanism
Prevention and Management
Neurologic Injury
Clinical Manifestations
Incidence
Risk Factors
Mechanism
ICH
AIS
Hypoxic Ischemic Encephalopathy
Seizures
Prognosis
Prevention
Management
Circulatory Complications
LV Dilation Complications
Harlequin Syndrome
Pulmonary Complication
Clinical Manifestations
Causes
Solution
Acute Kidney Injury
Definitions of ECMO-Associated Kidney Injury
Risk Factors
Pathophysiology of ECMO-Associated Kidney Injury
Prevention and Management
Vascular Complications
Limb Ischemia
Prevalence and Definition
Mechanism
Prevention
Treatment
Vessel Damage
Clinical Manifestations
Etiological Factor
Prevention
Treatment
Infection
Clinical Manifestations
Risk Factors
Etiology of Infection
Preventive Practices
Hemolysis
Diagnosis and Clinical Manifestations
Mechanisms
Patient-Related Factors
Circuit-Related Factors
ECMO Set-Up and Management Factors
Management and Prevention
References
10: Transport of the Patients Supported with Extracorporeal Life Support
Intra-Hospital Transport of Patients Supported with ECLS
Purpose of Transport
Preparation of Personnel and Equipment
Transport Points
Inter-Hospital Transport
Indications for Inter-Hospital ECLS Transport
Transport Logistics
Transfer Modes
Personnel Preparation
Transport Equipment
Management of Inter-Hospital ECLS Transport
Assessment of Patient
Lay Out a Scheme
Patient Transport
Monitoring in ECLS Transfer
Treatment and Care in ECLS Transfer
Complications Associated with Transport
References
11: Extracorporeal Life Support During Perioperative Transplantation
ECLS During Perioperative Heart Transplantation
ECLS Prior to Heart Transplant
Inclusion Criteria of ECLS Prior to Heart Transplant
Current State of ECLS as a BTT in Adult Candidates
ECLS as a BTT Before Pediatric Heart Transplantation
ECLS as Post-Transplant Support
Definition and Classification of PGD After Heart Transplant
Advantage of ECLS for PGD
Current State of ECLS for PGD
Outlook of ECLS During Perioperative Heart Transplantation
ECLS During Perioperative Lung Transplantation
ECLS as a Bridge to Lung Transplant
Advantage of ECLS as a Bridge to Lung Transplant
Recommendations on the Use of ECLS in Bridge to Lung Transplant
Factors That Affect Post-Transplant Survival in Patients on ECLS Support
Current State of ECLS as a Bridge to Lung Transplant
The Protocol of Implementation of ECLS as a BTT
ECLS During Lung Transplantation
Management of Ventilation and Oxygenation
Transfusion and Anticoagulation
Weaning from ECLS
ECLS Following Lung Transplantation
Clinical Experience
Indications
Time of Initiation
Technical Aspects
Outcomes of ECLS After Lung Transplantation
Outlook of ECLS During Perioperative Lung Transplantation
ECLS During Donor Storage
Organ-Preservation ECLS in DBD Donor
ECPR and Organ Donors
ECLS for Abdominal Organ Protection from Donors After Circulatory Death
Ethical Dilemmas of ECLS in Organ Donors
References
12: Topics of Extracorporeal Life Support
Novel ECLS Instruments
Animal Experiments with Newly Developed ECLS System
Clinical Experiments with Newly Developed ECLS System
The Timing of ECLS Initiation
Patient Selection and Timing for rECLS Support
Bridge to Recovery
Bridge to Transplant
Patient Selection and Timing for cECLS Support
Bridge to Recovery
Bridge to Transplant or Mechanical Circulatory Support
Extracorporeal Cardiopulmonary Resuscitation
The Timing of ECLS Termination
Weaning from VA ECLS
Hemodynamics
Respiratory Criteria
End-Organ Recovery Criteria
Flow Reduction
Echocardiographic Assessment
Weaning from VV ECLS
ECLS During Treatment of COVID-19
When ECLS Is Used for COVID-19 Patients
What Patients Are the Highest Priority?
What Patients Should Be Excluded?
ECLS During Donor Reconditioning of Lung Transplantation
Patient Selection for ECLS
ECLS and Protection During Reperfusion
Combination of Mechanical Assistance with ECLS
New Indications of ECLS in the Future
References
13: Extracorporeal Life Support Training
Teaching Theory
Cognitive Domain
Psychomotor Domain (Technical Skills)
Psychomotor Domain (Behavioral Skills)
Affective Domain
Training of ECLS Team
Training Content
Acquiring Competency
Didactic Course
Water Drills
Animal Lab
High-Fidelity Simulation
Verifying ECLS Competency
Evaluation Ability
Maintaining Competency
Credentialing
Ethics Training
Ethical Dilemmas
Ethics Content
Skills for Managing Ethical Dilemmas
ECLS Training in China Mainland
Future Perspectives
References

Citation preview

Feilong Hei Yulong Guan Kun Yu Editors

Extracorporeal life support

123

Extracorporeal life support

Feilong Hei • Yulong Guan • Kun Yu Editors

Extracorporeal life support

Editors Feilong Hei Fuwai Hospital Fuwai Hospital Beijing, Beijing, China

Yulong Guan Fuwai Hospital Fuwai Hospital Beijing, Beijing, China

Kun Yu Fuwai Hospital Fuwai Hospital Beijing, Beijing, China

ISBN 978-981-19-9274-2    ISBN 978-981-19-9275-9 (eBook) https://doi.org/10.1007/978-981-19-9275-9 © Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Extracorporeal life support (ECLS), which is previously named as “extracorporeal membrane oxygenation” (ECMO) by many practitioners, has emerged to describe the entire family of extracorporeal support modalities for long-term support and has been popularized widely and applied in various fields since the twenty-first century. The ECLS member units reported by Extracorporeal Life Support Organization (ELSO) Annual Reports have also increased year by year. In particular, the outbreak of SARS and COVID-19 has praised ECLS as a “magic tool” to control the epidemic. However, the clinical outcomes of patients using ECLS have not improved substantially in the past few decades. This has a lot to do with the type of basic primary diseases of patients, but it is also directly related to the timing of assistance, the selection of ECLS methods, the screening of implantation sites, the reasonable management during ECLS, prevention of various complications, and the timely removal of ECLS. In the past, most practitioners engaged in ECLS refer to The ELSO red book for management of ECLS. Many pilots of ECLS have propagated and promoted the professional development of ECLS with establishment and update of the ELSO database, compilation of ELSO red book, introduction of recommendations or guidelines. However, the emergence of new ECLS consumables, especially the emergence of new ECLS indications and the adapted population, requires professionals to reassess ECLS. Many clinical problems still need specific practitioners to report and communicate information with them, rather than covering up some iatrogenic errors and decision-making bias. With the continuous progress of other medical specialties, many patients and their relatives have higher requirements and expectations for such patients, urging us to re-examine the protocol of treatment, therapeutic strategies, and treatment concept of such critically ill patients. The development of multidisciplinary consultations helps to optimize the adjustment of treatment during ECLS. Therefore, we have organized domestic and some foreign experts to update the relevant content of this field. We hope that the publication of this work can provide the basic theoretical model of ECLS for front-line practitioners, and certain reference for the treatment of critically ill patients. Although all our three chief editors are from China and English is not our native language, the current world is a diversified world, and the geographical boundaries cannot block the communication and cooperation of such professionals. We hope that this work can become a form of academic exchange in ECLS. Beijing, China Beijing, China  Beijing, China 

Feilong Hei Yulong Guan Kun Yu

v

Introduction of Chief Editor, Feilong Hei

The Main Academic Title The Chairman of Continuing Education Committee of Chinese Biomedical Engineering Association; the Former Chairman of Chinese Society of Extracorporeal Circulation; the Chairman of Beijing Society of Extracorporeal Circulation; the Vice Chairman of Extracorporeal Life Support Professional Committee of Chinese Medical Doctor Association; the Vice Chairman of Extracorporeal Life Support and Circulation Committee of Chinese Research Hospitals Association; the Director of Beijing Society of Medical Education; the Editor in Chief of Chinese Journal of Extracorporeal Circulation.

Scientific Research and Clinical Achievements He is proficient in extracorporeal life support and cardiopulmonary bypass during cardiac surgery and heart transplantation. His research interests include “Myocardial Protection”, “Extracorporeal Membrane Oxygenation” and “Tissue Engineering—Artificial Lung”. Totally, he has published 34 SCI papers and 186 articles in Chinese; edited and participated in 17 monographs; invented 3 patents; presided 7 research projects, including four projects of the National Natural Science Foundation of China; participated in four projects, including two National Key Research and Development Programs of China and one Project in the National Science and Technology Pillar Program during the Eleventh Five-Year Plan period.

vii

Introduction of Chief Editor, Yulong Guan

The Main Academic Title Member of National Natural Science Foundation of China and Beijing Natural Science Foundation Expert Database; Member of National Expert Database of Science and Technology, Ministry of Science and Technology; Invited foreign reviewer for “Artif Organs”, “Journal of Clinical Case Studies”, “Journal of Pediatric Intensive Care”; member of Editorial Board, Journal of Cardiovascular and Pulmonary Disease; Standing member of the third Committee, Blood Management Branch of Chinese Society of Cardiothoracic Anesthesia; member of Editorial Board, Biomedical Engineering and Clinical Medicine; Invited reviewer, Chinese Journal of Trauma; Member of Cardiac Function Committee of Chinese Medical Information Society.

Scientific Research and Clinical Achievements For years engaged in the basic and clinical scientific research on central nervous system protection during the cardiovascular surgery, participated in and presided over a series of scientific research projects including: • National natural science fund funding project (81170233; 30371412, 39770733) • CAMS Innovation Fund for Medical Sciences (2020-I2M-C&T-B-066) • Independent project of National Clinical Research Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College (NCRC2020005) • Research Foundation of the Ministry of Education for returned overseas students (2013-LH01) • Beijing Science and Technology Plan (2011-BKJ04) • Union Youth Research Fund (2011-xh1) • University doctoral Foundation of Ministry of Education (2010-GB01, 200800231118, 2006-GB04) • Youth Foundation, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (2008F004) • Beijing Science and Technology New Star project (951871000) ix

x

Introduction of Chief Editor, Yulong Guan

Scientific Achievements • Young Investigator Award, Seventh international Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Bypass, Philadelphia, USA, 2011 • Second Prize of Beijing Science and Technology Progress Award (H01-2004-069)

Scientific Training As a post-doctoral fellow, received Specialist Training on extracorporeal life support and simulated training of pediatrics and extracorporeal circulation in Hershey Medical Center, Hershey, Pennsylvania, USA, from Oct 25th, 2008 to Nov 1st, 2009.

Scientific Monographs Participated in the compilation of more than 10 domestic monographs on extracorporeal circulation and extracorporeal life support.

Scientific Papers Up to now, more than 90 papers have been published including 15 SCI papers as the first author or corresponding author.

Introduction of Chief Editor, Kun Yu

The Main Academic Title Chief physician of Extracorporeal Circulation Center of Fuwai Hospital, Master tutor. Secretary General of Extracorporeal Life Support Branch of Chinese Society of Cardiothoracic and Vascular Anesthesia; Evaluation expert of Chinese Medical Doctor Association standardized training of resident physicians in the direction of cardiothoracic surgery; Member of Chinese Extracorporeal Circulation Society; Member of the Professional Committee of Extracorporeal Life Support and Society of Chinese Research Hospital Society, Member of Extracorporeal Life Support Branch of Chinese Medical Rescue Association.

Scientific Research and Clinical Achievements She has presided over and participated in a number of national and provincial scientific research projects, published more than 50 papers. She is the editor-in-chief of professional book Modern Cardiopulmonary Bypass, and the deputy chief editor of professional books Manual of Extracorporeal Circulation, and Manual of ECMO. Additionally, she is the principal translator of the Braunwald’s cardiology companion book Mechanical Circulatory Support. She is proficient in cardiopulmonary bypass techniques for complicated cases as well as extracorporeal life support (previously named as ECMO). She has participated in the quality control of cardiopulmonary bypass techniques in China and performed more than 3000 cases of CPB and 100 cases of ECMO.

xi

Contents

1 Physiology  of Extracorporeal Life Support�������������������������������������������������������������   1 Shigang Wang Cardiovascular Physiology�����������������������������������������������������������������������������������������    2 Heart�����������������������������������������������������������������������������������������������������������������������    2 Vasculature�������������������������������������������������������������������������������������������������������������    4 Blood�����������������������������������������������������������������������������������������������������������������������    4 Cardiovascular Pathophysiology���������������������������������������������������������������������������������    6 ECMO Circuit and Circuit Physiology�����������������������������������������������������������������������    6 Blood Pumps�����������������������������������������������������������������������������������������������������������    6 Gas Exchange Device: Artificial Oxygenator���������������������������������������������������������   10 Cannulas�����������������������������������������������������������������������������������������������������������������   11 Tubing and Connectors�������������������������������������������������������������������������������������������   12 Mechanism of Cardiorespiratory Support�������������������������������������������������������������������   12 Physiology of VA-ECMO���������������������������������������������������������������������������������������   13 Physiology of VV-ECMO���������������������������������������������������������������������������������������   15 VA-ECMO vs. VV-ECMO�������������������������������������������������������������������������������������   17 Pharmacokinetics During ECMO���������������������������������������������������������������������������   17 Pumpless Extracorporeal Lung Assist (pECLA) ���������������������������������������������������   17 Summary���������������������������������������������������������������������������������������������������������������������   18 References�������������������������������������������������������������������������������������������������������������������   19 2 Equipment  and Devices of Extracorporeal Life Support���������������������������������������  21 Qiang Hu Blood Pump ���������������������������������������������������������������������������������������������������������������   21 Centrifugal Pump Physics���������������������������������������������������������������������������������������   21 Components of a Centrifugal Pump�����������������������������������������������������������������������   22 Commercial Centrifugal Pumps�����������������������������������������������������������������������������   22 Membrane Oxygenator�����������������������������������������������������������������������������������������������   25 Commercial Gas Exchange Devices�����������������������������������������������������������������������   26 ECLS Tubing �������������������������������������������������������������������������������������������������������������   29 General Principles of Circuit Design ���������������������������������������������������������������������   29 Surface Coating Technology�����������������������������������������������������������������������������������   29 Heat Exchanger/Heater-Cooler Device�����������������������������������������������������������������������   31 Medicare Monitoring During ECLS���������������������������������������������������������������������������   32 Hemoglobin Saturation Measurement �������������������������������������������������������������������   32 Anticoagulation Monitoring�����������������������������������������������������������������������������������   32 Circuit Pressures�����������������������������������������������������������������������������������������������������   35 Colloid Osmotic Pressure���������������������������������������������������������������������������������������   36 Plasma Free Hemoglobin���������������������������������������������������������������������������������������   36 Temperature Monitoring�����������������������������������������������������������������������������������������   37 References�������������������������������������������������������������������������������������������������������������������   37

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3 Types  of Extracorporeal Life Support and Evolution of Extracorporeal Oxygenators�����������������������������������������������������������������������������������������������������������������  39 Ong Geok Seen, Huang Shoo Chay-Nancy, Clara Anne Lim, Chew Kai Hong Clement, and Goh Si Guim The Retrospective Glance on the Historical Development of ECLS/ECMO and Extracorporeal Oxygenators�����������������������������������������������������   39 Evolution of Extracorporeal Oxygenator and Its Use in Extracorporeal Life Support �����������������������������������������������������������   40 Development of High-Performance Extracorporeal Oxygenators for ECMO Use—High Gas Exchange Efficiency, Low Flow Resistance, and Plasma Leak-Tight Oxygenator�����������������������������������   41 Extracorporeal Membrane Oxygenation (ECMO)�����������������������������������������������������   43 Veno-Venous Extracorporeal Membrane Oxygenation (VV ECMO) Mode ���������   43 Veno-Arterial Extracorporeal Membrane Oxygenation (VA ECMO) Mode ���������   47 Venovenous-Arterial (VV-A) ECMO, Alternative Configuration of Peripheral VA Mode and Cannulation Strategies�����������������������������������������������   48 Veno-Veno-Arterial (V-VA) ECMO, a “Hybrid” Mode Configuration in North-South or Harlequin Syndrome or Differential Hypoxia���������������������������   50 Conclusion �����������������������������������������������������������������������������������������������������������������   53 References�������������������������������������������������������������������������������������������������������������������   53 4 Cannulation  and Decannulation of Extracorporeal Life Support�������������������������  57 Haiyun Yuan Cannulation Sites �������������������������������������������������������������������������������������������������������   57 Femoral Artery �������������������������������������������������������������������������������������������������������   57 Axillary Artery �������������������������������������������������������������������������������������������������������   58 Carotid Artery���������������������������������������������������������������������������������������������������������   58 Ascending Aorta�����������������������������������������������������������������������������������������������������   58 Femoral Vein�����������������������������������������������������������������������������������������������������������   58 Right Internal Jugular Vein�������������������������������������������������������������������������������������   59 Subclavian Vein�������������������������������������������������������������������������������������������������������   59 Right Atrium�����������������������������������������������������������������������������������������������������������   59 Cannula Selection�������������������������������������������������������������������������������������������������������   59 Single-Lumen Cannula�������������������������������������������������������������������������������������������   59 Dual-Lumen Cannula���������������������������������������������������������������������������������������������   61 Methods and Techniques of Cannulation�������������������������������������������������������������������   62 Surgical Cannulation�����������������������������������������������������������������������������������������������   62 Percutaneous Cannulation���������������������������������������������������������������������������������������   63 Semi-Percutaneous Cannulation�����������������������������������������������������������������������������   64 Decannulation�������������������������������������������������������������������������������������������������������������   64 Decannulation of Arterial Cannula�������������������������������������������������������������������������   65 Decannulation of Venous Cannula �������������������������������������������������������������������������   65 Left Ventricular Venting ���������������������������������������������������������������������������������������������   66 Surgical Venting �����������������������������������������������������������������������������������������������������   66 Percutaneous Venting ���������������������������������������������������������������������������������������������   67 References�������������������������������������������������������������������������������������������������������������������   67 5 Anticoagulation  During Extracorporeal Life Support �������������������������������������������  71 Ping Li Hemostatic Alterations�����������������������������������������������������������������������������������������������   71 Anticoagulation�����������������������������������������������������������������������������������������������������������   72 Unfractionated Heparin�������������������������������������������������������������������������������������������   72 Direct Thrombin Inhibitors�������������������������������������������������������������������������������������   73 Antiplatelet Agents�������������������������������������������������������������������������������������������������   73

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Anticoagulation Monitoring���������������������������������������������������������������������������������������   75 ACT�������������������������������������������������������������������������������������������������������������������������   75 aPTT�����������������������������������������������������������������������������������������������������������������������   75 Anti-Factor Xa Assay���������������������������������������������������������������������������������������������   75 Thromboelastography/Thromboelastometry-­Guided Algorithm ���������������������������   76 Anticoagulation Management During ECLS�������������������������������������������������������������   76 Bleeding �����������������������������������������������������������������������������������������������������������������   76 Thrombosis�������������������������������������������������������������������������������������������������������������   76 Conclusions�����������������������������������������������������������������������������������������������������������������   77 References�������������������������������������������������������������������������������������������������������������������   77 6 Management  of Pediatric Extracorporeal Life Support�����������������������������������������  79 Ju Zhao Overview and History�������������������������������������������������������������������������������������������������   79 Centrifugal Pump Takes the Place of Roller Pump�������������������������������������������������   79 Hollow Fiber Oxygenator Takes the Place of Silicon Membrane Oxygenator�������������������������������������������������������������������������������������������������������������   80 Cannula�������������������������������������������������������������������������������������������������������������������   80 Circuit and Coating Technique�������������������������������������������������������������������������������   81 Outcomes ���������������������������������������������������������������������������������������������������������������   81 Indications�������������������������������������������������������������������������������������������������������������������   82 Respiratory Failure�������������������������������������������������������������������������������������������������   82 Cardiac Support �����������������������������������������������������������������������������������������������������   82 Cannulation Strategies �����������������������������������������������������������������������������������������������   83 VA ECMO���������������������������������������������������������������������������������������������������������������   83 VV ECMO �������������������������������������������������������������������������������������������������������������   84 Decannulation���������������������������������������������������������������������������������������������������������   85 ECMO Circuit Priming�������������������������������������������������������������������������������������������   85 Initiation of ECMO�����������������������������������������������������������������������������������������������������   85 Selection of Cannula�����������������������������������������������������������������������������������������������   85 ECMO Flow�����������������������������������������������������������������������������������������������������������   86 ICU Management and Assessment of Support�����������������������������������������������������������   86 Ventilation���������������������������������������������������������������������������������������������������������������   86 Hypoxia�������������������������������������������������������������������������������������������������������������������   87 Cardiac Output �������������������������������������������������������������������������������������������������������   87 Fluid Management and Nutrition���������������������������������������������������������������������������   87 Sedation�������������������������������������������������������������������������������������������������������������������   87 Anticoagulation�������������������������������������������������������������������������������������������������������   88 Key Points in Management�����������������������������������������������������������������������������������������   89 Systemic and Local Hypoxia ���������������������������������������������������������������������������������   89 Left Heart Decompression �������������������������������������������������������������������������������������   89 VA ECMO for Single Ventricle�������������������������������������������������������������������������������   89 Special Situations���������������������������������������������������������������������������������������������������   90 Weaning from ECMO�������������������������������������������������������������������������������������������������   90 References�������������������������������������������������������������������������������������������������������������������   91 7 Management  of Adult Extracorporeal Life Support�����������������������������������������������  93 Dandong Luo, Jiaxin Li, and Jimei Chen Monitoring �����������������������������������������������������������������������������������������������������������������   93 Monitoring of ECLS Equipment�����������������������������������������������������������������������������   93 Patient’s Monitoring�����������������������������������������������������������������������������������������������   94 Respiratory and Circulatory Management �����������������������������������������������������������������   94 VV ECLS ���������������������������������������������������������������������������������������������������������������   94 VA ECLS����������������������������������������������������������������������������������������������������������������   95

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Blood Management�����������������������������������������������������������������������������������������������������   96 Hematocrit���������������������������������������������������������������������������������������������������������������   96 Destruction of Red Blood Cells �����������������������������������������������������������������������������   96 Anticoagulation During Extracorporeal Life Support �������������������������������������������   97 Kidney Function and Electrolytes�������������������������������������������������������������������������������   97 Kidney Function�����������������������������������������������������������������������������������������������������   97 Blood Gas Parameters and Electrolytes �����������������������������������������������������������������   97 Management of Edema and Fluids�������������������������������������������������������������������������   97 Central Nervous System���������������������������������������������������������������������������������������������   98 Assessment of Central Nervous System During ECLS �����������������������������������������   98 Central Nervous System Protective Measures During ECLS���������������������������������   99 Gastrointestinal Tract Management and Nutritional Support�������������������������������������   99 Parenteral Nutrition�������������������������������������������������������������������������������������������������   99 Enteral Nutrition�����������������������������������������������������������������������������������������������������  100 Nutritional Assessment�������������������������������������������������������������������������������������������  100 Analgesia and Sedation�����������������������������������������������������������������������������������������������  100 Evaluation and Goals ���������������������������������������������������������������������������������������������  100 Commonly Used Drugs�������������������������������������������������������������������������������������������  101 Conscious ECLS�����������������������������������������������������������������������������������������������������  101 Temperature Management������������������������������������������������������������������������������������������  101 Vascular Complications ���������������������������������������������������������������������������������������������  101 Blood Vessel Damage���������������������������������������������������������������������������������������������  101 Limb Ischemia �������������������������������������������������������������������������������������������������������  101 Infection and Antibiotics���������������������������������������������������������������������������������������������  102 Urinary Tract Infection�������������������������������������������������������������������������������������������  102 Pulmonary Infections ���������������������������������������������������������������������������������������������  102 Intravascular Infection Caused by Indwelling Catheter�����������������������������������������  103 Wound Infection�����������������������������������������������������������������������������������������������������  103 Intestinal Infection �������������������������������������������������������������������������������������������������  103 Fungal Infection �����������������������������������������������������������������������������������������������������  103 Discontinuation of ECLS�������������������������������������������������������������������������������������������  104 Requirements for ECLS Discontinuation���������������������������������������������������������������  104 Testing Before Discontinuation �����������������������������������������������������������������������������  104 Termination of Ineffective ECLS���������������������������������������������������������������������������  104 References�������������������������������������������������������������������������������������������������������������������  105 8 Extracorporeal  Life Support During Cardiac Arrest��������������������������������������������� 107 Chou Yueh-Ting Selection of ECPR Patients�����������������������������������������������������������������������������������������  108 No Flow Time and Low Flow Time�����������������������������������������������������������������������  108 Age�������������������������������������������������������������������������������������������������������������������������  108 CPR Quality: EtCO2�����������������������������������������������������������������������������������������������  108 Ventilator Setting ���������������������������������������������������������������������������������������������������  108 Strategies of Cannulation�������������������������������������������������������������������������������������������  109 Management���������������������������������������������������������������������������������������������������������������  109 Complications�������������������������������������������������������������������������������������������������������������  109 Neurological Outcome �������������������������������������������������������������������������������������������  110 References�������������������������������������������������������������������������������������������������������������������  110 9 Adverse  Events and Complications of Extracorporeal Life Support��������������������� 113 Kun Yu Categories of Complications and the Cumulative Incidence �������������������������������������  113 Mechanical Adverse Events ���������������������������������������������������������������������������������������  116 Pump Failure�����������������������������������������������������������������������������������������������������������  116

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Low Flow/Cutting Off���������������������������������������������������������������������������������������������  116 Air in Circuit�����������������������������������������������������������������������������������������������������������  117 Oxygenator Failure�������������������������������������������������������������������������������������������������  117 Thrombosis�������������������������������������������������������������������������������������������������������������  118 Tubing Rupture�������������������������������������������������������������������������������������������������������  118 Others���������������������������������������������������������������������������������������������������������������������  119 Cannulation-Related Complications���������������������������������������������������������������������������  119 Clinical Manifestations�������������������������������������������������������������������������������������������  119 Causes���������������������������������������������������������������������������������������������������������������������  119 Solution�������������������������������������������������������������������������������������������������������������������  120 Hematologic Disorders�����������������������������������������������������������������������������������������������  120 Thrombosis�������������������������������������������������������������������������������������������������������������  120 Bleeding �����������������������������������������������������������������������������������������������������������������  121 Neurologic Injury�������������������������������������������������������������������������������������������������������  122 Clinical Manifestations�������������������������������������������������������������������������������������������  123 Mechanism�������������������������������������������������������������������������������������������������������������  123 Prognosis�����������������������������������������������������������������������������������������������������������������  124 Prevention���������������������������������������������������������������������������������������������������������������  124 Management�����������������������������������������������������������������������������������������������������������  125 Circulatory Complications �����������������������������������������������������������������������������������������  126 LV Dilation Complications�������������������������������������������������������������������������������������  126 Harlequin Syndrome�����������������������������������������������������������������������������������������������  126 Pulmonary Complication �������������������������������������������������������������������������������������������  126 Clinical Manifestations�������������������������������������������������������������������������������������������  126 Causes���������������������������������������������������������������������������������������������������������������������  126 Solution�������������������������������������������������������������������������������������������������������������������  127 Acute Kidney Injury���������������������������������������������������������������������������������������������������  127 Definitions of ECMO-Associated Kidney Injury���������������������������������������������������  127 Risk Factors �����������������������������������������������������������������������������������������������������������  127 Pathophysiology of ECMO-Associated Kidney Injury �����������������������������������������  127 Prevention and Management�����������������������������������������������������������������������������������  128 Vascular Complications ���������������������������������������������������������������������������������������������  128 Limb Ischemia �������������������������������������������������������������������������������������������������������  128 Vessel Damage �������������������������������������������������������������������������������������������������������  129 Infection ���������������������������������������������������������������������������������������������������������������������  130 Clinical Manifestations�������������������������������������������������������������������������������������������  130 Risk Factors �����������������������������������������������������������������������������������������������������������  131 Etiology of Infection�����������������������������������������������������������������������������������������������  131 Preventive Practices �����������������������������������������������������������������������������������������������  131 Hemolysis�������������������������������������������������������������������������������������������������������������������  131 Diagnosis and Clinical Manifestations�������������������������������������������������������������������  131 Mechanisms �����������������������������������������������������������������������������������������������������������  132 Management and Prevention�����������������������������������������������������������������������������������  132 References�������������������������������������������������������������������������������������������������������������������  133 10 Transport  of the Patients Supported with Extracorporeal Life Support ������������� 135 Guodong Gao Intra-Hospital Transport of Patients Supported with ECLS���������������������������������������  135 Purpose of Transport�����������������������������������������������������������������������������������������������  135 Preparation of Personnel and Equipment���������������������������������������������������������������  135 Transport Points �����������������������������������������������������������������������������������������������������  136 Inter-Hospital Transport���������������������������������������������������������������������������������������������  136 Indications for Inter-Hospital ECLS Transport�������������������������������������������������������  136

