The ESC Textbook of Intensive and Acute Cardiovascular Care [3 ed.] 0198849346, 9780198849346

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The ESC Textbook of

Intensive and Acute Cardiovascular Care

EUROPEAN SOCIETY OF CARDIOLOGY PUBLICATIONS The ESC Textbook of Cardiovascular Medicine (Third Edition) Edited by A. John Camm, Thomas F. Lüscher, Gerald Maurer, and Patrick W. Serruys The ESC Textbook of Preventive Cardiology Edited by Stephan Gielen, Guy De Backer, Massimo Piepoli, and David Wood The EHRA Book of Pacemaker, ICD, and CRT Troubleshooting: Case-​based learning with multiple choice questions Edited by Harran Burri, Carsten Israel, and Jean-​Claude Deharo The EACVI Echo Handbook Edited by Patrizio Lancellotti and Bernard Cosyns The ESC Handbook of Preventive Cardiology: Putting prevention into practice Edited by Catriona Jennings, Ian Graham, and Stephan Gielen The EACVI Textbook of Echocardiography (Second Edition) Edited by Patrizio Lancellotti, José Luis Zamorano, Gilbert Habib, and Luigi Badano The EHRA Book of Interventional Electrophysiology: Case-​based learning with multiple choice questions Edited by Hein Heidbuchel, Matthias Duytschaever, and Harran Burri The ESC Textbook of Vascular Biology Edited by Robert Krams and Magnus Bäck The ESC Textbook of Cardiovascular Development Edited by José Maria Pérez-​Pomares and Robert Kelly The EACVI Textbook of Cardiovascular Magnetic Resonance Edited by Massimo Lombardi, Sven Plein, Steffen Petersen, Chiara Bucciarelli-​Ducci, Emanuela R. Valsangiacomo Buechel, Cristina Basso, and Victor Ferrari The ESC Textbook of Sports Cardiology Edited by Antonio Pelliccia, Hein Heidbuchel, Domenico Corrado, Mats Börjesson, and Sanjay Sharma The ESC Handbook of Cardiac Rehabilitation Edited by Ana Abreu, Jean-​Paul Schmid, and Massimo Piepoli The ESC Textbook of Intensive and Acute Cardiovascular Care (Third Edition) Edited by Marco Tubaro, Pascal Vranckx, Eric Bonnefoy-Cudraz, Susanna Price, and Christiaan Vrints

FORTHCOMING The ESC Textbook of Cardiovascular Imaging (Third Edition) Edited by José Luis Zamorano, Jeroen Bax, Juhani Knuuti, Patrizio Lancellotti, Bogdan Popescu, Fausto Pinto, and Udo Sechtem

The ESC Textbook of

Intensive and Acute Cardiovascular Care THIRD EDITION EDITORS

Marco Tubaro Pascal Vranckx CO-​E DITORS

Eric Bonnefoy-Cudraz  Susanna Price  Christiaan Vrints

1

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © European Society of Cardiology 2021 The moral rights of the authors have been asserted First Edition published in 2011 Second Edition published in 2015 Third Edition published in 2021 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2020941873 ISBN 978–​0–​19–​884934–​6 DOI: 10.1093/​med/​9780198849346.001.0001 Printed in Great Britain by Bell & Bain Ltd., Glasgow Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Preface

Intensive cardiac care (procedures) saves lives and reduce cardiac disability in acute cardiac patients. This treatment is to be delivered by specially trained and accredited cardiologists, nurses and paramedics working in specially designed and equipped facilities. The urgent nature of some acute cardiac presentations dictates the need to apply acute cardiac care as early as possible, at the prehospital and or emergency room scenario. Prompt and accurate diagnosis, meticulous monitoring and urgent treatment are indicated in a wide variety of cardiovascular conditions, including acute coronary syndromes, acute decompensated heart failure, life-threatening rhythm disturbances, myocarditis, pulmonary embolism, infective endocarditis, as well as complications of cardiac interventions and other acute maladies (i.e. infection, haemorrhage, trauma) whereby chronic heart disease may jeopardize the short-term prognosis. The Association for Acute CardioVascular Care (ACVC) of the European Society of Cardiology (ESC) has set out to pioneer this subspeciality of cardiology. The ESC Textbook of Intensive and Acute Cardiovascular Care is a major asset. It is the only textbook completely dedicated to the field of acute cardiovascular and intensive care. It contains all the basic necessary comprehensive, yet practical information needed for the optimal implementation of acute cardiac care. This includes the recommended organization and function of the service, detailed description of the laboratory tests, special cardiac evaluation techniques, procedures, pharmacological and invasive therapeutic interventions used for the practice of intensive cardiac care. A detailed description and recommendations for the management of the various diseases in need for acute cardiac care is also included. Cardiology in general, and specifically the field of intensive cardiac care, is constantly evolving. There is a constant new inflow of information, introduction of updated evidence-based guidelines and new and improved therapeutic techniques (including organ supportive therapy for the critically ill patients). Currently, the

ACVC has expanded the recommended treatment from a previous focus on in-hospital intensive care, with emphasis on the intensive cardiac care units (ICCUs), to intensive and acute cardiovascular care wherever it is needed (including pre-hospital, ambulances, emergency rooms, ICCUs, wards, operating theaters, etc.). This is in accord with the realization of the need for a continuum mode of treatment and the incorporation of the specific groups under the ACVC. Therefore, the effort for this new edition of the ESC Textbook of Acute and Intensive Cardiovascular Care is timely and highly appreciated. For simplicity and consecutiveness, the table of contents in the current edition has been maintained similar to that of the second edition. However, the content has been improved and updated and a new chapter (Chapter 50) is now fully dedicated to implanted cardiac support devices. A special mention is to be dedicated to Chapter 3 on ‘Intensive Cardiovascular Care Units: structure, organization and staffing’ which reflects the reality that three levels of acute cardiac care may function in different hospitals. Some can apply only limited acute coronary care, while others can provide the full scope of advanced, comprehensive, intensive, and acute cardiac care (level III). As in the previous editions, the print textbook is accompanied by an expanded and more comprehensive online edition, which is expected to be yearly updated. The editors and authors of the third edition of the ESC Textbook of Intensive and Acute Cardiovascular Care should be congratulated on the completion of this major task. I am confident that this endeavor will contribute to the daily conductance of acute cardiac care and provide mandatory learning material for the education of cardiologists and allied staff training in the field. Professor Yonathan Hasin Founding chairperson of the Working Group on Acute Cardiac Care of the ESC Ariel University Medical School

Contents

Symbols and abbreviations  xi Contributors  xxix 1 Intensive and acute cardiovascular care: an

introduction  1

Eric Bonnefoy-Cudraz, Susanna Price, Marco Tubaro, Pascal Vranckx, and Christiaan Vrints

SECTION I Intensive and acute cardiovascular care  2 Training and certification in intensive and acute cardiovascular care  5 Susanna Price and Eric Bonnefoy-Cudraz 3 Intensive cardiovascular care units: structure, organization, and staffing  11 Eric Bonnefoy-Cudraz and Tom Quinn 4 The heart team  25 Sergio Leonardi, Thomas Modine, and Stephan Windecker 5 Patient safety and clinical governance  33 Matthew Parkin and Tom Quinn 6 Ethical issues in cardiac arrest and acute cardiac care: a European perspective  43 Jean-​Louis Vincent and Jacques Creteur 7 Quality of care assessment in acute cardiac care  54 Fiona Ecarnot and François Schiele

SECTION II The pre-​hospital phase and the emergency department  8 The emergency medical system  65 Olivier Hoogmartens, Michiel Stiers, Koen Bronselaer, and Marc Sabbe 9 Out-​of-​hospital cardiac arrest  76 Jerry P Nolan and Christian Hassager 10 Chest pain in the emergency department and the chest pain unit  88 Christiaan Vrints, Janina Stepinska, and Marc J Claeys 11 Acute dyspnoea in the emergency department  103 Eleni Michou, Nikola Kozhuharov, Jasmin Martin, and Christian Mueller

SECTION III Monitoring and investigations in the intensive cardiovascular care unit  12 Pathophysiology and clinical assessment of the cardiovascular system (including pulmonary artery catheterization)  115 Alessandro Sionis, Etienne Gayat, and Alexandre Mebazaa 13 The respiratory system  127 Antoine Vieillard-​Baron

viii

C onte n ts 14 Neurological assessment of the acute cardiac care patient  134 Mathieu van der Jagt, Jeroen JH Bunge, and Fabio S Taccone 15 Monitoring of the kidneys, liver, and other vital organs  147 Karl Werdan, Brijesh Patel, Matthias Girndt, Henning Ebelt, Jochen Schröder, and Sebastian Nuding 16 Blood gas analysis: acid–​base, fluid, and electrolyte disorders  165 Farah Shariff and Richard Paul 17 Interpretation and clinical use of chest radiographs  181 Alexander Parkhomenko, Olga S Gurjeva, and Tetyana Yalynska 18.1 Echocardiography and thoracic ultrasound  201 Frank A Flachskampf, Pavlos Myrianthefs, and Ruxandra Beyer 18.2 Echocardiography and thoracic ultrasound  218 Frank A Flachskampf, Pavlos Myrianthefs, and Ruxandra Beyer 19 Computerized tomography: coronary angiography and cardiac imaging  224 Jeff M Smit, Mohammed El Mahdiui, Michiel A de Graaf, Arthur JHA Scholte, Lucia Kroft, and Jeroen J Bax 20 Cardiac magnetic resonance in the intensive and cardiac care unit  246 Juerg Schwitter and Jens Bremerich

SECTION IV Procedures in the intensive cardiovascular care unit  21 Non-​invasive ventilation  267 Josep Masip, Kenneth Planas, and Arantxa Mas 22 Mechanical ventilation  284 Luigi Camporota and Francesco Vasques 23 Temporary pacing  306 Bulent Gorenek

26 Chest tubes  331 Giulio Maurizi, Camilla Vanni, and Erino Angelo Rendina 27 Renal support therapy  338 Claudio Ronco, Stefano Romagnoli, and Zaccaria Ricci 28 Percutaneous (short-​term) mechanical circulatory support  351 Holger Thiele and Pascal Vranckx 29 Nutrition support in acute cardiac care  360 Michael P Casaer and Greet Van den Berghe 30 Physiotherapy in critically ill patients  373 Rik Gosselink and Jean Roeseler

SECTION V The laboratory in intensive and acute cardiovascular care 31 The use of biomarkers for acute cardiovascular disease  387 Allan S Jaffe 32 Biomarkers in acute coronary syndromes  400 Jasper Boeddinghaus, Thomas Nestelberger, Raphael Twerenbold, and Christian Mueller 33 Biomarkers in acute heart failure  409 Rajiv Choudhary, Nicholas Wettersten, Kevin Shah, and Alan Maisel 34 Biomarkers of coagulation and thrombosis  425 Anne-​Mette Hvas, Erik L Grove, and Steen Dalby Kristensen 35 Biomarkers of renal and hepatic failure  434 Mario Plebani, Monica Maria Mion, and Martina Zaninotto

SECTION VI Acute coronary syndromes 36 Atherosclerosis and thrombosis  447 Lina Badimon and Gemma Vilahur

24 Ultrasound-​guided vascular access in intensive/​acute cardiac care  314 Richard Paul

37 The universal definition of myocardial infarction  463 Kristian Thygesen, Joseph S Alpert, Allan S Jaffe, and Harvey D White

25 Pericardiocentesis  323 Caterina C De Carlini and Stefano Maggiolini

38 ST-​segment elevation myocardial infarction  479 Borja Ibanez and Stefan James

C on t e n ts 39 Fibrinolytic, antiplatelet, and anticoagulant drugs in acute coronary syndromes  494 Sigrun Halvorsen, Giuseppe Gargiulo, Marco Valgimigli, and Kurt Huber 40 Mechanical complications of myocardial infarction  513 Elena Puerto and Héctor Bueno 41 Non-​ST-​segment elevation acute coronary syndromes  531 Héctor Bueno and José A Barrabés 42 Percutaneous coronary interventions in acute coronary syndromes  549 Andreas Mitsis and Marco Valgimigli 43 Coronary artery bypass graft surgery  565 Piroze M Davierwala and Michael A Borger 44 Sex considerations in acute coronary syndromes  585 Eva Swahn, Joakim Alfredsson, and Sofia Sederholm Lawesson

SECTION VII Acute heart failure (including cardiogenic shock)

51 Donor organ management  691 Arne P Neyrinck, Patrick Ferdinande, Dirk Van Raemdonck, and Marc Van de Velde 52 Palliative care in the intensive cardiovascular care unit  706 Jayne Wood

SECTION VIII Arrhythmias 53 Atrial fibrillation and supraventricular arrhythmias  719 Demosthenes G Katritsis and A John Camm 54 Ventricular tachyarrhythmias  740 Paolo Della Bella, Dagmara Dilling, and Francesca Baratto 55 Pacemaker and ICDs: troubleshooting  755 Neasa Starr and Haran Burri

SECTION IX Specific acute cardiovascular conditions 56 Myocarditis and pericarditis  767 Massimo Imazio and Stephane Heymans

45 Acute heart failure: epidemiology, classification, and pathophysiology  603 Dimitrios Farmakis and Gerasimos Filippatos

57 Acute valve disease and endocarditis  778 Gregory Ducrocq, Franck Thuny, Bernard Iung, and Alec Vahanian

46 Acute heart failure: early pharmacological therapy  617 Kieran F Docherty, Jonathan R Dalzell, Mark C Petrie, and John JV McMurray

58 Congenital heart disease in adults  795 Susanna Price, Brian F Keogh, and Lorna Swan

47 Low cardiac output states and cardiogenic shock  633 Holger Thiele and Suzanne de Waha-​Thiele 48 Non-​pharmacological therapy of acute heart failure: when drugs alone are not enough  651 Jeroen Dauw, Wilfried Mullens, Johan Vijgen, and Pascal Vranckx 49 Heart failure surgery and transplantation  664 Felix Schoenrath, Jan Klages, and Volkmar Falk 50 Implanted cardiac support devices  680 Andrew C Morley-​Smith, André R Simon, and John Pepper

59 Aortic emergencies  805 Marc Schepens and Eric Graulus 60 Cardiac complications in trauma  820 Lydia Lam, Leslie Kobayashi, and Demetrios Demetriades 61 Cardiac emergencies in pregnancy  830 Mark Johnson and Jolien Roos-​Hesselink 62 Pulmonary hypertension  839 Massimiliano Palazzini, Nazzareno Galiè, and Alessandra Manes 63 Pulmonary embolism  849 Stavros Konstantinides, Marcin Kurzyna, and Adam Torbicki

ix

x

C onte n ts

SECTION X Concomitant acute conditions 64 Acute respiratory failure and acute respiratory distress syndrome  863 Luciano Gattinoni, Mattia Busana, and Eleonora Carlesso 65 Stroke  880 Didier Leys, Solène Moulin, and Valeria Caso 66 Acute kidney injury  895 Sofie A Gevaert, Eric Hoste, and John A Kellum 67 Stress hyperglycaemia and endocrine emergencies  912 Jan Gunst, Yves Debaveye, and Greet Van den Berghe 68 Bleeding and haemostasis disorders  926 Pier Mannuccio Mannucci and Maddalena Lettino 69 Anaemia and transfusion  938 Pascal Vranckx, Davide Cao, Philippe Vandekerckhove, and Roxana Mehran

70 Infection, sepsis, and multiorgan dysfunction syndrome  945 Jean-​Louis Vincent 71 Pain in the intensive cardiovascular care unit  956 Siân Jaggar and Helen Laycock 72 Delirium in the intensive cardiovascular care unit  969 Stephen Keane, Kevin Clarkson, and John W McEvoy 73 Special considerations in the immunosuppressed patient  979 Anne-​Sophie Moreau and Raphaël Favory 74 Perioperative cardiac care of the high-​risk non-​cardiac patient  990 Martin Balik 75 Perioperative management of the high-​risk surgical patient: cardiac surgery  1009 Marco Ranucci, Serenella Castelvecchio, and Andrea Ballotta

Index  1025

Symbols and abbreviations

£ pound sterling $ dollar € euro ° degree °C degree Celsius % per cent ± plus or minus = equal to > greater than < less than ≥ equal to or greater than ≤ equal to or less than α alpha β beta δ delta γ gamma κ kappa σ sigma Ω ohm π pi τ tau ® registered trademark © copyright ™ trademark Δ change ↑ increase ↓ decrease → leads to 3CPO Three Interventions in Cardiogenic Pulmonary Oedema (trial) 2D two-​dimensional 3D three-​dimensional 5-​FU 5-​fluorouracil AAD antiarrhythmic drug AAR aspartate transaminase-​to-​alanine transaminase ratio

ABC ABG ABMS ABOARD

ACCF ACCOAST

ACCP ACD ACE ACEF ACE-​I ACGME ACHD ACLS ACP ACPO ACR ACRIN ACS ACT ACTH ACTION

adenosine triphosphate-​binding cassette; airway, breathing, circulation arterial blood gas American Board of Medical Specialties Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes Randomized for an Immediate or Delayed Intervention (trial) American College of Cardiology Foundation Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention (PCI) or as Pretreatment at the Time of Diagnosis in Patients with Non-​ST Elevation Myocardial Infarction (trial) American College of Chest Physicians active compression–​decompression angiotensin-​converting  enzyme age, creatinine, and ejection fraction (score) angiotensin-​converting enzyme inhibitor Accreditation Council for Graduate Medical Education adult congenital heart disease advanced cardiac life support American College of Physicians acute cardiogenic pulmonary oedema albumin/​creatinine  ratio American College of Radiology Imaging Network-​Pennsylvania (trial) acute coronary syndrome activated clotting time adrenocorticotrophic hormone Acute Coronary Treatment and Intervention Outcomes Network

xii

Symb ols an d abbreviations ACTION Registry–​GWTG Acute Coronary Treatment and Intervention Outcomes Network Registry—​Get With The Guidelines ACUITY Acute Catheterization and Urgent Intervention Triage Strategy (trial) ACVC Association for Acute CardioVascular Care ADA adenosine deaminase ADAM a disintegrin and metalloproteinase ADAPT 2-​Hour Accelerated Diagnostic protocol to Assess Patients with chest pain symptoms using contemporary Troponins as the only biomarker (trial) ADCHF acutely decompensated chronic heart failure ADH antidiuretic hormone ADHERE Acute Decompensated HEart Failure National REgistry ADHF acute decompensated heart failure ADM adrenomedullin ADP accelerated diagnostic protocol; adenosine diphosphate ADQI Acute Dialysis Quality Initiative ADSORB Acute Dissection: Stent graft OR Best medical therapy (trial) AE adverse event AECC American-​European Consensus Conference AED automated external defibrillator; antiepileptic drug AER albumin excretion rate AF atrial fibrillation AFE amniotic fluid embolism AG anion gap AGI acute gastrointestinal injury AHA American Heart Association AHF acute heart failure AHFS acute heart failure syndromes AHQR Agency for Healthcare Quality and Research AI asynchrony index; aortic insufficiency; adrenal insufficiency; artificial intelligence AIDS acquired immune deficiency syndrome AIH amiodarone-​induced hyperthyroidism AIMS Australian Incident Monitoring System AIVR accelerated idioventricular rhythm AKD acute kidney disease

AKI AKIN ALARM-​HF ALD ALI ALS ALT AMACING AMI AMP AMPA AMPK AMR ANC ANCA ANP AP APACE APACHE APC APEX AMI APP APPRAISE-​2 APPROACH APROCCHSS APRI aPTT AR ARB ARC-​HBR ARDS ARF ARNI ARVC AS

acute kidney injury Acute Kidney Injury Network Acute Heart Failure Global Survey of Standard Treatment (registry) adjustable loop diuretics acute lung injury advanced life support alanine aminotransferase A MAastricht Contrast-​Induced Nephropathy Guideline (trial) acute myocardial infarction adenosine monophosphate α-​amino-​3-​hydroxy-​5-​methyl-​4-​ isoxazole propionic acid adenosine monophosphate-​ activated protein kinase antibody-​mediated rejection absolute neutrophil count anti-​neutrophilic cytoplasmic antibodies atrial natriuretic peptide action potential; anteroposterior Advantageous Predictors of Acute Coronary Syndromes Evaluation Acute Physiology and Chronic Health Evaluation adaptive pressure control Assessment of Pexelizumab in Acute Myocardial Infarction (trial) abdominal perfusion pressure Apixaban for Prevention of Acute Ischemic Events 2 (trial) Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (study) Activated Protein C and Corticosteroids for Human Septic Shock (trial) aspartate transaminase-​to-​platelet ratio index activated partial thromboplastin time aortic regurgitation angiotensin receptor blocker Academic Research Consortium for High Bleeding Risk acute respiratory distress syndrome acute respiratory failure; ascending reticular formation angiotensin receptor–​neprilysin inhibitor arrhythmogenic right ventricular cardiomyopathy aortic stenosis