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Transport Logistics�������������������������������������������������������������������������������������������������  136 Transfer Modes�������������������������������������������������������������������������������������������������������  137 Personnel Preparation���������������������������������������������������������������������������������������������  137 Transport Equipment�����������������������������������������������������������������������������������������������  138 Management of Inter-Hospital ECLS Transport���������������������������������������������������������  139 Assessment of Patient���������������������������������������������������������������������������������������������  139 Lay Out a Scheme���������������������������������������������������������������������������������������������������  139 Patient Transport�����������������������������������������������������������������������������������������������������  139 Monitoring in ECLS Transfer���������������������������������������������������������������������������������  139 Treatment and Care in ECLS Transfer�������������������������������������������������������������������  139 Complications Associated with Transport �������������������������������������������������������������  140 References�������������������������������������������������������������������������������������������������������������������  140 11 Extracorporeal  Life Support During Perioperative Transplantation ������������������� 141 Caihong Wan and Yulong Guan ECLS During Perioperative Heart Transplantation ���������������������������������������������������  141 ECLS Prior to Heart Transplant�����������������������������������������������������������������������������  141 ECLS as Post-Transplant Support���������������������������������������������������������������������������  144 Outlook of ECLS During Perioperative Heart Transplantation �����������������������������  145 ECLS During Perioperative Lung Transplantation�����������������������������������������������������  145 ECLS as a Bridge to Lung Transplant �������������������������������������������������������������������  145 ECLS During Lung Transplantation�����������������������������������������������������������������������  148 ECLS Following Lung Transplantation �����������������������������������������������������������������  151 Outlook of ECLS During Perioperative Lung Transplantation �����������������������������  152 ECLS During Donor Storage �������������������������������������������������������������������������������������  153 Organ-Preservation ECLS in DBD Donor�������������������������������������������������������������  153 ECPR and Organ Donors ���������������������������������������������������������������������������������������  153 ECLS for Abdominal Organ Protection from Donors After Circulatory Death�����  153 Ethical Dilemmas of ECLS in Organ Donors���������������������������������������������������������  154 References�������������������������������������������������������������������������������������������������������������������  154 12 Topics  of Extracorporeal Life Support��������������������������������������������������������������������� 157 Feilong Hei Novel ECLS Instruments �������������������������������������������������������������������������������������������  157 Animal Experiments with Newly Developed ECLS System���������������������������������  157 Clinical Experiments with Newly Developed ECLS System���������������������������������  160 The Timing of ECLS Initiation�����������������������������������������������������������������������������������  161 Patient Selection and Timing for rECLS Support���������������������������������������������������  162 Patient Selection and Timing for cECLS Support �������������������������������������������������  162 Extracorporeal Cardiopulmonary Resuscitation�����������������������������������������������������  162 The Timing of ECLS Termination �����������������������������������������������������������������������������  162 Weaning from VA ECLS�����������������������������������������������������������������������������������������  163 Weaning from VV ECLS ���������������������������������������������������������������������������������������  163 ECLS During Treatment of COVID-19 ���������������������������������������������������������������������  164 When ECLS Is Used for COVID-19 Patients���������������������������������������������������������  164 ECLS During Donor Reconditioning of Lung Transplantation���������������������������������  164 Patient Selection for ECLS�������������������������������������������������������������������������������������  164 ECLS and Protection During Reperfusion�������������������������������������������������������������  164 Combination of Mechanical Assistance with ECLS���������������������������������������������������  164 New Indications of ECLS in the Future���������������������������������������������������������������������  165 References�������������������������������������������������������������������������������������������������������������������  166

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13 Extracorporeal Life Support Training��������������������������������������������������������������������� 167 Chengbin Zhou Teaching Theory���������������������������������������������������������������������������������������������������������  167 Cognitive Domain���������������������������������������������������������������������������������������������������  168 Psychomotor Domain (Technical Skills) ���������������������������������������������������������������  168 Psychomotor Domain (Behavioral Skills) �������������������������������������������������������������  168 Affective Domain���������������������������������������������������������������������������������������������������  169 Training of ECLS Team ���������������������������������������������������������������������������������������������  169 Training Content���������������������������������������������������������������������������������������������������������  169 Acquiring Competency�������������������������������������������������������������������������������������������  169 Verifying ECLS Competency���������������������������������������������������������������������������������  171 Ethics Training �������������������������������������������������������������������������������������������������������  172 ECLS Training in China Mainland�����������������������������������������������������������������������������  173 Future Perspectives�����������������������������������������������������������������������������������������������������  174 References�������������������������������������������������������������������������������������������������������������������  174

1

Physiology of Extracorporeal Life Support Shigang Wang

The primary function of the heart and lungs is the provision of blood circulation, to provide oxygen (O2) and other nutrients to the cells and to remove the products of metabolism including carbon dioxide (CO2). During open heart surgery, cardiopulmonary bypass (CPB) may be used to isolate the heart and lungs and replace whole functions of the heart and lungs during aortic cross-clamp and provide quiet, bloodless field for the performance of surgery. The utilization of CPB involves the use of an oxygenator with a cardiotomy/venous reservoir, roller or centrifugal pumps, filters, tubing, and cardiotomy suction devices. Unlike CPB, extracorporeal life support (ECLS) is one modified CPB technology used in patients with life-threatening heart and/or lung failure, including venoarterial (VA), venovenous (VV), and venovenoarterial (VVA) extracorporeal membrane oxygenation (ECMO)

and VV and arteriovenous (AV) extracorporeal carbon dioxide removal (ECCO2R) [1]. The ECMO system partially takes the functions of the heart and lungs for prolonged cardiopulmonary support, allowing the heart and lungs to rest, stopping damaging heart and lung treatment, and recovering functions of the failing organs (bridge-to-­ recovery) or as a bridge to long-term ventricular assist (bridge-to-VAD), heart or lung transplantation (bridge-to-­ transplantation), or destination therapy (bridge-to-­ destination) for suitable candidates with irreversible disease (Fig. 1.1) [2]. Different ECMO types and strategies have strongly different effects on circulatory and respiratory support. To manage patients on ECMO, it is essential to thoroughly understand the cardiopulmonary physiology, pathophysiology, and ECMO physiology.

S. Wang (*) Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA e-mail: [email protected]

© Springer Nature Singapore Pte Ltd. 2023 F. Hei et al. (eds.), Extracorporeal life support, https://doi.org/10.1007/978-981-19-9275-9_1

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2

S. Wang

b

O2

Oxygenator

Oxygenator

a

O2

Centrifugal Pump

Centrifugal Pump

VA-ECMO

VV-ECMO

Fig. 1.1  The two main types of ECMO configuration. (a) venoarterial (VA) ECMO, (b) venovenous (VV) ECMO

Cardiovascular Physiology The cardiovascular system consists of the heart (as a pump), blood vessels (a closed tube), and the blood (carries and transports materials to and from all parts of the body). The heart drives blood through the lungs for pulmonary gas exchange (pulmonary circulation) and through a closed blood vessel system (including arteries, arterioles, capillaries, venules, and veins) for the exchange of materials (systemic circulation). The lungs receive all blood to perform gas exchange in the pulmonary microcirculation. They are only organs that communicate with the external environment in the cardiovascular system, where O2 and CO2 are exchanged. Most systemic organs are arranged in parallel with the cardiovascular system. They receive identical blood and different flow independently controlled by the body. Many of the systemic organs serve to recondition the composition of blood, such as the kidneys, abdominal organs, and skin. They can temporarily withstand severe reduction of blood flow, because their normal blood flow is much more than that necessary to maintain their basal metabolic needs. However, the brain and myocar-

dium cannot tolerate blood flow interruptions, because normal blood flow to the brain and myocardium is just slightly greater than that required for their metabolic needs. Therefore, unconsciousness will occur within a few seconds after any cease in cerebral blood supply, permanent brain damage will occur after only 4 min without oxygen, and brain death may occur as soon as 4–6  min later. The heart will reduce its pumping ability within beats of a coronary flow interruption, because the heart muscle consumes approximately 75% of the oxygen in supplied blood which only supplies the metabolic need of the heart [3].

Heart The heart is a muscular organ that is filled with blood (preload) from the venous side, rhythmically contracts ­(contractility), and ejects blood against pressure (afterload) to the arterial side. The heart generates a unidirectional blood flow with the help of the orderly contraction sequence of the different heart chambers and the presence of cardiac valves.

1  Physiology of Extracorporeal Life Support

3

Preload  The resting length of the myocardial sarcomeres (end-diastolic volume) or tension on the myocardial sarcomeres (end-diastolic pressure) just prior to contraction.

Systole  The ventricle is contracting and ejecting blood.

Contractility  The strength of the ventricular contraction at a given initial fiber length (end-diastolic volume), determined by preload, afterload, and heart rate (HR), as well as myocyte intracellular calcium concentration and temperature.

The LV end-diastolic volume (EDV) is typically about 120 mL, and the LV end-systolic volume (ESV) is approximately 50  mL.  Therefore, the LV stroke volume (SV) is about EDV-ESV = 120–50 = 70 mL. The LV ejection fraction (EF)  =  SV/EDV, normally >55%. The cardiac output (CO) = SV × HR, typically ranging from 5 to 6 L/min in a resting adult. The cardiac index (CI) = CO/body surface area (BSA), ranging from 2.6 to 4.2 L/min/m2. The left side and right side of the heart have a similar timing of contraction and relaxation. However, the pressures in the left side of the heart are much higher than those in the right side. For example, the LV pressure typically changes from 8 mmHg to 120 mmHg, while the RV pressure changes

Afterload  The resistance to ventricular ejection, a “load” against which the heart must contract to eject blood, consisting of two main determinant factors: myocardial wall stress and aortic input impedance. Cardiac Cycle  It begins with atrial contraction and ends with ventricular relaxation (Fig.  1.2), including two basic phases – systole and diastole [4].

Fig. 1.2  Cardiac cycle. AV, aortic valve; MV, mitral valve; PV, pulmonary valve; TV, tricuspid valve

Diastole  The ventricle is relaxing and filled with blood.

4

from 4  mmHg to 8  mmHg. Similarly, the pressures in the aorta (80–120 mmHg) and pulmonary artery (10–25 mmHg) are also very different. The LV pressure–volume loop describes the changes in LV pressure (y-axis) associated with the changes in LV volume (x-axis) which occur during the cardiac cycle. The area within the pressure–volume loop is the ventricular stroke work, which refers to the amount of blood pumped out of the LV in one cardiac cycle.  O2)  =  coroThe myocardial oxygen consumption (M V nary blood flow (CBF) × [arterial oxygen content (CaO2) − venous oxygen content (CvO2)], expressed as mL O2/min per 100 g (typically 8 mL O2/min per 100 g). It’s significantly influenced by changes in arterial pressure, HR, and inotropy.

Vasculature The vascular system is a closed blood vessel network connecting the heart with all other organs and tissues in the body, transporting blood to and away from organs and involving the movement of gases, nutrients, and fluid between the blood and tissues. It consists of distribution/ resistance vessels (aorta, large and small distributing arteries), exchange vessels (capillaries and small venules), and capacitance vessels (large venules, veins, and vena cavae). The small arteries and arterioles are the primary resistance vessels, being responsible for 50%–70% of the pressure drop within the vasculature. The capillaries have the greatest surface area for material exchange between the blood and tissues. The capacitance vessels contain about 60%–80% of the body’s blood volume [5]. In the aorta, blood is ejected from LV, and blood flows across the aorta into branch arteries. The force of pushing blood against the aortic wall is the aortic pressure. It has pulsatility  – peak pressure termed the systolic pressure (Psys) and minimal pressure termed the diastolic pressure (Pdias). The aortic pulse pressure is the difference between the systolic and diastolic pressures (Psys − Pdias), determined by ventricular stroke volume and aortic compliance. Increased LV preload and inotropy as well as decreased afterload and heart rate will increase the ventricular stroke volume and sequentially increase the pulse pressure. Decreased aortic ­compliance, such as arteriosclerosis and hypertension, also increases the pulse pressure. As the pressure pulse moves away from the heart, pulsatility diminishes. The mean aortic/arterial pressure (MAP) can be calculated as follows: MAP = Pdias + 1/3 (Psys − Pdias), determined by cardiac output (CO), systemic vascular resistance (SVR), and central venous pressure (CVP). Increased CO, SVR, and

S. Wang

CVP can increase blood pressure. Decreased SVR due to selective arterial dilation reduces arterial volume and pressure, while it increases CVP and venous volume. SVR can be estimated as follows: SVR = (MAP - CVP) / CO. CVP is the blood pressure in the thoracic vena cava near the right atrium. Elevated CVP increases CO, but may lead to peripheral edema.

Blood Blood Composition Blood consists of three main cellular elements – red blood cells (erythrocytes), white blood cells (leukocytes), and platelets, suspended in blood plasma. Blood makes up about 8% of total body weight. Red blood cells normally constitute about 44% of total volume of whole blood, white blood cells and platelets contribute less than 1% of blood volume, and plasma makes up 55% of whole blood. Blood performs a number of functions, including transporting O2 and CO2, nutrients, hormones, and wastes; maintaining appropriate body temperature, normal pH, and adequate fluid volume in the circulatory system; performing immune function; and preventing blood loss. Red blood cells (diameter 7.5  μm, 5 × 1012/L, life span around 120  days) are small, biconcave disc-shaped cells which are primarily involved in the transport of O2 and CO2 in blood. White blood cells (diameter 12–15 μm, 5 × 109/L, life span 13–20  days) play a defensive role in destroying infecting organisms and in the removal of damaged tissue. Platelets (diameter 1.5–3  μm, 300 × 109/L, life span 9–12 days) are small disc-shaped cell fragments which are important in clotting the blood to prevent the excess loss of body fluids. Plasma has about 90% of water, 9% of plasma proteins, and 1% of small molecules. Transportation of O2 in Blood Red blood cells are responsible for transporting O2. Only 2% of O2 in arterial blood is dissolved O2. Most O2 carried in blood is bound to oxygen-binding protein hemoglobin (Hb). Hemoglobin consists of four polypeptide chains: two alpha (α) chains and two beta (β) chains – each binding to an iron-­ containing heme group. Oxygen loading occurs in the lungs. When high-concentration O2 in lungs binds to the iron ion in each heme, hemoglobin forms ruby-red oxyhemoglobin (oxy-Hb). In the tissues surrounding systemic capillaries, oxygen concentrations are low, and hemoglobin releases O2 to become dark-red deoxyhemoglobin (deoxy-Hb). The oxygen–hemoglobin dissociation curve (the oxyhemoglobin dissociation curve) describes the relationship between percent hemoglobin saturation (SO2) and

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CaO 2  mL / dL   1.35  mL / g   Hb  g / dL   SaO 2 

  kO 2  mL / dL / mmHg   PaO 2  mmHg  

where SaO2 = arterial O2 saturation; kO2 = O2 solubility constant (0.0031  mL O2/100  mL blood/mmHg at 37  °C); and PaO2 = arterial oxygen partial pressure. Arterial oxygen content is approximately 20 g/dL, the venous oxygen content is 15 g/dL, and then arterial blood releases about 5 mL/dL of O2. Normal adult human oxygen consumption (VO2) is 3–5 mL/kg/min. Oxygen delivery (DO2) is a function of arterial oxygen content and cardiac output (CO). DO 2  mL / min   CaO 2  mL / dL   CO  L / min   10  dL / L 

Fig. 1.3 The oxygen–hemoglobin dissociation curve. 2.3-DPG: 2,3-diphosphoglycerate

partial pressure of oxygen (PO2) (Fig.  1.3) [6]. When PO2 is 100  mmHg, blood SO 2 is 100%. When PO 2 decreases below 60  mmHg, SO2 rapidly falls. The shift of the oxyhemoglobin dissociation curve will affect the ability to take up O 2 at the lung and unload O 2 from hemoglobin at the tissues. A shift to the left increases hemoglobin’s affinity for O2, resulting from increased blood pH, decreased body temperature, lower O2 affinity, and reduced 2,3-diphosphoglycerate (2,3-DPG) or partial pressure of arterial carbon dioxide (PaCO2) levels. In a leftward shift, less O2 is released to the tissues, but more O2 is bound to hemoglobin in the lungs; the SaO2 value is higher than normal for a given PaO2 value. A shift to the right decreases hemoglobin’s affinity for oxygen for a given PaO2 value, and the SaO2 value decreases below normal. Causes of a shift to the right include exercise, acidosis, increased body temperature, higher O2 affinity, and elevated 2,3-DPG or PaCO2 levels. Hemoglobin releases O2 to the tissues more readily for keeping tissues well-oxygenated. The normal range for hemoglobin is 13–18  g/100  mL blood in adult males and 12–16 g/100 mL in adult females. One gram of hemoglobin carries approximately 1.35 mL of O2, when 100% saturated [6]. Higher hemoglobin ­concentration increases O2-carriying capacity. Total O2 content (CaO2) of arterial blood is calculated as following:

Transportation of CO2 in Blood A small portion (5%) of CO2 in the blood is dissolved along a gradient of partial pressure from cells to interstitium to systemic capillary blood plasma (solubility coefficient = 0.06 mL/100 mL blood/mmHg, 20 times higher than O2 solubility). The rest of CO2 is chemically bound in form of HCO3− ions (90%) and carbamate residues (5%) of hemoglobin within the red blood cells [7]. CO2 is much more soluble. Dissolved CO2 can rapidly be converted to bicarbonate anion (HCO3−). Under a normal arterial PCO2 of 40 mmHg, about 2.4 mL of CO2 is dissolved per liter of blood. In the peripheral cells, CO2 diffuses into red blood cells and combines with water, forming H2CO3. Under carbonic anhydrase catalysis in red blood cells, H2CO3 dissociates into hydrogen ions and bicarbonate ions. CO 2  H 2 O  H 2 CO3

Carbonic Anhydrase



HCO3  H 

Hemoglobin (Hb) in the red cells is a key buffer for H+ ions. The binding of CO2 to Hb enhances O2 release (Bohr effect). The lower PO2 and lower Hb saturation with O2 help more CO2 to be carried by blood (Haldane effect). In red blood cells circulating in the periphery, small amounts of CO2 can also bind to Hb, forming carbaminohemoglobin. CO 2  Hb  NH 2

Hemoglobin Carbamate Formation



Hb  NH  COO   H  .

About 24–25  mmol/L of CO2 existed in mixed venous blood. In the pulmonary capillaries, these reactions proceed in the opposite direction. CO2 is released from HCO3− and Hb carbamate, and then CO2 diffuses into the alveoli because of lower PCO2 in alveoli than in venous blood. Finally, CO2 is expired into the atmosphere. About 22–23 mmol/L of CO2 remained in arterial blood.

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Cardiovascular Pathophysiology

Blood Pumps

For patients with chronic heart failure (HF), the ability of their heart to be filled with or to pump out sufficient blood is lost, resulting in inadequate blood flow and O2 delivery in peripheral tissues and organs. For patients with left-sided heart failure, the left ventricle of the heart has partially lost its ability to pump enough blood to systemic circulation. For patients with right-sided heart failure, the right ventricle of the heart is unable to pump enough blood to the lungs due to pre-existing left-sided heart failure, pulmonary diseases, or pulmonary hypertension. Patients with mild HF have reduced exercise capacity and shortness of breath during physical activity. Patients with severe HF may have virtually no capacity for physical exertion, dyspnea even while at rest, and, finally, significant pulmonary or systemic edema. In patients with severe HF, low cardiac output may result in reduced oxygen supply to tissues and organs. Oxygen consumption is relatively higher than oxygen delivery, causing more oxygen extracted from blood and less oxygen in venous blood. Aerobic metabolism will begin to decrease, and anaerobic metabolism will increase, producing lactic acid. Chronic heart failure may develop severe acute heart failure because of either fluid overload or progressive ventricular dysfunction. Acute cardiogenic shock is caused by severe impairment of myocardial performance that results in diminished cardiac output, end-organ hypoperfusion, and hypoxia and is a common cause of mortality. In the setting of acute cardiogenic shock, classic symptoms and signs are combined with increase in heart rate, peripheral resistance, and venoconstriction. Therefore, the LV end-diastolic pressure, ventricular volumes, pulmonary venous pressures, and even central venous pressures rapidly increase, and stroke volumes or ejection fractions decrease [8].

The blood pump provides kinetic energy to transfer the required blood flow to the patient against a degree of resistance. The ideal pump would provide satisfactory flow and pressure against resistance, has biocompatible features reducing thrombogenicity, would intrinsically regulate blood flow according to the patient’s internal volume status, has low priming volume, is easily primed and controlled, and carries lower risk of hemolysis, cavitation, or circuit rupture [9, 10]. There are mainly two types of pumps used in ECMO circuits up to now:

ECMO Circuit and Circuit Physiology A typical ECMO circuit consists of a blood pump, an oxygenator, inflow/outflow cannulas, conduit tubing, and connectors (Fig. 1.1). Other components such as ultrafiltration device or renal replacement device may be added to the basic configuration. A blood pump, the analogue of the left ventricle, is designed to suck blood from the drainage line and pumps it through the heat exchanger and the oxygenator into the patient via the inflow line. An oxygenator performs the function of the lung by adding oxygen to the blood whilst CO2 is removed; meanwhile, the integrated heater–cooler unit can regulate patient temperature. The inflow/outflow cannulas connect a closed ECMO circuit to the patient’s circulatory system. Different components of the ECMO circuit are connected by tubing and connectors.

1. Roller pumps – positive displacement pumps. 2. Rotary pumps  – including axial, mixed (diagonal), and centrifugal pumps.

Roller Pumps The roller pumps usually consist of an electric motor, a horseshoe-shaped rigid backing plate, two rollers (cylinders), and a segment of silicone tubing located inside the raceway and fixed by the tubing bushing (Fig.  1.4). Two rollers are mounted on the ends of rotating arms (180 degree apart) in order to assure that one roller is compressing the tubing at all times. As the rollers rotate, the rollers compress the raceway tubing and impel the blood forward to produce continuous blood flow. Pump flow rate depends on the size of the tubing, length of the raceway (or diameter of pump head), and the revolutions per minute (RPM) of the rollers. For a given pump and type and size of tubing, blood flow can be calculated by pump speed in RPM. Additionally, in conjunction with a special controlling unit, roller pumps can generate an ECG-synchronized pulsatile flow. The console of a roller pump may recognize R-waves of the electrocardiogram (ECG) signal to generate pulsatile flow with high RPM and produce high flow rate and pressure during diastole when the ventricles of the heart relax, similar to principle of intra-aortic balloon pump (IABP), and maintain low flow rate and pressure during systole. Therefore, by synchronizing the pulsatility of the pump to that of the patient’s innate heartbeat, cannon waves from simultaneous intrinsic pulse waves and ECMO-generated pulse waves can be avoided [11]. Most roller pumps are occlusive. If the outflow of the raceway tubing is occluded or twisted, pressure in it will progressively rise until the raceway tubing ruptures or connectors and the tubing separate. Once the inlet of the raceway tubing is blocked, the roller pumps will develop high negative pressures producing cavitation, microbubbles, and hemolysis [12]. The degree of occlusiveness of the raceway tubing by the rollers can be manually adjusted. Excessive compression may lead to more hemolysis and earlier tubing wear, whereas under-occlusion may also aggravate hemoly-

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Fig. 1.4  The working principle of roller pumps

sis by turbulent flow and may reduce forward blood and invalidate flow readings based on RPM. Once roller pump is utilized in a closed system, its occlusive character is associated with potential safety risk. Therefore, a silicon bladder reservoir [such as Medtronic bladder reservoir or Better-­ Bladder (Circulatory Technology Inc.)] and special pressure sensor should be incorporated in the system to prevent excessive negative pressure at the inlet of the pump and excessive positive pressure at the outlet of the pump. In addition, roller pumps must have its own battery back-up for transportation and hand cranks to manually operate with in the case of power failure. The commonly used roller pumps are the Maquet HL 20 perfusion system, Terumo Advanced Perfusion System 1 and Century heart lung machine (Century HLM), and Sorin Stöckert S3 and S5. Few roller pumps are non-occlusive, such as France Rhône-Poulenc 06 (RP06) [13], the Metaplus pump [14], and the M-Pump [15]. The three non-occlusive roller pumps have similar structure, including an electric motor, three (120 degree) rollers, and a pumping chamber (Fig. 1.5). The special collapsible pumping chamber is stretched over the rollers. When the pump is not rotating, the pumping chamber is normally flat. However, when the inlet pressure of the pumping chamber is above ambient levels, the pumping chamber can expand and fill with blood by gravity. The rollers rotate counterclockwise and squeeze the blood forward to produce forward flow. They cannot pump blood and cannot generate negative pressures when there is no blood in the inlet of the pumping chamber as the pump chamber will collapse into its flat shape. In addition, the rupture of the circuit may be avoided when the tubing downstream from the pump chamber is blocked or twisted. These safety features once made the non-occlusive roller pump the preferred pump for short-­ term ECMO or mechanic circulatory support (MCS) [16– 18]. However, they still have some disadvantages, such as big size pump drive, long boot tubing, long circuit tubing, and large priming volume.

Fig. 1.5  The nonocclusive roller pump

Another candidate blood pump is a special piston pump which is primarily designed for ventricular assist (Fig. 1.6) [19, 20]. It has two independently controlled pistons in a toroidal pumping chamber. One piston (A) acts as a valve, while another piston (B) rotates to push the blood forward to the outlet, and then the pistons exchange roles. The two pistons are driven via magnetic coupling to a motor to create pulsatile flow. And it can be synchronized with patient’s ECG to generate a counter-pulsatile blood flow like IABP.  This style of blood pump has not been used in an ECMO system. If it produces enough power output as well as use of a low resistance oxygenator, it is possible to be used in a low-resistance VV-ECMO system.

Rotary Pumps With advance in technology, rotary pumps have replaced the roller pump in ECMO because they are more durable, lighter,

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Fig. 1.6  The piston pump

Diagonal

Radial

Size Priming Volume

Hydraulic Power

Excellent

Excellent

Axial

Fig. 1.7  Rotary pumps

and more biocompatible. Depending on the geometry of impeller, rotary pumps can be categorized into three main types: axial flow pumps, mixed flow pumps, and radial centrifugal pumps. The output powers (hydraulic power) of three rotary pumps are very different (Fig. 1.7). Axial pumps have the characteristics of small size and generate high flow rates at low pressure difference, so they are very suitable for MCS systems. Although centrifugal pumps have larger priming volume, they can generate high flow rates at differential pressure lower than 500 mmHg. Centrifugal pumps are currently popular and became ideal blood pumps for producing high pressures and high flows in ECMO system for their non-occlusiveness and relative safety. The mixed pumps can also produce high flow rates at high pressures and easily generate pulsatile flow than others. All rotary blood pumps can

transport blood by the conversion of rotational kinetic energy to the hydrodynamic energy of the blood flow. The rotational energy typically comes from an electric motor. Rotary pumps are totally non-occlusive, are afterload dependent, and have a risk of backflow. However, the non-occlusive feature prevents generation of excessive pressure in the ECMO circuit and avoids circuit rupture. Centrifugal pumps consist of an impeller arranged with either vanes or a nest of smooth plastic cones inside a plastic housing driven by an electric motor. The impeller may directly connect with an electric motor through a shaft or couple magnetically with an electric motor. The shaftdriven centrifugal blood pumps are considered to be more hemolytic because of localized heat generation by mechanical friction between shaft and seal, which results in thrombus formation at the shaft–seal interface [21]. For magnetic-­driven centrifugal pumps, the magnet inside the pump head spins synchronously with another magnet or electromagnet spinning in the drive console. The shaftless design is ideal in reducing blood trauma during ECMO.  However, excessive rotational speed may cause decoupling that causes the pump to stop. When the impeller rotates rapidly, it generates a negative pressure at the inlet port of the pump head to suck blood into the inlet and a positive pressure at the outlet port to force blood out of the outlet. The centrifugal effect of impeller may transform the mechanical energy generated by the electric motor into kinetic energy and then into the pressure that allows the liquid to go out of the pump into the plant (Fig.  1.8). Therefore, a pressure difference between the inlet and outlet causes continuous blood flow. The resulting blood flow depends on preload, the pressure gradient, and the resistance at the outlet of the pump. Changes in preload and afterload can affect pump flow without changes in the rotational speed. Therefore, flow meters must be included in all ­centrifugal pumps using ultrasonic or electromagnetic principles to detect blood flow velocity accurately. Additionally, centrifugal pumps create suction, and hemolysis may occur when the suction pressure is high, so the inlet pressure should be monitored to prevent high suction.

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Fig. 1.8  Flow paths of centrifugal pumps (left) and mixed pump (right)

Inlet Inlet

Outlet Outlet

Table 1.1  Rotary blood pumps for ECMO

Rotary pump Type RPM Max. flow rate (L/min) Priming volume (mL) Max. outlet pressure (mmHg) Ports (in ID)

Medtronic Maquet Sorin Levitronix (Abbott) Terumo Xenios Biopump Affinity CP Rotaflow Revolution 5 CentriMag PediMag Sarns Capiox SP BP50/BPX80 i-cor Centrifugal pump Diagonal pump 4500/4500 4000 4000 5000 5500 5500 3600 3000 10,000 1.5/10.0 10.0 9.9 8.0 9.9 1.5 10.0 8.0 8.0 48/86 40 32 57 31 14 48 45 16 900/1100 760 750 800 600 540 700 800 600 1/4/3/8

3/8

3/8

3/8

The centrifugal pumps have better hydraulic efficiency than axial and mixed flow pumps. Because of their non-­ occlusiveness and high output power, rotary pumps can be used in CPB, ECMO, or MCS systems. Technical improvements, for example, low shear stress and shaftless magnetic coupling-driven pump, favor centrifugal pumps to be utilized longer in ECMO or MCS with less traumatic effect on the blood elements. New control system can keep the pump running at fixed flow rate without backflow or positive outlet pressure by automatically adjusting RPM. There are various centrifugal pumps available, such as the Medtronic Biopump Plus and affinity CP, the Maquet Jostra RotaFlow, the Sorin Revolution, the Levitronix CentriMag, the Terumo Capiox, and Sarns centrifugal pump (Table  1.1). The Maquet Cardiohelp is an integrated ECMO system with a Rotaflow centrifugal pump and a Quadrox oxygenator. The Xenios i-cor pump (former Medos Deltastream DP3) is a mixed flow pump which is the only rotary pump to provide an ECG-­ synchronized pulsatile flow.

3/8

1/4

3/8

3/8

3/8/1/4

I nteraction Between Centrifugal Pump and Patient Blood flow generated by a centrifugal pump is determined by rotational speed, preload, and afterload. The centrifugal pump must run at a certain speed to overcome resistance in order to generate blood flow. Under a constant speed, pump flow will increase with decreased resistance (the use of vasodilators) until blood flow reaches the maximum output for a given outflow resistance. Conversely, pump flow will decrease with increased resistance, such as thrombus formation in the oxygenator, kinking of the arterial tubing and canula, and excessive systemic vascular resistance (the use of vasoconstrictors). Preload augmentation (high CVP) results in proportionally increased flow for a given pump speed. In the presence of inadequate blood drainage (low CVP), the flow will be reduced automatically. Blood backflow may occur when the ECMO circuit is connected to the patient’s arterial system but blood pump is not running or when patient’s arterial pressure exceeds the driving pressure

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by a centrifugal pump. Note, the pump inlet and outlet pressures should not exceed minus 300  mmHg and positive 400  mmHg, respectively, to decrease a risk of hemolysis. Servocontrolled pressure sensors on the pump inlet and outlet sides are recommended [22].

Gas Exchange Device: Artificial Oxygenator In ECMO circuit, gas exchange device serves as artificial lung to add O2 to the blood and remove CO2 from the blood. Ideal oxygenator should provide safe and efficient oxygenation of venous blood and elimination of CO2, less trauma to blood component, low priming volume, safety, and ease of use [23]. There are three types of oxygenators: (1) Film oxygenators: These oxygenators use rotating cylinder or upright screen to spread blood in a continuous blood film to facilitate the exchange of gases. Direct gas–blood interface helps O2 and CO2 diffusion. (2) Bubble oxygenators: O2 is bubbled through the venous blood and gas exchange occurs. O2 diffuses from bubbles into the blood film surrounding the bubble. CO2 diffuses from blood film into the bubble. Bubble size influences O2 and CO2 gas exchange due to different solubility between O2 and CO2. Gas flow rate determines the number of bubbles. Bubbles in the blood must be defoamed and filtered within the oxygenator and the arterial filter before blood returns to the systemic circulation through the aorta. (3) Membrane oxygenators: The first two oxygenators had been abandoned for ECMO support. The membrane oxygenators completely eliminate the direct blood–gas interface with improved biocompatibility and have large surface area to separate blood and gas for blood oxygenation and decarbonization. The blood flow and the oxygen flow are countercurrents, and gas transfer is performed by diffusion. Membrane oxygenators have been widely used for standard CPB and ECMO, including flat sheet silicone membrane oxygenator and hollow-­ fiber membrane oxygenator.

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The wall of hollow fiber membranes has micropores (0.5– 1.0 μm), allowing gas exchange between gas and blood compartment while inhibiting plasma leakage into the gas compartment due to the surface tension of the blood. In general, a woven fiber sheet is wound onto the oxygenator core to create the fiber bundle. And then the latter is sealed in a hard, cylindrical, transparent housing. A heat exchanger is commonly integrated into the oxygenator for blood temperature regulation. Sweep gas passes through the internal lumen of the hollow fiber, and blood flows counter currently on the outside of the hollow fiber. Once exposed to blood, the micropores in the fiber are covered with plasma proteins, after which gas exchange takes place through the micropores by diffusion. Over time, the micropores on the fiber wall eventually allow plasma components across the micropores into the gas phase, resulting in plasma leakage and decreasing membrane performance [24]. Therefore, microporous hollow fiber oxygenators are usually used for short-term CPB support. Non-microporous polymethylpentene (PMP) membranes have a thin (80%) in the IVC and pre-­oxygenator site and low saturation (right hand 40%) in the SVC [28]. Therefore, Harlequin syndrome may have risks of coronary and cerebral hypoxemia and hypoperfusion, progressive LV dysfunction, neurological complications, and ineffective ECMO support in patients with poor LV and pulmonary reserve. Thus, arterial blood gas (ABG) analysis from the right hand may accurately reflect cerebral oxygen supply in peripheral VA-ECMO. The Harlequin syndrome may be treated by increasing ECMO flow and adjusting ventilator parameters to partially improve oxygenation of the upper body. Relocation of the arterial cannula into the right subclavian artery or aorta and converting to central VA-ECMO are considered as accepted therapeutic options [28, 40]. As central ECMO returns oxygenated blood to the ascending aorta, there is less concern for retrograde flow and Harlequin syndrome. In addition, the third cannula may be inserted into the SVC or internal jugular vein (IJV) to return part of oxygenated blood to the venous system and pulmonary circulation, increasing the oxygen content delivered by the LV output [41].

 dvantages and Disadvantages of VA-ECMO A The advantages of VA-ECMO include as follows:

(1) Provide complete hemodynamic support, including augment of arterial pressure and unloading of the right venCaO 2  C Post  oxygenator O 2  FECMO  C V O 2   CO  FECMO  tricle, resting the heart. (2) Provide more efficient gas exchange with higher syswhere CPost-oxygenatorO2 is the oxygen content at the post-­ temic PO2 and without possibility of recirculation, restoxygenator site; FECMO is the ECMO flow; CvO2 is the oxygen ing the lungs. content of the mixed venous blood; and CO is cardiac (3) Can be used as extracorporeal cardiopulmonary resuscioutput. tation (eCPR) in patients suffering full cardiac arrest If a patient’s lungs work well, the mixed arterial blood [42]. has normal SaO2 and PaCO2 and higher than normal PaO2 (4) Allow mobility in patients with closed chest on central and O2 content. Mechanical ventilation is not required for VA-ECMO than peripheral VA-ECMO. these patients. If a patient’s lungs are injured or failing, the mixed arterial blood is well oxygenated distal to the mixThe disadvantages of VA-ECMO include as follows: ing site, but lower oxygenation occurs proximal to the mixing site. This special phenomenon is usually related to (1) Bleeding, such as access site bleeding, upper and lower peripheral VA-ECMO, called Harlequin syndrome (North– gastrointestinal bleeding, hemopericardium, hemothoSouth syndrome or dual circulation) where upper body rax, intra- and retroperitoneal hemorrhage, and intracrahypoxia occurs. The reason is that there is an area of nial bleeding. watershed within the aorta where the well-oxygenated (2) Thrombus formation in the extracorporeal circuit. ECMO blood from the femoral artery meets the poor-oxy- (3) Infection, such as catheter-related infection, bloodgenated blood from the patient’s impaired lungs [39]. This stream infection.

1  Physiology of Extracorporeal Life Support

(4) Vascular complications, such as distal limb ischemia, posterior vascular wall perforation, vessel dissection, pseudoaneurysm formation, late arterial stenosis, and deep-vein thrombosis. (5) Involving sternotomy and direct surgical cannulation and decannulation of the right atrium and aorta in central ECMO. (6) Harlequin syndrome. (7) Create LV distention in the presence of severe left ventricular insufficiency. (8) Reduce arterial pulsatility.

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oxygenation of the systemic venous vascular bed can reduce acidosis. The high oxygenated blood perfuses the lungs, relieving hypoxic pulmonary vasoconstriction. Additionally, reduction in cardiovascular pharmacologic agents can minimize the common deleterious effects of these drugs. All these factors will benefit myocardial function.

Oxygenation in VV-ECMO The goal of VV-ECMO is providing circulating O2 to the tissues and organs. The venous blood with low O2 content (CvO2) from the peripheral tissue is partially drained from the right atrium into the ECMO circuit for extracorporeal gas exchange; subsequently an equal volume (high O2 conPhysiology of VV-ECMO tent) is returned to the right atrium, mixed with the remaining venous blood (low O2 content) into the lungs for The VV-ECMO can be performed by placing two cannulas in secondary gas exchange; and then infused into the systemic two different veins (Fig. 1.1b) or placing one special dual-­ circulation. Blood oxygenation is much difficult than CO2 lumen cannula (dl, such as Avalon and Origen) in a single removal. So, the selected circuit and expected blood flow vein. Dual cannula VV-ECMO uses bilateral femoral can- are usually planned for total oxygen supply. Under normal nulas (Vf − Vf) or a single femoral cannula (at least 2  cm physiological conditions, the oxygen delivery is usually of below the diaphragm) and an upper body return cannula 6  mL/kg/min for neonates; children 4–5  mL/kg/min; and (usually right internal jugular vein) (Vf − Vj). If higher adults 3 mL/kg/min [22]. The ECMO must provide oxygenECMO flows are expected, a single draining cannula may ation and CO2 removal equal or above the normal metabocause the vena cava to intermittently collapse (shudder) lism. The oxygenator should match patient’s size and be around the cannula due to higher negative pressure, and con- large enough to transfer adequate oxygen to the patient. The sequent hypoxia may occur. The third access cannula may ECMO blood flow for full support is usually 120  mL/kg/ need to boost the venous drainage volume. Single-site min for neonates, 100  mL/kg/min for children, and VV-ECMO can be established via the right internal jugular 60–80 mL/kg/min for adults. Oxygen delivery capability of vein with dual-lumen cannula tip located in the abdominal the VV-ECMO system is determined by oxygenator properinferior vena cava (IVC) and the outflow port facing the tri- ties, blood flow, hemoglobin concentration, and sweep gas. cuspid valve orifice [(dl) Vj − V]. VV-ECMO provides only The ECMO typically provides the oxygenated blood with respiratory support as alternative to invasive ventilation in PCO2 40 mmHg, PO2 500 mmHg, SaO2 100%, and oxygen patients with respiratory failure. content 22 mL/dL blood [22]. Because the ECMO blood mixes with systemic venous Hemodynamic Effects of VV-ECMO return blood (ratio, around 3:1), the amount of oxygen conVV-ECMO draws and returns blood into the same venous tributed by each flow is the sum of each oxygen content compartment. Blood volume in the venous system doesn’t (CO2) times blood flow (F) divided by total flow (cardiac change. With increased flow rate, only the oxygen content output, CO) as follows [44]. increases and CO2 content decreases in the venous blood. C O F C O F CMixed O 2  ECMO 2 ECMO  v 2 v The systemic arterial blood depends on native heart and is CO CO independent of the ECMO flow. Therefore, the VV-ECMO CECMO  C v CO  FECMO  does not affect central venous pressure and RV filling and CMixed  C v does not increase additional LV afterload. No direct hemodyFV  CO  FECMO namic modifications or heart support is generated, and all the effects on patient pathophysiology result from CO2 removal and O2 transfer by the oxygenators. where CMixedO2 is oxygen content of mixed venous blood from Despite the lack of hemodynamic support, the VV-ECMO the native venous and ECMO blood. CECMOO2 and CVO2 are can indirectly support myocardial function and cardiac output oxygen contents of the ECMO and native venous blood. FECMO [43]. With VV-ECMO, rest ventilator settings such as lower and Fv are flow rates of the ECMO and native venous blood. tidal volumes and positive end-expiratory pressure (PEEP) The oxygen saturation can be used to replace oxygen content can unload the right heart. The heart receives the high oxygen- for simplify at the bedside, but the result is less accurate. ated blood resulting in improved myocardial oxygenation and The systemic oxygen delivery should exceed the oxygen reversal of hypoxia-induced myocardial depression. Improved consumption. In severe respiratory failure, the native lungs

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may provide little or none to gas exchange. The arterial O2 and CO2 level depends on the mixture of the oxygenated ECMO blood and the deoxygenated native venous blood. Therefore, SaO2 is lower than the normal level. Even so the low-saturated blood still can provide normal systemic O2 delivery under adequate cardiac output and higher hemoglobin concentration. If the patient’s total O2 consumption (VO2) exceeds tissue delivery, O2 extraction increases and mixed-venous saturation decreases first, until hypoxia symptoms occur and biomarkers such as confusion, oliguria, and rising lactate levels increase. By this time, increasing the cardiac output and keeping ECMO flow rate will cause drops in the arterial SO2 and PaO2, but the systemic O2 delivery still increases. Decreasing the cardiac output will not affect much the arterial O2 saturation, but the mixed venous saturation will fall down. In addition, increasing hemoglobin level will improve the arterial O2 content and the systemic O2 delivery. Therefore, the ECMO oxygen supply should be increased by increasing ECMO flow and transfusing for higher hemoglobin. With ECMO support, the patient’s injured lungs may gradually recover under rest ventilator settings. When arterial PCO2 drops below 40 mmHg, the sweep gas can be proportionally decreased. When SaO2 exceeds 95%, the ECMO flow can be gradually decreased until approximately 50% ECMO support. It is a time to test the native lung function under briefly discontinued ECMO and moderate ventilator settings. If the native lung is capable of respiratory support, ECMO can be discontinued after several days of observation, allowing more lung recovery.

 O2 Removal in VV-ECMO C CO2 is a byproduct of physiological metabolism and is ultimately removed from the body through exhalation in lungs. Because of its physical properties, CO2 is much more soluble and diffusible in blood than O2. CO2 removal always exceeds oxygen delivery when the circuit is planned for full support, so all ECMO management is based on oxygenation [22]. The systemic PCO2 and CO2 content are the results of mixing ECMO blood with native venous blood. The actual amount of CO2 removed by the oxygenator is the difference of CO2 contents between the inlet and outlet blood. Because CO2 content is difficult to calculate, the accurate amount of CO2 removed by ECMO is not critical. Keeping systemic PCO2 around 40 mmHg by adjusting the sweep gas flow is a unique goal. The main determinations of CO2 removal in ECMO are ECMO blood flow, sweep gas flow, CO2 gradient, membrane size, and efficiency of CO2 removal of oxygenator. Higher blood flow and sweep gas flow can increase CO2 clearance. Using sweep gas without CO2 can improve the efficiency of CO2 removal. Oxygenator characteristics such

S. Wang

as membrane material, geometry, surface area, and gas and blood flow paths significantly affect CO2 clearance. Adding immobilized carbonic anhydrase on the surface of hollow fiber can help in accelerating the conversion of carbonic acid into CO2 and water, facilitating CO2 removal [45]. Water vapor condensed in the oxygenator will decrease CO2 clearance and can be blown out of the fibers by a higher sweep flow [22]. The efficient CO2 removal is beneficial to safely reduce the mechanical ventilation needs and lower hypercapnia, avoiding its effects upon the central nervous system and the right side of the heart and other adverse effects. If the patient suffered from hypercapnia without hypoxemia (such as chronic obstructive pulmonary disease, COPD), in other words, if CO2 clearance is the major goal, VV-ECCO2R may be used to provide decarboxylation without oxygenation at low blood flow (1 L/min) and high sweep flow (blood, gas = 1: 10–15) in order to maintain PaCO2 at 40 mmHg [46]. The hemoglobin concentration is not important. Therefore, the oxygenator and inflow/outflow cannulas can be smaller than that required for full support in ECMO.  However, there are increased risks of thrombosis and hemolysis. In another clinical scenario, if the patient has arterial–venous (AV) extracorporeal circulation such as hemodialysis, the AV route can be used for gas exchange. The CO2 removal can be easily achieved with lower blood flow and enough sweep gas flow, but total extracorporeal support is difficult because of the limited blood flow.

Recirculation During VV-ECMO One of the main technical problems of VV-ECMO is recirculation. Part of the already-bypassed flow is drained back to the ECMO circuit, resulting in a recirculating blood flow, which decreases the oxygenation efficiency of VV-ECMO, because the recirculating blood does not contribute to systemic oxygen delivery. The recirculation ranges from 20% to 50% when using the dual-lumen cannulas [47]. In other words, only 50%–80% oxygenated blood is actually available to the patient. The amount of recirculation is affected by heart rate; cardiac output; velocity and direction of extracorporeal flow; diameter, position, and number of side holes of return cannula; atrial volume; intra-thoracic, intra-cardiac, and intra-abdominal pressures; and blood viscosity. Recirculation will increase with increasing ECMO flow and decreasing cardiac output. If cardiac output drops below ECMO flow, the recirculation fraction will significantly elevate. Different catheterization approaches are significantly associated with recirculation. Dual cannula VV-ECMO is always associated with recirculation, because a single vena caval flow is lower than the circuit drainage, causing some oxygenated blood from the circuit being drained. An additional draining cannula may need to increase venous drainage and reduce recirculation. A single-site, dual-lumen

1  Physiology of Extracorporeal Life Support

17

cannula drains both vena cavae, but the open return port toward the tricuspid valve can also result in recirculation. However, single-site, dual-lumen cannulation for VV-ECMO creates less recirculation when compared with dual-site cannulation [48]. Percent recirculation can be evaluated by the following equation [47]: Recirculation  %  

SPreoxygenator O 2  Sv O 2 SPost oxygenator O 2  Sv O 2

 100

The mixed venous oxygen saturation (SvO2) from the pulmonary artery does not accurately reflect global saturation because of recirculation present in VV-ECMO. The measuring saturation of the inlet side is higher than the actual venous saturation, and the outlet–inlet O2 difference decreases. The use of larger cannulas allows higher blood flow rates with less negative pressure on the inlet side and reduces the amount of recirculation. Cannula repositioning, increased patient volume, or hematocrit is also useful to provide the desired amount of O2 delivery.

VA-ECMO vs. VV-ECMO Both of VA- and VV-ECMO can provide life support for critically ill patients, but there are significant differences of these two support modes (Fig.  1.9). Understanding these main differences between VA- and VV-ECMO is helpful for clinicians to determine which type of support is required, select circuit components and cannulation site, and manage ECMO patients.

Pharmacokinetics During ECMO

Critically ill patients with ECMO require the administration of multiple drugs to support patient care. Multiorgan failure alters the blood flow to vital organs like the liver, kidneys, lung, and brain, resulting in a reduced pharmacokinetics. ECMO therapy inevitably affects pharmacokinetics due to a larger volume of distribution and altered drug elimination. Increased volume of distribution and/or decreased clearance increases the half-life of a drug. The volume of the ECMO circuit affects the volume of distribution, especially during the start of ECMO or during replacement of ECMO circuit. Advantages and Disadvantages of VV-ECMO Specific chemical compounds used in the ECMO circuit The main advantages of VV-ECMO are as the following: may lead to inactivation, adsorption, and sequestration of drug by ECMO circuit components [51]. The octanol–water (1) Increase right atrial blood O2 content, lower CO2 con- partition coefficient of a drug determines the amount of drug tent, rest the lungs, improve systemic oxygenation, not lost to the ECMO circuit. Drugs with high octanol–water cause differential hypoxemia, such as Harlequin partition coefficient (such as midazolam and fentanyl) have syndrome. high solubility in organic materials such as plasticizers from (2) Maintain the pulsatility of the systemic circulation. uncoated PVC tubing, leading to considerable sequestration (3) Maintain patients non-intubated and spontaneously in an ECMO circuit [52]. Therefore, lipid-soluble drugs breathing: avoiding detrimental effects of ventilator-­ should be administered directly to the patient, whereas more induced lung injury and the incidence of ventilator/ hydrophilic drugs like morphine may be administered to the intubation-­associated pneumonia, improving ventila- circuit. The surface coating of ECMO circuit and ultrafiltration–perfusion (V/Q) mismatch, maintaining better tion rate also affect pharmacokinetics. In addition, ECMO tone of respiratory muscles and diaphragm, improv- type and flow pattern can significantly affect drug pharmaing venous return, optimizing cardiac filling, and cokinetics. Most blood pumps only provide continuous favoring lymphatic drainage with negative suction blood flow. Lack of arterial pulsatility during VA-ECMO technique. affects vital organ perfusion and therefore alters drug clear (4) Keep patients awake for active physical rehabilitation; ance. VA-ECMO reduces pulmonary blood flow, altering better communication with medical staff, family, and clearance of drugs that are metabolized by the lungs. friends; and less hemodynamic side effects due to less Additionally, in VV-ECMO, blood recirculation can also use of the sedative agents [49, 50]. reduce drug clearance due to incomplete distribution to the (5) Reduce risks of systemic embolism, such as cerebral or body [53]. coronary embolism; do not injure systemic arteries; reduce circuit failure due to low circuit pressure.

Pumpless Extracorporeal Lung Assist (pECLA)

The disadvantages of VV-ECMO include not supporting and resting the heart directly, much sensitivity to volume, recirculation from the return cannula into the drainage cannula, and diversion of a large portion of the cardiac output to support arterial oxygen saturation.

Pumpless extracorporeal lung assist is a special type of respiratory support for a patient with moderate hypoxia and normal cardiac output. If CO2 clearance is the major goal, pECLA is the same as AV ECCO2R [1]. Because of

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Characteristic Differences between VA-ECMO and VV-ECMO

VA-ECMO: VV-ECMO:

Lung Blood Decreased Increased

Lung Oxygenation None Increased

VA-ECMO: VV-ECMO:

Coronary Oxygenation Low(Peripheral)/Increased(Central) Increased

VA-ECMO: VV-ECMO:

RA Preload Decreased Normal

RA Afterload Increased Normal

VA-ECMO: VV-ECMO:

LA Preload Decreased No Change

LA Afterload Increased No Change

VA-ECMO: VV-ECMO:

RV Pr eload Decreased None

RV Afterload Decreased None

VA-ECMO: VV-ECMO:

LA Preload Decreased None

LV Afterload Increased None

VA-ECMO: VV-ECMO:

Recirculation Harlequin Syndrome None Yes Yes None

VA-ECMO: VV-ECMO:

Pulsatile Low/None Normal

Cardiac Support Partial/Full None

VA-ECMO: VV-ECMO:

Bleeding ++ +

VA-ECMO: VV-ECMO:

Oxygenation CO2 Remoral ++ ++ +/++

VA-ECMO: VV-ECMO:

Circuit Flow Circuit Pressure High High Low Low

VA-ECMO: VV-ECMO:

Cannula Two/Three One/Two

Air Emboli +++ +

Pump Yes Yes/Pumpless

VA-ECMO: VA-ECMO:

Cannulation Sites Inflow Outflow Femoral V Femoral A RA Aorta, Subclavian A Jugular V Axillary A Femoral V Femoral V Jugular V Jugular V(Single) Femoral V

Jugular V

Fig. 1.9  Characteristic differences between VA-ECMO and VV-ECMO. RA/LA, right/left atrium; RV/LV, right/left ventricle; V, vein; A, artery

no blood pump, the driving force is the patient’s arteriovenous pressure gradient, such as the femoral artery and vein or the pulmonary artery and the left atrium. A low-resistance oxygenator (such as Novalung) is connected to the patient via arterial/venous cannulas. The pressure gradient drives blood through the oxygenator to return oxygenated and decarbonated blood into the venous system, improving gas exchange and allowing lung-protective ventilation. The no-­pump design limits pECLA flow rates at around 0.8–1.5 L/min which is sufficient to remove excessive CO2 for ARDS patients. Simple pECLA circuit has some advantages, including less bleeding, low blood trauma, low coagulation disorders, uncomplicated handling, easy interhospital transfer, and use of lung-protective ventilation. But it cannot be used in low cardiac output patients, cannot provide full respiratory support, and has potentially

restricting perfusion of the lower limbs and system clotting or thrombus formation within the oxygenator due to low anticoagulation and low flow rate [54–56].

Summary ECLS is a life-saving and powerful tool for people who are critically ill, and it needs to be carefully used by specially trained physicians, nurses, technologists, and staff. Based on a thorough understanding of normal and abnormal cardiopulmonary physiology and fundamental principles of ECLS, the ECMO team is able to immediately provide partial and full cardiopulmonary support for patients with cardiac or pulmonary failure, optimally manage ECLS performance, and then significantly improve clinical outcomes.

1  Physiology of Extracorporeal Life Support

References 1. Conrad SA, Broman LM, Taccone FS, et al. The extracorporeal life support organization Maastricht treaty for nomenclature in extracorporeal life support. A position paper of the extracorporeal life support organization. Am J Respir Crit Care Med. 2018;198(4):447–51. 2. Ficial B, Vasques F, Zhang J, et al. Physiological basis of extracorporeal membrane oxygenation and extracorporeal carbon dioxide removal in respiratory failure. Membranes (Basel). 2021;11(3):225. 3. Goldhaber JI.  Metabolism in normal and ischemic myocardium. In: Langer GA, editor. The myocardium. Academic Press; 1997. p. 325–93. 4. TannerThies R.  The heart as a pump. In: TannerThies R, editor. Physiology  - an illustrated review. New  York: Thieme Medical Publishers; 2012. 5. Rothe CF. Venous system: physiology of the capacitance vessels. In: Shepherd JT, Abboud FM, editors. Comprehensive physiology. Bethesda: American Physiological Society; 2011. p. 397–452. 6. Feher J.  Oxygen and carbon dioxide transport. In: Feher J, editor. Quantitative human physiology: an introduction. Amsterdam: Elsevier; 2012. p. 586–94. 7. Geers C, Gros G. Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev. 2000;80(2):681–715. 8. Rao P, Khalpey Z, Smith R, et al. Venoarterial extracorporeal membrane oxygenation for cardiogenic shock and cardiac arrest. Circ Heart Fail. 2018;11(9):e004905. 9. Spurlock DJ, Ranney DN, Fracz EM, et  al. In vitro testing of a novel blood pump designed for temporary extracorporeal support. ASAIO J. 2012;58(2):109–14. 10. Machin D, Allsager C. Principles of cardiopulmonary bypass. BJA Educ. 2006;6(5):176–81. 11. Wang S, Izer JM, Clark JB, et  al. In vivo hemodynamic performance evaluation of novel electrocardiogram-synchronized pulsatile and nonpulsatile extracorporeal life support Systems in an Adult Swine Model. Artif Organs. 2015;39(7):E90–E101. 12. Hessel EA II, Shann KG.  Blood pumps, circuitry, and cannulation techniques in cardiopulmonary bypass. In: Gravlee GP, Davis RF, Hammon JW, Kussman BD, editors. Cardiopulmonary bypass and mechanical support: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2015. 13. Durandy Y, Wang S, Undar A. An original versatile nonocclusive pressure-regulated blood roller pump for extracorporeal perfusion. Artif Organs. 2014;38(6):469–73. 14. Montoya JP, Merz SI, Bartlett RH.  Significant safety advantages gained with an improved pressure-regulated blood pump. J Extra Corpor Technol. 1996;28(2):71–8. 15. Teman NR, Mazur DE, Toomasian J, et  al. A novel rotary pulsatile flow pump for cardiopulmonary bypass. ASAIO J. 2014;60(3):322–8. 16. Durandy Y, Chevalier JY, Lecompte Y. Single-cannula venovenous bypass for respiratory membrane lung support. J Thorac Cardiovasc Surg. 1990;99(3):404–9. 17. Chevalier JY, Durandy Y, Batisse A, et  al. Preliminary report: extracorporeal lung support for neonatal acute respiratory failure. Lancet. 1990;335(8702):1364–6. 18. Spurlock DJ, Koch K, Mazur DE, et al. Preliminary in vivo testing of a novel pump for short-term extracorporeal life support. Ann Thorac Surg. 2012;93(1):141–6. 19. Letsou GV, Pate TD, Gohean JR, et  al. Improved left ventricular unloading and circulatory support with synchronized pulsatile left ventricular assistance compared with continuous-flow left ventricular assistance in an acute porcine left ventricular failure model. J Thorac Cardiovasc Surg. 2010;140(5):1181–8. 20. Bartoli CR, Hennessy-Strahs S, Gohean J, et al. A novel toroidal-­ flow left ventricular assist device minimizes blood trauma: implica-

19 tions of improved ventricular assist device hemocompatibility. Ann Thorac Surg. 2019;107(6):1761–7. 21. Araki K, Taenaka Y, Masuzawa T, et al. Hemolysis and heat generation in six different types of centrifugal blood pumps. Artif Organs. 1995;19(9):928–32. 22. Extracorporeal Life Support Organization (ELSO). Guidelines for Adult Respiratory Failure V1.4. August 2017:[32]. https://www. elso.org/Resources/Guidelines.aspx 23. Hines MH. Principles of oxygenator function: gas exchange, heat transfer, and operation. In: Gravlee GP, Davis RF, Hammon JW, Kussman BD, editors. Cardiopulmonary bypass and mechanical support: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2015. 24. Wegner JA. Oxygenator anatomy and function. J Cardiothorac Vasc Anesth. 1997;11(3):275–2781. 25. Ng GW, Yuen HJ, Sin KC, et  al. Clinical use of venovenous extracorporeal membrane oxygenation. Hong Kong Med J. 2017;23(2):168–76. 26. Broman LM, Prahl Wittberg L, Westlund CJ, et al. Pressure and flow properties of cannulae for extracorporeal membrane oxygenation I: return (arterial) cannulae. Perfusion. 2019;34(1_suppl):58–64. 27. Pavlushkov E, Berman M, Valchanov K.  Cannulation techniques for extracorporeal life support. Ann Transl Med. 2017;5(4):70. 28. Lindholm JA.  Cannulation for veno-venous extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(Suppl 5):S606–12. 29. Sorokin V, MacLaren G, Vidanapathirana PC, et al. Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the potential dynamic process of organ support and importance of hybrid modes. Eur J Heart Fail. 2017;19(Suppl 2):75–83. 30. Chocron S, Perrotti A, Durst C, et al. Left ventricular venting through the right subclavian artery access during peripheral extracorporeal life support. Interact Cardiovasc Thorac Surg. 2013;17(1):187–9. 31. Su Y, Liu K, Zheng JL, et al. Hemodynamic monitoring in patients with venoarterial extracorporeal membrane oxygenation. Ann Transl Med. 2020;8(12):792. 32. Belohlavek J, Mlcek M, Huptych M, et al. Coronary versus carotid blood flow and coronary perfusion pressure in a pig model of prolonged cardiac arrest treated by different modes of venoarterial ECMO and intraaortic balloon counterpulsation. Crit Care. 2012;16(2):R50. 33. Williams B, Bernstein W.  Review of venoarterial extracorporeal membrane oxygenation and development of intracardiac thrombosis in adult cardiothoracic patients. J Extra Corpor Technol. 2016;48(4):162–7. 34. Cevasco M, Takayama H, Ando M, et al. Left ventricular distension and venting strategies for patients on venoarterial extracorporeal membrane oxygenation. J Thorac Dis. 2019;11(4):1676–83. 35. Donker DW, Brodie D, Henriques JPS, et al. Left ventricular unloading during veno-arterial ECMO: a review of percutaneous and surgical unloading interventions. Perfusion. 2019;34(2):98–105. 36. Rupprecht L, Florchinger B, Schopka S, et al. Cardiac decompression on extracorporeal life support: a review and discussion of the literature. ASAIO J. 2013;59(6):547–53. 37. Kara A, Akin S, Dos Reis MD, et al. Microcirculatory assessment of patients under VA-ECMO. Crit Care. 2016;20(1):344. 38. Ghodsizad A, Lai CM, Grant AA, et  al. Endovascular crossover perfusion of lower limb in patients supported on venoarterial extracorporeal membrane oxygenation: rescue therapy or thoughtful approach? J Thorac Cardiovasc Surg. 2018;156(1):168–70. 39. Gehron J, Schuster M, Rindler F, et al. Watershed phenomena during extracorporeal life support and their clinical impact: a systematic in vitro investigation. ESC Heart Fail. 2020;7(4):1850–61. 40. Al Hanshi SAM and Al Othmani F.  A case study of Harlequin syndrome in VA-ECMO.  Qatar Med J. 2017;2017(1). https://doi. org/10.5339/qmj.2017.swacelso.39.