Sym b ol s a n d a b b rev iat i on s ASCEND-​HF

Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (trial) ASIC acid-​sensing ion channel ASPECT ASia Pacific Evaluation of Chest pain Trial ASSENT-​2 Assessment of the Safety and Efficacy of a New Thrombolytic (trial) AST aspartate aminotransferase ASV adaptative servoventilation AT atrial tachycardia ATACH II Antihypertensive Treatment of Acute Cerebral Hemorrhage II (trial) ATC automatic tube compensation; Antithrombotic Trialists’ Collaboration ATG antithymocyte globulin ATIII antithrombin III ATLANTIC Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery ATLAS ACS 2 Anti-​Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome (trial) ATN acute tubular necrosis ATOLL Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short-​ and Long-​term follow-​up (trial) ATOMIC-​HF Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (trial) ATP adenosine triphosphate AUC area under the curve AUF adjustable ultrafiltration AUGUSTUS Open-​Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/​or Percutaneous Coronary Intervention (trial) AV atrioventricular

AVA AVM AVNRT AVOID-​HF AVP AVR AVRT BACH BARC BART BATTLESCARRED BAV BEST

bio-​ADM BiPAP BIS BITA BiVAD BLS BLS-​TOR BMI BMS BNP BOLD BPA bpm BPS BRIDGE

BRIGHT BSA

aortic valve area arteriovenous malformation atrioventricular nodal re-​entrant tachycardia Aquapheresis versus Intravenous Diuretics and Hospitalizations for Heart Failure (trial) arginine vasopressin aortic valve replacement atrioventricular re-​entrant tachycardia Biomarkers in Acute Heart Failure (trial) Bleeding Academic Research Consortium Blood Conservation Using Antifibrinolytics in a Randomized Trial NT-​proBNP-​Assisted Treatment To Lessen Serial Cardiac Readmissions and Death (trial) balloon aortic valvuloplasty Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-​Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease (trial) bioactive adrenomedullin bilevel positive airway pressure bispectral index; Berlin Initiative Study bilateral internal thoracic artery biventricular ventricular assist device basic life support basic life support termination of resuscitation body mass index bare-​metal  stent B-​type natriuretic peptide Beta-​agonists for Oxygenation in Lung Donors (trial) balloon pulmonary angioplasty beats per minute Behavioural Pain Scale Maintenance of Platelet inihiBition With cangRelor After dIscontinuation of ThienopyriDines in Patients Undergoing surGEry (trial) Bivalirudin in Acute Myocardial Infarction versus Heparin and GPI Plus Heparin (trial) body surface area

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xiv

Symb ols an d abbreviations BTC BTD BTR BTS BTT BUN BV Ca2+ CABG CAC CAD CADASIL CAM-​ICU cAMP CANGRELOR

CANTOS CANVAS CAP CARP CARRESS-​HF cART CAS CASTLE-​AF

CAV CAVH CAVHD CBF CBV CC CCB CCSS CCTA CCU CCW CD CE CEA CEC cEEG

bridge to transplantation candidacy bridge to decision bridge to recovery British Thoracic Society bridge to transplantation blood urea nitrogen biological variability calcium ion coronary artery bypass grafting coronary artery calcium/​calcification coronary artery disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Confusion Assessment Method for the Intensive Care Unit cyclic adenosine monophosphate CANgrelor and Crushed TICagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention (trial) Canakinumab Anti-​Inflammatory Thrombosis Outcomes Study CANagliflozin cardioVascular Assessment Study community-​acquired pneumonia Coronary Artery Revascularization Prophylaxis (trial) Cardiorenal Rescue Study in Acute Decompensated Heart Failure (trial) combination antiretroviral therapies carotid angioplasty and stenting Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (trial) cardiac allograft vasculopathy continuous arteriovenous haemofiltration continuous arteriovenous haemodiafiltration cerebral blood flow cerebral blood volume core curriculum calcium channel blocker Critical Care Safety Study coronary computerized tomography angiography coronary care unit; critical care unit compliance of the chest wall cluster of differentiation cholesterol ester carotid endarterectomy Clinical Event Committee continuous electroencephalogram

cfDNA cGMP CHAMPION

cell-​free deoxyribonucleic acid cyclic guanosine monophosphate Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (trial) CHAMPION PHOENIX Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (trial) CHANCE Clopidogrel in High-​Risk Patients with Acute Nondisabling Cerebrovascular Events (trial) CHD coronary heart disease; congenital heart disease CI critical incident; confidence interval; cardiac index CICU cardiac intensive care unit CIH cardiogenic ischaemic hepatitis CIN contrast medium-​induced nephropathy CIRCI critical illness-​related corticosteroid insufficiency CK creatine kinase CKD chronic kidney disease CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration CK-​MB creatine kinase isoenzyme subunit MB CL compliance of the lung Cl–​ chloride ion CLARITY Clopidogrel as Adjunctive Reperfusion Therapy CLOTS Clots in Legs Or sTockings after Stroke (trial) cm centimetre CM contrast medium CME continuing medical education cmH2O centimetre of water CMR cardiac magnetic resonance CMV continuous mandatory ventilation; cytomegalovirus c-​MyC cardiac myosin-​binding protein C CNS central nervous system CNST Clinical Negligence Scheme for Trusts CO2 carbon dioxide CoA coarctation of the aorta COCATS 4-​TF 13 Core Cardiovascular Training Statement 4 by Task Force 13 COGENT Clopidogrel and the Optimization of Gastrointestinal Events Trial COMET Carvedilol Or Metoprolol European Trial COMFORTABLE AMI Comparison of Biolimus Eluted from an Erodible Stent Coating with Bare-​ Metal Stents in Acute ST-​Elevation Myocardial Infarction (trial)

Sym b ol s a n d a b b rev iat i on s COMMIT COMPARE-​ACUTE

COPD COPERNICUS COX CP CPAP CPAP/​PS CPB CPC CpcPH CPM CPOT CPP CPR CPU CPVT CQC CR CRBSI CrCl CRISP-​AMI CRM CRP CRRT CRS CRS CRT CRT-​D CRT-​P CRUSADE

CS

ClOpidogrel and Metoprolol in Myocardial Infarction Trial Comparison Between FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With Multivessel disease (trial) chronic obstructive pulmonary disease Carvedilol Prospective Randomized Cumulative Survival (trial) cyclo-​oxygenase chest pain continuous positive airway pressure continuous positive airway pressure/​ pressure support ventilation cardiopulmonary bypass Cerebral Performance Category (score) combined post-​capillary pulmonary hypertension continuous passive motion; central pontine myelinolysis Critical Care Pain Observation Tool coronary perfusion pressure; cerebral perfusion pressure cardiopulmonary resuscitation chest pain unit catecholaminergic polymorphic ventricular tachycardia Care Quality Commission cardiac rupture catheter-​related bloodstream infection creatinine clearance Counterpulsation to Reduce Infarct Size Pre-​PCI Acute Myocardial Infarction (trial) crew resource management C-​reactive protein continuous renal replacement therapy compliance of the respiratory system cardiorenal syndrome cardiac resynchronization treatment cardiac resynchronization treatment defibrillator cardiac resynchronization treatment pacemaker Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/​AHA Guideline (registry) cardiogenic shock

CSD CSF CSS CT CTA

cardiac sympathetic denervation cerebrospinal fluid Clinical SYNTAX score computerized tomography computerized tomography angiography CTCA computerized tomography coronary angiography CTEPH chronic thromboembolic pulmonary hypertension cTn cardiac troponin cTnI cardiac troponin I cTnT cardiac troponin T CTP computerized tomography perfusion CTPA computerized tomography pulmonary angiography CTR cardiothoracic ratio CULPRIT-​SHOCK Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock CUORE Continuous Ultrafiltration for cOngestive heaRt failure (trial) CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events (trial) CUS compression ultrasonography CV coefficient of variation CVA cerebrovascular accident CVC central venous catheter CVD cardiovascular disease CvLPRIT Complete Versus Lesion-​Only Primary PCI trial CVP central venous pressure CVR cerebral vascular resistance CVST cerebral venous and sinus thrombosis CVVH continuous veno-​venous haemofiltration CVVHD continuous veno-​venous haemodialysis CVVHDF continuous veno-​venous haemodiafiltration CXR chest  X-​ray DAG diacylglycerol DahLIA Dexmedetomidine to Lessen ICU Agitation (trial) DANAMI DANish Study of Optimal Acute Treatment of Patients With ST-​ elevation Myocardial Infarction (trial) DANAMI 3-​DEFER Third DANish Study of Optimal Acute Treatment of Patients with ST-​segment Elevation Myocardial Infarction: DEFERred stent implantation in connection with primary PCI

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Symb ols an d abbreviations DANAMI-​3–​PRIMULTI Third DANish Study of Optimal Acute Treatment of Patients With STEMI: PRImary PCI in MULTIvessel Disease DAPT dual antiplatelet therapy DAWN DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-​Up and Late Presenting Strokes Undergoing Neurointervention with Trevo DBD donation/​donor after brain death DC dendritic cell; direct current DCD donation/​donor after circulatory death DCM dilated cardiomyopathy DDAVP 1-​deamino-​8-​d-​arginine-​vasopressin DECCA Delirium Epidemiology in Critical Care (study) DECLARE-​TIMI58 Dapagliflozin Effect on Cardiovascular Events–​Thrombolysis in Myocardial Infarction 58 (trial) DECREASE-​2 Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography-​2 (trial) DEFUSE 3 Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (trial) DELIVER Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (trial) DES drug-​eluting  stent DESTINY II Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (trial) DEXACET Dexmedetomidine and IV Acetaminophen for the Prevention of Postoperative Delirium Following Cardiac Surgery (trial) DEXCOM Dexmedetomidine Compared to Morphine (trial) DG diastolic gradient DIC disseminated intravascular coagulation DIPOM Diabetic Postoperative Mortality and Morbidity (trial) DKA diabetic ketoacidosis dL decilitre DNA deoxyribonucleic nucleic acid DNACPR do-​not-​attempt-​cardiopulmonary-​ resuscitation DNAR do-​not-​attempt-​resuscitation DO2 myocardial oxygen supply DOAC direct oral anticoagulant DOSE Diuretic Optimization Strategies Evaluation (trial)

DOSE-​AHF

Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (trial); Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (trial) DSE dobutamine stress echocardiography DSM Diagnostic and Statistical Manual of Mental Disorders DSM-​V Diagnostic and Statistical Manual of Mental Disorders, fifth edition DT destination therapy DTI direct thrombin inhibitor dTT dilute thrombin time DVT deep vein thrombosis DWI diffusion-​weighted imaging EACTA European Association of Cardiothoracic Anaesthesiology EACTS European Association of Cardio-​ Thoracic Surgery EACVI European Association of Cardiovascular Imaging EAdi electrical activity of the diaphragm EARLY-​ACS Early Glycoprotein IIb/​IIIa Inhibition in Non-​ST-​Segment Elevation Acute Coronary Syndrome (trial) EARLY-​BAMI Early-​Beta blocker Administration before reperfusion primary PCI in patients with ST-​elevation Myocardial Infarction (trial) EAST Eastern Association for the Surgery of Trauma EBCT electron beam computerized tomography EBM evidence-​based medicine EBV Epstein–​Barr  virus ECCO2R extracorporeal carbon dioxide removal ECF extracellular fluid ECG electrocardiogram ECLS extracorporeal life support ECM extracellular matrix ECMO extracorporeal membrane oxygenation ECOS extracorporeal organ support eCPR extracorporeal CPR ECS-​PSC European Society of Cardiology position statement criteria ED emergency department EDACS Emergency Department Assessment of Chest Pain Score Accelerated Diagnostic Pathway EDD extended daily dialysis EDTA ethylenediaminetetraacetic acid

Sym b ol s a n d a b b rev iat i on s EEG electroencephalography EES everolimus-​eluting  stent EF ejection fraction eGFR estimated glomerular filtration rate EHRA European Heart Rhythm Association EIT electrical impedance tomography ® ELF Enhanced Liver Fibrosis Test® ELISA Early or Late Intervention in unStable Angina (trial) EMA European Medicines Agency EMB endomyocardial biopsy EMD emergency medical dispatching EMI electromagnetic interference EMPA-​REG OUTCOME Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–​Removing Excess Glucose EMPA-​RESPONSE Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (trial) EMS emergency medical services/​system; electrical muscle stimulation EMT emergency medical technician EN enteral nutrition ENCHANTED Enhanced Control of Hypertension and Thrombolysis Stroke Study eNOS endothelial nitric oxide synthase ENTRUST-​AF Edoxaban-​Based Antithrombotic Regimen in Patients With Atrial Fibrillation (trial) EoLC end-​of-​life  care EOLCS End of Life Care Strategy EORP EURObservational Research Program EORTC/​MSG European Organization for Research and Treatment of Cancer/​Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group EP emergency medicine physician; evoked potential EPA entrustable professional activity EPaNIC Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (trial) EPAP expiratory positive airway pressure ePCR extracorporeal membrane oxygenation cardiopulmonary resuscitation ERC European Resuscitation Council EROA effective regurgitant orifice area ERTP early releasable troponin pool ES electrical storm ESA erythropoietin-​stimulating  agent ESC European Society of Cardiology

ESCAPE ESCeL ESICM ESKD ESPEN ESPVR ESR ET-​1 ETT EU EUNetPaS EUROMAX EuroSCORE EUROSTAR EV EVEREST

EVLP EVLW EVT EXAMINATION EXPIRA

EXTEND ExTRACT-​TIMI 25

F FABULOS-​PRO

Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (trial) European Society of Cardiology e-​Learning European Society of Intensive Care Medicine end-​stage kidney disease European Society for Clinical Nutrition and Metabolism end-​systolic pressure–​volume relationship erythrocyte sedimentation rate endothelin-​1 endotracheal tube European Union European Network for Patient Safety European Ambulance Acute Coronary Syndrome Angiography (trial) European System for Cardiac Operative Risk Evaluation European Collaborators on Stent Graft Techniques for Thoracic Aortic Aneurysm and Dissection Repair extracellular vesicle Endovascular Valve Edge-​to-​Edge Repair Study; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (trial) ex vivo lung perfusion extravascular lung water endovascular thrombectomy clinical Evaluation of the Xience-​ V stent in Acute Myocardial INfArcTION (trial) Thrombectomy With EXPort Catheter in Infarct-​Related Artery During Primary Percutaneous Coronary Intervention (trial) Extending the Time for Thrombolysis in Emergency Neurological Deficits (trial) Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–​Thrombolysis in Myocardial Infarction 25 French; factor Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-​segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse (trial)

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Symb ols an d abbreviations FAME

FFR vs Angiography for Multivessel evaluation (trial) FANTASTIC Full ANTicoagulation versus ASpirin and TIClopidine (trial) FAS full age spectrum FAST focused assessment with sonography for trauma FAST-​MI French registry of Acute ST-​elevation or non-​ST-​elevation Myocardial Infarction FBI fast, broad, irregular FDA Food and Drug Administration 18 FDG-​PET F-​fluorodeoxyglucose positron emission tomography FEV1 forced expiratory volume in 1 second FFR fractional flow reserve FFRct fractional flow reserve measured by coronary computerized tomography angiography FIMR functional ischaemic muscle rupture/​ mitral regurgitation FiO2 fraction of inspired oxygen FL fibrinolysis FLAIR fluid-​attenuated inversion recovery FMC first medical contact FMEA failure modes and effects analysis FO-​BAL fibreoptic bronchoscopy with bronchoalveolar lavage FOUR Full Outline of UnResponsiveness (score) FPR false positive ratio FRC functional residual capacity FRISC Fast Revascularisation in InStability in Coronary disease (score/​trial) FUTURA OASIS-​8 Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (trial) FWR free wall rupture g gram G gauge GABA gamma-​aminobutyric  acid GALACTIC-​HF Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (trial) GBD Global Burden of Diseases, Injuries, and Risk Factors (study) GCS Glasgow Coma Scale GDF-​15 growth differentiation factor-​15 GDMT guideline-​directed medical treatment GEMINI ACS 1 Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (trial) GFR glomerular filtration rate GGT gamma glutamyltransferase GI gastrointestinal

GICS GIF GIK GISSI

Gastrointestinal Complication Score gastrointestinal failure glucose–​insulin–​potassium Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico GLASSY GLOBAL LEADERS Adjudication Sub-​Study GLS global longitudinal strain GP glycoprotein GPI glycoprotein IIb/​IIIa inhibitor GRACE Global Registry of Acute Coronary Events GRC Global Risk Classification GRV gastric residual volume GUIDE-​IT Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (study) GUSTO Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (trial) h hour H+ hydrogen ion HAART highly active antiretroviral therapy Hb haemoglobin HBD heart-​beating  donor HBV hepatitis B virus HCM hypertrophic cardiomyopathy HCO3–​ carbonate ion H2CO3 carbonic acid HCV hepatitis C virus HDL high-​density lipoprotein HEAT-​PPCI How Effective Are Antithrombotic Therapies in Primary PCI (trial) HEMS helicopter emergency medical services HEPA high-​efficiency particulate air HES hydroxyethyl starch HF haemofiltration HFA Heart Failure Association HFD high-​flux dialysis HFmrEF heart failure with mid-​range left ventricular ejection fraction HFNC high-​flow nasal cannula HFOV high-​frequency oscillatory ventilation HFpEF heart failure with preserved left ventricular ejection fraction HFrEF heart failure with reduced left ventricular ejection fraction HFSS Heart Failure Survival Score H-​Hb protonated haemoglobin HHS hyperglycaemic hyperosmolar state HHV6 human herpesvirus 6 HIF hypoxia-​inducible  factor HIPA heparin-​induced platelet activation HIT heparin-​induced thrombocytopenia HIV human immunodeficiency virus

Sym b ol s a n d a b b rev iat i on s HOCM HORIZONS-​AMI

hypertrophic obstructive cardiomyopathy Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (trial) HPO42–​ hydrogen phosphate H2PO4–​ dihydrogen phosphate HR hazard ratio; hormonal resuscitation HSCT haematopoietic stem cell transplantation hs-​cTn high-​sensitivity cardiac troponin hs-​cTnI high-​sensitivity cardiac troponin I hs-​cTnT high-​sensitivity cardiac troponin T HSP-​27 heat shock protein 27 hs-​Tn high-​sensitivity troponin hs-​TnI high-​sensitivity troponin  I hs-​TnT high-​sensitivity troponin  T HTAD heritable thoracic aortic aneurysm/​ dissection HTx heart transplant HU Hounsfield unit HVHF high-​volume haemofiltration Hz hertz IABP intra-​aortic balloon pump IABP-​SHOCK II Intra-​Aortic Balloon Pump in Cardiogenic Shock II (trial) IACC intensive and acute cardiovascular care IAH intra-​abdominal hypertension IAP intra-​abdominal pressure IC indirect calorimetry ICA invasive coronary angiography ICAM-​1 intercellular adhesion molecule 1 ICCU intensive cardiovascular care unit ICD implantable cardioverter–​defibrillator ICDSC Intensive Care Delirium Screening Checklist ICF intracellular fluid ICG indocyanine green ICH intracranial haemorrhage ICNARC Intensive Care National Audit and Research Centre ICON-​RELOADED ICON: Re-​evaluation of Acute Diagnostic Cut-​Offs in the Emergency Department (study) ICP intracranial pressure ICU intensive care unit ICU-​AW intensive care unit-​acquired weakness IDF incident dark field (imaging) IDSA Infectious Diseases Society of America IE infective endocarditis IFCC International Federation of Clinical Chemistry and Laboratory Medicine IFI invasive fungal infection IFN interferon iFR instantaneous wave-​free ratio Ig immunoglobulin