20 41. Contento C, Battisti A, Agro B, et  al. A novel veno-­ arteriovenous extracorporeal membrane oxygenation with double pump for the treatment of harlequin syndrome. Perfusion. 2020;35(1_suppl):65–72. 42. Shinar Z, Plantmason L, Reynolds J, et al. Emergency physician-­ initiated resuscitative extracorporeal membrane oxygenation. J Emerg Med. 2019;56(6):666–73. 43. Bautista-Rodriguez C, Sanchez-de-Toledo J, Da Cruz EM. The role of echocardiography in neonates and pediatric patients on extracorporeal membrane oxygenation. Front Pediatr. 2018;6:297. 44. Robert H, Bartlett SAC. The physiology of extracorporeal life support. In: Lequier L, Brogan TV, Lorusso R, MacLaren G, Peek G, editors. Extracorporeal life support: The ELSO red book. 5th ed. Ann Arbor, MI: ELSO; 2017. p. 31–48. 45. Arazawa DT, Oh HI, Ye SH, et al. Immobilized carbonic anhydrase on hollow fiber membranes accelerates CO(2) removal from blood. J Memb Sci. 2012;404-404:25–31. 46. Pettenuzzo T, Fan E, Del Sorbo L. Extracorporeal carbon dioxide removal in acute exacerbations of chronic obstructive pulmonary disease. Ann Transl Med. 2018;6(2):31. 47. Walker JL, Gelfond J, Zarzabal LA, et al. Calculating mixed venous saturation during veno-venous extracorporeal membrane oxygenation. Perfusion. 2009;24(5):333–9. 48. Javidfar J, Wang D, Zwischenberger JB, et al. Insertion of bicaval dual lumen extracorporeal membrane oxygenation catheter with image guidance. ASAIO J. 2011;57(3):203–5.

S. Wang 49. Crotti S, Bottino N, Spinelli E.  Spontaneous breathing during veno-venous extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(Suppl 5):S661–9. 50. Haji JY, Mehra S, Doraiswamy P.  Awake ECMO and mobilizing patients on ECMO. Indian J Thorac Cardiovasc Surg. 2021;37:1–10. 51. Buck ML.  Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403–17. 52. Wildschut ED, Ahsman MJ, Allegaert K, et  al. Determinants of drug absorption in different ECMO circuits. Intensive Care Med. 2010;36(12):2109–16. 53. Mulla H, Nabi F, Nichani S, et al. Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation. Br J Clin Pharmacol. 2003;55(1):23–31. 54. Liebold A, Reng CM, Philipp A, et  al. Pumpless extracorporeal lung assist - experience with the first 20 cases. Eur J Cardiothorac Surg. 2000;17(5):608–13. 55. Florchinger B, Philipp A, Klose A, et al. Pumpless extracorporeal lung assist: a 10-year institutional experience. Ann Thorac Surg. 2008;86(2):410–7; discussion 417. 56. Hamid IA, Hariharan AS, Shankar NR. The advent of ECMO and pumpless extracorporeal lung assist in ARDS.  J Emerg Trauma Shock. 2011;4(2):244–50.

2

Equipment and Devices of Extracorporeal Life Support Qiang Hu

Extracorporeal life support (ECLS) is a direct extension of cardiopulmonary bypass technology used for providing supports to patient with cardiorespiratory failure despite maximum conventional therapy. The blood drained from an outflow cannula gets oxygenated and decarboxylated before it returns through an inflow cannula. The equipment of ECLS mainly includes blood pump, oxygenator, pipeline system, heater-cooler unit, various blood parameter monitoring, oxygen saturation monitoring, pressure monitoring, and so on.

Blood Pump Blood pumps are designed to direct the venous drainage of blood flow through membrane oxygenator and then return oxygenated blood back into the patient. Centrifugal pumps are the main type of blood pump currently used.

Centrifugal Pump Physics A hole is respectively opened at the center and the circumference of the closed circular container (pump head). As it spins at high speed, a negative pressure forms in the center of the circle, which sucks in blood. The circumference is positive pressure, which can fling the blood out. When the object moves in concentric circles, it produces an outward force, which is called centrifugal force. The magnitude of the force is proportional to the speed and mass. Centrifugal pump is designed according to this principle. The high-speed rotation of the pump head results in a differential pressure between the inlet and outlet ends of the pump (Fig. 2.1), thus facilitating the flow of liquid. Q. Hu (*) Department of Extracorporeal Circulation, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

Fig. 2.1  Principle of centrifugal pump

The final blood flow is determined by the differential pressure and the resistance at the outlet: Qb = (P0 − Pi)/R. P0 - outlet pressure, Pi - inlet pressure, R- resistance. The outlet resistance is composed of two parts. One is the resistance generated by the ECLS devices, including the oxygenator, the tubing, and the arterial cannula, and the other is the patient’s vascular resistance. A centrifugal pump uses rotation to impart velocity to a liquid and then converts that velocity into flow by a spinning rotor which applies suction to the blood inlet and then propels the blood outward from the pump housing by generating a positive pressure. This occurs without any tubing compression and allows for longer continuous pump operation with-

© Springer Nature Singapore Pte Ltd. 2023 F. Hei et al. (eds.), Extracorporeal life support, https://doi.org/10.1007/978-981-19-9275-9_2

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out replacement, as well the ability to clamp or occlude the circuit tubing without violating the circuit’s integrity.

Components of a Centrifugal Pump The centrifugal pump is composed of a pump head, a flow sensor, a driver, a control part, and a manual driving device. Pump Head  The first centrifugal pump used for ECLS was the Bio-Medicus constrained vortex pump. The pump head consisted of a series of concentric cones that created a centrifugal force which directed blood forward to a dedicated outlet. A fixed shaft anchored the cones, and a seal was incorporated within the blood path resulting in a stagnant blood zone at the pump head base. A consequence of this design was localized heat generation that was poorly dissipated and at high rpm. The use of early centrifugal blood pumps in conjunction with high resistance gas exchange devices required high rpm to generate forward flow. High levels of plasma-free hemoglobin due to heat generation, sheer stress, and resultant hemolysis were observed in some patients [1–5]. Newer centrifugal designs are more efficient primarily due to a key design feature described by Mendler [6]. This design features a hole located adjacent to the impeller that allows blood to continually wash the area around the rotor, reducing or eliminating any stagnant areas. This design decreases the mechanically induced hemolysis observed in earlier centrifugal pump designs. Bearing free magnetic levitation designs along with the incorporation of low resistance, short blood path gas exchange devices has allowed for safer use in more recent years [7].

Q. Hu

Drive and Control Parts  The driving and control parts use computer technology to achieve the characteristics of simple operation, precise adjustment, and comprehensive observation. Flow and speed display at the same time with internal power supply to prevent accidental power failure. The motor of the centrifugal pump has the advantages of small size, light weight, and small wear. The rotor of the centrifugal pump is connected with the wire of the motor, which increases the mobility. Manual Drive  Although the centrifugal pump is safe and reliable, due to the non-occlusive nature of the centrifugal pump, retrograde blood flow can occur if the electronic drive fails, is powered off, or malfunctions. The risk of retrograde flow can be reduced by a flow alarm or a shut-off valve. To prevent accidents, it is important to have a manual drive.

Commercial Centrifugal Pumps There are a variety of commercial centrifugal pumps that have been authorized for adult and pediatric ECLS. Individual device availability and regulatory status varies from country to country and by certifying agency. Medtronic Bio-Console 560  The AFFINITY CP centrifugal pump (Medtronic, Minneapolis, MN) is designed to propel blood by the centrifugal force generated by the combination of a smooth rotating cone and a low profile vane wheel (Fig. 2.2). To lessen friction and heat generation, the pump head uses a pivot bearing on a double ceramic pivot. The AFFINITY CP centrifugal pump is connected to a remote magnetic drive and is also equipped with an emergency manual drive. It has a smooth cone and low profile fins

Flow Sensor  There are two types of flow sensors: ultrasonic and electromagnetic. The ultrasonic sensor transmits the ultrasonic signal through the transducer to the red blood cells and then reflects back to the receiver. Ultrasound signals are used to determine blood flow velocity. However, Doppler signals become less sensitive at low blood flow speeds, and most ultrasound probes cannot accurately measure low-­ speed blood flow. The electromagnetic sensor uses the Faraday principle to measure the flow rate according to the local magnetic field change when the blood flow passes. The electromagnetic probe needs to be in contact with blood through a special connection between the probe and the pipeline and is not easily affected by factors such as turbulence and hematocrit. Extracorporeal blood flow is monitored most commonly with an ultrasonic flow detector/probe. The flowmeter may Fig. 2.2  Affinity CP centrifugal pump head (Reproduced with permisbe separate or integrated into the pump. Integrated flow mon- sion of Medtronic, Inc. Unless otherwise noted, product names are itors are common with modern centrifugal pumps. trademarks or registered trademarks of Medtronic)

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Fig. 2.4  Sarns™ disposable centrifugal pump (Reproduced with permission from https://www.terumocv.com/products/ProductDetail.aspx ?groupId=1&familyID=13&country=1) Fig. 2.3  Bio-Console 560 Controller System (Reproduced with permission of Medtronic, Inc. Unless otherwise noted, product names are trademarks or registered trademarks of Medtronic)

enabling maximal blood flow to 10 LPM with a ceramic heat-resistant pivot shaft. The pump head has a 40 mL priming volume and interfaces with Medtronic Bio-Console 560 console (Fig. 2.3). Sarns Delphin Pump  The blood inlet and outlet of the Delphin centrifugal pump introduced by Sarns 3M are at right angles to each other. The pump head has a 48 mL priming volume. The control panel is simpler and lighter. Blood flow is monitored by the ultrasonic detector on the pump outlet pipe. The flow is proportional to the pump speed (Fig. 2.4). MAQUET Rotaflow  The Rotaflow centrifugal pump (Maquet Cardiopulmonary AG, Hirrlingen, Germany) (Fig.  2.5) was introduced in 1995. This pump has the characteristics of reduced heat generation from the bearing and seal and improved hydraulic efficiency with minimal blood damage. In testing, the Rotaflow pump showed stronger hydraulic efficiency compared to other devices [8]. The disposable pump head features a low friction one-point pivot bearing that supports a multifinned impeller. The pump head is controlled by a

remote drive motor tethered to an integrated console. The pump head is compact with a priming volume of 32 mL, an outer diameter of 85.5 mm, a height of 48 mm, and a weight of 60 g. It is constructed to draw out the potential of the radial magnetic drive in eliminating a central shaft and seal with a blood-flushed bearing, avoiding stagnant zones, and reducing areas of high shear and turbulence. The drive magnets are uniquely embedded in a shrouded impeller with four blood channels. A single pivot bearing supports the impeller at its bottom, in which the sapphire ball bearing is held in the center of the completely open rotor by a 1 mm steel strut. MAQUET CARDIOHELP System  The integrated design of the drive and control device of the CARDIOHELP system (Maquet Cardiopulmonary AG, Hirrlingen, Germany) (Fig.  2.6) is the smallest portable life support system in the world (315 × 255 × 427 mm) and the lightest weight (10  kg). CARDIOHELP system has a built-in battery, which can keep the equipment running for 90  min. The CARDIOHELP system can continuously monitor blood temperature, hemoglobin content, hematocrit, and arteriovenous oxygen saturation, while the integrated sensors can accurately monitor pressure and flow. With advanced security management system, alarm, warning, restriction, intervention, and other measures can be set to make the

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Fig. 2.5  Rotaflow RF-32 centrifugal pump and controller system (Reproduced with permission from https://www.getinge.com/int/product-­ catalog/rotaflow-­32-­centrifugal-­pump/)

Fig. 2.6  Cardiohelp system (Reproduced with permission from https://www.getinge.com/int/product-­catalog/cardiohelp-­system/)

system more secure. Automatic screen lock function can prevent setting changes caused by accidental operation. Mixflow-N Pump  Mixflow-N centrifugal pump is a small blood pump developed by the Japanese JMS company. Its impeller diameter is 5  mm, priming volume 19  mL, outer diameter 58  mm, maximum speed 5500RPM, and weight 42 g. The blood contact surface of the Mixflow-N centrifugal pump is coated with a Legacoat. The Legacoat coating mimics the structure of phospholipid polar groups in biological cell membranes and can exert antithrombotic effects by inhibiting protein adsorption and denaturation.

CentriMag Magnetic Levitated Pump  The CentriMag pump technology (St. Jude Medical, St. Paul, MN) is based on the principles of magnetic levitation. The CentriMag features bearingless technology which contains no seals. The pump rotor is levitated within the disposable pump head housing by a magnetic field so that when the motor is powered up, the resultant magnetic field aligns and maintains the rotor in a position in which no direct contact to any other part of the pump head housing occurs. When the pump is engaged, the magnetic field fluctuates allowing the rotor to spin at the rate set by the control console. The risk of thrombus formation is reduced by uniform unidirectional flow and less stagnation, while reduced shear

2  Equipment and Devices of Extracorporeal Life Support

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Fig. 2.7  Medos Deltastream DP3 XENIOS CONSOLE and pump head (Cited from https://www.xenios-­ag.com/wp-­content/uploads/2019/07/ Xenios_console_brochure_2021_06.pdf)

stress attenuates hemolysis. The CentriMag adult unit can produce flows up to 10 LPM. These pumps require flow probes to enable the system. The pump head cannot be manually hand cranked, so a backup system is required. Medos Deltastream DP3  The Medos Deltastream DP3 pump (XENIOS AG, Im Zukunftspark 1, 74076 Heilbronn, Germany) (Fig. 2.7) is a hybrid of centrifugal and axial technologies that utilizes higher rotational speed but shorter transit time to generate blood flow. The DP3 has 3/8″ inlet and outlet connectors for adult use (a design with 1/4 size connectors for pediatric use is pending). The pump head has 16 mL of priming volume and a flow range of 0–8 LPM at a pump speed from 100 to 10,000 RPM.  The most featured pump head incorporates a ceramic bearing and magnetic coupling with an optional pulsatility mode (rate 40–90 beats/min). The MDC console is portable, is lightweight (10 kg), and contains two batteries (90-min power/battery) that allow the pump to be operated independently from the driving console. The detachable touch screen monitor can real-time display parameters such as blood flow, rpm, multiple site pressure monitoring, and temperature measurement. The controlling hardware has three integrated pressure channels with negative pressure regulation, zero-flow mode, and air bubble detection, as well as a display of residual level of both batteries. The zero-flow mode may automatically adjust the blood pump speed to avoid inadvertent retrograde flow. The only drawback is that the system cannot be manually hand cranked. LivaNova Revolution Centrifugal Pump  The Revolution centrifugal pump (LivaNova, Arvada, CO) features a seal-

less, low friction bearing. The pump head is controlled by the LivaNova Centrifugal Pump (SCP) system that can be integrated with S5™ and C5™ systems. When certain abnormal conditions are detected (low level, bubble, or retrograde flow), this feature allows for some servo-regulatory controls that are unavailable with other centrifugal pump technologies.

Membrane Oxygenator The membrane oxygenator should be able to deliver sufficient oxygen to the patient, as well as remove CO2 produced by the patient. The surface area and fiber types determine the maximum oxygenation capacity of any membrane oxygenator. Patient metabolic conditions determine the amount of oxygen delivery required. The maximal oxygen delivery of an oxygenator is the amount of oxygen delivered per minute at a certain blood flow. This is determined by calculating the difference in oxygen content between the outlet blood and the inlet blood of the oxygenator. The gas ventilated through the oxygenator is referred to as the sweep gas. Water vapor can condense within the gas compartment of the membrane oxygenator and may be cleared by intermittently higher sweep gas flow every 24 hours or so. Early generation of oxygenators was characterized by a longer blood path and a higher pressure gradient. These early designs incorporated flat sheet silicone rubber membranes and “blood inside” hollow fiber bundle configurations. Design modifications adopted a hollow fiber concept with

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“gas inside” and blood circulating outside the fibers. This configuration resulted in a significant decrease in the pressure gradient of the blood pathway [9]. This design has been applied to all subsequent design of oxygenators regardless of its hollow fiber material. The first widely used biomaterial for oxygenator was microporous polypropylene. Although this material could be manufactured as a flat sheet, fiber technology provided more effective surface area and was relatively inexpensive to manufacture. The membrane oxygenator made out of this material is smaller in size, less in pre-­ stuffing volume, and higher in oxygen exchange rate. This fiber has the merits of high mechanical strength, low toxicity, and satisfactory bio-compatibility. Microporous polypropylene hollow fiber membrane oxygenator is limited in longevity because over time, plasma leakage will result in oxygenator failure [10, 11]. Polymethylpentene (PMP) fibers that became available in the early 2000s showed promise as a plasma leakage-­resistant fiber. PMP oxygenator have many advantages, such as excellent performance in gas exchange and maximum solves the problem of polypropylene hollow fiber membrane plasma leakage. During process of manufacturing, the PMP fibers are compressed to form an outer surface or “skin” with properties similar to that of a solid membrane. However, gas can still be entrained across the PMP material into the blood path in the case of large negative pressure in the pipeline. Therefore, it is prerequisite to maintain positive pressure on the blood path side. The PMP fibers, produced by Membrana GmbH (Wuppertal, Germany), have similar gas exchange characteristic as polypropylene, but it is more challenging to handle, so PMP is typically matted and either wound or stacked in relatively short blood path configurations. Current PMP oxygenators have low pressure gradients, and the fibers mimic a “solid hollow-fiber” technology with low risk of

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plasma leakage [12]. In the two pilot clinical studies, PMP oxygenator has been reported as showing feasibility and longevity in long-­term ECLS support.

Commercial Gas Exchange Devices Many commercial membrane oxygenators are available, and some are listed in the sections below. The regulatory status for each individual device varies from country to country and by certifying agency. In the United States, most oxygenators are only cleared for up to 6  hours of use. In Europe, CE marking may be extended to days or weeks. PLS-i oxygenator  The Permanent Life Support (PLS) System from Maquet has been developed to support patients requiring prolonged respiratory and/or circulatory assistance with blood flows ranging from 0.5 to 7 L/min. The PLS-i oxygenator (Maquet Cardiopulmonary AG, Hirrlingen, Germany) (Fig.  2.11) is constructed of plasma-resistant hydrophobic PMP hollow fibers and contains an integrated heat exchanger. The design effectively prevents formation of microbubbles and protects against bacterial contamination from the gas side. The PLS Module membrane device has a low pressure drop across the fiber bundle. The designs for bundling the fibers within the oxygenator and the flow pattern through the device are key factors in decreasing the priming volume [13]. The HLS Module ADVANCED oxygenator is based on the PLS Module oxygenator, which integrates a centrifugal pump into the oxygenator to further reduce the priming volume and simplify the priming step. The HLS Module Advanced oxygenator integrates three major ECLS circuit components (gas exchange, pump head, and heat exchanger) into a single product (Fig. 2.8). The product has integrated

Fig. 2.8  PLS Module membrane oxygenator and HLS Module Advanced membrane oxygenator (Reproduced with permission from https://www. getinge.com/int/product-­catalog)

2  Equipment and Devices of Extracorporeal Life Support

sensors to detect inlet saturation, hemoglobin/hematocrit, and temperature. Three pressure parameters can be measured. The HLS module comes in two sizes: HLS Module Advanced 5.0 (blood flows up to 5.0 LPM) and HLS Module Advanced 7.0 (blood flows up to 7.0 LPM). The system is coated with the Maquet Bioline thromboresistant surface and has different regulatory clearances depending on country. The module can be positioned on a portable cart and may be used for patient transport. The Permanent Life Support (PLS) set is a long-lasting auxiliary for ECLS. It is a pre-connected standard set consisting of the PLS-i oxygenator and the Rotaflow centrifugal pump RF-32 both incorporated into a tubing set with tip-to-­ tip BIOLINE Coating. It can be used for up to 14 days in the CE region. The HLS Module Advanced oxygenator provides complete monitoring and is specifically developed for V-A or

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V-V ECLS support and can last up to 30 days (CE certification). The transmembrane pressure difference of the HLS Module oxygenator is currently the lowest in many markets. With each additional liter of flow, the pressure drop only increases by about 10 mmHg, which can effectively reduce blood damage. Hilite LT Oxygenator  The Medos Hilite LT (Medos Medizintechnik AG, Stolberg, Germany) is produced in three sizes with an integrated heat exchanger. Hilite LT oxygenators are available in three sizes whose characteristics are summarized in Table  2.1. The device is characterized by a low pressure differential between blood inlet and outlet and a smaller priming volume than the Quadrox­ID. The Hilite LT devices are suitable for use with all pump types. The Medos LT device is illustrated in Fig. 2.9 and is available with or

Table 2.1  Specifications of Hilite LT oxygenators (Cited from https://www.vingmed.dk/wp-­content/uploads/sites/3/2019/03/Hilite.pdf) Oxygenators Blood flow rate (L/min) Static priming volume (ml) Gas exchanger    Material    Surface (m2) Heat exchanger    Material    Surface (m2) Coating

Fig. 2.9  HILITE LT oxygenators (Cited from https://www.xenios-­ag. com/medos/products/ hilite-­oxygenators/)

Hilite 7000 LT 1–7 320

Hilite 2400 LT 0.35–2.4 95

Hilite 800 LT 0.1–0.8 55

Polymethylpentene fiber 1.9

Polymethylpentene fiber 0.65

Polymethylpentene fiber 0.32

Polyethylene 0.45 • Rheoparin • Uncoated

Polyethylene 0.16 • Rheoparin • Uncoated

Polyethylene 0.074 • Rheoparin • Uncoated

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without a surface coating. With each additional liter of flow, the pressure drop only increases by about 15–20 mmHg. Nautilus ECMO Oxygenator  The Nautilus ECMO oxygenator (Medtronic, Minneapolis, MN) with integrated heat exchanger is intended to support long-term extracorporeal circulation and physiologic gas exchange of the patient’s blood. The Nautilus oxygenator (Fig. 2.10) is constructed of PMP hollow fibers with Balance bioactive surface. The transverse flow-path design minimizes surface contact area while achieving a low blood-side pressure drop, and the circular profile eliminated corners where low flow and stasis are known to occur. Nautilus Smart ECMO Module  The Nautilus Smart ECMO Module (Medtronic, Minneapolis, MN, Fig.  2.11) improves long-term gas transfer and heat exchange while providing real-

Fig. 2.10 Nautilus oxygenator (Reproduced with permission of Medtronic, Inc. Unless otherwise noted, product names are trademarks or registered trademarks of Medtronic. Reproduced with the permission of MC3, Inc. Nautilus™ ECMO Oxygenator is manufactured by MC3, Inc. and Nautilus™ is a trademark owned by MC3, Inc. Balance™ is a trademark of Medtronic, and the technology is licensed under agreement from BioInteractions, Limited, United Kingdom)

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time device performance data accessible from an intuitive touch screen. Some sensors integrated in the circuit minimize the number of areas prone to blood clot formation and air entrainment from excessive connections. The monitored parameters contain pressure in/pressure out/Δ, O2 saturation in/ O2 saturation out, temperature out, set alarm limits, and receive visual and audio alert notifications. The design of transverse flow-path with a circular profile is the same as Nautilus ECMO oxygenator, which can effectively protect blood. Lilliput Oxygenator  LivaNova (London, UK) produces two sizes of extended use gas exchangers. The Lilliput 2 ECMO is a pediatric unit made with PMP fibers [10]. The device has a phosphorylcholine surface coating and has been validated for up to 5 days of extended support. The device requires the use of a blood pump. The D905 EOS ECMO unit is a large adult-sized device that is phosphorylcholine coated. The device has been validated for 5 days of use outside the United States. With each additional liter of flow, the pressure drop only increases by about 50–60 mmHg.

Fig. 2.11  Nautilus Smart ECMO Module (Reproduced with permission of Medtronic, Inc. Unless otherwise noted, product names are trademarks or registered trademarks of Medtronic. Reproduced with the permission of MC3, Inc. Nautilus™ Smart ECMO oxygenator is manufactured by MC3, Inc., and Nautilus™ is a trademark owned by MC3, Inc. Balance™ is a trademark of Medtronic, and the technology is licensed under agreement from BioInteractions, Limited, United Kingdom)

2  Equipment and Devices of Extracorporeal Life Support

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ECLS Tubing

Surface Coating Technology

General Principles of Circuit Design

The body treats ECLS circuits and other components as foreign bodies, and the blood contacts foreign bodies to activate platelets, complements, and other inflammatory mediators. Activation of the complement system and release of inflammatory mediators cause ARDS and other organ dysfunction. Surface coating technology can suppress complement, platelet, and inflammatory mediator activation.

The ECLS circuit is made from biomaterials and plastics commonly used in traditional CPB. The majority of conduit tubing is made from a formulation of polyvinylchloride (PVC) mixed with a plasticizer. The amount of plasticizer determines the tubing durometer or flexibility. Known as di-­2-­ethylhexyl phthalate (DEHP), DEHP is used to make PVC more flexible. The ECLS circuit may contain a number of affiliated sites that can monitor specific parameters such as blood flow, internal circuit pressures, oxygen saturations, hemoglobin or inline blood gases, temperature, and other metabolic parameters. Variations of this design exist and depend on necessity and feasibility of the parameters and availability of institutional philosophy. When designing the circuit, a goal would be to minimize or eliminate dispensable non-endothelial surface materials. The tubing that connects the patient to the essential circuit components should not be lengthy, but adequate in length to allow for patient movement and transport. Resistance to flow increases as tubing length increases [14]. Larger volume circuits expose the blood to additional foreign surface areas that may promote greater inflammatory response and chance of thrombosis [15]. Circuits that contain longer than required tubing lengths with an excessive number of stopcock connectors and access sites risk more circuit-related complications.

Carmeda Heparin Coating  Carmeda is a Sweden-based company in the field of hemocompatible coatings. CARMEDA® BioActive Surface (also known as the CBAS® Heparin Surface) is now the most clinically proven of all hemocompatible coating technologies. Free acetaldehyde molecules on the artificial coating surface can participate in various biological effects like heparin sulfate molecules binding to the vascular endothelium, while the rest of the molecule is inserted to the active binding site. The covalent bond bound to heparin is quite stable, so heparin will not escape from the surface and enter the circulation. It inhibits the coagulation reaction on the inner surface of the duct and the hollow fiber membrane. Trillium Heparin Coating  Trillium coating (Fig.  2.12) is one biological coating technology of Medtronic that simulates the characteristics of vascular endothelial cells. It has the following characteristics: Covalently bound heparin molecules have the same anticoagulant effect as heparin sulfate on

Fig. 2.12  Trillium heparin coating (Reproduced with permission of Medtronic, Inc. Unless otherwise noted, product names are trademarks or registered trademarks of Medtronic)

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the surface of endothelial cells and can guarantee the longterm effectiveness of heparin binding, and it is not easy to fall off. Because the coating material contains high concentrations of sulfuric acid and sulfonic acid groups, it has a negative charge similar to the surface of endothelial cells. It can repel platelets that also carry negative charges, thereby reducing the aggregation of platelets on the surface of the material and inhibiting coagulation. The oxidized polyethylene chain (PEO) in the coating material has strong hydrophilicity, which can form a water interface between the surface of the artificial material and the blood, and its surface free energy is low, which can prevent cell adhesion and protein deposition. Xcoating™ Surface Coating  Xcoating™ surface coating is Terumo’s exclusive biopassive surface coating comprised of an amphiphilic polymer that has both hydrophobic and hydrophilic features (Fig.  2.13). It is the dichotomy that a new surface is formed in the extracorporeal circuit with this coating; afterwards protein denaturation and platelet adhesion may be alleviated or eliminated. The coating technology is a coating formed by an amphoteric polymer. This special

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coating is non-heparin-based biopassive polymer [poly(2-­ methoxyethylacrylate) or PMEA]. The amphoteric molecule has both hydrophobicity and hydrophilicity. The hydrophobic segment is connected to the surface of the artificial material, while the hydrophilic end is in contact with the blood on the duct side. After the blood flows over the surface of the artificial material, the moisture in the blood accumulates on the hydrophilic surface of the artificial material, and the protein in the blood and this layer of water interface can freely combine to form a contact surface composed of water and protein. The protein structure in the contact layer will not change or denature, so platelets will not stick to the surface of the artificial material. The Xcoating™ surface coating has the characteristics of insolubility in water, flexibility, and adhesion, which makes it not fall off and remains stable. This coating technology has no effect on various physical properties of raw materials and does not change the gas exchange function after coating the oxygenator, so it can be used on almost all material surfaces, and because it does not contain heparin, so those materials can be used in patients who cannot tolerate heparin.

Fig. 2.13  The Xcoating surface coating molecules bind to each other as well as to the surface material, forming a very thin, very supple layer. (Reproduced with permission from https://www.terumocv.com/doc/876640_Xcoating-­Brochure_JULY2018_FINAL_LowRes.pdf)

2  Equipment and Devices of Extracorporeal Life Support

Both heparin coating and Xcoating™ surface coating can protect platelets, but the mechanism is different. Xcoating™ surface coating prevents platelet aggregation, while heparin coating technology works by inhibiting platelet adhesion and fibrinogen degeneration. SMARxT® Coating  The surface-modifying additive (SMA) developed by COBE company is used to treat the surface of artificial materials, so that the surface of artificial materials is composed of alternating hydrophilic and hydrophobic regions to form a microphase structure. This structure can simultaneously bind to different sites on fibrinogen, inhibit its ability to bind to other proteins, and activate platelets, theoretically reducing platelet adhesion. In 1999, Sorin purchased COBE cardiovascular, a leading manufacturer of advanced cardiopulmonary and autologous blood processing products. The cross-border merger of Sorin with and into LivaNova plc (formerly called Sand Holdco PLC) (“HoldCo”), the new company that was established to acquire entitlement both Cyberonics and Sorin as part of the proposed merger, was approved by Sorin’s shareholders at its extraordinary shareholders’ meeting held on May 26, 2015. Mimesys Coating  Mimesys coating technology is a phosphorylcholine polymer coating developed by Dideco. Phospholipid phosphocholine is an important component on the surface of red blood cells and a key factor in preventing protein deposition on the cell surface. Mimesys coating technology uses artificially synthesized phospholipid choline to form a continuous and uniform molecular layer on the surface of various artificial materials. The coating is insoluble in water and can form a water molecule layer on the surface of artificial materials to prevent protein adsorption. The results show that the choline phosphate coating can reduce the deposition of proteins and cells, especially the reduction of fibrin, and vWF factor adsorption can inhibit platelet activation and accumulation caused by it, thereby reducing the formation of thrombus and activation of the endogenous coagulation system. BIOLINE Coating  The BIOLINE® Heparin Coating was originally developed by Jostra AG and is now a technology owned by Maquet Medical (Getinge Group). It is a coating that mimics natural endothelial cells composed of peptides and active heparin. The peptide in the coating is tightly adsorbed on the surface of the artificial material, forming a heparin molecule binding system. This peptide layer can be used on the surface of many synthetic materials. The coating makes the heparin form a stable coating on the surface of the polypeptide through two methods: covalent bond and ionic bond. Bioline-coated artificial materials can reduce the activation of cells and plasma

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components, thereby reducing the formation of emboli and complement activation, and effectively protect the function of platelets and white blood cells. Safeline Coating  The heparin-free SOFTLINE Coating technology is a physical modification of the QUATROX oxygenator membrane by Marquet Company, which makes the surface contacting the blood show hydrophilic properties, so that the blood can adapt to the surface of foreign bodies at a faster rate, forming a layer of quasi-endothelial surface. The combination of Safeline on the membrane is achieved by van der Waals and electrostatic forces. This bond is quite stable, and the coating does not come off during surgery. Duraflo II Heparin Coating  Duraflo technology significantly reduces fibrinogen adsorption by changing the order of plasma protein adsorption, thereby reducing platelet activation and adhesion and maintaining platelet numbers. In addition, Duraflo interacts with antithrombin III, inhibiting some early activated contact enzymes, thereby reducing the activation of the coagulation, complement, and fibrinolytic systems, thereby reducing postoperative systemic inflammatory response (SIRS). Various coating technologies have different performances due to differences in manufacturing principles and processes, but the role of blood compatibility is very close. Any coating technology used in clinical practice is not significantly superior to other coating technologies. There are different opinions on clinical prognosis and whether heparin can be reduced. The various coating materials currently used cannot completely prevent the activation of the blood system. The ideal blood-compatible material should be a smart material that completely mimics the function of endothelial cells, and its development is still being explored.

Heat Exchanger/Heater-Cooler Device ECLS constantly exposed the blood to the ambient temperature of the environment. The circuit should be capable of maintaining the patient at normothermia (37 °C). The oxygen in the sweep gas comes from a cold liquid oxygen source, and the evaporative vapor losses across the membrane dissipate heat, also cooling the patient. Therefore, a heat exchanger may be integrated into the gas exchange device, but can be a stand-alone component. ECLS patients, especially infants and small children, may require active warming to maintain normal body temperature with a heater-­cooler device. Heat exchangers require an external recirculating water bath which circulates water through a coil or network of fibers in the blood path. The coil, or fiber network, is often integrated within the shell of the gas exchange device. The temperature

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Hemoglobin Saturation Measurement

Fig. 2.14  ECLS heater-cooler device (Reproduced with permission from https://www.getinge.com/int/product-­catalog/hu-­35-­heater-­unit/)

of the circulating water bath is regulated to control the patient or blood path temperature. In general, the temperature of the water is maintained between 36 and 6 days) without plasma leakage [27], which far exceeds that of earlier oxygenator models. In the early to mid-2000s, the non-microporous PMP membrane oxygenators have replaced the silicone membrane lung in long-term ECMO support and gained widespread acceptance by the ECMO community. In general, oxygenators have been divided into two main classes with respect to duration of use, namely, the microporous oxygenator for short-term use in cardiac operating room, and non-­ microporous PMP oxygenator for long-term use of ECMO in intensive care units.

3  Types of Extracorporeal Life Support and Evolution of Extracorporeal Oxygenators

 xtracorporeal Membrane Oxygenation E (ECMO) ECMO is a form of closed-system extracorporeal life support. In its simplest form, the console-controlled centrifugal pump pulls deoxygenated venous blood via a venous drainage (access) cannula, directing it through a membrane oxygenator where exchange of oxygen and carbon dioxide between blood and a fresh oxygen-enriched sweep gas takes place. Oxygenated blood then returns to the body via a second reinfusion (return) cannula. ECMO is commonly indicated as a rescue intervention for patients who suffered from severe respiratory failure, cardiogenic shock, and severe septic shock refractory to conventional therapy. Unlike conventional cardiopulmonary bypass system commonly seen in heart surgery, the closed system extracorporeal membrane oxygenation is able to provide end-organ support over extended periods of weeks to months for the affected organ(s) to recover from acute insults. ECMO is also used as a bridge to destination or transplant, such as heart and lung transplantations and left ventricular assist device, by temporarily optimizing recipient blood gases and hemodynamic parameters. ECMO applications are divided into: 1. Traditional mode configurations of Veno-Venous (VV) for respiratory support, and Veno-Arterial (VA) for cardiorespiratory support.

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2. VenoVeno-arterial (VV-A), an alternative configuration of VA mode is used to improve drainage and unloading of left ventricle and in certain adult congenital intra-cardiac shunt. 3. Veno-Veno-arterial (V-VA), a “Hybrid” mode configuration is used to provide mechanical circulatory and respiratory supports in patients exhibiting differential hypoxia, North-South, Harlequin syndrome on femoral VA ECMO.

 eno-Venous Extracorporeal Membrane V Oxygenation (VV ECMO) Mode VV ECMO is predominantly used in treating ARDS population as a bridge-to-recovery or bridge-to-decision. With technological breakthroughs in extracorporeal circuit components, such as the novel introduction of PMP membrane oxygenators, the ECMO systems have become more durable and easy to manage. This coupled with growing collective knowledge and experience during the 2009 influenza A (H1N1) pandemic [30], good publication results from 2009 CESAR [31] and 2018 EOLIA (Extracorporeal Membrane Oxygenation to Rescue Lung Injury in Severe ARDS) [32] trials, ECMO use in treating ARDS has since markedly increased [33]. CESAR and EOLIA randomized study showed improved survival benefits in adults with severe ARDS in ECMO group compared to conventional group [34] (Table 3.1) (Fig. 3.5).

Table 3.1  ECMO randomized trials and analysis outcomes Year 1970s

Trial/Publication Multicenter National Institutes of Health sponsored trial

Outcomes Survival rate- 9.5% vs 8.3% traditional management group.

1991

Morris et al. Single center trial

Survival rate- 45% ECMO management vs 47% conventional management. p  240 mg/dL Acidosis pH < 7.2 Alkalosis pH > 7.6 Hyperbilirubinemia Limb Ischemia Compartment syndrome Fasciotomy Amputation

Neonatal (18y, n = 14,580) Reported Survived (%) (%) 2.7 38 0 100 0.1 13 1 43 0 80 9.8 42 0.2 41 1 24 3.2 35 1 38 12.5 38 14.5 33 4.3 24 1.8 16

0.6 2.9 9.6 7.7 0.1 12.2 4.3 0.9 34.6 35.2 2.1 11.5 9.6 1.6 4.2 1.8 2.8 4.2 0.7 1.5 8.3 7.4 3.5 6.1 1.4 0

2 5.9 5.6 6.5 0.4 8.9 6.8 2 34.6 32 2.5 10.3 11 0.2 3.6 1.8 4.3 7.1 1.5 1 8.4 5.2 2.4 4.6 2.2 0.8 0.7 0.2

2.1 3.5 1.9 1.5 0.2 3.4 17.1 8.7 29.6 31.1 2.6 13.3 2.6 0.0 4.7 1.3 2.3 7.6 1.6 1.2 7.2 6.5 2.1 9.7 5.3 1.5 2.5 0.7

0 30 25 32 50 19 24 40 32 36 22 33 49 25 45 33 14 28 29 36 36 25 43 31 16 0

0 33 26 39 20 37 45 42 42 50 32 51 59 33 47 36 37 40 26 33 56 32 57 31 32 42 41 50

0 22 10 28 18 32 37 32 31 39 16 37 57 13 37 32 23 40 35 8 43 19 51 28 30 23 32 52

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Mechanical Adverse Events Despite the improvement in ECMO devices, some complications have reduced in frequency. The reason that adverse events occur is due to that ECMO consists of long-term use of disposable parts and high-tech equipment. A recent report of the ELSO Registry database showed that prevalence of mechanical adverse events was 31% [1]. Device malfunction varies by type of MCS. VA-ECMO has a relatively high rate of device malfunction, which has increased in recent years likely secondary to increased application [2]. Malfunction of ECMO is often related to oxygenator dysfunction. It is essential to recognize the importance of the ECMO circuit and its impact on helping to minimize adverse events. Most adverse events can be prevented with early recognition and appropriate treatment [2, 3]. Common mechanical complications are as follows.

Pump Failure Symptoms • No lights on equipment • Pump without power • Pump shutting off or not turning on • Pump rotating but no flow Causes • Power failure • Power cords dislodged to the pump • Battery malfunction/not charged • Individual pieces of device not turned on • Pump power switched off • Pump not plugged in • System pressures alarming • Pump on/off knob turned off • Flow knob turned to zero • Bubble detector alarming and set to control pump • Inadequate occlusion • Pump malfunction • Flow detector malfunction Solution • Hand crank until power is available. • Plug in properly. • Use portable power supply. • Turn switch on. • Check for defective alarms. • Correct reasons for pressure alarms. • Check for air and de-air. • Check flow knob for appropriate settings. • Turn pump power button off and back on to reset.

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• Adjust occlusion. • Replace pump. • Add coupling agent.

Low Flow/Cutting Off Symptoms • Mismatch between the rotating speed and the flow rate in centrifugal pump; high rotation speed with low flow rate. • Low flow rate alarm. • Flow rate flicker instability. • Negative pressure alarm (bladder or venous line). • Positive pressure alarm (oxygenator). • Low flow rate leads to insufficient perfusion of the terminal organ. In addition, the attraction caused by shear stress and the high negative pressure caused by high rotational speed can cause blood cell damage and cavitation, resulting in hemolysis and gas embolism. Causes • Malposition of the venous/cephalic catheter. • Too small cannula. • Kink in tubing between the body and the pump. • Flow knob bump too high flow. • Pressure transducer malfunction. • Clot in a cannula, connector, tube line, or oxygenator. • Intravascular volume depletion. • Inadequate venous drainage due to patient factors (e.g., pericardial tamponade or increased abdominal pressure). • The height of the pump is too high for the bed. • Improper setting of pressure alarm limits or thresholds. Solution • Check cannula position and reposition the catheter and body position as needed; ensure the catheter position is appropriate. • Consider replacing a larger catheter or adding a second catheter. • Remove the tubing kinks. • Check flow scale and lower rotating speed; reduce the blood flow. • Flush, zero, and replace pressure transducer as needed. • Check for clots in the circuit and replace the ECMO system as needed. • Consider treating hypervolemia by rapid fluid infusion. • Assess and treat patient condition resulting in inadequate venous return. • Raise the height of the bed or lower the pump. • Recalibrate the zero of pressure and set reasonable alarm limits or threshold.

9  Adverse Events and Complications of Extracorporeal Life Support

Air in Circuit Symptoms • Pre-oxygenator air (venous line or bladder, compliance chamber, raceway, pump head) • Oxygenator air • Pre-oxygenator air (arterial line) The clinical presentation of air in circuit can range from small bubbles visualized in the venous line to a massive air embolus to the patients.

Causes • Cracked or open pigtails, stopcocks, or connectors in venous line • Air from intravenous infusions or volume push into circuit • Venous cannula connector cracked or loose • Venous catheter dislodged, side hole out of vessel • Tube misconnection, the pump placed behind the oxygenator • Air in right atrium-patient source (e.g., from central line infusion) • Air leak in oxygenator or gas outlet obstruction • Air leak from venous line, bladder, compliance chamber, and raceway • Prime problem Solution Tiny bubbles in the venous line should be promptly recognized, and the source should be found out and adjusted. While the air is trapped in the bladder or top of the oxygenator and presented easily to remove, one can aspirate the air safely by briefly stopping pump flow. The visualization of air moving through the circuit should be noted and dealt with immediately. Firstly, stopping the pump flow ceases the air from travelling with flow. Next, clamping the arterial side tube close to the patient prevents further movement of air upward and into the patient. Then the venous line is clamped, and the patient is off bypass. Check the line and connectors  for leaks and secure the connection to stop air leak, and replace the cracked pigtails or connectors as needed. Cannula or oxygenator problems should be correct. Then we can clear the air by walking the air to the removal location or recirculation through the bridge. After removing the air completely from the circuit, restart the ECMO support. If the air has already entered the patient, additional cerebral protective strategies should be taken. During this period, ventilator parameters and vasoactive drugs were adjusted to maintain the relative stability of circulation and respiration. The gas bubble in the circuit should be monitored closely for recurrence. Bubble detection is critical to maintain the steady-­flowing circuit and prevent

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complications from air embolism especially with veno-arterial ECMO circuits. This can remind ECMO specialists to remove air from the circuit or replace equipment in time to avoid more serious consequences.

Oxygenator Failure The extract criteria used for documenting oxygenator failure from each center are not well defined; the report of failure to the ELSO Registry database usually includes the need for changing the component. The adequate function of the oxygenator is usually assessed by monitoring the transmembrane pressure (TMP) as well as postoxygenator blood gas analysis.

Symptoms • Low/decreasing pump arterial PO2, decreased PCO2 clearance, and increased pressure gradient across the membrane. • Plasma leakage or blood leakage of the oxygenator, and the oxygenator gas exhaust drips. • Cracks or leaks in the oxygenator, and blood leakage into the water circulation, resulting in infection and insufficient capacity of the patient. • Pressure gradient across membrane increased significantly. Causes Several reasons that the oxygenator may fail include gas exchange alterations, such as when oxygen or CO2 transfer is diminished. The increase of pressure gradient across membrane obviously reflects clot formation within the oxygenator. Plasma leakage or blood leakage of the oxygenator is another trouble. The detailed reasons are as follows: • Swept gas line to oxygenator is loose, cracked, or disconnected. • Sweep gas FiO2 changed or source is empty. • FiO2 is too low or ventilation volume is insufficient. • Oxygenator clotting off. • Increased condensation in gas phase. • Oxygenator rated flow/efficiency exceeded. • Oxygenator or hollow fiber leak.

Solution Adequate function of the oxygenator is assessed by monitoring the TMP as well as postoxygenator blood gas analysis. The oxygenator failure should be recognized properly bedside, and a planned change-out procedure would carry out. Every ECMO center should design their specific criteria for identifying oxygenator failure and indications for change.

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• Reattach gas line to the oxygenator. • Troubleshoot gas line connections, and ensure the gas line is connected correctly without twisting and blocking. • Increase sweep gas flow rate and FiO2. • Check oxygenator rated flow, and turn down pump blood flow. • Check arterial cannula or tube for kinks causing increased pressure. • Increase sweep gas flow to maximum manufacture’s recommendations at regular intervals to blow out the condensed water in the gas phase of hollow fiber. • Troubleshoot pressure monitors or transducers. • Replace oxygenator.

Thrombosis Clots in the circuit are the most common complication during ECMO.  Adequate anticoagulation cannot completely prevent clot formation.

Symptoms • Clot formation in the circuit is easy to see and can be defined as dark clots or stringy pale fibrin strands after a few hours or days into the ECMO run. • Clot formation in the centrifugal pump head is often accompanied by pump noise and hemolysis. • It is often accompanied by the increase of the transmembrane pressure gradient of the oxygenator, activation of the coagulation and fibrinolytic system, consumption of coagulation factors, and blood damage. Causes • Clotting cascade is activated with any exposure to an artificial surface. This causes clot to form in the ECMO circuit. Dark clots often form where there is stagnation. • Clots occur whenever there is stagnation that is not preventable, such as at the margin of the oxygenator. • Turbulence generates abnormal shear force resulting in pyrolysis of blood cells, which promote coagulation cascade and clot formation. • Clot formation within the oxygenator may lead to occlusion of blood flow, causing increased pressure gradient across the membrane. • Once the clots travels further downstream where it can block, it may result in the occlusion of blood flow or embolism. • The coating surface of the circuit is passivated with an extension of time. • Insufficient anticoagulation. • HIT.

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Solution • Regular use of a bright halogen light will assist in the visualization of the clots deposited. • Heparin should be infused to maintain adequate anticoagulation during ECMO. • Monitor the coagulation parameters and make them achieve the target value by adjusting anticoagulant’s dosage. • When the clots are small and localized, they usually have no potential harmful effect to the circuit or patient. As long as the clot doesn’t encroach upon the blood inlet or outlet or cause significant pressure change within the membrane, they are not considered dangerous. • Once clot formation has been identified as causing failure of the component, occlusion of tubing, severe hemolysis, or at risk of moving into the patient, the component should be removed and replaced. • Replace the anticoagulant.

Tubing Rupture It is also possible for any part of the ECMO circuit to fail or rupture (break open). The rupture will occur suddenly and without warning.

Symptoms • Blood in the roller pump. • Tubing connectors are loose or cracked and blood leaked out. • Tubing separated accompanied with bleeding. • Air entering the circuit. Causes • The raceway becomes damaged or cracked from wear and tear in a roller pump. • The connector without tie-banded. • Accidental increase in circuit pressure. • Use penetrating towel clamps or sharp instrument cut the tube. Solution • Walking the raceway at regular intervals to avoid raceway wear. • Ensure the connector is tie-banded. • Avoid pulling the tube violenly. • Use non-penetrating towel clamps. • Using servo-regulated system to prevent the accidental increase in circuit pressure.

9  Adverse Events and Complications of Extracorporeal Life Support

Once the circuit fails or ruptures, the ECMO specialists must respond right away to deal with the problem. The patient must be taken off ECMO prior to repairing or replacing the ECMO circuit. The actual procedure for changing out the damaged section of the tube should be carried out as soon as possible. Tubing ruptured not only requires the suspension of ECMO assistance but also can lead to immediate bleeding. Treatment includes fluid infusion to correct hypervolemia.

Others In addition to the above common mechanical complications of ECMO, every artificial equipment may have an accidental malfunction. The functional and structural integrity of the relevant equipment should be checked regularly during ECMO. The bedside replacement of ECMO devices sometimes requires the close cooperation of the perfusionist, surgeon, ICU, anesthesiologist, and nurse.

Cannulation-Related Complications Cannulation-related complications are a known source of morbidity in patients supported on ECMO, with reported incidence rates up to 30%. Complications can vary depending on three different cannulation strategies: axillary, femoral, and central [4, 5]. The most common cannulation-related complications encountered were hemorrhage and limb ischemia. Any abnormal pulsatile neck mass after ECLS must be viewed as a pseudoaneurysm of the carotid artery, which requires urgent surgical intervention to prevent catastrophic hemorrhage [6]. Limb ischemia and vascular complications also comprise a substantial number of cannula-related complications in this patient cohort. As mentioned above, a combination of means to mitigate these complications includes the use of a distal perfusion catheter, close monitoring of systemic anticoagulation, and careful selection of catheter size with good fixation of distal perfusion catheter to avoid bending and dislodging. The effect of femoral artery damage and/or significant reduced limb perfusion can be devastating because limb ischemia can lead to compartment syndrome, requiring fasciotomy and, occasionally, even limb amputation. However, multiple studies have shown that patients who experienced a cannula-related complication with preventive and therapeutic strategies showed no increase in mortality and were able to be successfully discharged. VA-ECMO is still a complex, resource-intense, and high-risk type of mechanical support. Mortality prediction models have been developed to predict

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the risk of mortality in these acutely ill patients. The SAVE, ENCOURAGE, and SOFA scores have been developed to predict overall patient survival and prognosis in those with VA-ECMO.  More contemporary scores have being developed such as the Simple Score, the EuroSCORE, and the CardShock Risk Score [7–9].

Clinical Manifestations Complications caused by cannula include immediate injury of the catheterized vessels and adjacent sites and late injury of improper placement, bleeding infection at the access site, and limb complications. • Vasospasm leads to the inability to insert the appropriate cannula and insufficient flow. • Vascular injury such as vein torn, arterial dissection, arterial perforation, arterial plaque shedding, etc. • Damage to adjacent tissues and organs like hemopneumothorax, mediastinal hematoma, cardiac perforation, pericardial tamponade, arrhythmia, pelvic viscera perforation, and nerve injury. • Bleeding can occur at the site of access and is sometimes insidious, such as mediastinal bleeding, hemothorax, retroperitoneal hematoma, etc. • Thrombosis and embolism: including thrombus formation, air embolism, and abscission plaques of arteries. • Improper access for approach. • Limb ischemia or edema. • Arrhythmia or bradycardia.

Causes • Difficult cannulation and excessive manipulation of the blood vessels. • The size of the cannula does not match the blood vessel. • The guidewire is not properly placed. • Atherosclerosis or tortuous arteries in the elderly lead to increased risk of arterial dissection, plaque shedding, arterial perforation, etc. • The angle between the cannula and the blood vessel is too large, and continuous bleeding may occur at the access site. • Limb ischemia due to femoral artery vasospasm, large catheter occupied most of the vessel lumen, and lack of distal perfusion. Children were cannulated through the common carotid artery, and the distal carotid artery was ligated after cannulas. • Cannulation without systematic anticoagulation. • The cannula or tube is not firmly fixed, and it is easy for patients to detach during restlessness and handling.

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• The vascular repair was not successful post-decannulation. • The vagus nerve is injured during the process of dissociating blood vessels or cannulation.

Solution • Monitoring vital signs during cannulation. • Ensure that the patient is paralyzed and sedated before placement of the catheter. • Cannulation technique precautions: administration of an appropriate amount of heparin before cannulation, choosing proper cannula and cannulation approach, learning about the vascular status by ultrasound or angiography, using guidewire, avoiding violent catheterization, and avoiding injury to surrounding tissues. • Monitor the blood flow of the distal limb during ECMO, and place the branch catheter for distal perfusion if necessary during periphery cannulation. • Confirm the position of the cannula after cannulation by X-ray or ultrasonic examination. • Fixation of cannula and tube after cannulation; check the status of venous drainage and perfusion resistance as well as an access site. • Once the artery is injured, vascular repair and re-­ intubation are required. Once in situ re-cannulation can’t be performed, the position should be changed, and the vessels should be repaired. • Clamp the catheter during decannulation, complement blood volume, and carefully repair the blood vessels.

Hematologic Disorders Thrombosis and bleeding are frequent and challenging complications for even the most experienced of ECMO specialists and are variably associated with increased risk for mortality and morbidity [10]. Anticoagulation is necessary in most cases to prevent the circuit from clotting although no additional anticoagulants will be administered for the patients shortly after cardiovascular surgery. Generally, this is achieved with UFH. Balancing the relative risks of bleeding and thrombosis remains a major challenge because there are a number of related factors such as the patients’ underlying diseases and comorbidities, the type of ECLS, and the balance of proinflammatory and anti-inflammatory pathways [10, 11].

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Thrombosis Incidence The real-world thromboembolic complications of ECMO are unknown, and autopsy studies suggest that clinical evaluation underestimates the occurrence of thrombosis [12]. According to the ELSO Registry data 2014, clots in the oxygenator occurred in 12.9% of patients, whereas clots in the circuit were more common in patients on ECMO for cardiac support than those for respiratory support [13]. Clinical Manifestations Thrombosis can form in the vascular system or the extracorporeal circuit. Thrombosis is not commonly seen in vivo clinically, but often deposits in the extracorporeal circuit despite adequate anticoagulation. Thrombosis forms primarily at the oxygenator as well as areas where blood flow is stagnant in the circuit and may lead to dysfunction of the oxygenator and thromboembolism. Clots in the circuit and oxygenator can be monitored by visual observation. If uncontrolled cascade of thrombus formation formed in the pump head, it will present a noisy pump, severe intravascular hemolysis, and hemoglobinuria, which can impair blood pump function and induce renal failure quickly. Thrombosis can be rinsed into the systemic or pulmonary circulation resulting in pulmonary artery embolisms or stroke. In patients on VA-ECMO with little or no native cardiac function, stasis within the pulmonary circulation and chambers of the heart can lead to thrombus formation at the site of culprit lesion. Peripheral thrombus formation may result in limb ischemia or deep vein thrombosis. Mechanisms Exposure of blood to large non-endothelial surfaces of the ECMO circuit initiates the contact coagulation and fibrinolytic pathway activation, and vessel injury at insert sites or thoracotomy leads to the extrinsic pathway activation, then activates platelets, and induces inflammatory responses. Initial fibrinogen deposition and subsequent activation of coagulation factors and complement allow platelets and leucocytes to adhere to oxygenator surfaces and enhance thrombin generation. From a coagulation standpoint, certain areas of ECMO circuits remain problems. Adaptors, connectors, and access points in ECLS circuit are not pre-coated units and distort the internal diameter of the circuit, presenting a procoagulant, pro-inflammatory surface with surrounding turbulent flow and areas of stasis. These sites are prone to thrombosis.