IGFBP

insulin-​like growth factor-​binding protein IGFBP-​7 insulin-​like growth factor-​binding protein-​7 IgG immunoglobulin G IgM immunoglobulin M IHCA in-​hospital cardiac arrest IHD intermittent haemodialysis; ischaemic heart disease IHI Institute for Healthcare Improvement IIE ineffective inspiratory efforts IL interleukin ILCOR International Liaison Committee on Resuscitation IL-​2RA interleukin-​2 receptor antagonist IM intramuscular IMACS International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support IMCA Independent Mental Capacity Advocate IMH intramural haematoma IMPROVE-​CHF Improved Management of Patients With Congestive Heart Failure (study) IMPROVE-​IT Improved Reduction of Outcomes: Vytorin Efficacy International Trial IMV intermittent mandatory ventilation iNOS inducible nitric oxide synthase INR international normalized ratio INSTEAD INvestigation of STEnt grafts in patients with type B Aortic Dissection (trial) INTERACT 2 Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support IO intraosseous IoM Institute of Medicine IP3 inositol triphosphate IPAH idiopathic pulmonary arterial hypertension IPAP inspiratory positive airway pressure IpcPH isolated post-​capillary pulmonary hypertension IPPV intermittent positive pressure ventilation IPTW inverse probability of treatment weight IPV intrapulmonary percussive ventilation IQR interquartile range IRA infarct-​related  artery IRAD International Registry of Acute Aortic Dissection IRI ischaemia and reperfusion injury IS incentive spirometry; ischaemic stroke ISAR Intracoronary Stenting and Antithrombotic Regimen (trial)

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Symb ols an d abbreviations ISAR-​CABG

Is Drug-​Eluting-​Stenting Associated with Improved Results in Coronary Artery Bypass Grafts (trial) ISAR-​COOL Intracoronary Stenting With Antithrombotic Regimen Cooling-​Off (trial) ISAR-​REACT 4 Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4 (trial) ISDN isosorbide dinitrate ISICEM International Symposium on Intensive Care and Emergency Medicine ISIS International Study of Infarct Survival (trial) ISMICS International Society of Minimally Invasive Coronary Surgery ISS Injury Severity Score ISTH International Society on Thrombosis and Haemostasis ITA internal thoracic artery ITD impedance threshold device ITP intrathoracic pressure IU international unit IV intravenous IVIG intravenous immunoglobulin I-​VT International Ventricular Tachycardia (score) IVUS intravascular ultrasound IVUS-​VH intravascular ultrasound virtual histology J joule JCAHO Joint Commission on Accreditation of Healthcare Organizations JVP jugular venous pressure K+ potassium ion kcal kilocalorie kDa kilodalton KDIGO Kidney Disease: Improving Global Outcomes kg kilogram KIM 1 kidney injury molecule 1 KLF4 kruppel-​like factor 4 km kilometre kV kilovolt Kw dissociation constant L litre LA left atrial; left atrium LAD left anterior descending (artery) LAP left atrial pressure LAVA local abnormal ventricular activity LAX long-​axis (view, ultrasound) LBBB left bundle branch block LCX left circumflex LDB load-​distributing  band LDH lactate dehydrogenase

LDL LFA-​1 LFABP LGE LGE-​CMR

low-​density lipoprotein lymphocyte associated antigen-​1 liver fatty acid-​binding protein late gadolinium enhancement late gadolinium enhancement cardiac magnetic resonance LGE-​MRI late gadolinium enhancement magnetic resonance imaging LiDCO lithium dilution cardiac output LIDO Levosimendan Infusion versus Dobutamine (trial) LIMA left internal mammary artery LIS lung injury score LITA left internal thoracic artery LMWH low-​molecular-​weight heparin LOC loss of consciousness LoE level of evidence LOX1 lectin-​like oxidized low-​density lipoprotein receptor 1 Lp(a) lipoprotein (a) LPS lipopolysaccharide LQTS long QT syndrome LRP-​1 low-​density lipoprotein receptor-​related protein 1 LT laryngeal tube LUCAS Lund University Cardiac Arrest System LV left ventricular LVA left ventricular aneurysm LVAD left ventricular assist device LVEDD left ventricular end-​diastolic diameter LVEDP left ventricular end-​diastolic pressure LVEF left ventricular ejection fraction LVESD left ventricular end-​systolic diameter LV-​ESV left ventricular end-​systolic volume LVOT left ventricular outflow tract LVWR left ventricular wall rupture m metre mA milli ampere MAAVR minimal-​access aortic valve replacement MAC mitral annulus calcification MAC-​1 macrophage antigen 1 MACCE major adverse cardiac and cerebrovascular event MACE major adverse cardiac event MACS Manchester Acute Coronary Syndromes MAP mean arterial pressure MAPSE mitral annular plane systolic excursion MATRIX Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (trial) MATTIS Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (trial) MaVS Metoprolol after Vascular Surgery (trial) MBG myocardial blush grade

Sym b ol s a n d a b b rev iat i on s MC

myxoedema coma; mechanical complication MCEP medicine community educational programme MCQ multiple choice question MCS mechanical circulatory support M-​CSF macrophage colony-​stimulating factor MDRD Modified Diet in Renal Disease MELD Model for End-​Stage Liver Disease MELD-​XI Model for End-​stage Liver Disease eXcluding INR MENDS Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (trial) MEq milli equivalent MESA Multi-​Ethnic Study of Atherosclerosis METOCARD-​CNIC Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (trial) MFI Microvascular Flow Index mg milligram Mg2+ magnesium ion mGFR measured glomerular filtration rate mGluR metabotropic glutamate receptor mGy milligray MHI manual hyperinflation MHz mega hertz MI myocardial infarction MIC myocardial intervention centre MIDCAB minimally invasive direct coronary artery bypass MIDEX Midazolam Compared to Dexmedetomidine (trial) MI-​E mechanical insufflator–​exsufflator min minute MINAP Myocardial Ischaemia National Audit Project MIND-​USA Modifying the Impact of ICU-​ Associated Neurological Dysfunction–​ USA (trial) MINOCA myocardial infarction with non-​ obstructive coronary arteries MIP maximum intensity projection miRNA micro ribonucleic acid mL millilitre MLA minimal lumen area MLD minimal lumen diameter mm millimetre MMF mycophenolate mofetil mmHg millimetre of mercury MMI methimazole mmLDL minimally modified low-​density lipoprotein

mmol millimole MMP matrix metalloproteinase MODS multiorgan dysfunction syndrome MOF multiorgan failure mol mole MOMENTUM-​3 Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (trial) MONICA MoNItoring of trends and determinants in CArdiovascular disease mOsmol milliosmole MOST multiorgan support therapy MP microparticle mPAP mean pulmonary arterial pressure MPI myocardial perfusion imaging MPO myeloperoxidase MPR multiplanar reconstruction MPS myocardial perfusion scanning MR magnetic resonance; mitral regurgitation MRA mineralocorticoid receptor antagonist MRC Medical Research Council MRI magnetic resonance imaging mRNA messenger ribonucleic acid MR-​proADM mid-​regional pro-​adrenomedullin MR-​proANP mid-​regional pro-​atrial natriuretic peptide mRS modified Rankin scale MRSA methicillin-​resistant Staphylococcus aureus ms millisecond MS mitral stenosis MSCT multi-​slice computerized tomography mSv milli sievert MTHFR methylenetetrahydrofolate reductase mTOR mammalian target of rapamycin mU milli unit MULTISTRATEGY Multicentre Evaluation of Single High-​ Dose Bolus Tirofiban vs Abciximab With Sirolimus-​Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study mV millivolt MV minute ventilation MVA mitral valve area MVO microvascular obstruction n number Na+ sodium ion NAC N-​acetylcysteine NaCl sodium chloride NAFLD non-​alcoholic fatty liver disease NaHCO3 sodium bicarbonate

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Symb ols an d abbreviations NASA

National Aeronautics and Space Administration NASH non-​alcoholic steatohepatitis NAVA neurally adjusted ventilatory assist NCC MERP National Coordinating Council on Medical Error Reporting and Prevention NCEPOD National Confidential Enquiry into Patient Outcome and Death NEFA non-​esterified fatty acid NEMS neuromuscular electrical stimulation NET neutrophil extracellular trap NF nuclear factor ng nanogram NG nasogastric NGAL neutrophil gelatinase-​associated lipocalin NH3 ammonia NH4+ ammonium ion NHANES National Health and Nutrition Examination Survey NHBD non-​heart-​beating  donor NHS National Health Service NHSLA National Health Service Litigation Authority NICE National Institute for Health and Care Excellence NICE-​SUGAR Normoglycemia in Intensive Care Evaluation–​Survival Using Glucose Algorithm Regulation (trial) NIH National Institutes of Health NIPPV non-​invasive positive pressure ventilation NIPSV non-​invasive pressure support ventilation NIRS near-​infrared spectroscopy NIS Nationwide Inpatient Sample NIST National Institute of Standards and Technology NIV non-​invasive ventilation NK natural killer NLRP3 NLR family pyrin domain-​containing 3 NMDA N-​methyl-​D-​aspartate nmol nanomole NO nitric oxide NOAC non-​vitamin K antagonist oral anticoagulant NOMI non-​occlusive mesenteric ischaemia NORSTENT Norwegian Coronary Stent Trial NOS nitric oxide synthase NP natriuretic peptide NPV negative predictive value; negative pressure ventilation NRCPR National Registry of Cardiopulmonary Resuscitation NRLS National Reporting and Learning System NRS numerical rating scale NSAID non-​steroidal anti-​inflammatory  drug NSE neuron-​specific enolase

NSTE-​ACS

non-​ST-​segment elevation acute coronary syndrome NSTEMI non-​ST-​segment elevation myocardial infarction NSVT non-​sustained ventricular tachycardia NT-​proBNP N-​terminal pro-​B-​type natriuretic peptide NYHA New York Heart Association O2 oxygen OASIS Organization for the Assessment of Strategies for Ischemic Syndromes OASIS-​5 Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (trial) OASIS 6 Organization for the Assessment of Strategies for Ischemic Syndromes 6 (trial) OAT Occluded Artery Trial OCT optical coherence tomography O2ER oxygen extraction ratio OFA omega-​3 fatty acid OFR oxygen free radical OH–​ hydroxide ion OHCA out-​of-​hospital cardiac  arrest OI oxygenation index OMT optimal medical treatment ONT Organización Nacional de Trasplantes OPCABG off-​pump coronary artery bypass graft OPTIMA-​CC Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock OPTIME-​CHF Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure OPTIMIZE-​HF Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (registry) OR odds ratio ORBI Observatoire Régional Breton sur l’Infarctus OSA obstructive sleep apnoea OSCAR Oscillation in ARDS (trial) OSCILLATE Oscillation for Acute Respiratory Distress Syndrome Treated Early (trial) oxLDL oxidized low-​density lipoprotein P probability PA posteroanterior PAC pulmonary artery catheter/​ catheterization PaCO2 arterial partial pressure of carbon dioxide PACO2 alveolar pressure of carbon dioxide PADIS Prevention and management of pain, Agitation/​sedation, Delirium, Immobility, and Sleep disruption PAF platelet-​activating  factor PAH pulmonary arterial hypertension

Sym b ol s a n d a b b rev iat i on s PAI-​1 PAIRWAY PALS PALV PAMI

plasminogen activator inhibitor type-​1 airway pressure Patient Advice and Liaison Service alveolar pressure Primary Angioplasty in Myocardial Infarction (trial) PAMP pathogen-​associated molecular pattern PaO2 arterial partial pressure of oxygen PAO2 alveolar pressure of oxygen PAOP pulmonary artery occlusion pressure PAP pulmonary artery pressure PAPI pulmonary artery pulsatility index PAR protease-​activated receptor PAR-​1 protease-​activated receptor  1 PARAGON Platelet IIb/​IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (trial) PARP-​1 poly(ADP-​ribose) polymerase  1 PAU penetrating aortic ulcer PAV proportional assist ventilation PAWP pulmonary artery wedge pressure PBW predicted body weight PCA patient-​controlled analgesia PC-​ACV pressure-​controlled assist-​control ventilation PC-​APRV pressure-​controlled airway pressure release ventilation PCAS post-​cardiac arrest syndrome PC-​BIPAP pressure-​controlled biphasic positive airway pressure PCBS percutaneous cardiopulmonary bypass support PCC prothrombin complex concentrate PC-​CMV pressure-​controlled continuous mechanical ventilation PCI percutaneous coronary intervention PCI-​CURE Percutaneous Coronary Intervention-​ Clopidogrel in Unstable angina to prevent Recurrent Events (trial) PCOS polycystic ovary syndrome PCR polymerase chain reaction PCS pulse contour system; post-​cardiotomy cardiogenic shock PC-​SIMV pressure-​controlled synchronized intermittent mandatory ventilation PCSK9 proprotein convertase subtilisin/​ kexin type 9 PCT procalcitonin PCWP pulmonary capillary wedge pressure PD peritoneal dialysis PDIRRT prolonged daily intermittent renal replacement therapy PDRICG plasma disappearance rate of indocyanine green

PE PEA PEEP PEEPi PEGASUS-​TIMI 54

pulmonary embolus/​embolism pulseless electric activity positive end-​expiratory pressure intrinsic positive end-​expiratory pressure Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–​Thrombolysis in Myocardial Infarction 54 PER protein excretion rate PERT Pulmonary Embolism Response Team PESI Pulmonary Embolism Severity Index PET positron emission tomography PFT platelet function test pg picogram PGI2 prostacyclin PH pulmonary hypertension; prolyl hydroxylase PH-​LHD pulmonary hypertension secondary to left heart disease PI protease inhibitor PICC peripherally inserted central catheter PiCCO pulse-​induced contour cardiac output PIO2 inspired pressure of oxygen PIONEER-​HF Comparison of Sacubitril–​Valsartan versus Enalapril on Effect on NT-​proBNP in Patients Stabilized from an Acute Heart Failure Episode (trial) PIRRT prolonged intermittent renal replacement therapy PIS pulmonary interstitial syndrome PLATO Study of Platelet Inhibition and Patient Outcomes (trial) PLC phospholipase C pLVAD percutaneous left ventricular assist device PM performance measure PMC percutaneous mitral commissurotomy PMI perioperative myocardial ischaemia pmol picomole pmp patient per million (inhabitants) PMR papillary muscle rupture PN parenteral nutrition PO orally pO2 partial oxygen pressure POCT point-​of-​care  test POINT Platelet-​Oriented Inhibition in New TIA and Minor Ischemic Stroke (trial) POISE Perioperative Ischemic Evaluation (trial) PP plasmapheresis PPCM peripartum cardiomyopathy Ppeak airway peak pressure PPI proton pump inhibitor PPL pleural pressure PPLATEAU plateau pressure

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Symb ols an d abbreviations PPV

positive predictive value; positive pressure ventilation PRAGUE PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency thrombolysis (trial) PRAGUE-​18 Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction (trial) PRAMI Preventive Angioplasty in Acute Myocardial Infarction (trial) PRECISE-​DAPT Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (trial) PRECOMBAT Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-​Eluting Stent in Patients with Left Main Coronary Artery Disease (trial) PRESERVE Prevention of Serious Adverse Events Following Angiography (trial) PRIDE Pro-​BNP Investigation of Dyspnea in the Emergency Department (trial) PRODEX Propofol Compared to Dexmedetomidine (trial) PROTECT Placebo-​controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Over-​load to Assess Treatment Effect on Congestion and Renal Function (trial) PRR pattern recognition receptor PS pressure support ventilation PSI patient safety incident P-​SILI patient-​self-​induced lung  injury PT prothrombin time PTA percutaneous transluminal angioplasty PTCA percutaneous transluminal coronary angioplasty PTLD post-​transplantation lymphoproliferative disorder PTU propylthiouracil PURSUIT Platelet Glycoprotein IIb/​IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (trial) P/​V pressure/​volume PVA patient–​ventilator asynchrony PVC premature ventricular contraction; premature ventricular complex PVR pulmonary vascular resistance; paravalvular regurgitation pVT pulseless ventricular tachycardia

PWI PWR QCT QD QI Qp Qs qSOFA RAAS RALT RAS RBBB RBC RBF RCA RCRI RCT RCV REDEEM RELAX-​AHF REM REMATCH REPLACE-​2 RHC RI RIFLE

RIFLE-​STEACS RITA RITA 3 RIVAL RNA ROC ROPAC ROSC ROSE-​AHF rpm

perfusion-​weighted imaging papillary wall rupture quantitative computerized tomography angiography dialysate flow quality indicator pulmonary flow systemic flow quick SOFA renin–​angiotensin–​aldosterone system; Richmond Agitation Sedation Scale right anterolateral thoracotomy radiological 5-​point atelectasis score right bundle branch block red blood cell renal blood flow right coronary artery Revised Cardiac Risk Index randomized controlled trial reference change value Randomised Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes (trial) Serelaxin, Recombinant Human Relaxin-​ 2, for Treatment of Acute Heart Failure (trial) rapid eye movement Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (trial) Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2 (trial) right heart catheterization resistive index Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, End-​stage kidney disease Radial Versus Femoral Randomized Investigation in ST-​Elevation Acute Coronary Syndrome (trial) right internal thoracic artery Randomized Intervention Trial of Unstable Angina 3 (trial) RadIal Vs femorAL access for coronary intervention (trial) ribonucleic acid receiver operating characteristic Registry of Pregnancy and Cardiac disease return of spontaneous circulation Renal Optimization Strategies Evaluation in Acute Heart Failure (trial) revolution per minute

Sym b ol s a n d a b b rev iat i on s RR respiratory rhythm RRT renal replacement therapy RSCD Regional Study of Care for the Dying rSO2 regional oxygen saturation RT resuscitative thoracotomy rtPA recombinant tissue plasminogen activator RT-​PCR real-​time polymerase chain reaction RV right ventricular; right ventricle RVAD right ventricular assist device RVEF right ventricular ejection fraction RVOT right ventricular outflow tract RWPT R wave peak time s second SAH subarachnoid haemorrhage SALT San Antonio Lung Transplant SaO2 arterial oxygen saturation SAPS Simplified Acute Physiology Score SAT spontaneous awakening trial SAVR surgical aortic valve replacement SAX short-​axis (view, ultrasound) SBP systolic blood pressure SBT spontaneous breathing trial SC subcutaneous SCAAR Swedish Coronary Angiography and Angioplasty Register SCAD spontaneous coronary artery dissection SCAI Society for Cardiovascular Angiography and Interventions SCD sudden cardiac death SCr serum creatinine SCUF slow continuous ultrafiltration ScvO2 central venous oxygen saturation; superior vena cava oxygenation saturation SD standard deviation SDF sidestream dark field (imaging) SDI sidestream dark field imaging SE sentinel event SEDCOM Safety and Efficacy of Dexmedetomidine Compared with Midazolam (trial) SEES Sentinel Events Evaluation Study SFL Stent for Life (initiative) SGA supraglottic airway SGLT2 sodium–​glucose cotransporter 2 SGOT serum glutamic-​oxaloacetic transaminase SHFM Seattle Heart Failure Model SHOCK Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (trial) SHOCK-​COOL Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction (trial) SIADH syndrome of inappropriate antidiuretic hormone SILI self-​inflicted lung injury SIMV synchronized intermittent mandatory ventilation

SIRS SLEDD SMUR SNF SNP SOAP SOAP II SOD SOFA SOLOIST-​WHF S1P SPC SPECT sPESI SQTS SR SSEP SSFP sST2 ST2 STARRT-​AKI STARS STARS-​BNP STE-​ACS STEMI STEMI-​RADIAL STICH STICHES STREAM STS SUPPORT SURVIVE SV SvO2 SVR SVT

systemic inflammatory response syndrome slow low-​efficiency extended daily dialysis emergency mobile resuscitation services systemic nephrogenic fibrosis sodium nitroprusside Sepsis Occurrence in Acutely Ill Patients (trial) Sepsis Occurrence in Acutely Ill Patients II (trial) superoxide dismutase Sequential Organ Failure Assessment (score) Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (trial) sphingosine-​1-​phosphate specialist palliative care single-​photon emission computerized tomography simplified Pulmonary Embolism Severity Index short QT syndrome scavenger receptor somatosensory evoked potential steady-​state free precession soluble suppression of tumorigenicity-​2 suppression of tumorigenicity 2 STandard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (trial) Stent Anticoagulation Restenosis Study Systolic Heart Failure Treatment Supported by BNP (trial) ST elevation acute coronary syndrome ST-​segment elevation myocardial infarction ST Elevation Myocardial Infarction treated by RADIAL or femoral approach (trial) Surgical Treatment for Ischemic Heart Failure (trial); Surgical Trial in Spontaneous Intracerebral Haemorrhage (trial) STICH Extension Study Strategic Reperfusion Early after Myocardial Infarction (trial) Society of Thoracic Surgeons Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (trial) stroke volume mixed venous oxygen saturation systemic vascular resistance supraventricular tachycardia

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Symb ols an d abbreviations SYNTAX

Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (score/​trial) T tesla T3 triiodothyronine T4 thyroxine TACO transfusion-​associated circulatory overload TACTICS TIMI 18 Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)–​ Thrombolysis in Myocardial Infarction 18 (trial) TAFI thrombin-​activatable fibrinolysis inhibitor TAG transluminal attenuation gradient TAH total artificial heart TAO Treatment of Acute Coronary Syndrome with Otamixaban (trial) TAPAS Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study TAPSE tricuspid annular plane systolic excursion TAR traumatic aortic rupture TAVI transcatheter aortic valve implantation TBW total body water TCD transcranial Doppler TDI tissue Doppler imaging TdP torsades de pointes TE expiratory time; thromboelastometry/​ thromboelastography TEA thoracic epidural analgesia TECOS Trial Evaluating Cardiovascular Outcomes with Sitagliptin TENS transcutaneous electrical nerve stimulation TEVAR thoracic endovascular aortic repair TF tissue factor TFPi tissue factor pathway inhibitor TGF transforming growth factor TI inspiratory time TIA transient ischaemic attack TICACOS Tight Calorie Control Study TIMACS Timing of Intervention in Acute Coronary Syndrome (trial) TIME-​CHF Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (trial) TIMI Thrombolysis in Myocardial Infarction TIMP tissue inhibitor of metalloproteinase TITRe2 Transfusion Indication Threshold Reduction (trial) TLR toll-​like receptor TMP transmembrane pressure

TNF TNK-​tPA TOE TOF tPA TPE TPG TPP TR TRACER

tumour necrosis factor tenecteplase transoesophageal echocardiography time-​of-​flight tissue plasminogen activator therapeutic plasma exchange transpulmonary pressure gradient transpulmonary pressure tricuspid regurgitation Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (trial) TRA 2P-​TIMI 50 Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–​Thrombolysis in Myocardial Infarction 50 (trial) TRALI transfusion-​related lung injury TRANSITION Comparison of Pre-​and Post-​discharge Initiation of Sacubitril/​Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event (trial) TREAT Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis (trial) TRICS Transfusion Requirements in Cardiac Surgery (trial) TRILOGY Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (trial) TRIM transfusion-​induced immunomodulation TRITON Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (trial) TRIUMPH Translational Initiative on Unique and novel strategies for Management of Patients with Heart failure (study) TROPICAL-​ACS Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes (trial) TRP transient receptor potential TRUE-​AHF TRial of Ularitide’s Efficacy and safety in patients with Acute Heart Failure TRUST Triage Rule-​out Using high-​Sensitivity Troponin TS thyroid storm TSAT transferrin saturation TSH thyroid-​stimulating hormone TTE transthoracic echocardiography TTM targeted temperature management TTP thrombotic thrombocytopenic purpura TUS thoracic ultrasound TXA2 thromboxane A2 U unit

Sym b ol s a n d a b b rev iat i on s UA unstable angina UAG urine anion gap UF ultrafiltration UFH unfractionated heparin UK United Kingdom UK MINAP United Kingdom Myocardial Ischaemia National Audit Project UNOS United Network for Organ Sharing URL upper reference limit US United States; ultrasonography; ultrasound V volt VA ventricular arrhythmia VAD ventricular assist device VA-​ECMO veno-​arterial extracorporeal membrane oxygenation VALIDATE-​SWEDEHEART Bivalirudin versus Heparin in ST-​Segment and Non–​ST-​ Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-​based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial VAP ventilator-​associated pneumonia VAS visual analogue scale VASP vasodilator-​stimulated phosphoprotein VASS-​T Vasopressin and Septic Shock Trial VC-​AC volume-​controlled assist-​ control ventilation VCAM vascular cell adhesion molecule VC-​CMV volume-​controlled continuous mechanical ventilation VC-​SIMV volume-​controlled synchronized intermittent mandatory ventilation

VD VDS VEGF

dead space verbal descriptor scale vascular endothelial growth factor VF ventricular fibrillation VHD valvular heart disease VHVHF very high-​volume haemofiltration VILI ventilator-​induced lung injury ViR valve-​in-​ring VIRGO Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (trial) ViV valve-​in-​valve VKA vitamin K antagonist VO2 myocardial oxygen demand V/​Q ventilation/​perfusion VRS verbal rating scale VSD ventricular septal defect VSMC vascular smooth muscle cell VSR ventricular septal rupture VT tidal volume VT ventricular tachycardia VTE venous thromboembolism VV-​ECMO veno-​venous extracorporeal membrane oxygenation vWF von Willebrand factor VWR ventricular wall rupture W watt WCD wearable cardioverter–​defibrillator WHO World Health Organization WLST withdrawal of life-​sustaining treatment WOEST What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing (trial) WPW Wolff–​Parkinson–​White (syndrome) WRF worsening of renal function WU Woods unit

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Contributors

Alfredsson, Joakim Department of Cardiology, University Hospital, Linköping, Sweden

Borger, Michael A University Clinic for Cardiac Surgery, Heart Center, Leipzig, Germany

Alpert, Joseph S University of Arizona College of Medicine, Tucson, AZ, USA

Bremerich, Jens Department of Radiology, University Basel, Basel, Switzerland

Badimon, Lina Program ICCC-​Institut Català de Ciències Cardiovasculars IR-​ Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Bronselaer, Koen Emergency Department, University Hospitals Leuven, Leuven, Belgium

Balik, Martin Department of Anaesthesia and Intensive Care, First Medical Faculty, General University Hospital, Charles University, Prague, Czech Republic

Bueno, Héctor Cardiology Department, Hospital Universitario 12 de Octubre, Centro Nacional de Investigaciones Cardiovasculares, CIBER Cardiovascular (CIBER-​CV), Madrid, Spain

Ballotta, Andrea Department of Cardiothoracic Anaesthesia and Intensive Care, IRCCS Policlinico S Donato, Milan, Italy

Bunge, Jeroen JH Departments of Intensive Care Adults and Cardiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

Baratto, Francesca Arrhythmia Unit and Cardiac Electrophysiology, Ospedale San Raffaele, Milan, Italy

Burri, Haran Cardiac Pacing Unit, Cardiology Department, University Hospital of Geneva, Switzerland

Barrabés, José A Unidad Coronaria, Servicio de Cardiologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain

Busana, Mattia Department of Anesthesiology, Emergency Medicine and Critical Care, University of Göttingen, Göttingen, Germany

Bax, Jeroen J Department of Cardiology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands

Camm, A John Department of Clinical Cardiology, St George’s Hospital, University of London, London, UK

Beyer, Ruxandra University of Cluj-​Napoca, Cluj-​Napoca, Romania

Camporota, Luigi Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK

Boeddinghaus, Jasper Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Switzerland Bonnefoy-​Cudraz,  Eric Department of Acute Cardiovascular Care, University Hospital L Pradel, Hospices Civils de Lyon, Lyon, France

Cao, Davide The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA Carlesso, Eleonora Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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C ontribu tors Casaer, Michael P Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

Demetriades, Demetrios Division of Trauma, Emergency Surgery, and Surgical Critical Care, USC Medical Center, Los Angeles, CA, USA

Caso, Valeria University of Perugia Stroke Unit, Perugia, Italy

Dilling, Dagmara Department of Cardiology and Electrophysiology, Jessa Ziekenhuis, Hasselt, Belgium

Castelvecchio, Serenella Department of Cardiothoracic Anaesthesia and Intensive Care, IRCCS Policlinico S Donato, Milan, Italy

Docherty, Kieran F Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Choudhary, Rajiv VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA, USA

Ducrocq, Gregory Université de Paris, AP-​HP, French Alliance for Cardiovascular Trials (FACT), INSERM U1148, Paris, France

Claeys, Marc J Department of Cardiology, University Hospital Antwerp, Belgium Clarkson, Kevin Department of Anaesthesia and Critical Care Medicine, University Hospital Galway, National University of Ireland Galway School of Medicine, Galway, Ireland Creteur, Jacques Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium Dalzell, Jonathan R Scottish National Advanced Heart Failure Service, Golden Jubilee National Hospital, Glasgow, UK Dauw, Jeroen Department of Cardiology, Ziekenhuis Oost-​Limburg, Genk, Belgium Davierwala, Piroze M University Clinic for Cardiac Surgery, Heart Center, Leipzig, Germany De Carlini, Caterina C Cardiology Unit, SL Mandic Hospital, Merate (Lecco), Italy De Graaf, Michiel A Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands De Waha-​Thiele, Suzanne German Center for Cardiovascular Research (DZHK), partner site Hamburg/​Kiel/​Lübeck, and University Heart Center Lübeck, University Hospital Schleswig-​Holstein, Lübeck, Germany Debaveye, Yves Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium Della Bella, Paolo Arrhythmology Department, IRCCS San Raffaele Hospital, Milan, Italy

Ebelt, Henning Department of Internal Medicine III, Heart Center, Martin-​ Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Saale, Halle/​Saale, Germany Ecarnot, Fiona Department of Cardiology, University Hospital Besançon and EA3920, University of Franche-​Comté, Besançon, France El Mahdiui, Mohammed Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands Falk, Volkmar Klinik für Herz-​Thorax-​Gefässchirurgie, Deutsches Herzzentrum Berlin, Germany Farmakis, Dimitrios University of Cyprus Medical School, Nicosia, Cyprus Favory, Raphaël Intensive Care Department, Université de Lille, Inserm, CHU Lille, U995, Lille Inflammation Research International Center (LIRIC), Lille, France Ferdinande, Patrick Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium Filippatos, Gerasimos Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece Flachskampf, Frank A Department of Medical Sciences, Uppsala University, Uppsala, Sweden Galiè, Nazzareno Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Bologna, Italy

C on t ri bu tor s Gargiulo, Giuseppe Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy

Hoogmartens, Olivier Leuven Institute for Healthcare Policy, Leuven University, Leuven, Belgium

Gattinoni, Luciano Department of Anesthesiology, Emergency Medicine and Critical Care, University of Göttingen, Göttingen, Germany

Hoste, Eric Intensive Care Unit and Transplant Center, Ghent University Hospital, Ghent, Belgium

Gayat, Etienne Department of Anesthesiology and Critical Care, Hôpital Lariboisière (AP-HP), Paris, France; Inserm U942 MASCOT, Paris, France; Université de Paris, Paris, France

Huber, Kurt Department of Cardiology, Wilhelminenhospital, Montleartstrabe 37, 1160 Wien, Austria

Gevaert, Sofie A Coronary Care Unit, Department of Cardiology, Ghent University Hospital, Ghent, Belgium Girndt, Matthias Department of Internal Medicine III, Heart Center, Martin-​ Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Saale, Halle/​Saale, Germany Gorenek, Bulent Eskisehir Osmangazi University Cardiology Department, Eskisehir, Turkey Gosselink, Rik Department Rehabilitation Sciences, Faculty Movement and Rehabilitation Sciences, University Hospitals Leuven, Leuven, Belgium Graulus, Eric AZ Sint-​Jan, Department of Cardiac Surgery, Brugge, Belgium Grove, Erik L Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Gunst, Jan Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium Gurjeva, Olga S Emergency Cardiology Department, National Scientific Center ‘MD Strazhesko Institute of Cardiology’, Kyiv, Ukraine Halvorsen, Sigrun Department of Cardiology, Oslo University Hospital Ulleval, and University of Oslo, Oslo, Norway

Hvas, Anne-​Mette Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark Ibanez, Borja Clinical Research Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Spain Imazio, Massimo University Cardiology, AOU Città della Salute e della Scienza di Torino, Torino, Italy Iung, Bernard Hôpital Bichat, APHP, Paris, Université de Paris and INSERM 1148, Paris, France Jaffe, Allan S Mayo Clinic, Rochester, MN, USA Jaggar, Siân Royal Brompton & Harefield NHS Foundation Trust, London, UK James, Stefan Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Johnson, Mark Department of Clinical Obstetrics, Imperial College, Chelsea and Westminster Hospital, London, UK Katritsis, Demosthenes G Department of Cardiology, Hygeia Hospital, Athens, Greece Keane, Stephen Department of Cardiology, University Hospital Galway, National University of Ireland Galway School of Medicine, Galway, Ireland

Hassager, Christian The Heart Centre, Rigshospitalet, Copenhagen, Denmark

Kellum, John A Center of Critical Care Nephrology, Department of Critical Care Medicine, Pittsburgh University, Pittsburgh, PA, USA

Heymans, Stephane Department of Cardiology, Maastricht University Medical Centre (MUMC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Keogh, Brian F Royal Brompton Hospital & Harefield NHS Foundation Trust, London, UK

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C ontribu tors Klages, Jan Institute of Anesthesiology, German Heart Centre Berlin, Berlin, Germany

Mannucci, Pier Mannuccio IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan, Italy

Kobayashi, Leslie Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health, San Diego, CA, USA

Martin, Jasmin Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland

Konstantinides, Stavros Centre for Thrombosis and Haemostasis, University Medical Centre Mainz, Germany and Department of Cardiology, Democritus University of Thrace, Greece

Mas, Arantxa Intensive Care Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain

Kozhuharov, Nikola Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland Kristensen, Steen Dalby Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Kroft, Lucia Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands Kurzyna, Marcin Department of Pulmonary Circulation, Thromboembolic Disease and Cardiology, Center for Postgraduate Medical Education, ECZ-Otwock, Poland

Masip, Josep Intensive Care Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain Maurizi, Giulio Department of Thoracic Surgery, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy McEvoy, John W Department of Cardiology, University Hospital Galway, National University of Ireland Galway School of Medicine, Galway, Ireland McMurray, John JV Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Lam, Lydia USC School of Medicine, Los Angeles, CA, USA

Mebazaa, Alexandre Department of Anesthesiology and Critical Care, Hôpital Lariboisière (AP-HP), Paris, France; Inserm U942 MASCOT, Paris, France; Université de Paris, Paris, France

Laycock, Helen Department of Anaesthetics and Pain Medicine, Great Ormond Street Hospital, London, UK

Mehran, Roxana The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA

Leonardi, Sergio University of Pavia, Coronary Care Unit, Fondazione IRCCS Policlinico S Matteo, Pavia, Italy

Michou, Eleni Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland

Lettino, Maddalena Cardiovascular Department, San Gerardo Hospital, Monza, Italy Leys, Didier University of Lille, Inserm U1172, Lille, France Maggiolini, Stefano Cardiology Unit, SL Mandic Hospital, Merate (Lecco), Italy Maisel, Alan Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA, USA Manes, Alessandra Cardiovascular and Thoracic Department, Bologna University Hospital, Bologna, Italy

Mion, Monica Maria Department of Laboratory Medicine, University-​Hospital, Padova, Italy Mitsis, Andreas Department of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland Modine, Thomas Centre Hospitalier Regional et Universitaire de Lille, Lille, France Moreau, Anne-​Sophie Intensive Care Department, Université de Lille, Inserm, CHU Lille, U995, Lille Inflammation Research International Center (LIRIC), Lille, France

C on t ri bu tor s Morley-​Smith, Andrew C St Bartholomew’s Hospital, London, UK Moulin, Solène Centre Hospitalier Universitaire de Reims, Reims, France Mueller, Christian Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland Mullens, Wilfried Department of Cardiology, Ziekenhuis Oost-​Limburg, Genk, Belgium Myrianthefs, Pavlos National & Kapodistrian University of Athens ‘Agioi Anargyroi’ Hospital Nea Kifisia, Athens, Greece Nestelberger, Thomas Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland Neyrinck, Arne P Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium Nolan, Jerry P Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UK Nuding, Sebastian Department of Internal Medicine III, Heart Center, Martin-​ Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Saale, Halle/​Saale, Germany Palazzini, Massimiliano Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Pepper, John Royal Brompton and Harefield NHS Foundation Trust, London, UK Petrie, Mark C Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK and Scottish National Advanced Heart Failure Service, Golden Jubilee National Hospital, Glasgow, UK Planas, Kenneth Intensive Care Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain Plebani, Mario Department of Laboratory Medicine, University-​Hospital of Padova, Padova, Italy Price, Susanna Royal Brompton Hospital & Harefield NHS Foundation Trust, London, UK Puerto, Elena Cardiology Department, Instituto de Investigación imas12, Hospital Universitario 12 de Octubre, Madrid, Spain Quinn, Tom Emergency, Cardiovascular, and Critical Care Research Group, Joint Faculty, Kingston University & St George’s, University of London, London, UK Ranucci, Marco Department of Cardiothoracic Anaesthesia and Intensive Care, IRCCS Policlinico S Donato, Milan, Italy Rendina, Erino Angelo Department of Thoracic Surgery, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy Ricci, Zaccaria Pediatric Cardiac Intensive Care Unit, Department of Pediatric Cardiac Surgery, Bambino Gesù Children’s Hospital, Rome, Italy

Parkhomenko, Alexander Emergency Cardiology Department, National Scientific Center ‘MD Strazhesko Institute of Cardiology’, Kyiv, Ukraine

Roeseler, Jean Cliniques Universitaires St Luc, Département de Médecine Aiguë, Service des Soins Intensifs, Brussels, Belgium

Parkin, Matthew Adult Critical Care Unit, Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Romagnoli, Stefano Department of Anesthesiology and Intensive Care, Azienda Ospedaliero-​Universitaria Careggi, Florence, Italy

Patel, Brijesh Department of Intensive Care, Royal Brompton & Harefield Adult Intensive Care Units, London, UK

Ronco, Claudio Department of Nephrology Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy

Paul, Richard NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK

Roos-​Hesselink,  Jolien Erasmus Medical Center, Rotterdam, The Netherlands Sabbe, Marc Emergency Department, University Hospitals Leuven, Leuven, Belgium

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C ontribu tors Schepens, Marc AZ Sint-​Jan, Department of Cardiac Surgery, Brugge, Belgium Schiele, François Department of Cardiology, University Hospital Besançon and EA3920, University of Franche-​Comté, Besançon, France Schoenrath, Felix Department of Cardiothoracic and Vascular Surgery, German Heart Centre, Berlin, Germany Scholte, Arthur JHA Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands Schröder, Jochen Department of Internal Medicine III, Heart Center, Martin-​ Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Saale, Halle/​Saale, Germany Schwitter, Juerg Cardiac MR Centre of the CHUV, University Hospital Lausanne and University of Lausanne FBM, Lausanne, Switzerland Sederholm Lawesson, Sofia Department of Cardiology, University Hospital, Linköping, Sweden

Swahn, Eva Department of Cardiology, University Hospital, Linköping, Sweden Swan, Lorna Division of Cardiology, Peter Munk Cardiac Centre; Toronto Congenital Cardiac Centre for Adults, University of Toronto, Toronto ON, Canada Taccone, Fabio S Department of Intensive Care, Hôpital Erasme, Brussels, Belgium Thiele, Holger Heart Center Leipzig at University of Leipzig, Department of Internal Medicine/​Cardiology, Leipzig, Germany Thuny, Franck Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center, Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France Thygesen, Kristian Department of Cardiology, Aarhus University Hospital, Denmark

Shah, Kevin Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, Utah, USA

Torbicki, Adam Department of Pulmonary Circulation, Thromboembolic Disease and Cardiology, Center for Postgraduate Medical Education, ECZ-Otwock, Poland

Shariff, Farah NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK

Tubaro, Marco Intensive Cardiac Care Unit, San Filippo Neri Hospital, Rome, Italy

Simon, André R Royal Brompton and Harefield NHS Foundation Trust, London, UK

Twerenbold, Raphael Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland

Sionis, Alessandro Hospital de la Santa Creu i Sant Pau IIB Sant Pau, Carrer de Sant Quintí, 89, 08041 Barcelona, Spain Smit, Jeff M Department of Cardiology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands Starr, Neasa Cardiac Pacing Unit, Cardiology Department, University Hospital of Geneva, Geneva, Switzerland Stepinska, Janina Institute of Cardiology, Warsaw, Poland Stiers, Michiel Emergency Department, University Hospitals Leuven, Leuven, Belgium

Vahanian, Alec Department of Cardiology, Bichat Claude Bernard Hospital, Assistance Publique Hôpitaux de Paris, Paris, France Valgimigli, Marco Department of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland Van De Velde, Marc Department of Anesthesiology, Leuven University Hospital, Leuven, Belgium Van Den Berghe, Greet Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium Van Der Jagt, Mathieu Department of Intensive Care Adults, Erasmus MC University Medical Center, Rotterdam, The Netherlands

C on t ri bu tor s Van Raemdonck, Dirk Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium

Vrints, Christiaan Department of Cardiology, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium

Vandekerckhove, Philippe Belgian Red Cross-​Flanders, Mechelen, Belgium and Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium

Werdan, Karl Department of Internal Medicine III, Heart Center, Martin-​ Luther-​University Halle-​Wittenberg, University Hospital Halle/​ Saale, Halle/​Saale, Germany