9  Adverse Events and Complications of Extracorporeal Life Support

Thrombus can deposit in the membrane oxygenator and elsewhere in the circuit. Activation of the coagulation system is also initiated by the shear stresses of the circuit, especially from device pumps. Circulating free hemoglobin promote thrombosis in circuit failure and systemic thromboembolism. The risk of thrombus formation is increased during ECMO/ECLS therapy due to the above-described inflammatory reaction with activation of the coagulation cascade. If the patient has other thrombotic risks such as congenital antithrombin, protein C or protein S deficiency, or antiphospholipid antibodies, the risk of thrombosis may be higher. Heparin-induced thrombocytopenia (HIT) is a life-­ threatening immune response to heparin (and its derivatives) that is associated with a high risk of thromboembolic complications [14]. Since the exposure of ECMO patients to heparin is almost universal, the complication of HIT cannot be dismissed lightly [15]. The etiology of thrombosis during ECMO/ECLS therapy is due to the activation of the above inflammatory reactions with coagulation cascade, heparin resistance, and platelet activation.

Management of Thrombosis To prevent the circuit from clotting, anticoagulation is necessary. Generally, this is achieved by unfractionated heparin (UFH). UFH is the current international standard for anticoagulation during ECMO.  Activated partial thromboplastin time (aPTT), activated clotting time (ACT), anti-factor Xa (anti-Xa) levels, thromboelastography, heparin dose, and/or a combination of some or all of the above are used in different centers to monitoring of anticoagulation. The ideal strategy for monitoring anticoagulation is unknown. The Extracorporeal Life Support Organization has released a specific anticoagulation guideline [16]. Where it is used, the target of ACT suggested is generally 180–220 s. Therapeutic target of aPTT range is usually 1.5 to 2.5 times increase in baseline aPTT.  The typical target of anti-factor Xa activity range is 0.3 to 0.7 IU/mL. However, titrating the intensity of anticoagulation to prevent the ECMO circuit from clotting and prevent bleeding in the patient remains a major challenge. In addition to systemic anticoagulation, it is a more effective means to avoid this complication with bioactive coatings of circuit components using heparin, polymethoxyethyl acrylate, or phosphorylcholine to ameliorate the inflammatory and coagulation response to circuit exposure. These

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various coating techniques are adopted in different brands of ECLS equipment [17, 18]. Monitoring clot burden using daily D-dimer estimation can predict developing oxygenator failure. A sudden rise can signify the incipient failure of the oxygenator and is a predictor that a circuit change is likely within the next few days [19]. In addition to anticoagulation strategies, it is important to maintain flow through the blood circulatory system and the extracorporeal circuit wherever possible. Peripheral thrombus formation is primarily diagnosed with color Doppler ultrasonography. Computed tomography is needed to detect thrombi that have been delivered to the deep tissue in the body or into intracranial vascular branches. An ischemic stroke can be treated, for example, primarily with interventional neuroradiology via thrombectomy depending on the affected vascular segments. The treatment of confirmed or suspected HIT in patients on ECMO can be tricky. In such cases, other anticoagulants, including direct thrombin inhibitors (argatroban and bivalirudin), are usually switched. Argatroban and bivalirudin are parenteral direct thrombin inhibitors (DTIs) that have been explored successfully in patients on ECMO. Bivalirudin can be monitored using PTT, titrating 1.5 to 2 times the normal value.

Bleeding Definition and Incidence The most common complication of ECMO is bleeding. Minor bleeding is defined in terms of blood loss less than 20 mL/kg/day and one 10 mL/kg PRBC transfusion or less. Major bleeding is defined in terms of clinically overt bleeding associated with a hemoglobin (Hgb) fall of at least 2 g/dL in a 24-h period, blood loss greater than 20 mL/kg over a 24-h period, or a transfusion requirement of one or more 10 mL/kg PRBC transfusions over that same time period. Except for the amount of blood lost, bleeding that is retroperitoneal, is pulmonary, or involves the central nervous system or bleeding that requires surgical intervention is generally regarded as major bleeding [20]. Clinical Manifestations Bleeding can occur both systemically and locally, particularly at the site of peripheral cannulation. Bleeding sites may include cannula insertion sites, recent surgical incisions, vas-

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cular access sites, the lung, the gastrointestinal tract, the mouth, the nose, the thoracic cavity, the abdominal cavity, and the brain. Most often, bleeding occurs around the ECMO cannula sites or other surgical sites on the body. A greater occurrence of postoperative bleeding, particularly after thoracotomy, has been observed. Gastrointestinal bleeding occurs in the case of esophagitis, gastritis, or gastroduodenal ulcers. The most dangerous bleeding may happen in or around the brain. Massive bleeding in the brain (brain hemorrhage) is a serious medical condition accompanied by many complications, and it may also be lethal that requires prompt and suitable treatment. Pulmonary hemorrhage may cause irreversible lung damage. Management should be swift and precise to prevent fatal bleeding.

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Bleeding in patients receiving ECMO support can be catastrophic, out of proportion to the degree of coagulation abnormalities, and may occur in the absence of trauma. If significant bleeding occurs, strategies to prevent bleeding include cessation of anticoagulation as well as transfusion, antifibrinolytics, local measures, and surgical control as needed [21]. In neonatal ECMO, discontinuation of support is required once obvious intracranial hemorrhage or expansion of the original hemorrhage foci occurs [13]. In order to avoid bleeding at the catheterization sites or vascular access sites, when selecting the type of cannulation, peripheral percutaneous should be the first choice, followed by peripheral incision and finally central. Developing procedures to reduce bleeding risk, such as ultrasound-guided vascular cannulation, and ensuring that  experienced staff Mechanism perform these, can effectively prevent bleeding. Percutaneous The causes have a multifactorial genesis. The known etiolo- cannulation with the Seldinger technique is one of the effecgies of bleeding include heparin effect or overdose, coagu- tive means to avoid bleeding. Sutures should also be avoided lopathy, thrombocytopenia, platelet dysfunction, acquired as these can cause ongoing bleeding from suture sites. von Willebrand syndrome, and hyperfibrinolysis. Cannulas should be secured, and unnecessary procedures Preoperatively, impaired hepatic and renal dysfunction are that could lead to bleeding should be avoided [13]. the primary risk factors that influence the incidence of bleedFor serious local bleeding, surgical control or intervening during ECMO. In addition, the use of preoperative anti- tional radiology methods should be considered. Local comcoagulation, such as platelet inhibitors, exacerbates the pression can also be used to control bleeding, such as bleeding. insertion sites and nasal fillers. Some local hemostatic agents The ECLS circuit may result in inflammatory reaction, such as thrombin glue are also effective. In addition, antifiplatelet activation, and consumption of coagulation factors brinolytic drugs can be helpful to hemostatic. If hyperfibriand ultimately lead to disseminated intravascular coagula- nolysis is thought to be mediated by clots in the circuit, we tion (DIC), and DIC score at day 1 is associated with short-­ should change the circuit. term mortality in patients undergoing VA-ECMO after Some patients on ECMO require further surgery, such as cardiac surgery. cardiac or thoracic surgery, with a high risk of bleeding. Cannula-related bleeding may be derived from loosening Modern tip-to-tip heparin-bonded circuits make it possible or dislodging of the cannulas. Oozing hemorrhage from the to run ECMO for a prolonged time without anticoagulation. cutaneous or subcutaneous vessels is frequent phenomena. Anticoagulation in a postsurgical patient requires careful Damage to the mucosa in intensive care treatment, such as consideration; ideally, anticoagulation should not begin until placement of tracheal cannula or feeding tube, can also result postsurgical bleeding has resolved. in bleeding. Gastrointestinal bleeding occurs in the case of It is clear that both bleeding and thrombotic complicagastritis or gastroduodenal ulcers. tions are multifactorial and optimizing risk factors may improve prognosis of ECLS patients. In addition to anticoPrevention and Management agulation, these factors include device design and hemocomAchieving the optimal anticoagulation to prevent thrombosis patibility, surgical considerations, flow parameters, blood and bleeding in ECMO patients is challenging. Therefore, pressure, inflammation, and infection. the ECMO team should constantly monitor and assess for bleeding. Local bleeding, especially at the site of peripheral cannulation, is not life-threatening but requires frequent Neurologic Injury dressing changes and blood transfusions. More severe bleeding, such as pericardial tamponade, intracranial, GI tract, and Neurologic injury represents a major complication during retroperitoneal haemorrhage, can have serious conse- ECMO therapy, often with devastating outcomes. It is a leadquences  and  requires urgent and appropriate treatment in ing cause of morbidity, mortality, increased hospital stay, such critically ill patients. and cost.

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Clinical Manifestations

Mechanism

Central neurologic system adverse events in ECLS were categorized using the ELSO Registry complication code and included the following: (1) brain death, (2) seizures clinically determined, (3) seizures determined by electroencephalography, (4) cerebral infarction, and (5) intracerebral hemorrhage. The definite diagnosis of cerebral infarction or hemorrhage was determined by CT.

Neonates have the highest rates of neurologic complications on ECMO. There are several predisposing factors, including fragile vasculature, high metabolic activity, and immature cerebral autoregulation. Neonates are more susceptible to cerebral ischemia-reperfusion injury.

Incidence A recent meta-review showed acute neurologic complication in ECLS is 13% [22]. Intracranial hemorrhage (ICH) is the most frequent and dreaded neurologic complication with a median proportion of 5% [23]. Acute ischemic stroke (AIS) is not uncommon in subjects receiving ECMO support (5%) with independent risk factor being a pre-ECMO lactic acid greater than 10 mmol/L. Epileptic seizures have the lowest occurrence rate among reported ECMO complications with a median of 2% [24]. Hypoxic ischemic encephalopathy (HIE) is a serious complication in ECLS (3%–61%). HIE and brain deaths are reported in greater than 50% of the patients with neurologic complications during ECMO [25]. Risk Factors Patient factors prior to ECMO support including hypoxia, acidosis, hypotension, infection, and organ failure will further increase the likelihood of neurologic injury. Underlying diseases and ECMO itself may lead to coagulopathies and hemorrhages during support, and large cannula in the cervical vessels may disrupt cerebral circulation. In a multivariable model, age, pre-ECMO cardiac arrest, administration of inotropes on ECMO, and hypoglycemia were shown to be associated with CNS complications [23]. Recent studies indicated that neurologic complications are more frequent in VA-ECMO compared with VV-ECMO [26]. Hemorrhage is associated with female gender, duration of ventilation and ECMO, heparin, decreased serum fibrinogen, serum creatinine greater than 2.6 mg/dL, hemodialysis, and thrombocytopenia. AIS is associated with a pre-ECMO serum lactic acid level above 10 mmol/L [24]. Once on ECMO support, hemorrhage, infarction, seizures, disrupted cerebral circulation, and new-onset organ failure can further aggravate neurologic outcomes.

ICH The pathophysiology of ICH in ECMO is still uncertain. One hypothesis is a two-step mechanism in the development of ICH.  First, impairment of BBB could occur, leading to plasma and even erythrocyte extravasation. Then, disorders of hemostasis could further result in hematoma formation. ECLS and the underlying disease that cause ICH play roles in both steps [27]. Many disease-related processes such as acute respiratory failure, profound shock, and cardiac arrest break the balance between oxygen supply and oxygen demand of the brain and may disrupt the BBB [28]. Influenza and sepsis can also be involved in the initial damage to the BBB [24]. ECMO may also directly trigger the process of brain injury through the activation of coagulation, fibrinolysis, and complement pathways [13]. The ECLS circuit also induces platelet dysfunction and consumption [29]. High-­ molecular-­ weight (HMW) von Willebrand factor (vWF) multimers are crucial for primary hemostasis. Loss of HMW vWF multimer bands occurred in patients undergoing ECMO support, causing an acquired von Willebrand syndrome in as much as 79% of patients [30]. The fibrinolytic pathway may be also activated in the patients on ECLS. It tends to happen as clot builds up in the circuit, paradoxically causing bleeding in the patient. Microthrombi in the cerebral circulation may cause strokes, especially in VA-ECMO. Hemolysis may also contribute to the development of ICH by the highly deleterious release of free hemoglobin in the plasma [23]. Hyperoxemia, especially after tissue hypoxia, may cause the generation of ROS and BBB damage [31]. Finally, improper control of blood gas exchange and a large decrease in PaCO2 with ECMO initiation may cause cerebral vasoconstriction, resulting in decreased brain tissue oxygen supply. Various procedures and complications associated with the disease may also impair hemostasis. Antithrombotic medication before ECMO directly increases the risk of ICH.  Sepsis is also linked to ICH and can cause DIC, thrombocytopenia, and platelet dysfunction [32]. Other significant risk factors,

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such as renal failure and RRT, can cause platelet dysfunction and thrombocytopenia.

AIS The causes of the events are multifactorial; embolic episodes play a substantial role in AIS. These are usually attributed to (1) abnormal low flow states or areas of flow stagnation within the device, (2) thrombogenic surfaces, (3) hypercoagulable states in the body, (4) ineffective or overzealous anticoagulation therapy, or (5) thrombus within the left atrioventricular cavities. Small AIS related to microemboli of clot or air, large AIS related to major thromboembolic events triggered by coagulopathies or procoagulating effects of ECMO surfaces, both may have influence on the outcomes. A study of 517 adult patients receiving ECMO support for postcardiotomy cardiogenic shock  illustrated a linear relationship between VA-ECMO duration and thromboembolic events [33]. Besides coagulopathy caused by the patient’s underlying disease, cardioembolic events from atrial fibrillation, arterial thromboembolisms, cerebral hypoperfusion following low cardiac output, and side effects of inotropes, ECMO may directly cause AIS. Impaired cerebral autoregulation following severe and fast arterial pressure variation during ECMO initiation and secondary injury from reactive edema around focal brain injury are implicated [23].  ypoxic Ischemic Encephalopathy H HIE following cardiac arrest and/or pulmonary failure has a high mortality (−100%) [34]. Many factors may be involved in the development of hypoxic ischemic encephalopathy. A series of studies demonstrated that increased risk of decreased regional cerebral oxygen saturation is linked to rapid serum PaCO2 fluctuation following the initiation of VV-ECMO. Besides, cerebral hypoxia can occur as a consequence of desaturated blood within the aorta caused by mixing of oxygenated and deoxygenated blood or watershed. This phenomenon, known as “Harlequin syndrome,” is characterized by upper body, myocardial, and cerebral hypoxia. Mechanical ventilation should be maximized to ensure optimal arterial oxygen capacity and positive end-expiratory pressure (PEEP). Monitoring pulse oximetry and arterial blood gases via the right radial artery allows for ongoing evaluation of cerebral oxygenation. The ECMO flow rate, arterial pressure, or cannulation site and size may also have an impact on cerebral blood flow. Several studies, particularly in patients resuscitated from cardiac arrest, have shown that glycemic control may play a critical role in the occurrence of neurological complications [35]. The brain is a well-­ known glucose-dependent organ. Abnormal glucose metabolism occurs under stress, particularly after prolonged hypoperfusion such as cardiac arrest.

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Seizures Many seizures may result from cerebral hypoxia or focal brain lesions. However, detailed information is scarce on the types of seizures and the rate at which persistent seizures convert to a persistent state of seizure. As continuous electroencephalography is not a routine monitoring tool, the incidence of seizure is likely to be underestimated, as non-convulsive seizures are the majority of epileptic events in ICU populations.

Prognosis CNS complications in ECMO patients, regardless of type, are associated with dismal prognosis. Previous studies have indicated that 10–25% of ECMO patients die in-hospital with tangible proof of CNS complications. Acute neurological injury has been associated with exponential increased risk of mortality, and even survival can be accompanied by certain disabilities. This disability can manifest as motor deficits, behavior problems, diminished processing speed, and verbal, visuospatial, and working memory deficits. Long-term neurocognitive and developmental issues have also been reported. In the ELSO Registry, only 11% of patients on VA-ECMO and 26% of VV-ECMO who developed ICH survived to hospital discharge. In a large American administrative registry including both adult and pediatric VV- and VA-ECMO patients, those with ICH had worse outcomes, including significantly lower survival (40% vs. 50%, p < 0.0001), longer hospital stay (41.8 days vs. 31.9 days, p = 0.01), and higher hospitalization costs compared to those without ICH [24]. In another cohort of 65 patients on VA- and VV-ECMO, the overall in-hospital survival was only 26%. At 6 months, 59% of the survivors had an acceptable neurological outcome, defined as Glasgow Outcome Scale of 4 or 5 [36]. The better prognosis can be explained as the management prompted by the early diagnosis and timely treatment.

Prevention Clinicians should consider and assess both patient- and disease-­related factors associated with neurological injury prior to ECMO initiation. In order to prevent ICH in high-­ risk patients, it would be reasonable to use an initial heparin dosing in the lower end of the 50–100 units/kg range recommended by ELSO [13]. As thrombocytopenia is an independent risk factor for ICH, it may be better to maintain platelet counts above the relative transfusion threshold of 50,000 platelets/μL recommended by the ELSO Registry to prevent

9  Adverse Events and Complications of Extracorporeal Life Support

ICH [37]. It is important to optimize the speed setting of blood pump to reduce shear force and decrease its harmful effects on red blood cells, platelets, and HMW vWF multimers [13]. Strategies to prevent the incidence of AIS should be considered. One should avoid cannulation of atheromatous arteries in VA-ECMO. After initiation of ECMO, the position of the cannulation should be confirmed by ultrasound or X-ray, and the local blood flow status should be evaluated. For patients who have poor perfusion of brain tissue, adjust the cannulation position or establish additional perfusion or drainage channels in time. Repair the blood vessel as much as possible when the neck vessel is removed. Avoiding rapid shifts in PaCO2 upon ECMO initiation by using very low initial sweep gas flows may help reduce harmful cerebral vasoconstriction. Some scholars suggest that targeting a PaO2 between 60 and 100 mmHg may help prevent the harmful effects of both hypoxemia and hyperoxemia. One should maintain adequate anticoagulation to prevent circuit clots. To decrease cerebral embolism, we should avoid a large number of air bolts in ECMO system and ECMO system thrombus shedding, especially at the membrane-lung outlet. Computed tomography is the main imaging modality for acute neurological assessment of the suspicious cases. Methods for neuromonitoring are limited, although cerebral near-infrared spectroscopy is useful to assess oxygen delivery to the brain [38], and it is very limited to guide the management of specific complications such as intracranial hemorrhage. Early CT-brain screening, although not preventing the occurrence of ICH, allows affected patients to be diagnosed and treated as soon as possible to improve the prognosis. Prompt diagnosis can help initiate measures to limit hematoma expansion, such as withholding anticoagulation [28]. It is important to perform daily neurological assessments since patients wean from sedation and neuromuscular blockers to avoid drug accumulation and to recognize neurological deficits earlier. Early recognition of neurological deficits may allow timely treatment adaptions to prevent further progression of secondary neurological injuries. Anti-seizure medication should  be start  to terminate seizures and status epilepticus before glutamatergic cytotoxic effects lead to neuronal damage. Targeting recommended blood pressure control in patients with ischemic strokes can provide optimal perfusion of penumbras, thereby preventing the emergence of progressive strokes. If pathological signs of unclear causes

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appear, cranial CT has an important role to reveal or exclude severe structural intracranial complications and should be carried out actively.

Management Cerebral bleeding, thrombus, or air emboli can contribute to the development of neurologic adverse events and should be managed proactively to minimize its devastating impact. For patients with central nervous system injury, corresponding treatment is required according to the type and degree of injury, including adjustment of coagulation function, anti-­ epilepsy, brain tissue dehydration, ultrafiltration, diuresis, catheter drainage, etc. Hyperbaric oxygen therapy should be performed as soon as possible. Once it’s a confirmed diagnosis of ICH, alternative treatment strategies are needed to save patients’ lives. Standard neuroprotective measures should be initiated as soon as possible. Hypertension should be managed conservatively. Neurosurgery should be invited for consultation and targeted treatment, although surgical interventions have been associated with 75–80% mortality in these patients. If the prognosis is reasonable, weaning from ECMO should be considered because this greatly facilitates the management of ICH.  If this is not possible, one should consider withholding anticoagulation and weigh carefully against the risk of circuit thrombosis. Hemoglobin, platelets, international normalized ratio (INR), and fibrinogen should be corrected according to the neurosurgical consultation. A deficit in AT3 is common in ECMO patients, resulting in heparin resistance. Thus, fresh frozen plasma (FFP) administration could increase the anticoagulation effect of heparin [39]. Some authors recommend administration of platelets regardless of the platelet count because of possible platelet dysfunction [40]. Strategies should be taken to achieve proper support blood flow, stable arterial blood pressure, and adequate oxygenation. Sufficient sedation can reduce the oxygen consumption of brain tissues, the occurrence of agitation, and epilepsy during ECMO. If a severe brain injury is shown before ECMO, ECMO should not be used. Patients with the severely damaged central nervous system during ECMO, such as patients with obvious cerebral hemorrhage or significant expansion of the

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original hemorrhage, or patients whose clinical and physical examination showed irreversible damage to brain tissue or even brain death should give up ECMO support.

hand, ECMO provides support for the heart and lung; on the other hand, ECMO may also lead to circulatory complications [44].

Circulatory Complications

Harlequin Syndrome

LV Dilation Complications

Harlequin syndrome is a known peripheral VA-ECMO complication in which the differential oxygen saturations are observed between the upper and lower parts of the body [45]. This occurs when the native heart function recovered whereas the respiratory function is still compromised. LV ejects inadequately oxygenated blood from the lungs. Forward deoxygenated blood from failing native lungs in the ascending aorta mixes with retrograde flow from the oxygenator, which can result in the inadequate delivery of oxygenated blood into the upper part of the body, such as coronary artery and aortic arch. The upper body and brain hypoxia may cause cyanosis of the upper body, while the lower body appears pink. The specific level of demarcation depends on the ratio of left ventricular output to retrograde perfusion from peripheral ECLS blood flow. Saturation monitoring for Harlequin syndrome is performed at the right hand, forehead, nose, or right ear, and arterial blood gas should be obtained from a right arm arterial line. Therapeutic options include repositioning the arterial cannula into the right subclavian artery or aorta, and converting to central VA-ECMO. It can also be solved by converting the system into a VA-V setting [46].

LV dilatation is a complication unique to VA-ECMO. One of the biggest problems with VA-ECMO is the effect of retrograde flow toward the LV in the aorta. In some patients, this phenomenon leads to an increase in LV afterload, which ultimately results in the deterioration of LV function. Finally, the left ventricle dilates, myocardial perfusion decreases, left atrial (LA) pressures increase, and pulmonary edema develops. Due to the lack of a unified definition, LV dilatation has not been well documented or reported. Increased LV afterload combined with depressed LV contractility will cause atrioventricular valve (AV) opening impairment, which leads to blood stagnation in the LV, increasing the risk of thrombus formation, and, ultimately, CVA or AMI. It is essential to monitor and achieve clinically acceptable LV unloading in VA-ECMO patients. The use of a hemodynamic catheter is crucial in assessing volume status and filling pressure, and the overall goal is to reduce volume overload, which can sometimes be achieved through the use of noninvasive methods such as vasodilators or contractile drugs, high-dose diuretics, or hemofiltration. Large-size ECMO catheter should be considered if placed peripherally; however, this can be self-limiting for this type of approach, and the central cannulation may be a better choice as needed. If conservative treatment is insufficient, other approaches to assist with volume reduction may be considered, including placement of left atrial or left ventricular venting catheters, atrial septostomy, transaortic catheter venting, transpulmonary artery drainage, and indirect left ventricular ventilation via IABP, TandemHeart, or Impella. LVD is caused by a weakened ventricular pumping against an increased blood flow produced by VA-ECMO. Truby et al. reported that 9 patients (7%) developed clinical LVD requiring immediate decompression and 27 patients (22%) met the definition of subclinical LVD [41]. Subclinical LVD was described as pulmonary artery diastolic pressure greater than 25 mmHg and radiographic evidence of pulmonary edema, whereas clinical LVD required decompression immediately. Many studies have attempted to unload LVD by using concurrent IABP and Impella as a mechanism for left ventricular offloading, thereby improving overall prognosis [42, 43]. Patients with ECMO may have preoperative myocardial hypoxia and/or significant cardiac dysfunction. On the one

Pulmonary Complication Clinical Manifestations • • • • • •

Pneumothorax, hemothorax, and hemopneumothorax Pulmonary edema and lung consolidation Pulmonary hemorrhage Atelectasis Pulmonary infection Pulmonary fibrosis

Pulmonary complications not only lead to further respiratory dysfunction but also have a negative impact on the recovery of cardiopulmonary function and prolong the support time of ECMO [47].

Causes • Lung tissue was injured during ECMO cannulation or puncture. • Barotrauma resulting from high ventilator pressure.

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• Left to right shunt: neonatal patent ductus arteriosus, VA-­ ECMO continuous left to right shunt through the patent ductus arteriosus, and increased pulmonary blood flow, resulting in pulmonary edema. • Overload of volume, left ventricular dysfunction, and excessive left atrial pressure. • Since ischemia or hypoxia before ECMO, reperfusion or reoxygenation injury of lung tissue occurred after ECMO initiation, which leads to pulmonary capillary leakage and pulmonary edema [48]. • Deposition of sputum or bleeding in the trachea or bronchi due to long-time use of mechanical ventilation results in atelectasis and pulmonary infection. • Poor chest drainage may lead to atelectasis; pulmonary hemorrhage may cause lung consolidation. • The contact between blood and the abiotic surface of the ECMO system leads to a systemic inflammatory response, impairment of the function and structure of the pulmonary capillaries, presenting inflammatory exudation, pulmonary edema, pulmonary hemorrhage, and further pulmonary infection [48]. • Massive infusion of bank blood [49].

Solution • Careful operation to avoid injury to lung tissue during puncture. • Reduce ventilation parameters setting and set protective ventilation strategy during ECMO [50]. • If systemic circulation perfusion is influenced by PDA, ligation is needed. • Avoid volume overload. • Maintain normal range of COP to avoid the lung edema. • Reduce blood loss and unnecessary transfusions. • Patients with pneumothorax, hemothorax, and hemopneumothorax need immediate thoracic puncture tube drainage and the elimination of the causes. • Aspirate sputum and remove bronchial secretions timely. • In patients with circulatory assistance, awake support and spontaneous breathing can reduce pulmonary complications. • If  intrathoracic hemorrhage does not be minimized despite anticoagulation reduction  and clotting factor administration, thoracotomy should be  performed  promptly  to remove  blood clots and hematoma, and careful surgical hemostasis should be carried out. • Avoid iatrogenic infection by aseptic operation and sensitive antibiotic treatment.

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Acute Kidney Injury Acute kidney injury (AKI) is the most frequent complication in patients with ECMO and can occur before and after ECMO initiation. A meta-analysis which enrolled 41 cohort studies with a total of 10,282 adult patients receiving ECMO showed the incidences of AKI (using standard AKI definitions) and severe AKI requiring RRT were 62.8% (95%CI: 52.1%–72.4%) and 44.9% (95%CI: 40.8%–49.0%), respectively [51].

Definitions of ECMO-Associated Kidney Injury AKI is defined as an abrupt (within hours) decrease in kidney function, characterized by an abrupt loss in renal excretory function leading to the retention of nitrogenous waste products and dysregulation of extracellular volume and electrolytes. The RIFLE (risk, injury, failure, loss, and end stage) criteria and the revised Acute Kidney Injury Network (AKIN) criteria are now commonly used and well established for the definition and classification. Furthermore, these definitions have been consolidated into the KDIGO Clinical Practice Guidelines for AKI Definition. RIFLE and AKIN have been validated in various population settings, including patients on ECMO [49].

Risk Factors Important AKI risk factors among patients requiring ECMO include older age, elevated lactate levels before ECMO initiation, high dose of inotropic drugs, severely reduced left ventricular ejection fraction, cirrhosis, postcardiotomy shock as an indication for ECMO, and finally ECMO pump speed and its duration [52]. The type of ECMO may also affect AKI risk, and a higher incidence of AKI among patients requiring VA-ECMO (60.8%) than those requiring VV-ECMO (45.7%) has been demonstrated [50].

 athophysiology of ECMO-Associated Kidney P Injury It is clear that the pathophysiological features of AKI during ECLS are complex and multifactorial, including contributing factors such as profiles of patient (primary disease progression, altered hemodynamics, low cardiac output

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syndrome, new-onset sepsis, ischemia-reperfusion injury), drug toxic factors (nephrotoxic agents), management of patient (high intrathoracic pressures, fluid overload), inflammatory mediators (release of pro-inflammatory mediators and oxidative stress), hematological factors (hemolysis and hemoglobin-­ induced renal injury), and coagulation management (hypercoagulable state resulting in renal macro-/microcirculatory dysfunction and renal microembolisms) [52]. The artificial ECMO interface leads to a hypercoagulable state, which may result in the formation of microemboli and microthrombi within renal vasculature. It may cause renal parenchyma obstruction and precipitate AKI.  These processes occur within the pre-ECMO, ECMO, and post-ECMO setting and may be prevented or exacerbated by ECMO initiation. In VA-ECMO, there is a mixture of pulsatile arterial flow from the native heart and non-pulsatile arterial flow from the ECMO pump. Plus, patients treated with VV-ECMO with respiratory failure often have prolonged hypercapnia. This induces significantly altered hemodynamics and renal blood flow which may further exacerbate renal injury. In special cases, raised intrathoracic pressure secondary to high positive end-expiratory pressure (PEEP) on ECMO may induce renal hypoperfusion and impair the kidney’s excretory function.