Vanni, Camilla Department of Thoracic Surgery, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy

Wettersten, Nicholas Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA, USA

Vasques, Francesco Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK

White, Harvey D Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland, New Zealand

Vieillard-​Baron, Antoine Intensive Care Unit, University Hospital Ambroise Paré, Boulogne-​Billancourt,  France

Windecker, Stephan Department of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland

Vijgen, Johan Department of Cardiology, Jessa Ziekenhuis, Hasselt, Belgium

Wood, Jayne Symptom Control and Palliative Care Team, The Royal Marsden NHS Foundation Trust, London, UK

Vilahur, Gemma Program ICCC-​Institut Català de Ciències Cardiovasculars IR-​ Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Vincent, Jean-​Louis Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium Vranckx, Pascal Cardiac ITU, Virga Jesse Ziekenhuis, Hasselt, Belgium

Yalynska, Tetyana Ukranian Children’s Cardiac Centre (UCCC), Kyiv, Ukraine Zaninotto, Martina Department of Laboratory Medicine, University-​Hospital, Padova, Italy

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CHAPTER 1

Intensive and acute cardiovascular care: an introduction Eric Bonnefoy-Cudraz, Susanna Price, Marco Tubaro, Pascal Vranckx, and Christiaan Vrints

Cardiovascular diseases (CVDs) are a major cause of premature death worldwide and an important cause of loss of disability-​adjusted life years [1]‌. For most types of CVD, early diagnosis (within minutes) and intervention are independent drivers of patient outcome. Clinicians must be properly trained and centres appropriately equipped in order to deal with these critically ill cardiac patients [2]. Desmond Julian was the first to suggest the concept of the coronary care unit (CCU) to the British Cardiothoracic Society in 1961 [3]‌—​an innovation widely recognized as one of the great developments in cardiology. In 1962, he set up the first CCU for the monitoring of patients with acute myocardial infarction (AMI) in Sydney (Australia), and in 1964 he established the first European CCU in Edinburgh. A few years later, Killip and Kimball demonstrated that ‘aggressive’ pharmacological therapy in a CCU could significantly reduce mortality (from 28% to 7%) in AMI patients without shock [4]. Since the inception of the intensive cardiovascular care unit (ICCU) in the early 1960s, the patient mix has drastically evolved [2, 3]. Due to the ageing population, growing medical complexity of treated patients, and improved survival from complex cardiovascular and medical conditions, patients with advanced cardiac disease complicated by severe non-​ cardiovascular comorbidities [e.g. sepsis or kidney injury in a patient on extracorporeal membrane oxygenation (ECMO)] have become increasingly common in the ICCU [5–​7]. In concert, due to advances in procedural techniques, patients with severe non-​ cardiovascular illness complicated by secondary cardiovascular comorbidities [e.g. type II myocardial infarction (MI) or septic cardiomyopathy] are also growing in prevalence in the ICCU environment. Hospitalizations complicated by multiorgan failure (MOF) are frequent, while patient admissions with isolated primary cardiac dysfunction [e.g. acute coronary syndrome (ACS), arrhythmias] are becoming less common [2]. As a result, this environment led to the emergence of the cardiac intensivist, who should be trained in intensive care medicine and emergency medicine, as well as internal medicine and cardiology [2, 5, 7, 8]. The actual intensive and acute cardiovascular care (IACC) model makes the patient the centre of care, with continuous management by a core team of acute cardiovascular physicians and nurses—​all in collaboration with cardiologists, cardiovascular surgeons, and affiliated health care workers [2]‌. Strategic planning of a patient’s diagnosis and management over the course of a hospitalization is grounded in multidisciplinary discussion, giving patients the benefit of not only the full spectrum of a hospital’s resources (an additive benefit), but also the wisdom of multidisciplinary deliberation (a multiplicative benefit greater than the sum of its parts) [9].

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In ten sive and acu te cardiovas cu l a r ca re: a n i n trodu cti on

The Association for Acute CardioVascular Care (ACVC) of the European Society of Cardiology (ESC) has been at the forefront of establishing best practice in acute cardiac and intensive care, first as a working group and subsequently, from 2012 onwards, as an association. The ACVC promotes research and education and spreads knowledge of new and emerging science in the field of acute cardiac care. The ESC Textbook of IACC, third edition, follows the IACC training core curriculum (CC) and is designed to be used as a text of teaching and a guide for learning. The chapters also serve as the basis for the European Society of Cardiology e-​Learning (ESCeL) teaching modules. It is sufficiently large in scope to provide an overview of important areas related to acute cardiovascular care and makes it relevant to both trainees and non-​trainees in cardiology, emergency and intensive care medicine, and beyond. Section I focuses on the definition, structure, organization, and function of ICCUs and on ethical issues and quality of care. Section II addresses the pre-​hospital and immediate in-​hospital [emergency department (ED)] emergency cardiac care. In Sections II–​V, patient monitoring, diagnosis, and specific procedures are described. Laboratory medicine is widely used in IACC, both for prompt diagnosis of acute conditions and for prognostic stratification, which frequently drives patient allocation and treatment strategies. ACS, acute decompensated heart failure (ADHF), and serious arrhythmias deserve a whole section each, being the three most important groups of cardiac diseases managed in ICCUs (Sections VI–​VIII). These entities are dealt with in great detail, including

pharmacological and non-​pharmacological treatments. The other main cardiovascular acute conditions are grouped in Section IX. Last, but not least, Section X is dedicated to the many concomitant acute non-​cardiovascular conditions that contribute to the patient case mix in the ICCU. The acute and intensive management of this variety of acute illnesses requires deep and, at the same time, wide clinical training in all aspects of critical care. The ESC Textbook of Intensive and Acute Cardiovascular Care, third edition, contains in total two brand new chapters: Chapter 47 (Low cardiac output states and cardiogenic shock) and Chapter 55 (Pacemakers and ICDs: troubleshooting). More than one-​third of all chapters have benefited from a major revision. As in the previous editions, each chapter has been written by a real expert in the field and is in line with the ESC guidelines and the CC in IACC; multiple choice questions (MCQs) on many of the chapters are available for continuing medical education (CME). A  particular asset of this textbook is the online edition (available at: M oxfordmedicine.com/ESCIACC3e). Purchasers of the print, as well as of the online-​only bundle, can access the online material via an access code. The online version contains all the material from the printed book, as well as many more figures and tables, an extended reference list for each chapter, and original material like photos and videos, to better illustrate diagnostic and therapeutic techniques and procedures in IACC. We believe that this textbook will be very useful in establishing a common basis of knowledge and a uniform and improved quality of care in all European countries and beyond, for the benefit and improved care of our patients. Enjoy reading!

References 1. Roth GA, Johnson C, Abajobir A, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017;70:1–​25. 2. Bonnefoy-​Cudraz E, Bueno H, Casella G, et  al. Editor’s Choice—​ Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units:  an update on their definition, structure, organisation and function. Eur Heart J Acute Cardiovasc Care 2018;7:80–​95. 3. Julian DG. Treatment of cardiac arrest in acute myocardial ischaemia and infarction. Lancet 1961;2:840–​4. 4. Killip T, 3rd, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol 1967;20:457–​64. 5. Katz JN, Minder M, Olenchock B, et al. The genesis, maturation, and future of critical care cardiology. J Am Coll Cardiol 2016;68:67–​79.

6. Katz JN, Shah BR, Volz EM, et  al. Evolution of the coronary care unit:  clinical characteristics and temporal trends in healthcare delivery and outcomes. Crit Care Med 2010;38:375–​81. 7. Morrow DA, Fang JC, Fintel DJ, et al. Evolution of critical care cardiology: transformation of the cardiovascular intensive care unit and the emerging need for new medical staffing and training models:  a scientific statement from the American Heart Association. Circulation 2012;126:1408–​28. 8. Walker DM, West NE, Ray SG. From coronary care unit to acute cardiac care unit:  the evolving role of specialist cardiac care. Heart 2012;98:350–​2. 9. Dudzinski DM, Januzzi JL, Jr. The evolving medical complexity of the modern cardiac intensive care unit. J Am Coll Cardiol 2017;69:2008–​10.

SECTION 1

Intensive and acute cardiovascular care 2 Training and certification in intensive and acute cardiovascular care 

5

Susanna Price and Eric Bonnefoy-Cudraz

3 Intensive cardiovascular care units: structure, organization, and staffing 

11

Eric Bonnefoy-Cudraz and Tom Quinn

4 The heart team 

25

Sergio Leonardi, Thomas Modine, and Stephan Windecker

5 Patient safety and clinical governance 

33

Matthew Parkin and Tom Quinn

6 Ethical issues in cardiac arrest and acute cardiac care: a European perspective  Jean-​Louis Vincent and Jacques Creteur

7 Quality of care assessment in acute cardiac care  Fiona Ecarnot and François Schiele

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Training and certification in intensive and acute cardiovascular care Susanna Price and Eric Bonnefoy-Cudraz

Contents Summary  5 Introduction  5 Training in acute cardiovascular care  6 First step  6 Second step  6 Third step  6 Curricula in acute cardiovascular care  7

Competency-​based training  7 Simulation for training in acute cardiovascular care  7 Acute cardiovascular care EPA in the ESC core curriculum for the general cardiologist  7 The ESC-​ACVC acute cardiovascular care curriculum  7 The American College of Cardiology COCATS 4-​TF 13  8 Assessment of competencies  8 Certification in acute cardiovascular care  9 Personal perspective  9 References  10

Summary Acute cardiovascular care is now a complex and technical subspecialty of cardiology. Specific training in acute cardiovascular care is warranted, in addition to skills acquired during the initial phase of cardiology training. Data are available that show that this training brings benefits to patients and improves their outcome. The Association for Acute CardioVascular Care (ACVC) of the European Society of Cardiology (ESC) offers a comprehensive postgraduate programme in acute cardiovascular care. This programme is in line with the three levels of expertise described for intensive cardiac care unit organization. A curriculum focused on initial training is also available through the American College of Cardiology. Both curricula are competency-​based. Teaching practical knowledge and skills through simulation should be integrated throughout training in acute cardiovascular care. To measure specific and overall achievement in competencies, different and complementary tools are available. Diffusion of the certification process, like the one provided by the ESC-​ACVC, is important for acute cardiovascular care to be recognized as a cardiology subspecialty.

Introduction Acute cardiovascular care is now a well-​defined, complex field. A typical ICCU is a collaboratively managed multidisciplinary unit, admitting a wide range of patients with acute cardiovascular conditions and comorbidities [1–​3]. Acute cardiovascular conditions managed in ICCUs, such as acute heart failure (AHF) or ACS, are most often the acute expression of a CVD that will require long-​term follow-​up in a specialized cardiovascular setting. In addition to managing patients’ immediate presenting clinical issues and prevention of adverse events (AEs), ICCUs should contribute to the initiation of secondary prevention strategies. Care requirement for a given patient is a dynamic process that may change rapidly, depending on the success or failure of initial management strategies. Many cardiologists working in ICCUs have gained expertise and skills over time with experiential learning. Some have relevant additional training in other subspecialties of cardiology, in general critical care, or in acute cardiac care. As with other critical care specialties [4]‌, there is evidence that a specialized environment for the initial management of acutely ill cardiovascular patients is related to better in-​hospital and long-​term outcomes [5–​7]. Therefore, patients deserve

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to be managed by appropriately trained physicians in the specialty, and beyond their general cardiology education, physicians working in an ICCU must have specific training in acute cardiovascular care [7]. Cardiovascular societies should provide curricula that set standards for training in acute cardiovascular care. Providing frameworks for certification is also of importance for acute cardiovascular care to evolve as a subspecialty of cardiology.

Training in acute cardiovascular care Training in acute cardiovascular care should provide cardiologists the appropriate knowledge and technical skills for managing confidently acute cardiovascular patients. In line with intensive care societies, the ESC has recently proposed a grading of ICCUs in three levels, according to the monitoring and care requirements of the patients they manage [8]‌. The three levels are presented in E Table 2.1. Not all physicians will have to master the techniques required to work in the most demanding ICCUs. A  one-​size-​fits-​all approach is not adapted to the challenges of training in acute cardiovascular care. Expertise and technical skills should match the ICCU gradation. A  stepwise approach in training is more appropriate. It should encompass the full spectra of expertise needed to manage acute cardiovascular patients for a given level of ICCU, as well as accompany the cardiologist during all his/her professional life. For the sake of clarity and effectiveness, in line with the available curricula, training materials, and ICCU organization, training in acute cardiovascular care will be presented following a three-​step approach, each step with increasing expertise. E Table 2.2 presents technical competencies for each step. This approach is a little arbitrary because the actual level of acuity and risk of a patient is not always known immediately. Moreover, the response to initial treatment might dramatically change the expertise needed for managing an acute clinical condition.

Beyond a common basis that provides the minimal expertise needed to manage level 1 patients and work in level I ICCUs, additional training will allow for additional expertise and technical skills to care for more demanding acute cardiovascular patients managed in higher-​level ICCUs [8–​12].

First step The first step (Step 1) refers to the essentials in acute cardiovascular care that should be common to all cardiologists. There is the need of a common basis in knowledge and skills in acute cardiovascular care shared by all cardiologists. It enables them to approach the critically ill cardiac patient in a systematic fashion, understand the range of acute cardiovascular conditions and therapeutic options, and ensure appropriate referral is made where required. Therefore, this level of training should be done during the fellowship, as is advocated in the ESC general cardiology CC and the American College of Cardiology Core Cardiovascular Training Statement 4 by Task Force 13 (COCATS 4-​TF 13).

Second step This second step (Step 2) will provide for specific expertise in advanced acute cardiovascular care. This level of training should be sanctioned by a qualifying examination that measures specific knowledge, skills, and competence. It supposes additional training after a fellowship, especially in some aspects of critical care. The full ESC-​ACVC CC, complete with the practical assessment, fulfils this prerequisite [13]. Some university diplomas also do.

Third step The third step (Step 3) draws as much from acute cardiology as from critical care [7]‌. It focuses on complete autonomy and advanced expertise in specific fields, i.e. ventilator management, multiorgan dysfunction management, end-​of-​life care (EoLC), and assist devices. This level of expertise might be reached through advanced training in acute cardiovascular care and additional education in critical care on top of what is already required in Step 2 [8–​10, 14].

Table 2.1  Level of intensive cardiac care units according to the ESC Level I

◆ Level I ICCUs are designed to manage patients with cardiovascular conditions demanding level 1 care, i.e. cardiovascular conditions requiring careful cardiac rhythm and non-​invasive haemodynamic monitoring, as well as some specific treatments (vasoactive drugs, non-​invasive bi-​level positive airway pressure or continuous positive airway pressure, chest tube insertion, and monitoring) ◆ These units mainly focus on the care of patients with ACS, congestive heart failure without shock (or rapidly improving patients with low cardiac output), or complex, not life-​threatening arrhythmias. These units may also offer specific monitoring to patients post-​structural and endovascular interventions

Level II

◆ Level

Level III

◆ Level III ICCUs are designed to care for level 3 patients who have acute cardiac conditions that are severe enough to require, or be at high risk of needing, invasive mechanical ventilation, renal replacement therapy, extracorporeal life support, emergent heart surgery, or surgical cardiovascular assistance

II ICCUs are designed to manage level 1 and level 2 patients ◆ Level 2 patients refers to those with acute cardiovascular conditions whose risk requires central venous access and/​or an arterial line for monitoring central venous pressure and arterial pressure, respectively, and/​or sampling of central venous or arterial blood, as well as continuous infusion of multiple cardioactive drugs (because of low cardiovascular output or compromised organ perfusion) ◆ Additional relevant interventions considered as level 2 include temporary transvenous pacing, percutaneous cardiac assist device (intra-​aortic balloon pump or percutaneous axial pump), and pericardiocentesis. Level II ICCUs should provide initial evaluation and management of severe or high-​risk patients with congestive heart failure and/​or low cardiac output complicating acute or chronic cardiac conditions

Source data from Bonnefoy-​Cudraz E, Bueno H, Casella G, et al. Editor’s Choice—​Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units: An update on their definition, structure, organisation and function. Eur Heart J Acute Cardiovasc Care 2018;7(1):80–​95. doi:10.1177/​2048872617724269.

The ES C- ACVC acu te ca rdi ovas cu l a r ca re c urri c ulum Table 2.2  Techniques with expected full competency according to training step Step 1 training

Step 2 training

Step 3 training

◆ All non-​invasive clinical parameter monitoring ◆ 24/​7 echocardiography and thoracic ultrasound ◆ Direct current cardioversion ◆ Non-​invasive ventilation ◆ Transcutaneous temporary pacing ◆ Chest tubes

◆ All invasive haemodynamic monitoring ◆ Ultrasound-​guided central venous line insertion ◆ Pericardiocentesis ◆ Transvenous temporary pacing ◆ Transoesophageal echocardiography ◆ Pulmonary artery catheterization/​right heart catheterization ◆ Percutaneous circulatory support (intra-​aortic balloon pump, Impella®) ◆ Targeted temperature management

◆ Extracorporeal life support ◆ Mechanical circulatory support expertise (left ventricular assist device, biventricular ventricular assist device) ◆ Renal replacement therapy ◆ Mechanical ventilation

Curricula in acute cardiovascular care The ESC and American College of Cardiology provide curricula on Step 1 training in acute cardiovascular care [12,  13]. These curricula use a well-​defined, competency-​based framework that comprehensively describes individual aspects of training in the subspecialty and presents the requirements for training institutions and trainers. The ESC-​ACVC presents a specific curriculum for Step 2 training in acute cardiovascular care that is associated with a certification process and defines the minimum requirements to qualify as a cardiovascular intensivist.

Competency-​based training Training in acute cardiovascular care is well suited for competency-​ based curricula [15]. Competency-​based education states that a trainee is ready to graduate from the training programme only after mastering the knowledge (core competencies) and specific skills (or actions, decisions, and activities) called ‘entrustable professional activities’, or EPAs, of a specialty [16, 17]. In theory, a curriculum based on learning objectives permits flexibility in the duration of training, allowing for personalized and/​or adjusted training pathways. Competency-​based curricula allow to insert competencies drawn from curricula of other specialties. This is of interest in acute cardiovascular care where many fields imply cross-​sectional knowledge and multidisciplinary collaboration [18]. As EPAs are observable and measurable, this allows formal and objective assessment. However, this training model is demanding. It requires generating a comprehensive list of EPAs, disciplined and rigorous assessment/​self-​assessment, and potentially difficult and comprehensive evaluation by the faculty. EPAs can be relatively difficult to define and even more difficult to assess. That is why it might be interesting to base this training on available training materials like the ones provided by the ESC-​ACVC.

Simulation for training in acute cardiovascular care Clinical hours can be substituted, in part, with simulation [19]. The simulation world has expanded. Components of a successful simulation programme—​faculty members trained in simulation pedagogy, experts providing debriefing, and simulation settings

that create a realistic environment—​are now well defined and becoming largely available [20, 21]. Beyond procedural skills, there is strong evidence that simulation is effective in teaching communication and teamworking skills that are so important in acute cardiovascular care [22]. Simulation-​based training and education should be integrated throughout the acute cardiovascular care programme and must be consistent with the curriculum vision and end-​of-​programme outcomes [23]. Therefore, it is important to review the end-​of-​ programme outcomes and map the simulation courses to the curriculum. This allows for simulation training to coincide with the level of the learner and to precisely determine how the simulation courses are expected to contribute to the overall development of trainees graduating from the acute cardiovascular care curriculum [21].

Acute cardiovascular care EPA in the ESC core curriculum for the general cardiologist A general cardiologist should be able to work and take night-​time duties in a level I ICCU. Training in acute cardiovascular care of such a physician is described in the Acute Cardiovascular Care section of the ESC General Cardiology Core Curriculum. It consists in the following EPAs: ◆ Managing pharmacologic agents. ◆ Advanced diagnostic and therapeutic techniques in the ICCU. ◆ Acute complications of chronic cardiac conditions and patients with complications of invasive cardiovascular procedures. ◆ Cardiac patients in the context of critical illness and organ dysfunction. ◆ Patients with haemodynamic instability and shock. It also emphasizes multidisciplinary teamwork skills and coordination of care in the ICCU, as well as participating in decision-​ making and end-​of-​life issues.

The ESC-​ACVC acute cardiovascular care curriculum The ESC-​ACVC curriculum concerns primarily cardiologists who have already completed advanced training in cardiology to the

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level required for certification as a cardiologist at a national level. It is relevant to those board-​certified or country-​recognized cardiologists who wish to be certified in acute cardiac care. Therefore, it is Steps 2 to 3 training that presents the range of knowledge, skills, behaviours, and attitudes required to independently manage cardiovascular emergencies and critically ill cardiac patients and their comorbidities in level II and level III ICCUs. It emphasizes the importance of a step-​up and step-​down strategy from the ICCU and teamworking. Beyond recommendations for training of those intending to be expert in acute cardiac care, it provides a framework for continuing education of those already practising in the area. The ESC-​ACVC curriculum is divided into around 20 acute cardiovascular critical care topics. Each topic presents a list of objectives, knowledge, skills, behaviour, and attitude. The curriculum is closely related to ESC teaching resources. The ESC-​ACVC’s ESC Textbook of Intensive and Acute Cardiovascular Care maps the knowledge, skills, and professional domains of the subspecialty. Therefore, it is at the core of the theoretical knowledge required in the curriculum. Other learning tools available for training are the current ESC guidelines, the ESCeL programme, and other teaching materials from the different and relevant associations and working groups of the ESC. The ESC-​ACVC curriculum puts special emphasis on practical training. Beyond a precise description of skills and behaviours, it asks for rotations in specific environments that will provide a cardiologist with the competencies to work in a level II or III ICCU. The first part covers 9  months in general cardiology training (3 months in general intensive care, 6 months in an ICCU), with on-​call/​night-​time/​weekend duties with the equivalent of at least 1 night per week for at least 3 years. This will give the physician in training the autonomy in managing patients in a level II ICCU. Additional training of 12 months post-​residency as a junior attending physician [6 months in a level II or III ICCU, 6 months in a post-​operative cardiovascular intensive care unit (ICU) or general medical critical care ICU] will allow the physician to be fully in charge of a level II ICCU and contribute confidently to the management of patients in a level III ICCU.

The American College of Cardiology COCATS 4-​TF 13 The American College of Cardiology states that the essentials in acute cardiovascular care should be integrated in the cardiovascular disease fellowship training programme [3 years in the United States (US)]. The COCATS 4-​TF 13 is a competencies-​based curriculum in acute cardiovascular care that focuses on Step 1 competencies. The minimum duration of practical training is 8 weeks in ICCUs over the course of the first 24 months of training. Many knowledge and skills relevant to acute cardiovascular care will be acquired through other rotations, especially in electrophysiology, cardiac catheterization, imaging, and heart failure. As in most documents on training provided by the American College of Cardiology [24], training in acute cardiovascular care addresses the six general competencies promulgated by the Accreditation Council for Graduate Medical Education (ACGME)/​ American Board of Medical

Specialties (ABMS). This allows for consistencies between training for acute cardiovascular care and other training recommendations provided by the American College of Cardiology. These general competencies are:  (1) medical knowledge; (2)  patient care and procedural skills; (3)  practice-​based learning and improvement; (4) systems-​based practice; (5) interpersonal and communication skills; and (6) professionalism (see E Box 2.1) [25]. For each competency and domain, the document provides milestones with the stage of fellowship training by which a trainee should achieve the designated level. Contrary to the ESC-​ACVC curriculum, there are no specific guidelines for advanced training in acute cardiovascular care beyond suggesting an additional 3–​6 months of clinical training within the 3-​year cardiovascular medicine fellowship.

Assessment of competencies For the practical part of the training, there is a consensus that learning outcomes are preferred to recommendations based solely on the amount of time spent in a department and/​or on the number of procedures performed [24]. In Europe, practical training in acute cardiovascular care also depends upon the training pathways in cardiology already in place throughout the ESC member states. As in many medical fields, statements on what is practical competencies achievement are mainly based on expert experience and opinion [26]. The methods and tools used to assess competency in acute cardiovascular care training are in line with those recommended in acute and critical care [27]. Assessment and validation processes need to be under the control of the programme director or his/​her equivalent [12,  13]. They are responsible for confirming experience and Box 2.1  ACGME core competencies ◆ Patient care—​that is compassionate, appropriate, and effective for treating health problems and promoting health ◆ Medical knowledge—​about established and evolving biomedical, clinical, and cognate (e.g. epidemiological and social–​ behavioural) sciences and application of this knowledge to patient care ◆ Practice-​based learning and improvement—​that involve investigation and evaluation of a fellow’s patient care, self-​appraisal, and assimilation of scientific evidence and improvements in patient care ◆ Interpersonal and communication skills—​that result in effective information exchange and teaming with patients, their families, and other health professionals ◆ Professionalism—​as manifested by a commitment to carrying out professional responsibilities, adherence to ethical principles, and sensitivity to a diverse patient population ◆ Systems-​based practice—​as manifested by actions that demonstrate an awareness of, and a responsiveness to, the larger context and system of health care and the ability to effectively call on system resources to provide care that is of optimal value

Per s ona l  pe r spe c t i v e Box 2.2 Evaluation tools ◆ Direct observation by instructors ◆ In-​training examinations ◆ Case logbooks ◆ Conferences ◆ Case presentations ◆ Multisource evaluations ◆ Trainee portfolios ◆ Simulation

competence and for reviewing the overall progress of individual trainees. The clearer and more precise the process, the easier it will be for the programme director to assume this role. Defining representative curricular milestones during training will help in identifying trainees and areas that require additional focused attention. Most curricula state that trainees should maintain records of participation and advancement in the form of a logbook that summarizes predefined pertinent information. Some evaluation tools that may be part of this logbook are presented in E Box 2.2. Competency to perform procedures should be based on evaluation by a supervising physician [28]. There are some controversies on the need of defining the number of procedures required to achieve technical competencies [12, 13, 24]. The number of procedures performed (as well as the length of exposure) are uncertain proxies of proficiency and outcome. When they exist, these numbers are based on consensus about the educational needs and progress of typical trainees and are intended as general guidance, not absolute thresholds. In some cases (e.g. central venous access, echocardiography), more robust evidence exists [29]. Procedural volume targets are not provided by the American College of Cardiology, but it suggests anyway the completion of a logbook. The ESC-​ACVC curriculum does not provide specific numbers either but suggests the numbers of procedures are made available for those preparing for the acute cardiovascular care certification exam as a guidance.

Certification in acute cardiovascular care Ideally, any curriculum in acute cardiovascular care should lead to a process of formal certification. Step 1 training that is part of the fellowship, as with the COCATS 4-​TF 13 curriculum or the ESC general cardiology CC, does not suppose formal dedicated certification.

The full ESC-​ACVC certification process provides an example of a Step 2 certification in acute cardiovascular care. Certification consists of two parts: (1) demonstration of theoretical knowledge; and (2) demonstration of competence. The first part is validated through an MCQ-​based exam. The second part, which is demonstration of competence, is validated through a logbook confirming the procedures undertaken and countersigned by the trainee’s educational supervisor (or equivalent) to confirm they have met the required levels of competence. It should also show that the required training programme (9 or 21 months) has been undertaken and evidence of ongoing training and assessment during the training period. The whole certification is presented in detail [30]. The ESC-​ACVC certification is prestigious and, in some cases, nationally recognized. That it does not yet confer recognized additional privilege is mainly related to the absence of a recognized acute cardiovascular care subspecialty in most European countries. The ESC-​ACVC certification provides important standards of knowledge and skills in acute cardiovascular care and a clear roadmap to reach these standards. Such standards should help national cardiology societies to promote training and education in acute cardiovascular care, thereby improving the quality of care and outcomes of patients with acute CVD. Level III ICCUs are highly specialized cardiovascular critical care units. Physicians managing patients in such environments should demonstrate advanced expertise in acute cardiovascular care, as well as competencies in critical care. There is evidence that these specific competencies improve patient care [5]‌. Provided full practical training (21  months) has been validated, the ESC-​ACVC certification is the nearest to Step 3 training, drawing from both critical care and acute cardiovascular care. Other options are available at national levels. Some universities provide a diploma after validating the specific training in acute cardiovascular care they organize [11]. A  dual certification in cardiology and critical care is possible in some European countries and the US [9, 10, 14, 31, 32]. The training consists of a full curriculum in cardiology and at least 12 additional months in critical care, allowing the certification process of both specialties to be validated.

Personal perspective ◆ How

many physicians will be willing to focus their practice in this field, and will it justify the development and multiplication of national programmes? ◆ Moreover, there is a large gender disparity in this field (only 3.3% of dual-​certified critical care cardiologists are women) [7]‌. It has been suggested that improved mentorship for women considering critical care cardiology and ongoing diversity task force implementation will aid in closing the gender gap [7, 33]. ◆ Lifelong education in acute cardiovascular care.

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Train ing and certif ication i n  i n ten si ve a n d acu te ca rdi ovas cu l a r  ca re

References 1. Katz JN, Shah BR, Volz EM, et  al. Evolution of the coronary care unit:  clinical characteristics and temporal trends in healthcare delivery and outcomes. Crit Care Med 2010;38:375–​81. 2. Dudzinski DM, Januzzi JL. The evolving medical complexity of the modern cardiac intensive care unit. J Am Coll Cardiol 2017;69:2008–​10. 3. Holland EM, Moss TJ. Acute noncardiovascular illness in the cardiac intensive care unit. J Am Coll Cardiol 2017;69:1999–​2007. 4. Wilcox ME, Chong CAKY, Niven DJ, et al. Do intensivist staffing patterns influence hospital mortality following ICU admission? A systematic review and meta-​analyses. Crit Care Med 2013;41:2253–​74. 5. Na SJ, Chung CR, Jeon K, et al. Association between presence of a cardiac intensivist and mortality in an adult cardiac care unit. J Am Coll Cardiol 2016;68:2637–​48. 6. Na SJ, Park TK, Lee GY, et al. Impact of a cardiac intensivist on mortality in patients with cardiogenic shock. Int J Cardiol 2017;244:220–​5. 7. Brusca SB, Barnett C, Barnhart BJ, et al. Role of critical care medicine training in the cardiovascular intensive care unit: survey responses from dual certified critical care cardiologists. J Am Heart Assoc 2019;8:e011721. 8. Bonnefoy-​Cudraz E, Bueno H, Casella G, et al. Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units:  an update on their definition, structure, organisation and function. Eur Heart J Acute Cardiovasc Care 2018;7:80–​95. 9. Katz JN, Minder M, Olenchock B, et al. The genesis, maturation, and future of critical care cardiology. J Am Coll Cardiol 2016;68:67–​79. 10. Morrow DA, Fang JC, Fintel DJ, et  al. Evolution of critical care cardiology:  transformation of the cardiovascular intensive care unit and the emerging need for new medical staffing and training models: a scientific statement from the American Heart Association. Circulation 2012;126:1408–​28. 11. Le May M, van Diepen S, Liszkowski M, et al. From coronary care units to cardiac intensive care units:  recommendations for organizational, staffing, and educational transformation. Can J Cardiol 2016;32:1204–​13. 12. O’Gara PT, Adams JE, Drazner MH, et  al. COCATS 4 Task Force 13:  training in critical care cardiology. J Am Coll Cardiol 2015;65:1877–​86. 13. Price S, Heras M; ACCA education committee members 2012–​2014. ACCA Core Curriculum November 2014. Available from: M http://​ www.escardio.org/​static_​f ile/​Escardio/​Subspecialty/​ACCA/​core-​ curriculum-​ACCA-​2014-​FINAL.pdf. 14. Geller BJ, Fleitman J, Sinha SS. Critical care cardiology. J Am Coll Cardiol 2018;72:1171–​5. 15. CoBaTrICE Collaboration, Bion JF, Barrett H. Development of core competencies for an international training programme in intensive care medicine. Intensive Care Med 2006;32:1371–​83. 16. Institute of Medicine (US) Committee on the Health Professions Education Summit; Greiner AC, Knebel E, editors. Health

Professions Education: A Bridge to Quality. 2003. National Academies Press:  Washington, DC; 2003. Available from: M  http://​www.ncbi. nlm.nih.gov/​books/​NBK221528/​. 17. Frank JR, Snell LS, Cate OT, et al. Competency-​based medical education: theory to practice. Med Teach 2010;32:638–​45. 18. Mebazaa A, Tolppanen H, Mueller C, et al. Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance. Intensive Care Med 2016;42:147–​63. 19. Harrison CM, Gosai JN. Simulation-​based training for cardiology procedures:  are we any further forward in evidencing real-​world benefits? Trends Cardiovasc Med 2017;27:163–​70. 20. Gosai J, Purva M, Gunn J. Simulation in cardiology: state of the art. Eur Heart J 2015;36:777–​83. 21. Barakat K. The role of simulation-​based education in cardiology. Heart 2019;105:728–​32. 22. Aggarwal R, Mytton OT, Derbrew M, et al. Training and simulation for patient safety. Qual Saf Health Care 2010;19(Suppl 2):i34–​43. 23. Moran V, Wunderlich R, Rubbelke C. Simulation:  Best Practices in Nursing Education. Springer: Cham; 2018. 24. Halperin JL, Williams ES, Fuster V. COCATS 4 introduction. J Am Coll Cardiol 2015;65:1724–​33. 25. American College of Cardiology. ACGME Core Competencies. Available from:  M https://​www.acc.org/​education-​and-​meetings/​ products-​and-​resources/​competencies/​acgme-​core-​competencies. 26. Kuvin JT, Williams ES. Defining, achieving, and maintaining competence in cardiovascular training and practice. J Am Coll Cardiol 2016;68:1342–​7. 27. Swing SR. Assessing the ACGME general competencies:  general considerations and assessment methods. Acad Emerg Med 2002;9:1278–​88. 28. Kuvin JT, Soto A, Foster L, et  al. The cardiovascular in-​training examination. J Am Coll Cardiol 2015;65:1218–​28. 29. Moureau N, Lamperti M, Kelly LJ, et al. Evidence-​based consensus on the insertion of central venous access devices: definition of minimal requirements for training. Br J Anaesth 2013;110:347–​56. 30. European Society of Cardiology. Certification for Individuals in Acute Cardiovascular Care ACVC. Available from: M  https://​ www.escardio.org/​Education/​Career-​Development/​C ertification/​ Acute-​cardiac-​care. 31. Ramjee V. Cardiac intensivism:  a view from a fellow-​in-​training. J Am Coll Cardiol 2014;64:949–​52. 32. Kenigsberg BB, Barnett CF. Cardiovascular Intensive Care Training. 2018. Available from: M  https://​www.acc.org/​membership/​s ections-​and-​councils/​cardiology-​training-​and-​workforce​ c ommittee/ ​ s ection- ​ updates/ ​ 2 018/ ​ 0 7/ ​ 3 1/ ​ 1 0/ ​ 4 2/ ​ c ardiovascular​intensive-​care-​training. 33. Douglas PS, Williams KA, Walsh MN. Diversity matters. J Am Coll Cardiol 2017;70:1525–​9.

CHAPTER 3

Intensive cardiovascular care units: structure, organization, and staffing Eric Bonnefoy-Cudraz and Tom Quinn

Contents Summary  11 Introduction  11 Grading of the level of acute cardiovascular care  12 The three levels of ICCU  12 Level I ICCU (first level; enhanced cardiovascular care units)  17 Level II ICCU (intermediate; cardiovascular high dependency units)  17 Level III ICCU (highest level; cardiovascular critical care units)  17

Structure and equipment  17 Level I ICCU  17 Level II ICCU  19 Level III ICCU  19

Premises  19 Number of beds  19 Clinical governance and continuous improvement  19 The ICCU team  19 Nurses and advanced nurse practitioners  20 ICCU medical staff and cardiovascular intensivists  20 On-​duty physicians  20 Interaction with other specialties  20 ICCU—​part of a regional network  21 Telemedicine  21 Personal perspective  21 References  23

Summary The nature and complexity of acute cardiovascular care have changed markedly since the early days of the coronary care unit, introduced in the 1960s to prevent and treat life-​threatening arrhythmias associated with acute myocardial infarction. In the present day, the patient population is older and has more multimorbidity, which comprises a range of conditions, alongside critical cardiovascular disease, and associated multiple organ failure, requiring increasingly sophisticated management. To reflect this, the Association for Acute CardioVascular Care of the European Society of Cardiology published a comprehensive update of recommendations in 2018, developed by a multinational working group of experts. These recommendations, which inform this chapter, address the definition, structure, organization, and function of the contemporary intensive cardiovascular care unit (ICCU). Reflecting the modern case mix, three levels of acuity of care are described and the corresponding requirements for ICCU organization defined. Recommendations on ICCU staffing (medical, nursing, and allied professions), equipment, and architecture are presented, alongside considerations of the role of the ICCU within the wider hospital and cardiovascular care network.

Introduction ICCUs are physically and administratively identified hospital units dedicated to, and specialized in, the management of acute cardiovascular conditions. They serve as the primary site of care in that hospital for patients with these conditions [1, 2]. They have a well-​defined organizational model, providing 24/​7 expertise in acute cardiovascular care, in close cooperation with cardiovascular and non-​cardiovascular specialties both in and out of the hospital.

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The traditional CCU has largely disappeared. Nowadays, an ICCU delivers acute cardiovascular care in a wide variety of acute cardiovascular conditions [3,  4]. These conditions rarely exist alone but are complicated by additional acute or chronic non-​ cardiovascular comorbidities in the context of a rapidly changing demographic with increasing numbers of elderly patients. There is evidence that a specialized cardiovascular environment for the initial management of cardiovascular patients is closely related to in-​hospital and long-​term patient follow-​up and outcome [5–​7]. Many acute cardiovascular conditions, such as AHF or ACS, are the acute expression of a CVD that will require long-​ term follow-​ up in a specialized cardiovascular setting. A one-​ size-​ fits-​ all-​ ICCU organizational model is not relevant. Even if all ICCUs were to have specific technical capabilities and specialized medical/​ nursing and allied professional staff, all ICCUs will not have to manage the full range of acute cardiovascular conditions. Further, organizational models will also depend on external factors like the type of hospital (large, tertiary, and/​or university versus community hospitals) and historical and regulatory constraints.

Grading of the level of acute cardiovascular care Acute cardiovascular patients will present with different levels of acuity and requirements for care [3, 4, 8, 9]. The level of care (in terms of nurses, physicians, allied professionals, techniques, and environment) to manage a given acute cardiovascular condition may be defined and graded. This grading system was originally developed for trauma centres and then extended to most specialties of critical care [10–​12]. In this setting, it contributes to a better understanding of patient management, a more efficient allocation of resources, and improvements in outcome, including

mortality rate and hospital length of stay [13,  14]. In addition, it enhances the networking between tertiary/​university and district/​ community hospitals and associated emergency medical services, facilitating an efficient use of resources [15]. Applying this process to acute cardiovascular care has the full spectrum of acute cardiovascular conditions classified according to risk and levels of care required. The Association for Acute CardioVascular Care (ACVC) of the ESC has suggested a stratification into three levels of care [16]. Level 1 refers to patients with acute cardiovascular pathologies whose needs cannot be met through care provided by a general cardiology ward because they are at risk of their condition deteriorating, demand special expertise or additional facilities, or need a higher level of observation. Level 2 refers to patients who require advanced observation and monitoring or treatment. Lastly, level 3 refers to patients with acute cardiovascular conditions commanding a level of care or intervention that is equivalent to critical care. E Table 3.1 presents the monitoring and techniques, the requirement of which for managing a patient contributes to the grading of his/​her acute cardiovascular condition. E Table 3.2 presents the classification of common acute cardiovascular conditions. Of note, care requirement for a given patient is a dynamic process that may change rapidly, depending on the success or failure of initial management strategies. A favourable response to initial treatment will allow stabilization and rapid improvement of the clinical condition. If not, demand in care may rapidly increase to much higher levels than those initially provided or to institution of palliative care or EoLC where appropriate.