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patients, CRRT can be provided via an integrated approach or independently via parallel systems [50]. The administration of intravenous haptoglobin has shown prophylactic and therapeutic benefits in AKI, mitigating the detrimental effect of hemolysis on renal function. Novel treatment strategies that prevent thrombosis partly by preserving glycocalyx integrity, such as soluble thrombomodulin (sTM) and activated protein C, are being investigated in the setting of sepsis-associated AKI; however, the efficacy in AKI has not been validated in large populations.

Vascular Complications Most adult patients received ECMO are cannulated via femoral artery and vein since the accessibility of the vessels. Access to the femoral vessel may cause serious vascular complications, including inadequate perfusion of the distal arterial cannula, limb ischemia, thromboembolic complications, retroperitoneal bleeding, anatomy, pseudoaneurysm, and groin infection.

Limb Ischemia

Prevalence and Definition Limb ischemia is a common complication in patients with VA-ECMO. Peripheral artery disease is an independent risk Prevention and Management factor of limb ischemia in patients with VA-ECMO via femoral artery catheterization, with reported occurrence rates of Prevention and early identification of AKI among patients at 17% in adult VA-ECMO patients [53]. Limb ischemia is risk of AKI could potentially play a crucial role in improved defined as loss of pulses or Doppler signals and arterial outcomes. Timely initiation of ECMO may mitigate pre-­ thrombus requiring thrombectomy or surgical intervention. ECMO risk factors for organ dysfunction. Diagnosis of acute limb ischemia includes physical examiImprovements in ECMO device design have led to less nation demonstrating ischemia, including pain, pallor, poikithrombus formation and an enhanced ability of the circuit to lothermia, gangrene, motor or sensor deficit, and loss of trap larger emboli. pedal Doppler signals. Recent studies have shown that pulsatile flow may provide beneficial effects over non-pulsatile flow, especially Mechanism protective effects on microcirculation and renal perfusion. The mechanism of limb ischemia is most often arterial Pulsatile mode in ECLS has been pre-programmed in some thrombus or interruption of flow in the distal perfusion artery specific ECLS instruments. in patients with VA-ECMO via femoral artery catheterizaTo prevent hemolysis-mediated kidney injury, it is sug- tion. Thromboembolic complications are responsible for gested to optimize pump revolutions/min (RPM) to safe lev- most limb complications associated with femoral arterial els in order to avoid excessive negative pressures generated cannulation. To some degree, difficult cannulation was prewithin the pump. dictive of future limb ischemia while on VA-ECMO.  The Fluid overload is the most common phenomena during risk of arterial vascular occlusion with an increase in apposithe initiation of ECMO, and continuous renal replacement tional thrombus formation, particularly arising from existing therapy (CRRT) is often required for patients with severe arteriosclerosis, is increased. AKI. The optimal timing for initiation of CRRT should be There is wide variability in the incidence of limb ischemia individualized based on the degree of fluid overload and in patients receiving VA-ECMO. This is mainly influenced severity of AKI-related metabolic derangements but not by the disease processing needing VA-ECMO support, canplasma creatinine levels as the sole indicator. In ECMO nulation techniques, definition of limb ischemia, caliber of

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the femoral blood vessels, and the use of distal perfusion cannula or not. Smaller vessel diameter and large pannus covering the groin are risk factors of vascular complications on VA-ECMO.  Large-bore cannula is inserted in the common femoral artery that may compromise blood flow to the ipsilateral limb that is already most likely hypoperfused. This impeded circulation can cause lower limb ischemia and compartment syndrome that without prompt intervention may lead to amputation. Those requiring high-dose vasopressors are also at risk for compromised circulation and peripheral spotted phenomenon. Rhabdomyolysis due to limb ischemia may lead to acute renal failure and can result in life-threatening complications.

Prevention Critical unrecognized or untreated limb ischemia may lead to gangrene and tissue loss, ultimately requiring amputation. ICU nursing, physician extenders, and physicians should be all trained to perform daily detailed physical examinations on these patients to identify limb ischemia earlier. Ultrasound findings and clinical judgment are usually used to estimate vessel size and guide cannula selection. It will be helpful to prevent limb ischemia by the suitable catheter selection and skilled intubation technique. Placement of a distal arterial perfusion catheter (DPC) has been demonstrated in all series to prevent or reverse limb ischemia after cannulation in both adult and pediatric patients. DPC should be placed to provide antegrade flow to the distal superficial femoral artery (SFA) and distal limb. The DPC is performed with either a 5 or 7 French catheter depending on the patient’s size and vessel diameter [54]. At the time of decannulation, open repair of the femoral arteriotomy, with or without patch angioplasty, can avoid arterial stenosis and long-term postoperative complications of arterial catheterization. Some centers recommended to establish VA-ECMO with subclavian or axillary artery cannulation to reduce the risk of lower limb ischemia. However, this application has its own set of inherent risks, including upper extremity edema and inability to achieve high flow rates, and needs skilled intubation technique. Some centers have reported experience with the effective use of near-infrared spectroscopy (NIRS) to monitor the amount of oxygenated blood circulating to the lower extremities in addition to physical examination. Baseline NIRS of peripheral capillary oxygen saturation (SpO2) greater than 40 to 50 has been demonstrated in the literature to correlate with good limb perfusion. Any decline in baseline NIRS or NIRS SpO2 less than 40 suggests suspected limb ischemia, and prompt further differential diagnosis is required [55]. Therapeutic anticoagulation during cannulation and while on the VA-ECMO may help prevent ischemia.

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Treatment Management of early arterial vascular complications depends on the etiology and degree of ischemia. Once limb ischemia occurs, it is important to correct underlying cause and restore blood circulation in the ischemic limb. Limb ischemia after decannulation may occur related to arterial stenosis from preexisting peripheral arterial disease or arteriotomy closure. If thromboembolic complications occur at the time of decannulation or in the perioperative period, a thrombectomy as well as endovascular methods including balloon angioplasty or stenting can be performed. Additionally, open reconstruction of the femoral vessels with endarterectomy and patch angioplasty or femoral-femoral bypass grafting may definitely restore blood flow to the affected vessels. In particular, limb revascularization with a distal perfusion catheter after acute limb ischemia may lead to reperfusion injury, ­including lower extremity compartment syndrome. In patients with irrecoverable limb ischemia, aggressive treatment is needed, and amputation may be required in some patients. Following this strict protocol, most patients can avoid serious limb ischemia complications without the need for amputation and preservation of a functional limb.

Vessel Damage Clinical Manifestations In addition to ischemia, other vascular complications may occur at the time of cannulation, including pseudoaneurysm formation, dissection, or most seriously development of retroperitoneal bleed. These complications typically occur at the time of cannulation, with increased risk when cannulation is difficult [56, 57]. Clinical manifestations of pseudoaneurysm can be manifested as bruising of groin involved, a palpable bulge, or new thigh numbness. Presentation of dissection can be variable, from asymptomatic to absence of flow and disappearance of arterial blood pressure following initiation of ECMO. Retroperitoneal bleed may present with flank pain and an unexplained decline in hemoglobin, which often can be associated with oliguria, all signs of major bleeding. Computerized tomographic arteriography is the gold standard imaging test to evaluate all of these complications. Etiological Factor Although vessels are often easily accessible, the diameter of blood vessels varies greatly, and they are usually not directly visualized during percutaneous cannulation. Small vessel size and difficulty with cannulation, including large pannus covering the groin, are risk factors leading to vascular complications while placing patients on ECMO. As such, vascular access is not always smooth, particularly in morbidly

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obese patients or patients with peripheral vascular disease. Given these factors, peripheral femoral cannulation is prone to vascular complications related to ECMO.

Prevention Each arterial and venous cannula has its specific flow pressure curve based on the specifications of different brands of cannula. The larger cannula promises larger flow rates in the in vitro situation. ECMO flow is recommended to achieve a goal cardiac index greater than 2.2 L/(m2.min) or less. If the vessels are known to be small or cannulation is difficult related to small vessel caliber, a smaller cannula may be chosen to avoid catastrophic vascular injury, or alternative intubation sites may be considered. Double-lumen bicaval cannula (Avalon cannula) for VV-ECMO has the following advantages: (1) single-site cannulation, (2) excellent flow characteristics and kink protected, (3) avoidance of femoral cannulation, and (4) decreased risk of recirculation. Limitations of the Avalon cannula include its ridged design and limited cannula options via the right internal jugular vein (RIJV) [58]. Care must be taken during placement of the Avalon cannula via the RIJV to prevent wire or cannula migration into or through the right ventricle. In particular, echo can assist with the correct placement of the guidewire into the IVC (as opposed to the hepatic vein). Ensuring cannula position in the IVC prevents the inadvertent migration of the cannula into the right ventricle or more serious right ventricle perforation resulting in pericardial tamponade. Prevention of the complications of limb ischemia is based upon prompt diagnosis. When positioning the ECLS cannulas, local puncture-related complications can typically be diagnosed bedside via ultrasound. Projection radiography including both chest X-rays and plain films of the abdomen is used to ensure that the cannulas are in the correct position if the need arises. A combination of approaches should be used to minimize the incidence of access site complications (pseudoaneurysm, dissection, and retroperitoneal bleed). Careful cannula placement with ultrasound guidance is the gold standard for peripheral femoral intubation [57]. Treatment To prevent vascular complications following ECLS, arterial reconstruction with thromboendarterectomy and patch reconstruction can be performed at the time of ECMO explantation for patients with peripheral vascular disease [59]. Once diagnosis of pseudoaneurysm, dissection, or retroperitoneal bleed is confirmed, the choice of conservative management and surgical intervention needs to be weighed and balanced. Pseudoaneurysms at the cannula site can be repaired at the time of decannulation with an open arteriotomy repair. Dissections can be either observed conserva-

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tively or stented at the vascular site involved. In the event that the dissection is symptomatic and ECMO is still needed, new alternative arterial catheterization site and method are required. The patient with retroperitoneal bleeding may be managed conservatively with blood product transfusion and temporary discontinuation of anticoagulation and transition to a P2Y12 inhibitor infusion when blood loss is small and the patient is hemodynamically stable. A drainage tube may be installed retroperitoneally for drainage. Temporary discontinuation of anticoagulation is of primary importance. Abdominal imaging is necessary to confirm the diagnosis, and exploratory laparotomy is necessary to control bleeding in some cases. A previously placed inferior vena cava (IVC) filter may cause venous injury at the time of venous cannulation; thus, fluoroscopy is necessary, and removal of the filter may be necessary to place the venous cannula.

Infection Infection is one of the most common complications of ECMO and occurs either systemically or locally (i.e., at the cannula insertion site) with potential or definite threat to patient survival and quality of life. The rate of nosocomial infections, with a reported incidence ranging from 8 to 64%, is more frequent than  in other critically ill patients. These account for bloodstream or peripherally inserted cannula infections and ventilator-associated pneumonia. Nosocomial infection will prolong the duration of ECMO run, the incidence of other complications, and the duration of mechanical ventilation [60]. The most likely infectious complications of VA-ECMO are bacteremia and sepsis. Prevalence of infection increased with duration of ECMO support. Rates were highest in the adult vs. the pediatric and neonatal populations (30.6 vs. 20.8 vs. 10.1 infections per 1000 ECMO days, respectively) and in those necessitating extracorporeal cardiopulmonary resuscitation (24.7 infections per 1000 ECMO days). Those with an infection acquired during ECMO support had a higher prevalence of death, and overall mortality reaches 60%. Strict aseptic technique during cannulation and adjustment of patients’ immune status are of paramount importance, especially considering the urgent or emergent nature of the procedure.

Clinical Manifestations Access Site Infection  Access site infection is a common complication in ECMO, with incidence ranging from 3.5 to 17.7%. This may represent an underestimate, as most studies sum up all access site-related complications together, which include bleeding, infection, and vascular injury [61]. Many

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centers utilize prophylactic antibiotics to reduce the risk of both CRI and other nosocomial infections.

Sepsis and Bacteremia  The prevalence of bloodstream infection during ECMO ranges from 3 to 18% [60]. Sepsis and bacteremia cannot always be ascribed exclusively to ECLS, as patients on ECLS have a multitude of potential sources of infection including mechanical ventilation, venous and arterial catheterization, urinary catheterization, additional surgical intervention, and impairing immunity. Sepsis-induced cardiomyopathy (SICM), or sepsis-induced myocardial dysfunction (SIMD), is an increasingly recognized form of transient cardiac dysfunction in the septic patients. In addition, patients with sepsis often have acute respiratory distress syndrome that might necessitate VV-ECMO support for poor respiratory mechanics. However, there was no clear correlation between infections, ECMO therapy, and outcome. The pathophysiological course needs careful definition to reveal causal relationships.

Risk Factors The high prevalence of infections on ECMO is multifactorial. Patients treated with ECMO are at risk for acquired infection due to underlying patient characteristics and the extracorporeal circuit itself. ECMO patients are at high risk for invasive candidiasis since they are critically ill. In addition to blood exposure to the ECMO circuit, they often  received mechanical ventilation support, prolonged length of ICU stay, exposed to broad-spectrum antibiotics and steroids, cannulated with multiple central lines, and fed via parenteral nutrition. In cardiac patients, an open chest, transthoracic cannulation and increased bleeding and clot formation all contribute to increased infection risk. Analysis of ELSO infection data has shown the following risk factors for a cumulative number of infection adverse events: predisposing to infections, chronic immunosuppressive therapy, greater severity illness before cannulation (i.e., higher SOFA score), the duration of the ECMO run, imperfect circuit configuration, and cannulation technique.

Etiology of Infection A brief consideration of the microbiology of device infection is important to understand how these infections occur, how to prevent them, how to manage them, and how to develop rationally new therapies to prevent or eradicate infections. According to the ELSO Registry, coagulase-negative staphylococci are the most frequent causative pathogens of bloodstream infection (BSI) during ECMO, followed

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by Candida spp., Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. Colonization of ECMO cannulas and oxygenators could have a role in causing bloodstream infections. Enterobacteriaceae are the most frequent agents of ventilator-associated pneumonia in this setting [61].

Preventive Practices Standard aseptic technique and the rational use of antibiotics can prevent and control multi-site hospital infection. Preoperative cleansing of the patient’s skin with antimicrobial substances may decrease the microbial burden at the arteriovenous puncture and intubation site. Despite all of these basic measures, some inoculation of bacteria into the surgical wound and onto the exterior surface of the cannula is inevitable. Consistent stabilization of the cannula to minimize or avoid any pulling or twisting of the circuit and ­periodically disinfecting the puncture site and exchange of dressing, all of these procedures are essential to prevent latent infections of the percutaneous cannula site. The optimal management for the percutaneous site has not yet been defined but probably involves periodic cleaning to remove clots and destroy microbes followed by a dry dressing to minimize contamination. Some strategies have been endorsed by scholars to help identify impending nosocomial infections early as follows: (I) routine cultures of blood samples, secretions, and excreta should be performed regularly and (II) empiric antibiotic use; however, ECLS specialists should be vigilant about the risk for developing multi-drug-resistant organisms and ready for adoption of upgraded combination of antibiotics prior to initiating antibiotic prophylaxis [62, 63]. Wound and blood cultures are used to guide antimicrobial therapy and are prescribed in consultation with infectious disease experts. The risk of sepsis progressing to multisystem organ failure is a major concern, which justifies the present clinical practice for early initiation of antibiotic therapy.

Hemolysis Almost all patients who support with ECMO have some degree of hemolysis.

Diagnosis and Clinical Manifestations Hemolysis is the lysis of red blood cells and subsequent release of hemoglobin into the plasma, which can be measured by increased plasma free hemoglobin (PFH) concentration. The ELSO Registry defines hemolysis as PFHb > 0.5 g/L

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accompanied by clinical signs of hemolysis during ECMO support such as anemia, hyperbilirubinemia, and increased lactate dehydrogenase. Hemoglobinuria can be found once hemolysis is severe. Because PFHb is cytotoxic in the plasma, it may cause endothelial dysfunction and depletion of nitric oxide leading to vasoconstriction. Hemolysis results in an increase of bilirubin production. Hyperbilirubinemia can cause inflammation, apoptosis, and oxidative stress, which ultimately causes thrombocytopenia. Therefore, hemolysis is associated with significant complications including thrombotic events, renal failure, need for renal replacement, multiorgan failure, and mortality [64].

with a mismatch between blood flow and cannula size used [65, 66]. As blood flows through a  smaller-caliber cannulas, pump head thrombosis also produces more shear stress. In addition to the different fluid dynamics of ECMO, the blood biocompatibility of various materials has an effect on the resistance of thrombogenic deposits and hemolysis.

Circuit-Related Factors Increased shear stress can lead to red blood cell damage. Hemolysis is related to the design of the ECMO pump and circuit that is associated with the shear stress of pumps and high resistance through the oxygenator. These high shear regions vary between pumps and oxygenators but are usually beyond the physiologic range. Centrifugal pumps can generate high negative pressures if the blood flow inlet is obstructed or hypovolemia occurs. The negative pressure will cause a suction effect inevitably, with cavitation of blood inside the blood pump causing significant blood trauma and hemolysis. This can be manifest as kicking or chattering in the lines and falling pump outputs. This problem can become worse by increasing the pump rate in a misguided attempt. High pump speed produces higher shear force related to hemolysis. Hemolysis can occur with high shear stress conditions associated

Due to the risk of hemolysis during ECMO, daily routine fHb monitoring is recommended in all patients. It can be helpful to detect problems at early stage and elucidate the cause of hemolysis. In recent years, new technically optimized ECMO systems have been developed. Optimised pump design, integrated circuit configuration, low-resistance and plasma-tight oxygenators made of polymethylpentene, and surface coating of all compartments reduce the need for systemic anticoagulation and improve biocompatibility. The latest ECLS circuits are safe and generally do not cause significant hemolysis during long-term use. Selecting the  appropriate ECMO circuit and cannula adapted blood flow and setting optimal pump speed and flow rate can be helpful to prevent blood cell damage base on the patient's condition, size, diagnosis, and expected duration of use.

 CMO Set-Up and Management Factors E Insufficient anticoagulation during ECMO can lead to hemolysis. Pump head thrombosis was the most severe form of ECMO-induced hemolysis. Once thrombus forms inside of pump head, it is not only a threat of embolization, but a mechanical threat to the pump because of abnormal bearing Mechanisms wear. The slightest clot on an impeller blade may disrupt the delicate magnetic balance. It creates turbulent flow and Hemolysis in ECMO is multifactorial, including circuit-­ extreme shear stress, which directly injure the blood cells related factors (type of pump and oxygenator, pressure, and lead to hemolysis. pump speed, cavitation, clot), ECMO set-up and managePatients requiring ECMO support following cardiac surment factors (cannulation strategies, anticoagulation), and gery often presented hemolysis due to previous cardiopulpatient-related factors (neonatal). Once PFHb increased monary bypass. The  use of any form of inline CRRT is obviously, it reveals that there is an underlying circuit or associated with higher fPFH levels. These therapies contribpatient problem leading to the hemolysis. ute to hemolysis by diverting blood flow away from the ECMO circuit, thereby providing additional areas of turbuPatient-Related Factors lent flow or increasing red cell destruction by mechanical Heidi JD and colleagues reported lower body weight was an stresses within the CRRT system. independent predictor of hemolysis in neonate [65]. The Both increased risk of hemorrhage and RBC transfusion mechanism may be associated with higher fetal red blood have been reported to be accompanied by higher levels of cells which are more susceptible to mechanical stress. Higher plasma fHb [58, 67]. This may be due to either the release of hemoglobin levels increase blood viscosity and result in fHb from hematoma or faster destruction of transfused more red cell damage as blood traverses the ECMO pump erythrocytes. head and oxygenator; it is a stronger predictor of hemolysis [64]. Hypovolemia may generate excessive negative pressure in the circuit resulting in cavitation and hemolysis. Management and Prevention

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The optimal hemoglobin level during ECMO is individualized. Some studies focused on transfusion thresholds that may improve rates of hemolysis and mortality. Whenever excessive negative pressure of the circuit is detected, the correct approach is to decrease pump speed while dealing with the issue leading to access insufficiency. A rotating clot in the pump head will cause excessive shear forces and mechanical destruction of erythrocytes. The treatment is circuit exchange with ongoing adequate anticoagulation. Exchange of the pump head will often normalize fHb within 2 days. Higher heparin infusion doses usually achieve better anticoagulation, which will help to prevent thrombus forming in the circuit. If platelets fall in parallel, heparin-induced thrombocytopenia must be ruled out; a change of anticoagulation is advisable until receipt of laboratory values. Improved anticoagulation is contributed to hemolysis preventing. The success of ECMO depends largely on the understanding and management of related complications. When the circulatory and respiratory functions are improved enough, ECMO support should be removed in time to reduce the incidence of complications.

References 1. ECLS registry report. International summary. January, 2019. 2. Bille LS, Lisa W. ECMO specialist training manual. 3rd ed. Ann Arbor, MI: Extracorporeal Life Support Organization; 2010. 3. Brogan TV, Laurance L, Robert L, Graeme M, Gile P. Extracorporeal life support: the ELSO red book. 5th ed. Ann Arbor, MI: Extracorporeal Life Support Organization; 2017. 4. Lamb KM, Hirose H.  Vascular complications in extracorporeal membrane oxygenation. Crit Care Clin. 2017;33(4):813–24. 5. Sorokin V, MacLaren G, Vidanapathirana PC, Delnoij T, Lorusso R.  Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the potential dynamic process of organ support and importance of hybrid modes. Eur J Heart Fail. 2017;19(Suppl 2):75–83. 6. Jacobs JP, Goldman AP, Cullen S, et  al. Carotid artery pseudoaneurysm as a complication of ECMO.  Ann Vasc Surg. 1997;11(6):630–3. 7. Akin S, Caliskan K, Soliman O, et al. A novel mortality risk score predicting intensive care mortality in cardiogenic shock patients treated with veno-arterial extracorporeal membrane oxygenation. J Crit Care. 2020;55:35–41. 8. Schrutka L, Rohmann F, Binder C, et al. Discriminatory power of scoring systems for outcome prediction in patients with extracorporeal membrane oxygenation following cardiovascular surgery†. Eur J Cardiothorac Surg. 2019;56(3):534–40. 9. Muller G, Flecher E, Lebreton G, et al. The ENCOURAGE mortality risk score and analysis of long-term outcomes after VA-ECMO for acute myocardial infarction with cardiogenic shock. Intensive Care Med. 2016;42(3):370–8. 10. Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost. 2018;44(1):20–9.

133 11. Winkler AM. Managing the precarious hemostatic balance during extracorporeal life support: implications for coagulation laboratories. Semin Thromb Hemost. 2017;43(3):291–9. 12. Rastan AJ, Lachmann N, Walther T, et  al. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int J Artif Organs. 2006;29(12):1121–31. 13. Murphy DA, Hockings LE, Andrews RK, et  al. Extracorporeal membrane oxygenation-hemostatic complications. Transfus Med Rev. 2015;29(2):90–101. 14. Cuker A.  Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost. 2014;40(1):106–14. 15. Lee GM, Arepally GM.  Heparin-induced thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2013;2013:668–74. 16. ELSO Registry. ELSO anticoagulation guidelines; 2014. p. 1–17. 17. Hohlfelder B, Kelly D, Hoang M, et  al. Activated clotting times demonstrate weak correlation with heparin dosing in adult extracorporeal membrane oxygenation [published online ahead of print, 2019 Nov 29]. Am J Ther. 2019;29(4):e385. https://doi. org/10.1097/MJT.0000000000001113. 18. Colman E, Yin EB, Laine G, et al. Evaluation of a heparin monitoring protocol for extracorporeal membrane oxygenation and review of the literature. J Thorac Dis. 2019;11(8):3325–35. 19. Lubnow M, Philipp A, Dornia C, et al. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation. J Crit Care. 2014;29(3):473.e1–473.e4735. 20. Lequier L, Annich G, Al-Ibrahim O, et al. Extracorporeal life support organization (ELSO) Anticoagulation guideline; 2014. https:// www.elso.org/portals/0/files/elsoanticoagulationguideline8-­2014-­ table-­contents.pdf 21. National Blood Authority, Australia, Critical bleeding massive transfusion; 2011. p.  1–113. http://www.blood.gov.au/pbm-­ module-­1. Accessed 19 Oct 2014. 22. Sutter R, Tisljar K, Marsch S. Acute neurologic complications during extracorporeal membrane oxygenation: a systematic review. Crit Care Med. 2018;46(9):1506–13. 23. Lorusso R, Barili F, Mauro MD, et  al. In-hospital neurologic complications in adult patients undergoing venoarterial extracorporeal membrane oxygenation: results from the Extracorporeal Life Support Organization Registry. Crit Care Med. 2016;44(10):e964–72. 24. Nasr DM, Rabinstein AA.  Neurologic complications of extracorporeal membrane oxygenation. J Clin Neurol. 2015;11(4):383–9. 25. Lorusso R, Gelsomino S, Parise O, et  al. Venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock in elderly patients: trends in application and outcome from the Extracorporeal Life Support Organization (ELSO) Registry. Ann Thorac Surg. 2017;104(1):62–9. 26. Kazmi SO, Sivakumar S, Karakitsos D, Alharthy A, Lazaridis C. Cerebral pathophysiology in extracorporeal membrane oxygenation: pitfalls in daily clinical management. Crit Care Res Pract. 2018;2018:3237810. 27. Cavayas YA, Del Sorbo L, Fan E. Intracranial hemorrhage in adults on ECMO. Perfusion. 2018;33(1_suppl):42–50. 28. Lockie CJA, Gillon SA, Barrett NA, et al. Severe respiratory failure, extracorporeal membrane oxygenation, and intracranial hemorrhage. Crit Care Med. 2017;45(10):1642–9. 29. Malfertheiner MV, Philipp A, Lubnow M, et  al. Hemostatic changes during extracorporeal membrane oxygenation: a prospective randomized clinical trial comparing three different extracorporeal membrane oxygenation systems. Crit Care Med. 2016;44(4):747–54. 30. Tauber H, Ott H, Streif W, et  al. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers. Anesth Analg. 2015;120(4):730–6.

134 31. Munshi L, Kiss A, Cypel M, Keshavjee S, Ferguson ND, Fan E. Oxygen thresholds and mortality during extracorporeal life support in adult patients. Crit Care Med. 2017;45(12):1997–2005. 32. Fletcher-Sandersjöö A, Bartek J Jr, Thelin EP, et al. Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: an observational cohort study [published correction appears in J Intensive Care. 2020 Jan 3;8:2]. J Intensive Care. 2017;5:27. 33. Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc Surg. 2010;139(2):302–311.e1. 34. Stevens RD, Sutter R. Prognosis in severe brain injury. Crit Care Med. 2013;41(4):1104–23. 35. Padkin A.  Glucose control after cardiac arrest. Resuscitation. 2009;80(6):611–2. 36. Fletcher-Sandersjöö A, Thelin EP, Bartek J Jr, Elmi-Terander A, Broman M, Bellander BM. Management of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation (ECMO): an observational cohort study. PLoS One. 2017;12(12):e0190365. 37. Extracorporeal Life Support Organization. ELSO guidelines for cardiopulmonary extracorporeal life support. Extracorporeal Life Support Organization; 2017. p. 1–26. 38. Wong JK, Smith TN, Pitcher HT, Hirose H, Cavarocchi NC. Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation. Artif Organs. 2012;36(8):659–67. 39. Esper SA, Levy JH, Waters JH, Welsby IJ.  Extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion. Anesth Analg. 2014;118(4):731–43. 40. Mazzeffi M, Tanaka K.  Platelets and ECMO: should we worry about count, function, or both? Intensive Care Med. 2016;42(7):1199–200. 41. Truby LK, Takeda K, Mauro C, et al. Incidence and implications of left ventricular distention during venoarterial extracorporeal membrane oxygenation support. ASAIO J. 2017;63(3):257–65. 42. Jumean M, Pham DT, Kapur NK.  Percutaneous bi-atrial extracorporeal membrane oxygenation for acute circulatory support in advanced heart failure. Catheter Cardiovasc Interv. 2015;85(6):1097–9. 43. Desai SR, Hwang NC.  Strategies for left ventricular decompression during venoarterial extracorporeal membrane oxygenation - a narrative review. J Cardiothorac Vasc Anesth. 2020;34(1):208–18. 44. Antoniucci ME, De Paulis S, Bevilacqua F, et al. Unconventional cannulation strategy in peripheral extracorporeal membrane oxygenation to achieve central perfusion and prevent differential hypoxia. J Cardiothorac Vasc Anesth. 2019;33(5):1367–9. 45. Alexis-Ruiz A, Ghadimi K, Raiten J, et al. Hypoxia and complications of oxygenation in extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2019;33(5):1375–81. 46. Epis F, Belliato M.  Oxygenator performance and artificial-native lung interaction. J Thorac Dis. 2018;10(Suppl 5):S596–605. 47. Thalji L, Thum D, Weister TJ, et al. Incidence and epidemiology of perioperative transfusion-related pulmonary complications in pediatric noncardiac surgical patients: a single-center, 5-year experience. Anesth Analg. 2018;127(5):1180–8. 48. Gattinoni L, Tonetti T, Quintel M. How best to set the ventilator on extracorporeal membrane lung oxygenation. Curr Opin Crit Care. 2017;23(1):66–72. 49. Razo-Vazquez AO, Thornton K.  Extracorporeal membrane oxygenation-­what the nephrologist needs to know. Adv Chronic Kidney Dis. 2016;23(3):146–51.