The three levels of ICCU The level of an ICCU is directly related to its case mix, i.e. the levels of acuity and requirements for care of the most severe

Table 3.1  Techniques which contribute to defining the level of care for acute cardiovascular conditions Level 1 acute cardiovascular conditions

Level 2 acute cardiovascular conditions

Level 3 acute cardiovascular conditions

◆ Need for continuous observation based on clinical condition ◆ Need for observation because of serious risk of aspiration pneumonia ◆ Need for continuous O2 therapy because of clinical hypoxaemia ◆ Need for frequent daily respiratory physiotherapy to treat/​prevent respiratory failure ◆ Need for bi-​level positive airway pressure or continuous positive airway pressure (CPAP) ◆ Need for chest drain monitoring ◆ Need for intravenous (IV) rhythm-​controlling drug(s) to support or control supraventricular arrhythmias

◆ Need for central venous line for monitoring of central venous pressure ◆ Need for arterial line for monitoring arterial pressure and/​or sampling of arterial blood ◆ Need for central venous access: ● To deliver titrated fluids to treat hypovolaemia ● For boluses or continuous infusion of IV drugs ◆ Need for single IV vasoactive drug to support or control arterial pressure, cardiovascular output, or organ perfusion ◆ Need for temporary cardiovascular pacemaker ◆ Need for percutaneous cardiac assist device (e.g. IABP, axial pumps) ◆ Need for pericardiocentesis or myocardial biopsies

◆ Need for invasive mechanical ventilator support ◆ Need for RRT for acute condition ◆ Need for TTM ◆ Need for surgically implanted mechanical circulatory support ◆ Need for ECLS

Table 3.2  Grading the demand of care for some common acute cardiovascular diseases Overall demand in care

Specific Specific Specific monitoring: monitoring: monitoring: low risk intermediate high risk risk

Non-​invasive haemo­ dynamic monitoring

Central venous line for CVP

Arterial Clinical NIV or line hypoxaemia CPAP requiring continuous O2

Invasive mechanical ventilator support

Central venous access for continuous infusion of drugs

IV vasoactive drugs

Percutaneous cardiac assist device (e.g. IABP, axial pumps)

ECLS

IV rhythm Temporary OTHER controlling pacemaker drug(s)/​ cardioversion

ACUTE CONDITIONS acting as modifier AHF with hypoperfusion as dominant clinical expression

Level 2

AHF with venous congestion as dominant clinical expression

Level 1

Acute renal failure with oliguria

Level 2

Condition (e.g. sepsis, RV dysfunction) requiring IV vasopressor

Level 2

Acute pulmonary oedema with low arterial pressure

Level 2

CS

Level 3

Cardiac arrest with Level 3 coma Ventricular tachyarrhythmia with no haemodynamic complication

Level 1

Cardiac arrhythmias with heart failure

Level 2

VT/​VF electrical storm

Level 3

RRT

RRT

RRT Hypothermia

ACUTE CORONARY SYNDROME Uncomplicated Level 1 STEMI after initial cath lab admission and successful reperfusion

(continued )

Table 3.2 Continued Overall demand in care

Uncomplicated-​ type NSTEMI before transfer to the cath lab

Level 1

NSTEMI type 2—​ no complication

Level 1

Ischaemic complication of PCI

Level 2

Specific Specific Specific monitoring: monitoring: monitoring: low risk intermediate high risk risk

Acute ST-​segment Level 2 elevation AMI, with no or unsuccessful reperfusion High-​risk NSTEMI before PCI

Level 2

NSTEMI/​STEMI complicated by congestive heart failure—​no shock

Level 2

ACUTE CARDIOVASCULAR PATHOLOGIES AHF with pulmonary oedema and high systolic arterial pressure

Level 1

Third-​degree AVB with heart failure

Level 1

AF or supraventricular arrhythmias with heart failure

Level 1

Myopericarditis—​ Level 1 uncomplicated Myocarditis or peripartum cardiomyopathy, with no/​minimal EF alteration

Level 1

Non-​invasive haemo­ dynamic monitoring

Central venous line for CVP

Arterial Clinical NIV or line hypoxaemia CPAP requiring continuous O2

Invasive mechanical ventilator support

Central venous access for continuous infusion of drugs

IV vasoactive drugs

Percutaneous cardiac assist device (e.g. IABP, axial pumps)

ECLS

IV rhythm Temporary OTHER controlling pacemaker drug(s)/​ cardioversion

Peripartum MCP Level 2 or myocarditis with reduced EF with no symptoms of AHF Primary pulmonary Level 2 hypertension with right heart failure PE—​not high risk

Level 1

High-​risk PE at risk of or requiring thrombolysis

Level 2

Heart transplant patient with suspected acute rejection and LV dysfunction

Level 3

Free wall rupture after MI

Level 3

Non-​complicated type B dissection

Level 2

Type A aortic dissection

Level 3

Cardiac tamponade

Level 2

Prosthetic valve thrombosis without heart failure

Level 3

Pericardiocentesis

Acute endocarditis Level 3 with heart failure Acute aortic regurgitation with heart failure

Level 3

Mitral stenosis—​ complicated

Level 1

Aortic stenosis with heart failure—​initial management

Level 2

Acute mitral Level 2 regurgitation with heart failure—​ initial management

(continued )

Table 3.2 Continued Overall demand in care

Specific Specific Specific monitoring: monitoring: monitoring: low risk intermediate high risk risk

Non-​invasive haemo­ dynamic monitoring

Central venous line for CVP

Arterial Clinical NIV or line hypoxaemia CPAP requiring continuous O2

Invasive mechanical ventilator support

Central venous access for continuous infusion of drugs

IV vasoactive drugs

Percutaneous cardiac assist device (e.g. IABP, axial pumps)

ECLS

IV rhythm Temporary OTHER controlling pacemaker drug(s)/​ cardioversion

All conditions Level 3 considered as level 2 care that does not respond rapidly to treatment, stabilize, or improve Patients with post-​structural or endovascular interventions

Level 1

AF, atrial fibrillation; AHF, acute heart failure; AMI, acute myocardial infarction; AVB, atrioventricular block; CPAP, continuous positive airway pressure; CS, cardiogenic shock; CVP, central venous pressure; ECLS, extracorporeal life support; EF, ejection fraction; IABP, intra-​aortic balloon pump; IV, intravenous; LV, left ventricular; MI, myocardial infarction; NIV, non-invasive ventilation; NSTEMI, non-​ST-​segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PE, pulmonary embolism; RRT, renal replacement therapy; RV, right ventricular; STEMI, ST-​segment elevation myocardial infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.

Stru ctu re a n d   e qui p m e n t patients it commonly manages (see E Figure 3.1). Most recent position papers present three levels of ICCU, each implying a different organization [16–​19]. The level and organization of an ICCU will be linked to the structure and range of services provided by the host hospital. However, there is no obligatory relationship between the level of an ICCU and the overall capabilities of the hospital. Beyond hospital size and technical capabilities, many parameters will contribute to the case mix of an ICCU:  geographical distribution; history of acute cardiovascular care development; and interaction with other specialties such as general critical care, cardiothoracic intensive care, internal medicine, and emergency medicine.

Level I ICCU (first level; enhanced cardiovascular care units) Level I  ICCUs are designed to manage patients with cardiovascular conditions demanding level 1 care. They mainly focus on the care of patients with ACS, congestive heart failure without shock (or rapidly improving patients with low cardiac output), or complex, not life-​threatening arrhythmias. A  level I  ICCU will offer specialized cardiovascular care in different hospital settings. In community hospitals, they will offer first-​line management of many acute cardiovascular conditions. In hospitals with higher technical capabilities, level I ICCUs may also admit patients following PCI for ACS or post-​structural or endovascular interventions. They might act as step-​down units for level II or III ICCUs, sharing management and resources.

Level II ICCU (intermediate; cardiovascular high dependency units) Level II ICCUs are designed to manage level 1 and level 2 patients. Level II ICCUs should provide initial evaluation and management of severely ill or high-​risk patients with congestive heart failure and/​or low cardiac output complicating acute or chronic

cardiac conditions. Level II ICCUs require immediate access to a 24/​7 coronary interventional catheter laboratory. With round-​ the-​clock service for PCI, level II ICCUs will usually form the hub of a STEMI network. A general critical care unit must be present on the same site as the ICCU, and intensivists should be available 24/​7 for consultation, co-​management of complex patients, and urgent support [10].

Level III ICCU (highest level; cardiovascular critical care units) Level III ICCUs are designed to care for level 3 patients who have acute cardiac conditions that are severe enough to require, or be at high risk of requiring, invasive mechanical ventilation, RRT, ECLS, emergency cardiac surgery, or surgical cardiovascular assistance.

Structure and equipment Whatever the functional organization of a hospital, ICCUs have the responsibility to provide services and personnel that ensure optimal patient care according to their case mix and level. There is a large consensus among recommendation and position papers that all ICCUs must have appropriate diagnostic facilities available to inform delivery of pharmacological and invasive treatment according to the current guidelines [16–​19]. A summary of suggested equipment is presented in E Tables  3.3 and 3.4. All equipment must conform to the relevant safety standards and be regularly serviced. All staff members must be appropriately trained, competent, and familiar with the use of equipment [10].

Level I ICCU A level I  ICCU will be fully equipped for the needs of level 1 patients. Accordingly, level I  ICCUs should provide all types

Acute cardiac care Intensity of care Prehospital care

Non-intensive cardiovascular care

Acute cardiovascular pathologies → demand in intensive care Level 1

Level 2

Level 3

Case mix, hospital type, capability, and organization Cardiology ward

Intensive cardiovascular care units Levels I to III

Figure 3.1  From demand in care for acute cardiac conditions to the level of ICCUs. All ICCUs provide a higher degree of care in relation to other cardiology

units up to a telemetry cardiovascular ward. The grade of intensive cardiovascular care refers to both the quantity and expertise of medical and paramedical care being provided for management of a given cardiovascular condition. A given ICCU will present a case mix of acute cardiovascular patients with conditions needing different intensities of care. The level of expertise and technical requirements of an ICCU will depend on this case mix, along with external factors, mainly the hospital’s type, capability, and organization.

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Table 3.3  Levels of ICCUs: technical capabilities and expertise of the ICCU and its hospital Technical capabilities and expertise of the ICCU Level I ICCU: basic cardiovascular intensive care

Level II ICCU: advanced cardiovascular intensive care

Level III ICCU: cardiovascular critical care

◆ All non-​invasive clinical parameter monitoring ◆ 24/​7 echocardiography and thoracic ultrasound ◆ Direct current cardioversion ◆ NIV ◆ Transcutaneous temporary pacing ◆ Chest tubes ◆ Nutrition support ◆ Physiotherapy on ward

As in level I ICCU, plus: ◆ Ultrasound-​guided central venous line insertion ◆ Pericardiocentesis ◆ Transvenous temporary pacing ◆ Transoesophageal echocardiography ◆ Pulmonary artery catheterization/​right heart catheterization ◆ Percutaneous circulatory support (IABP, Impella®) ◆ TTM (in many centres)

As in level II ICCU, plus: ◆ ECLS ◆ Mechanical circulatory support expertise (LVAD, bi-ventricular assist device) ◆ RRT ◆ Mechanical ventilation

Technical capabilities and expertise that should be available in hospital Level I ICCU

Level II ICCU

Level III ICCU

◆ ED ◆ CT scanner ◆ Transoesophageal echocardiography ◆ Palliative care programme ◆ Ultrasound-​guided central venous line insertion ◆ X-​ray system for fluoroscopy in the vicinity of the unit ◆ 24/​7 chest radiographs ◆ 24/​7 computerized tomography angiography ◆ 24/​7 blood gas analysis ◆ 24/​7 biomarkers: ACS ◆ 24/​7 biomarkers: AHF ◆ 24/​7 biomarkers: coagulation and thrombosis ◆ 24/​7 biomarkers: renal and hepatic function/​ failure

As in level I ICCU, plus: ◆ 24/​7  PCI ◆ Pacing and cardiovascular resynchronization therapy programme ◆ Implantable cardioverter–​defibrillator programme ◆ Ablation therapy programme ◆ Renal support therapy ◆ Cardiovascular magnetic resonance ◆ Post-​cardiovascular arrest treatment ◆ Neuromonitoring for prognostic evaluation ◆ Endomyocardial biopsy

As in level II ICCU, plus: ◆ Comprehensive cardiovascular surgery (coronary artery bypass graft surgery; surgical management of acute disorder of the aorta, valves, and any other cardiovascular structure) ◆ Interventional vascular radiology, including expertise in complicated aortic dissection, embolization, and neuro-​interventional radiology ◆ Any percutaneous structural heart intervention, valvuloplasty, and transcatheter aortic valve implantation ◆ Donor organ and transplantation programme

Table 3.4  Suggested monitoring and equipment according to ICCU level Level I ICCU

Level II ICCU

Level III ICCU

◆ At least two ECG channels ◆ Non-​invasive blood pressure monitor ◆ At least one invasive pressure channel ◆ Pulse oximeters ◆ Electronic prescribing and chart access (advisable) ◆ Nurse station to be used for central monitoring of at least one ECG lead from each patient, and relevant haemodynamic and respiratory data should continuously be present on a central screen ◆ Slave monitors to enable monitoring of patients from different sites in the unit ◆ Working stations for retrospective analysis of index events ◆ Volumetric pump/​automatic syringes ◆ CPAP delivery systems to use with face mask ◆ At least one mechanical ventilator for the unit with NIV capacity ◆ Biphasic defibrillators ◆ At least one external pacemaker for the unit ◆ Temporary VVI pacemakers and at least one DDD for the unit advisable ◆ Mobile echocardiography machine ◆ Glucose level measurement kits ◆ If blood chemistry tests cannot come back from the central lab within 5 minutes: blood clot meter (ACT), blood chemical marker kits, blood gas and electrolyte analyser, multiparametric blood analyser

Same as level I ICCU, plus: ◆ Additional ECG channels ◆ Invasive haemodynamic channels ◆ End-​tidal  CO2 ◆ Non-​invasive cardiovascular output ◆ Non-​invasive thermometers ◆ Mechanical ventilators ◆ Mobile echocardiography machine, including transoesophageal echocardiography probe, vascular probe ◆ At least one echography device for ultrasound guidance for central venous line ◆ Percutaneous circulatory assist devices (IABP, percutaneous axial pump) ◆ X-​ray system for fluoroscopy in the unit ◆ Haemodialysis/​haemofiltration machine through the nephrology department (advisable) ◆ Hypothermia maintenance devices (advisable)

Same as level II ICCU, plus all techniques and equipment that place this unit on par with a general critical care unit, including: ◆ Specific additional monitoring ◆ Haemodialysis/​haemofiltration machine ◆ Mechanical ventilators And more specifically: ◆ ECLS ◆ Hypothermia maintenance devices

The I C C U  t e a m of non-​invasive monitoring, have the expertise and the means to administer NIV for respiratory failure and inotropes for low cardiovascular output, and provide immediate resuscitation of cardiovascular arrest.

Level II ICCU All invasive and non-​invasive monitoring should be available in a level II ICCU. Advanced techniques, including invasive ventilation or institution of percutaneous mechanical circulatory support, should be available and staff trained in their use, even if patients will subsequently be transferred rapidly to a higher-​level unit. Percutaneous circulatory support (IABPs, percutaneous axial pumps) should be available. In many centres, level II ICCUs will manage patients following resuscitation from cardiac arrest, including provision of targeted temperature management.

Level III ICCU A level III ICCU should be fully equipped for the needs of level 3 patients. Level III ICCUs should have all forms of invasive and non-​invasive monitoring capabilities, as well as invasive ventilation and RRT. These units should be able to manage patients receiving ECLS. Advanced technologies, such as mechanical circulatory assist devices, should also be available. Level III ICCUs require a hospital environment that provides specific and highly specialized professionals required at times for the support of patients with advanced and severe acute cardiovascular conditions. Immediate access to interventional cardiology, anaesthesiology, and cardiovascular surgical support is required.

Premises Recent documents in cardiology [1, 20] and general critical care [21–​24] provide detailed information on the specific design and engineering requirements applicable to level II or III ICCUs. Some facilities should be provided in all level II ICCUs: single (isolation) rooms, a central nurse station, a procedure room with X-​ray and equipment for invasive monitoring, space for staff facilities, including restrooms, catering facilities, changing rooms, en-​suite overnight accommodation for on-​call (on-​duty) staff, and education and training facilities. It is important when designing an ICCU to anticipate support facilities for relatives and carers and the patient’s right to privacy and dignity, and strategies for noise reduction and maximizing natural light. Most countries have specific national standards for ‘high-​end’ ICU provision, to which level III ICCUs must comply.

Number of beds There is no definitive formula for the number of ICCU beds needed in a hospital. It is, of course, important for the number to be commensurate with the workload and case mix. The minimum

number of beds in an ICCU is not clearly defined either and is often constrained by staffing regulatory requirements. Due to its specific function and staffing, it is reasonable to advise a level II ICCU to have at least six beds. Possible formulae for calculation of level II ICCU beds are [1]‌: ◆ For every 100 000 inhabitants: 4–​5 ICCU beds. ◆ For every 100 000 visits per year in the ED: ten ICCU beds. For any ICCU, additional factors to be considered when devising the number of beds required in a hospital include [25]: ◆ Acute beds in the hospital (medical and surgical). ◆ Previously calculated occupancy of wards, high dependency units, and critical care units and target occupancy of the ICCU. ◆ History of inability to admit patients due to lack of ICCU capacity. ◆ Number and location of other high-​care areas in the hospital or in other hospitals in the surrounding catchment area. ◆ Number of on-​site operating theatres. ◆ Presence of specialist services which may require cardiovascular support. ◆ Ability to transfer patients to an off-​site location.

Clinical governance and continuous improvement ICCUs must operate within established frameworks for clinical governance that comply with local, regional, and national requirements [26]. Within each unit, a lead for clinical governance and quality improvement should be designated. Uniform protocols and processes may reduce mortality and are recommended [27, 28]. An audit programme, including assessment of compliance with guidelines (local, national, international) and quality indicators (e.g. out-​of-​hours transfer, readmission, morbidity, and mortality versus risk stratification, nosocomial infection rates), should be implemented. Data collection on bed occupancy, diagnosis, mortality, and morbidity is recommended. Measurement of additional relevant quality indicators is required, and, where possible, data should be submitted to local or national databases [29,  30] and participation in relevant national or international registries [31] encouraged. Benchmarking against approved standards and outcomes is recommended, as well as participation in regional/​national critical care networks. Data collection and clinical governance strategies should be sustainable, with appropriate administrative and technological support. Institutions should provide the adequate technical means and financing for any ICCU to provide high-​quality clinical governance.

The ICCU team Since the functional level of an ICCU must be tailored to the level of care of the most demanding or severe patients that it is required to manage, so should be the expertise of physicians, nurses, and allied professionals.

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With an organization based on cardiac intensivist-​directed care, an ICCU will deliver the best care for acute cardiovascular patients [7]‌. The wider ICCU team comprises a range of allied professionals, including (but not limited to) respiratory physiotherapists, pharmacists, dietitians, psychologists, cardiac scientists, and perfusionists, alongside physicians from clinical pharmacology, palliative care, and infectious diseases. The ICCU should be under the full medical responsibility of a dedicated cardiovascular team (closed unit). The situation where the non-​ICCU physician admitting the patient retains responsibility for orchestrating and implementing care for this patient (open unit) is not compatible with the objectives of a modern ICCU [22, 32, 33]. The ICCU team must liaise with patients’ primary physicians to include them in important discussions such as the appropriateness of high-​risk procedures and end-​of-​life decisions [2, 17].

Nurses and advanced nurse practitioners High-​quality nursing is the cornerstone of acute cardiovascular care. The nurse:patient ratio and the quality of nurse education and clinical experience have a direct impact on the quality of patient outcomes [34–​37]. More specifically, in acute cardiovascular care, the nurses’ expertise extends also to monitoring rhythm disturbances, evaluating the potential for complications, especially after interventional procedures or deterioration, and coordinating the communication within the ICCU interdisciplinary team [35–​ 39]. ICCU nurses should have a specialist post-​ registration qualification in acute cardiovascular care and clinical expertise in this area. The ESC-​ ACVC recommends advanced nurse practitioners to be part of the ICCU team. Additional education (Master’s degree or other postgraduate education) allows them to undertake specialist roles, which have been associated with improved efficiency and better patient satisfaction and long-​term outcomes [34, 40]. All ICCUs should have a nursing team leader with managerial responsibility (level I ICCU) or a nursing director (level II and III ICCUs). Even if there are national regulatory requirements for nurse:patient ratios in different levels of ICCU, the nurse:patients ratio should be related to the level of care that patients are needing. The ESC-​ACVC recommends a minimum ratio of one nurse to four level 1 patients, a nurse:patients ratio of 1:2 to 1:3 for patients with level 2 acute cardiovascular conditions, and a ratio of 1:1 or 1:2 for patients with level 3 acute cardiovascular conditions.