K. Yu 50. Kilburn DJ, Shekar K, Fraser JF. The complex relationship of extracorporeal membrane oxygenation and acute kidney injury: causation or association? Biomed Res Int. 2016;2016:1094296. 51. Thongprayoon C, Cheungpasitporn W, Lertjitbanjong P, et  al. Incidence and impact of acute kidney injury in patients receiving extracorporeal membrane oxygenation: a meta-analysis. J Clin Med. 2019;8(7):981. 52. Ostermann M, Connor M Jr, Kashani K. Continuous renal replacement therapy during extracorporeal membrane oxygenation: why, when and how? Curr Opin Crit Care. 2018;24(6):493–503. 53. Elmously A, Bobka T, Khin S, et al. Distal perfusion cannulation and limb complications in venoarterial extracorporeal membrane oxygenation. J Extra Corpor Technol. 2018;50(3):155–60. 54. Kreibich M, Benk C, Leitner S, et al. Local and lower limb complications during and after femoral cannulation for extracorporeal life support. Thorac Cardiovasc Surg. 2019;67(3):176–82. 55. Shah AG, Peahota M, Thoma BN, Kraft WK. Medication complications in extracorporeal membrane oxygenation. Crit Care Clin. 2017;33(4):897–920. 56. Subramaniam AV, Barsness GW, Vallabhajosyula S, Vallabhajosyula S. Complications of temporary percutaneous mechanical circulatory support for cardiogenic shock: an appraisal of contemporary literature. Cardiol Ther. 2019;8(2):211–28. 57. Roussel A, Al-Attar N, Khaliel F, et  al. Arterial vascular complications in peripheral extracorporeal membrane oxygenation support: a review of techniques and outcomes. Future Cardiol. 2013;9(4):489–95. 58. Muszynski JA, Reeder RW, Hall MW, et al. RBC transfusion practice in pediatric extracorporeal membrane oxygenation support. Crit Care Med. 2018;46(6):e552–9. 59. Jayaraman AL, Cormican D, Shah P, Ramakrishna H. Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: techniques, limitations, and special considerations. Ann Card Anaesth. 2017;20(Supplement):S11–8. 60. Haneke F, Schildhauer TA, Schlebes AD, Strauch JT, Swol J. Infections and extracorporeal membrane oxygenation: incidence, therapy, and outcome. ASAIO J. 2016;62(1):80–6. 61. Allou N, Lo Pinto H, Persichini R, et al. Cannula-related infection in patients supported by peripheral ECMO: clinical and microbiological characteristics. ASAIO J. 2019;65(2):180–6. 62. Grasselli G, Scaravilli V, Di Bella S, et  al. Nosocomial infections during extracorporeal membrane oxygenation: incidence, etiology, and impact on patients’ outcome. Crit Care Med. 2017;45(10):1726–33. 63. Castagnola E, Gargiullo L, Loy A, et  al. Epidemiology of infectious complications during extracorporeal membrane oxygenation in children: a single-center experience in 46 runs. Pediatr Infect Dis J. 2018;37(7):624–6. 64. Dalton HJ, Cashen K, Reeder RW, et  al. Hemolysis during pediatric extracorporeal membrane oxygenation: associations with circuitry, complications, and mortality. Pediatr Crit Care Med. 2018;19(11):1067–76. 65. Williams DC, Turi JL, Hornik CP, et al. Circuit oxygenator contributes to extracorporeal membrane oxygenation-induced hemolysis. ASAIO J. 2015;61(2):190–5. 66. Toomasian JM, Bartlett RH. Hemolysis and ECMO pumps in the 21st century. Perfusion. 2011;26(1):5–6. 67. Dufour N, Radjou A, Thuong M.  Hemolysis and plasma free hemoglobin during extracorporeal membrane oxygenation support: from clinical implications to laboratory details. ASAIO J. 2020;66(3):239–46.

Transport of the Patients Supported with Extracorporeal Life Support

10

Guodong Gao

As an effective means of cardiopulmonary support, extracorporeal life support (ECLS) plays an important role in the treatment of various severe cardiopulmonary failures [1, 2]. The emergency establishment of ECLS in critically ill patients can be used as a means of life support, to strive for more effective and thorough treatment opportunities for the next step, and to provide a new choice for critically ill patients with high mortality and disability rate under the conventional transport mode. The transport of patients supported with ECLS is not only suitable for intra-hospital transport and inter-hospital transport to obtain better treatment but also suitable for the establishment of ECLS transport outside the hospital (such as natural disasters, traffic accidents, battlefields, etc.). The transfer route can be completed by ambulance, helicopter or fixed-wing aircraft, etc. Due to the complex operation of ECLS and the large number of facilities involved, the transport of ECLS requires coordination of a skilled multidisciplinary team as well as clear communication between the referring and receiving institutions. This chapter will introduce in detail the problems involved in the ECLS transfer process.

Purpose of Transport

Intra-Hospital Transport of Patients Supported with ECLS

Preparation of Personnel and Equipment

The need of ECLS patients for further diagnostic or therapeutic interventions outside of ICU arises regularly, and the ECLS patients need to be transported in-hospital when necessary. Intra-hospital transport requires coordination of many departments, such as emergency, ICU, CCU, operating room, catheter room, imaging room, etc. [3–6].

G. Gao (*) Department of Extracorporeal Circulation, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

Inpatient Ward  Transport from the site of ECLS establishment to ICU or ECLS center for treatment. If conditions permit, it is better to directly push the sickbed, and ECLS transfer cart runs on the side of the sickbed. Try to avoid moving the patient directly. Definite Diagnosis or Evaluation  While the bedside examination cannot identify diagnosis or the cause of the disease, it is necessary to go to the functional department for examination; or in order to further evaluate the therapeutic effect and find out the possible hidden dangers, such as we suspect if there are intracranial complications, we need to carry out CT scan to guide the future treatment plan. Further Treatment  Transport for further advanced therapies, such as some patients with ECLS support who need interventional therapy such as PDA paracentesis; some patients with ECLS who need cardiopulmonary transplantation or permanent artificial heart; etc.

Personnel Preparation  The ECLS transport team involves a large number of personnel, which at least include surgeons, perfusionist, anesthesiologists, ICU doctors, nurses, and other personnel with special needs, so as to ensure timely and accurate response and appropriate treatment in case of any unexpected situation during the transport. Equipment Preparation  ECLS basic equipment shall include centrifugal pump, ECLS supporting pipeline, intubation, air oxygen mixer, blood oxygen saturation monitor, ACT monitor, pressure gauge, thermostat, UPS, and medical bottled oxygen. A checklist of items shall be established for all ECLS equipment. ECLS transfer cart is used

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to load the basic equipment. It is required to be compact and convenient to access the elevator lobby.

Transport Points 1. Identify the transfer destination and contact the referring to arrange the reception. 2. Check the necessary relevant items of ECLS, such as if standby power supply works normally and power supply is sufficient and whether bottled oxygen is enough to maintain the demand on the way; check whether the pipeline is broken and easy to move; prepare manual handle of centrifugal pump or rolling pump to a reasonable position; prepare pipeline clamp; and check whether the liquid delivery pump is charged. 3. During the process of transportation, pay attention to the ECLS system pipeline not to twist, squeeze, or pull, and fix the pipeline and intubation to prevent accidental slippage. Equipped with electrocardiogram monitoring and arterial blood pressure monitor, convenient to observe the patient’s condition change, if necessary, carry defibrillator, emergency medicine, bag/mask oxygen inhalation equipment. If you need to take the elevator midway, please contact in advance to avoid delay. Due to the narrow space in the elevator lobby, pay attention to the piping system not to be squeezed. Control the distance between the ECLS transfer vehicle and the hospital bed during the uphill, downhill, and passing, so as to prevent collision and extrusion, resulting in equipment hardware damage. Reduce the number of moves, reduce the transfer time, keep moving smoothly, and finally arrive safely. 4. For the sake of safety, necessary monitoring shall be maintained on the way. For example, the negative pressure monitoring reflects whether the drainage of the venous pipeline is smooth; the arterial and venous blood oxygen saturation monitoring reflects the condition of the air source and the oxygenator; the pump console monitoring reflects whether the centrifugal pump or the rolling pump operates normally; the patient’s vital signs monitoring prevents the occurrence of accidents; the rolling pump continuously monitors the pump pressure to prevent the resistance from being too large, resulting in the collapse of the arterial connector and the rupture of the pump pipe; and so on.

G. Gao

Inter-Hospital Transport Patients transported with ECLS support have essentially equaled survival rates to whom ECLS was initiated locally and to international outcomes reported to the Extracorporeal Life Support Organization (ELSO) Registry [7–9].

Indications for Inter-Hospital ECLS Transport The most common indication is that the patient cannot be conventionally transferred to the experienced ECLS center for initial ECLS due to the critical condition, so ECLS needs to be established at a center that does not provide ECLS and then transferred to the experienced ECLS center. These critical patients are at high risk of conventional transportation and high mortality [10, 11]. Another common reason is that the established ECLS patients cannot be provided with further treatment by local hospitals, such as heart transplantation and lung transplantation, which need to be transferred to the superior hospital for further treatment. Some centers have the ability to initiate ECLS treatment in an emergency situation but not to continue for the whole treatment period. These patients may thus be transferred to an established ECLS center. Another occasional situation is the lack of ECLS staff and equipment, which needs to be transferred to another ECLS center [12, 13]. In another case, the patient’s family members ask for transfer.

Transport Logistics The purpose of transportation is to transfer the extremely critical and unstable patients supported with ECLS from the referring to an ECLS center and use their own equipment. The transfer process consists of three stages, namely, (1) transportation of the team, including equipment arrival at transfer out-hospital; (2) procedures at the referring hospital: comprehensive assessment of the risks and feasibility of transshipment, including whether the patient’s condition is relatively stable, whether the ECLS operation is stable, whether the patient can tolerate the transport, whether the transport is safe and suitable, whether the ECLS team can

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provide safe transport, etc.; and (3) transfer to destination ECLS center. In most instances, transport starts with a phone call from the referring hospital, and a decision is made to launch the team for patients who fulfill ECLS criteria. Once the transfer is determined, contact team members, pack equipment, organize transfer vehicles, and arrive at the transfer out-hospital in the shortest time to rescue patients. The most important thing when transporting the patients to the ECLS center is patient safety. Remember that the consent of the patient family must be obtained before ECLS transfer.

the safety time of ECLS power and gas supply. The vehicles needed for the ground ECLS transfer are mainly ambulances to load the transfer personnel and equipment. Even if it is air transfer, it is still necessary to transfer to or from the airport through the ground. The ambulance is required to be broad enough for the ECLS transfer vehicle to enter and the accompanying personnel to be in place, to be able to fix the ECLS transfer vehicle, to provide emergency power and oxygen supply for the ambulance, to have necessary rescue facilities and first-aid drugs, and to have complete communication system and vehicle maintenance equipment.

Transfer Modes

Air Transportation  It requires professional rescue flight equipment, necessary medical rescue equipment and drugs, and the participation of trained professional medical personnel. It is necessary to ensure that all kinds of equipment meet the national aviation medical equipment standards and pass the corresponding electrical tests to ensure that there is no interference to the navigation and control system of the aircraft. Air transport service has a wide range and a short transit time, but it involves many departments and requires specialized agencies to be responsible for it, which is expensive.

The vehicles for ECLS transfer between hospitals are determined by many factors, including distance, weather, team composition, vehicle reliability, etc. Each mode of transportation has its own advantages and disadvantages (Table 10.1). Transportation with fixed-wing aircraft also needs ground transfer between airport and hospital at both ends. Units equipped with helicopters can directly load patients into helicopters without the need for ground transportation. ELSO guidelines suggest as follows: (a) ground transportation, 250–300  miles; (b) helicopter transportation, 300– 400  miles [14]; and (c) fixed-wing aircraft transportation, any distance. Ground Transportation  It is suitable for hospitals close to the two places or neighboring cities that are expected to reach the destination in a few hours, and it will not exceed

Personnel Preparation

Inter-hospital transport team includes perfusionists, anesthesiologists, surgeons, nurses, physicians, etc. Special patients also need professional doctors to follow. Relevant personnel must be trained, be familiar with the operation process, master the use and maintenance of various equipment, have resTable 10.1  Properties of ground ambulance, helicopter, and fixed-­ cue experience, and have been cooperated for many times. wing aircraft (Cited from ELSO guidelines [14]) Set up a team leader, manage uniformly, coordinate internally and externally, and be responsible for liaison, dispatchGround Fixed-wing ambulance Helicopter aircraft ing, and consultation. Space for team Sufficient More limited Variable > = 4 The ELSO guidelines provide an example of the compoand equipment 4–5 team 3–5 team team members sition of a transport team [14]. This team consists of a canmembers members nulation surgeon, a surgical assistant, an ECLS physician, an Noise Relatively Very loud Loud ECLS specialist, and a transport nurse/a respiratory little therapist. Distance for Up to Up to 650 km Any distance reasonable 400 km (300– When configuring the transfer team, each member’s transport times (250– 400 miles) responsibilities and tasks must be clearly defined, including 300 miles) the capability to make the final patient evaluation decision Weight Unlimited Limited Variable regarding candidacy for and mode (VA, VV) of ECLS, intulimitations (impacted by (depending on distance and aircraft and bate patients, assemble and prime the ECLS circuit, initiate weather) conditions) ECLS treatment, stabilize the patient, check cannula position Loading and Relatively Relatively Variable using radioactivity or ultrasonic guidance, and safely transsecuring easy easy (depending on port patients supported with ECLS to destination. equipment and equipment and The team should also be prepared for troubleshooting ECLS circuit/ aircraft model) patient when unexpected difficulties arise. All responsibilities must Cost ++ +++ ++++ be met by experienced personnel as there will be no backup.

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G. Gao

Transport Equipment There are different ECLS equipment which was intra-­ hospital and inter-hospital utilized (Figs. 10.1 and 10.2). The transport stretchers vary in different centers. The design of the cart shall be compact, and it shall be able to enter the ambulance, elevator room, and even the aircraft smoothly. Unlike intra-hospital transport, inter-hospital transport does not require the use of another flatcar to load patients. Generally, the top of the bed is designed as a hospital bed, and children should be equipped with a small-size bed, which can be fixed or replaced, and equipped with a variable temperature blanket. The bed is divided into several functional areas, and the main equipment area is at the bottom, including centrifugal pump, uninterruptible power supply, bottled compressed air and oxygen, variable temperature water tank, etc.; the upper layer is monitoring equipment, including oxygen saturation monitor, air oxygen mixer, ACT and aPTT monitor, ECG and arterial pressure monitor, ventilator, infusion pump, etc. In addition, it also needs to be Fig. 10.2  Portable ECLS accessories

Fig. 10.1  Sprinter cart with optional accessories of QUADROX PLS and Rotaflow system

equipped with ECLS circuit package, intubation package, accessories box, medicine box, disinfection equipment required for surgery, surgical clothing, laying sheet, suture, and other items. The necessary items shall be miniaturized, easy to carry, well prepared, and provided with a list for searching. At present, most centers use centrifugal pump for transfer [15–17], which can improve functionality and safety in combination with a shorter circuit. Many centers have developed their own system, where stretcher and the ECLS components are assembled in one unit. This configuration shortens the length of tubing and minimizes the risk for tubing kinking, etc. during loading and unloading (Figs. 10.1 and 10.2). Again, the ECLS transfer team must be familiar with all equipment through multiple drills and be self-sufficient with regard to all supplies. This does include not only disposables, medications, and intravenous fluids but also backup components of the ECLS circuits (e.g., extra oxygenator, pump head, tubing, and connectors). An uninterruptible power supply UPS unit must be prepared on the transfer vehicle in case that the vehicle is not properly equipped with a generator at the outside facility. Redundancy is a crucial principle in planning equipment for inter-hospital ECLS transport to ensure a backup is available for any critical failed component.

10  Transport of the Patients Supported with Extracorporeal Life Support

 anagement of Inter-Hospital ECLS M Transport Assessment of Patient For transferring, it is necessary to know the basic situation of the patient, the development of the disease, the treatment plan, the equipment of ECLS used at referring hospital, etc., and the equipment and supplies should be carried according to the understanding. It is recommended to bring all the items needed for initialing ECLS and transportation. All equipment and materials should be stored in the mobile box separately and indicated in a checklist.

Lay Out a Scheme Make transfer plan: determine transportation mode and arrange reception procedures. Once the ECLS transport team arrived the referring hospital, the vital signs of the hospital, drug application and ECLS flow of the patients were checked again and the situation of the patients were discussed again. The list of blood products required for the patient supported by ECLS is sent to the referring hospital, because for those patients who must be transported by long distance, more blood products must be prepared for use on the return trip.

Patient Transport The patient is usually transported to the ECLS transfer vehicle after the ECLS is initiated, and then the membrane oxygenation of ECLS and pipeline system are adjusted. The pipeline shall be fixed firmly and protected to prevent extrusion, twist, and scratch. The membrane oxygenation shall be installed in place to avoid collision. The centrifugal pump is installed in the vehicle, and the oxygen pipe, power supply, oxygen saturation monitor, and variable temperature water tank were connected, ECG and arterial blood pressure are monitored, and the ventilator is installed. All items should be loaded in the ECLS transfer vehicle, which is convenient to be transported to the ambulance, and the transfer vehicle shall be fixed. The vital signs of patients shall be observed at any time during the journey, and problems shall be reported and solved in time to ensure the safe arrival of patients. After arriving at the hospital, arrange the hospital bed, transport the patients to the right place, adjust the ECLS equipment, report the condition, formulate the next treatment plan, and manage the patients according to the routine ECLS.

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Monitoring in ECLS Transfer First of all, continuous attention should be paid to the operation of centrifugal pump or rolling pump. Pay attention to whether the power supply and air source are normal, whether the pipeline is twisted, whether the pump speed flow matches, whether the position of the membrane lung is appropriate, etc. Observe the patient’s condition, vital signs, tissue perfusion, and distal limb perfusion of arterial intubation; observe the patient’s respiratory, manage the respiratory tract, and keep the respiratory tract unobstructed. ECG, arterial pressure, central venous pressure, and SO2/ Hct should be monitored continuously. Blood gas and electrolyte should be monitored when necessary. Heparin was used for anticoagulation to maintain ACT 160–200  s and aPTT 50–80 s.

Treatment and Care in ECLS Transfer Surgeons, anesthesiologists, and ICU doctors should accompany ECLS patients outside the hospital. Surgeons and ICU doctors should continue to maintain the patients’ routine necessary treatment measures, observe the patients’ conditions, timely deal with the changes of patients’ conditions during the transportation process, and adjust the medication. Anesthetists should pay attention to the depth of anesthesia, sedation and analgesia of patients, and the use of anesthetics, muscle relaxants, etc. For conscious ECLS patients, we should pay attention to sedation, analgesia, and respiratory status. During ECLS transport, patients are exposed to relatively unclean environment, such as ICU or operating room. More attention must be paid to keep the sterility of articles and the cleanness of patients. The air in the transport environment should be disinfected, and the patients should be regularly treated with strong antibiotics to prevent infection. In the process of ECLS transport, careful nursing cooperation is also very important for patients. In addition, because of the long-term heparinization and tracheal intubation of ECLS patients, it is easy to cause bleeding in the oral cavity and nasal cavity. The above parts should be cleaned frequently. Pay attention to aseptic operation of wound; change dressing in time to prevent infection complications. Due to the critical condition of patients, we should always consider for patients during transportation and try to provide patients with comfortable environment and careful care.

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Complications Associated with Transport

G. Gao

7. Bryner B, Cooley E, Copenhaver W, et al. Two decades’ experience with interfacility transport on extracorporeal membrane oxygenation. Ann Thorac Surg. 2014;98(4):1363–70. There was no significant difference outcomes between 8. Clement KC, Fiser RT, Fiser WP, et al. Single-institution expepatients transported on ECLS and those established in-­ rience with interhospital extracorporeal membrane oxygenation transport: a descriptive study. Pediatr Crit Care Med. hospital [7–9, 18–20]. 2010;11(4):509–13. A variety of equipment malfunctions during transport may 9. Broman LM, Holzgraefe B, Palmér K, Frenckner B. The Stockholm occur [8, 9, 18–21]. Adverse events also occur frequently, are experience: interhospital transports on extracorporeal membrane reported in 27% of transports [9], and are categorized into oxygenation. Crit Care. 2015;19(1):278. five groups: patient, staff, equipment, vehicle, and environ- 10. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorment. Loss of tidal volume was the most common adverse poreal membrane oxygenation for severe adult respiratory failure event that occurred in the patient category. Other patient (CESAR): a multicentre randomised controlled trial [published corevents included bleeding, cardiac stun, hypovolemia, etc. rection appears in Lancet. 2009 Oct 17;374(9698):1330]. Lancet. 2009;374(9698):1351–63. Adverse equipment events included clotting of the ECLS cir11. Boedy RF, Howell CG, Kanto WP Jr. Hidden mortality rate assocuit, broken lab device, syringe pump failure, broken heater, ciated with extracorporeal membrane oxygenation. J Pediatr. ambulance traffic accident, and freezing of intravenous lines. 1990;117(3):462–4. When complications happened, first of all, we should dis- 12. White DB, Angus DC. Preparing for the sickest patients with 2009 influenza A (H1N1). JAMA. 2009;302(17):1905–6. tinguish the primary and secondary accidents, deal with 13. Turner DA, Williford WL, Peters MA, et al. Development of a colthem in different order, quickly find solutions, and restore laborative program to provide extracorporeal membrane oxygennormal circulation support. The only purpose is to ensure the ation for adults with refractory hypoxemia within the framework of safe arrival of patients. a pandemic. Pediatr Crit Care Med. 2011;12(4):426–30. 14. https://www.elso.org/ecmo-­resources/elso-­ecmo-­guidelines.aspx. 15. Forrest P, Ratchford J, Burns B, et  al. Retrieval of critically ill adults using extracorporeal membrane oxygenation: an Australian References experience. Intensive Care Med. 2011;37(5):824–30. 16. Lucchini A, De Felippis C, Elli S, et al. Mobile ECMO team for 1. Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B. Review inter-hospital transportation of patients with ARDS: a retrospective of ECMO (extra corporeal membrane oxygenation) support in criticase series. Heart Lung Vessel. 2014;6(4):262–73. cally ill adult patients. Heart Lung Circ. 2008;17(Suppl 4):S41–7. 17. Raspé C, Rückert F, Metz D, et al. Inter-hospital transfer of ECMO-­ 2. Brown KL, Goldman AP.  Neonatal extra-corporeal life support: assisted patients with a portable miniaturized ECMO device: 4 indications and limitations. Early Hum Dev. 2008;84(3):143–8. years of experience. Perfusion. 2015;30(1):52–9. 3. Booth KL, Roth SJ, Perry SB, del Nido PJ, Wessel DL, Laussen 18. Ericsson A, Frenckner B, Broman LM.  Adverse events during PC. Cardiac catheterization of patients supported by extracorporeal inter-hospital transports on extracorporeal membrane oxygenation. membrane oxygenation. J Am Coll Cardiol. 2002;40(9):1681–6. Prehosp Emerg Care. 2017;21(4):448–55. 4. Lidegran MK, Mosskin M, Ringertz HG, Frenckner BP, Lindén 19. Broman LM, Frenckner B.  Transportation of critically ill VB. Cranial CT for diagnosis of intracranial complications in adult patients on extracorporeal membrane oxygenation. Front Pediatr. and pediatric patients during ECMO: clinical benefits in diagnosis 2016;4:63. and treatment. Acad Radiol. 2007;14(1):62–71. 20. Wilson BJ Jr, Heiman HS, Butler TJ, Negaard KA, DiGeronimo 5. Lidegran MK, Ringertz HG, Frenckner BP, Lindén VB.  Chest R. A 16-year neonatal/pediatric extracorporeal membrane oxygenand abdominal CT during extracorporeal membrane oxygenation transport experience. Pediatrics. 2002;109(2):189–93. ation: clinical benefits in diagnosis and treatment. Acad Radiol. 21. Cabrera AG, Prodhan P, Cleves MA, et  al. Interhospital trans2005;12(3):276–85. port of children requiring extracorporeal membrane oxygen6. Prodhan P, Fiser RT, Cenac S, et  al. Intrahospital transport of ation support for cardiac dysfunction. Congenit Heart Dis. children on extracorporeal membrane oxygenation: indications, 2011;6(3):202–8. process, interventions, and effectiveness. Pediatr Crit Care Med. 2010;11(2):227–33.

Extracorporeal Life Support During Perioperative Transplantation

11

Caihong Wan and Yulong Guan

Over the past two decades, extracorporeal life support (ECLS) has made progress in evolving from an acute rescue therapy to a semi-elective procedure. The concept of using ECLS devices for bridging to transplantation has opened a whole new field of treatment alternative for patients with advanced stages of organ failure. With the development of new devices and cannulas and improvement of technical skills and management, ECLS may protect the organ from acute deterioration with encouraging outcomes [1]. Now ECLS plays an important role in the perioperative management of transplantation.

 CLS During Perioperative Heart E Transplantation ECLS has been reserved for use in the advanced stages of heart failure when the patient is unresponsive to medical therapy and a durable left ventricular assist device (LVAD) is not an option. Increased experience with ECLS as a mode of transitory cardiac support has expanded its use to diverse patient populations including patients requiring a bridge to heart transplantation and patients requiring post-transplant support for primary graft dysfunction (PGD) to accelerate the recovery of graft.

ECLS Prior to Heart Transplant Heart transplantation is still widely recognized as the best treatment alternative for patients with advanced heart failure that is unresponsive to medical therapy. Due to donor shortages and the current allocation policies, time on the waitlist for a donor heart can be prolonged and cannot be predicted exactly in advance. According to the data submitted by the Registry of the International Society for Heart and Lung Transplantation (ISHLT), there were over 4500 patients undergoing heart transplantation each year, and the proportion of transplant recipients who received some form of mechanical circulatory support prior to heart transplant had a steady increase from 22% to 50% in the most recent era (Fig. 11.1) [2].

I nclusion Criteria of ECLS Prior to Heart Transplant “Bridge to Bridge”  Although durable LVAD implant is the prior approach as the bridge to heart transplant, several different series have confirmed the safe use of ECLS as a double bridge or bridge to bridge (bridge to LVAD) to stabilize patients and optimize clinical condition before LVAD implantation. Sequential organ failure assessment may be also performed prior to a durable LVAD implant or heart transplant [3, 4]. Bridge to Heart Transplant  Once an LVAD is not an ideal option because of profiles of patients or unavailability of LVAD in some centers, ECMO may be adopted selectively as a bridge to transplantation (BTT) [2].

C. Wan Department of Extracorporeal Circulation, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Diseases, Capital Medical University, Beijing, People’s Republic of China Y. Guan (*) Department of Extracorporeal Circulation, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

 urrent State of ECLS as a BTT in Adult C Candidates The use of ECMO as a direct BTT in adult populations is extremely infrequent worldwide, particularly in the United States. According to the revised Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) proposal, candidates who are supported with

© Springer Nature Singapore Pte Ltd. 2023 F. Hei et al. (eds.), Extracorporeal life support, https://doi.org/10.1007/978-981-19-9275-9_11

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% of Patients

40

ECMO

VAD+ECMO

TAH

LVAD+RVAD

RVAD

LVAD

30

20

10

0 2005

2006

2007

2008

2009

2010

2011

2012

2013

Year of Transplant

Fig. 11.1  Use of mechanical circulatory support at time of heart transplant by year of transplant. ECMO, extracorporeal membrane oxygenation; LVAD, left ventricular assist device; RVAD, right ventricular assist device; TAH, total artificial heart. (Cited from Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, Levvey

BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Thirty-­ second Official Adult Heart Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015;34(10):1244–1254)

ECMO have the highest priority (status 1) to receive donor because of their high waiting list mortality rates and because the number of these specific candidates is relatively low [5]. Fukuhara and colleagues conducted a comprehensive analysis on 25,168 adult heart transplant recipients’ data from the UNOS Thoracic Registry between 2003 and 2016. There are 107 (0.4%) patients bridged with ECMO whereas 6148 (24.4%) bridged with continuous-flow left ventricular assist device (CF-LVAD). Kaplan-Meier analysis demonstrated significant better survival of ECMO group compared with CF-LVAD group (73.1% vs 93.1% at 90 days, P