ICCU medical staff and cardiovascular intensivists To ensure high standards in ICCU patient management, formalized education in acute cardiovascular care should be available in any national health care system. The ESC-​ACVC CC for acute cardiovascular care provides guidance with a well-​defined

framework for this education. Cardiologists working in ICCUs should at least have the competences required by the CC. Beyond level I ICCU, all physicians must have specialized skills in critical care. To qualify as a cardiovascular intensivist, the ESC-​ACVC suggests a minimum of 12 months of full-​time training after completion of the core cardiology training. All ICCUs should be coordinated by a cardiology director. He/​ she should be appropriately trained and qualified in acute cardiovascular care and ICCU management [1, 9]. According to the ESC-​ACVC, a level I  ICCU should be directed and managed by cardiologists and a level 2 ICCU must be directed and managed by cardiovascular intensivists. In a level 3 ICCU, the director of the unit and the core team of cardiologists should all be cardiovascular intensivists. General critical care physicians working collaboratively with cardiologists can be an alternative option. For most aspects of staffing and organization, level III ICCUs should follow the relevant national rules that apply for general critical care units in their country. There is no clear recommendation for the senior physician or consultant-​to-​patient ratio [1, 10]. It is acknowledged, however, that requirements for senior physicians to provide direct clinical care in ICCUs vary greatly, with additional support provided by fellows and specialized nurses.

On-​duty physicians In any ICCU, continuity of medical cover must be provided 24/​7. A level I  ICCU should provide round-​the-​clock echocardiography and expertise for acute cardiovascular conditions in its hospital and the on-​duty physician should have the corresponding expertise. In a level II ICCU, the on-​duty physician should be a cardiovascular intensivist based in the unit. The director of the unit may approve provision of night cover by other cardiologists competent in the emergency techniques required in a level II ICCU. Night shifts could potentially be covered by fellows or residents trained in acute cardiovascular care and techniques needed for the corresponding ICCU level. In that case, an attending member of the ICCU team must be available on call for senior consultation and assistance [1, 30]. A recent study in general critical care reported that adding a night-​time intensivist to an ICU already staffed with physicians in training at night appeared to offer no or marginal improvements in outcomes [41, 42]. In level III ICCUs, the organization of on-​site 24/​7 continuity of care should follow the national regulations applicable in the country for general critical care units [10]. On-​duty physicians should have both advanced acute cardiovascular care and critical care expertise that is required for working in a level III ICCU.

Interaction with other specialties The close relationship between the ICCU and other subspecialties of cardiology and other medical specialties is pivotal to running

Per s ona l  pe r spe c t i v e an excellent unit. Beyond collaborating closely with different subspecialties of cardiology, the specialized ICCU staff must also establish close relationships with non-​ cardiovascular specialties [43]. Typically specialists who collaborate on a regular basis with the ICCU team are cardiovascular surgeons, cardiovascular anaesthesiologists, critical care physicians, nephrologists, infectious disease specialists, clinical pharmacologists, palliative care teams, and emergency physicians for the pre-​cardiology part of patient management [44, 45]. Frequently, the initial, sometimes lifesaving, interventions do not demand a multidisciplinary expertise; however, following stabilization, a wider multidisciplinary and multiprofessional team will be required to plan, coordinate, and manage patients’ care [46]. In many institutions, ‘heart teams’ combining relevant specialties are held weekly or more frequently, especially for heart failure, coronary revascularization, extracorporeal support, and infective endocarditis [47]. ICCU patients with complex issues should be discussed during the relevant multidisciplinary specialist meetings, as well as the ICCU multidisciplinary team meetings. Patients admitted to current ICCUs have increasingly advanced and complex medical conditions, and palliative care is an integral component of their care. Palliative care education and training must be a standard among clinicians who are involved in cardiovascular intensive care [48, 49]. Care of acute cardiovascular patients extends beyond the ICCU. The ICCU team should provide acute cardiovascular care consults to inpatients with a potential need for ICCU admission. In critical care, outreach services have had a positive impact on patient outcomes [50].

ICCU—​part of a regional network The ESC-​ACVC recommends that all ICCUs participate in a formalized regional network of acute cardiovascular care. These networks should follow the ‘hub and spoke’ model developed so successfully for STEMI [9, 51, 52], with each level referring acute cardiovascular patients to higher-​level ICCUs when escalation is required [9]‌. Developing ICCUs as part of a network, rather than as isolated units serving a limited area, facilitates good coverage of the population and optimizes the management of acute cardiovascular patients across an entire region [53]. The benefits observed in STEMI networks rely on the development of a well-​established transfer protocol, shortening delays and standardizing procedures between centres [49, 51]. The optimal ICCU network configuration for a region should be collectively and consensually organized and precisely define the clinical conditions that meet the criteria for transfer, transfer modalities, and treatment protocols before and during transfer and also ensure communication between participating parties and on-​time information on bed availability, as well as return policy [54]. It should also address any potential legal or financial challenges (e.g. reimbursement of transfer).

Telemedicine Level II and III ICCUs should behave as a hub for emergency consultations and should be organized to provide expert opinion on patients with acute cardiovascular conditions in hospitals without cardiology or PCI facilities. This can be achieved through secure video-​conferencing, with visualization of cardiovascular examinations such as coronary angiography or echocardiography [55]. Such programmes can streamline the transfer of patients for higher-​intensity care and help reduce costs. Telemedicine should be seen as a delivery tool or system in support of acute cardiovascular care [56]. Video-​conferencing, secure transmission of images and other data, and CME should all be part of an ICCU’s way of working and interaction with colleagues elsewhere. Video-​ conferencing equipment should be available for the ICCU team and should be located as near as possible to the unit [57]. Health care organizations should establish a budget that encompasses the cost of implementation, which may include items such as staff education programmes, hardware, software, and their upgrades and replacements.

Personal perspective Acute cardiovascular care is facing many challenges. The organization of ICCUs in three levels (as summarized in E Table 3.5) in close relation to intensity of care is not arbitrary but essential to face these challenges and eventually ensure optimal quality in care. ◆ A first

challenge corresponds to the fast evolution in the type of pathologies managed in ICCUs. Initially designed to secure and support the management of MI, ICCUs have seen their recruitment evolve into different forms of AHF, rhythm disorders, and the recognition and treatment of acute non-​cardiac conditions in cardiac patients. This evolution has been neither programmed nor anticipated. Remaining clearly cardiologic in relation to their nature and/​or their background, these pathologies are more intricate and complex. They require more attention during ICCU stay, more extensive and often multidisciplinary expertise, and, at the end, insertion of patient follow-​up in a precise cardiologic setting. Managing patients with these conditions is becoming always more specialized. ◆ A  second challenge is the evolution of cardiology. The components of the specialty of cardiology (e.g. rhythmology, interventional cardiology, heart failure) have also evolved considerably in the last 20  years and have become highly technical and specific. These highly specialized cardiologists are less apt and less inclined to participate directly in ICCUs’ activity. Therefore, specialization of the ICCU medical team is made necessary not only by evolution of pathologies, but also by evolution of the cardiology specialty.

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Table 3.5  Intensive cardiovascular care units: summary

Population and disease

Level I ICCU

Level II ICCU

Level III ICCU

Level 1 cardiovascular conditions (see % Table 3.2), monitoring of patients post-​ structural and endovascular interventions (see % Table 3.2 and text)

Level 1 and 2 patients (see % Table 3.2); severe or high-​risk patients with congestive heart failure and/​or low cardiac output complicating acute or chronic cardiac conditions

Mainly level 3 patients, some level 2 patients; acute cardiac conditions needing invasive mechanical ventilation, RRT, ECLS, emergent heart surgery, or surgical cardiovascular assistance

◆ Technology ◆ All non-​invasive clinical parameter All invasive and non-​invasive cardiovascular and therapy monitoring monitoring in ICCU ◆ 24/​7 echocardiography and thoracic ◆ Idem level I ICCU, plus: ultrasound-​guided ultrasound; direct current cardioversion; central venous line insertion; transvenous NIV; transcutaneous temporary pacing temporary pacing; transoesophageal echocardiography; pulmonary artery catheterization/​right heart catheterization; percutaneous circulatory support; X-​ray system for fluoroscopy

Hospital

◆ ED; CT scanner; transoesophageal echo; X-​ray system for fluoroscopy

◆ Level of Head: cardiologist competence ◆ Team: cardiologists ◆ On site: intensivist consultation 24/​7

◆ All advanced invasive and non-​invasive cardiovascular monitoring ◆ Idem level II ICCU, plus: ECLS; mechanical circulatory support; RRT; mechanical ventilation

◆ 24/​7 coronary interventional cath lab; hub centre ◆ Tertiary or university hospital of an STEMI network ◆ Idem for level II ICCU, plus: percutaneous ◆ Idem for level I ICCU, plus; pacing; cardiovascular structural heart intervention; resynchronization therapy; implantable endomyocardial biopsy; donor organ and cardioverter–​defibrillator programme; ablation transplantation programme; interventional therapy; renal support therapy; scanner and vascular radiology; comprehensive cardiac magnetic resonance cardiovascular surgery ◆ Head: cardiovascular intensivist ◆ Team: cardiovascular intensivists ◆ On site: intensivist consultation 24/​7

◆ Head: cardiovascular intensivist or co-​ directorship with a general critical care specialist ◆ Team: cardiovascular intensivists with additional education in critical care; may include general intensivists with additional education in cardiology

◆ Education Recommended: written exam towards ◆ Required: specific national curriculum for acute programmes ESC-​ACC certification for individuals; cardiovascular care or ESC-​ACVC curriculum for should master all techniques required in cardiovascular intensivist level I ICCU ◆ Residents or fellow cardiovascular intensive care ◆ Residents or fellow in cardiology

◆ Idem level II ICCU, plus: specific curriculum for general critical care training ◆ Residents and fellow cardiovascular intensive care; critical care

On-​duty physicians

◆ Cardiologists with level I ICCU expertise; ◆ Cardiovascular intensivists; trained cardiologists; if approved by the unit’s director, physicians advanced in their cardiovascular trained residents or other physicians, intensivist training, provided availability of a provided availability of an on-​call cardiovascular intensivist or an interventional member of the ICCU team cardiologist

◆ Should have all the requirements and expertise for working in a level III ICCU

Nursing/​ other personnel

◆ Nursing director (could be shared with ◆ Nursing director ◆ regular ward) Dedicated nurses: nurse-​to-​patient ratio 1:2 or ◆ Dedicated nurses: nurse-​to-​patient ratio 1:3 for level 2 acute cardiovascular conditions 1:4 for level 1 patients

◆ Nursing director ◆ Dedicated nurses: nurse-​to-​patient ratio 1:2 or 1:1 for level 3 acute cardiovascular conditions

Research

◆ Encouraged to be part of outcome research

◆ Strong commitment to perform clinical research

◆ The

◆ Encouraged to conduct clinical research

number of cardiologists in training is limited and only a small proportion can be trained as cardiovascular intensivists. This is one reason why the ESC-​ACVC recommends that specialization in acute cardiovascular care be gradual and follows the organization of ICCUs into three levels (see E Chapter 2). This is also why setting up networks is essential. Networks allow all patients to access the necessary expertise.

◆ The

regulatory aspects are finally essential. Acute cardiovascular care is a young, and unfortunately insufficiently known, specialty. To adjust to changes in intensive care cardiology, recognition of acute cardiovascular care as a subspecialty and its positioning in relation to other intensive specialties, with the possible establishment of bridges, is an urgent and important step.

Re f e re n c e s

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32. Brilli RJ, Spevetz A, Branson RD, et al. Critical care delivery in the intensive care unit: defining clinical roles and the best practice model. Crit Care Med 2001;29:2007–​19. 33. Wilcox ME, Chong CAKY, Niven DJ, et al. Do intensivist staffing patterns influence hospital mortality following ICU admission? A systematic review and meta-​analyses. Crit Care Med 2013;41:2253–​74. 34. Aiken LH, Sloane DM, Bruyneel L, et al. Nurse staffing and education and hospital mortality in nine European countries:  a retrospective observational study. Lancet 2014;383:1824–​30. 35. Diya L, Van den Heede K, Sermeus W, Lesaffre E. The relationship between in-​hospital mortality, readmission into the intensive care nursing unit and/​or operating theatre and nurse staffing levels. J Adv Nurs 2012;68:1073–​81. 36. McHugh MD, Ma C. Hospital nursing and 30-​day readmissions among Medicare patients with heart failure, acute myocardial infarction, and pneumonia. Med Care 2013;51:52–​9. 37. Adomat R, Hewison A. Assessing patient category/​dependence systems for determining the nurse/​patient ratio in ICU and HDU: a review of approaches. J Nurs Manag 2004;12:299–​308. 38. Kim MM, Barnato AE, Angus DC, Fleisher LA, Fleisher LF, Kahn JM. The effect of multidisciplinary care teams on intensive care unit mortality. Arch Intern Med 2010;170:369–​76. 39. Hatchett R, Thompson DR. Cardiovascular Nursing: A Comprehensive Guide, second edition. Churchill Livingstone: Edinburgh; 2007. 40. Van den Heede K, Lesaffre E, Diya L, et  al. The relationship between inpatient cardiac surgery mortality and nurse numbers and educational level:  analysis of administrative data. Int J Nurs Stud 2009;46:796–​803. 41. Kerlin MP, Small DS, Cooney E, et  al. A randomized trial of nighttime physician staffing in an intensive care unit. N Engl J Med 2013;368:2201–​9. 42. Wallace DJ, Angus DC, Barnato AE, Kramer AA, Kahn JM. Nighttime intensivist staffing and mortality among critically ill patients. N Engl J Med 2012;366:2093–​3101. 43. Bourke ME. Coronary care unit to cardiac intensive care unit: acute medical cardiac care—​adapting with the times. Can J Cardiol 2016;32:1197–​9. 44. Vader JM, Rich MW. Team-​based care for managing noncardiac conditions in patients with heart failure. Heart Fail Clin 2015;11:419–​29. 45. Sabbe M, Bronselaer K, Hoogmartens O. The emergency medical system. In: M Tubaro, P Vranckx, S Price, C Vrints (editors). The ESC

Textbook of Intensive and Acute Cardiovascular Care, second edition. Oxford University Press: Oxford; 2015. pp. 47–​55. 46. Kappetein AP, Windecker S. The heart team in acute cardiac care. In:  M Tubaro, P Vranckx, S Price, C Vrints (editors). The ESC Textbook of Intensive and Acute Cardiovascular Care, second edition. Oxford University Press: Oxford; 2015. pp. 87–​90. 47. Davidson P, Driscoll A, Huang N, et  al. Multidisciplinary care for people with chronic heart failure:  principles and recommendations for best practice. 2010. Available from: M M http://​dro.deakin.edu.au/​ eserv/​DU:30056042/​driscoll-​multidisciplinarycare-​2010.pdf. 48. Swetz KM, Mansel JK. Ethical issues and palliative care in the cardiovascular intensive care unit. Cardiol Clin 2013;31:657–​68,  x. 49. Naib T, Lahewala S, Arora S, Gidwani U. Palliative care in the cardiac intensive care unit. Am J Cardiol 2015;115:687–​90. 50. Marsh S, Pittard A. Outreach: ‘the past, present, and future’: Table 1. Contin Educ Anaesth Crit Care Pain 2012;12:78–​81. 51. Huber K, Quinn T. Systems of care for patients with acute ST elevation myocardial infarction (STEMI networks). In:  M Tubaro, P Vranckx, S Price, C Vrints (editors). The ESC Textbook of Intensive and Acute Cardiovascular Care, second edition. Oxford University Press: Oxford; 2015. pp. 365–​71. 52. Pavesi PC, Nobilio L, De Palma R, Casella G, Di Pasquale G, Grilli R. [The evolution of intensive cardiac care units and the effects of interhospital networks for reperfusion implementation. Analysis of the Emilia-​Romagna regional data, 2002 to 2007]. G Ital Cardiol (Rome) 2011;12:31–​42. 53. Graham KJ, Strauss CE, Boland LL, et  al. Has the time come for a national cardiovascular emergency care system? Circulation 2012;125:2035–​44. 54. Warren J, Fromm RE, Orr RA, Rotello LC, Horst HM. Guidelines for the inter-​and intrahospital transport of critically ill patients. Crit Care Med 2004;32:256–​62. 55. Park JH, Kim YK, Kim B, et  al. Diagnostic performance of smartphone reading of the coronary CT angiography in patients with acute chest pain at ED. Am J Emerg Med 2016;34:1794–​8. 56. Davis TM, Barden C, Dean S, et  al. American Telemedicine Association Guidelines for TeleICU Operations. Telemed J E Health 2016;22:971–​80. 57. LeRouge C, Garfield MJ, Collins RW. Telemedicine: technology mediated service relationship, encounter, or something else? Int J Med Inf 2012;81:622–36.

CHAPTER 4

The heart team Sergio Leonardi, Thomas Modine, and Stephan Windecker

Contents Summary  25 Introduction  25 General considerations on heart teams  26 Definition and composition  26 Function  26 Indications  26 Considerations for optimal interaction  26

Heart teams in patients with complex coronary artery disease requiring revascularization  27 Indications  27 Non-​urgent (elective) indications (patients with stable CAD or stabilized NSTE-​ACS)  27 Urgent or emergent indications  27 Patient communication strategies  27 Roles and responsibilities of team components  28 Considerations on decision-​making and optimal mode of revascularization  28 Optimal use (and potential limitations) of scores of anatomical complexity  28 PCI: anatomical and procedural considerations  29 CABG: anatomical and procedural considerations  29 Completeness of revascularization  29 Conduit selection  30

Final decision-​making considerations  30 Conclusion  31 References  31

Summary Modern cardiovascular medicine is complex, dynamic, and interactive. Therefore, a multidisciplinary dialogue between different cardiovascular specialists is required to deliver optimal patient care. This requirement has led to the concept of teams of different specialists caring for patients with complex cardiovascular diseases—​hence the concept of ‘heart teams’. These teams are particularly valuable when complex and/​or rapid decision-​making is essential. This chapter is intended to provide conceptual and practical considerations for the composition, structure, and function of multidisciplinary teams involved in the treatment of complex cardiovascular diseases; to discuss strategies for clear and transparent patient communication and promotion of a patient-​centric approach; and to provide guidance on optimal implementation of the heart team concept in patients requiring myocardial revascularization of a broad spectrum of complex coronary artery disease, from stable angina to acute coronary syndrome patients with mechanical complications and haemodynamic instability.

Introduction There is increasing emphasis on multidisciplinary decision-​making by clinical practice guidelines in different patient populations [1–​5]. Team-​based care has relevant potential merits and is often advocated to optimize patient care. By bridging together specialists of different expertise, this approach may promote interdisciplinary dialogue, as well as continuity of care, with the goal of offering a balanced and complementary approach to the care of patients. On the other hand, multidisciplinary decision-​making may increase logistical complexity, may cause diagnostic and treatment delays, and has therefore been criticized  [6]‌. Despite being consistently recommended as the favoured decision-​making approach by European and American guidelines [1–​5] and proving to be beneficial and consistent in diverse patient populations [7–​9], heart teams still remain poorly implemented [10]. The substantial variation in coronary artery bypass grafting (CABG)-​to-​PCI ratios across countries, as well as different geographical locations within the same country, cannot be solely explained by different geographical patterns of CAD and may be driven by local expertise, reimbursement, and economic considerations and likely reflect variability in multidisciplinary decision-​making and specialty bias [11]. Several strategies to optimal heart team utilization have been proposed, including optimization of logistical, professional, and interdisciplinary barriers [12–​14].

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CHAPTER 4  

The heart  t eam

In this chapter, we will discuss composition, structure, and function of heart teams, attempting to provide conceptual and practical considerations for multidisciplinary decision-​making in patients with complex CVD; discuss strategies for patient communication and promotion of a patient-​centric approach; and provide guidance on optimal implementation of the heart team concept in the historical first and still one of the most important settings, i.e. patients with complex CAD requiring myocardial revascularization.

General considerations on heart teams Definition and composition The heart team is defined as a group of different specialists that optimally interact to provide a balanced, unbiased, timely, and—​whenever possible—​evidence-​based decision-​making to patients with complex heart diseases. The types of specialists involved depend on the disease of interest:  anaesthesiologists, cardiac surgeons, and interventional cardiologists for patients with complex CAD and/​or valvular heart disease (VHD) [1]‌; invasive electrophysiologists and specialized surgeons in patients with complex arrhythmias [3]; and infectious disease specialists for patients with complicated endocarditis [2]. Clinical (i.e. non-invasive) cardiologists (typically the treating physicians) are always part of heart teams and are generally responsible for synthesizing the discussion and communicating with the patient. Other specialists may be needed, depending on specific concomitant conditions or patients’ comorbidities such as geriatricians for elderly patients.

Function Indications A heart team is usually indicated when important decisions that intersect multiple specialties are being undertaken, typically requiring percutaneous or surgical interventions. Examples include the choice of the mode of myocardial revascularization (surgical or percutaneous) in patients with complex CAD [1]‌; management of patients with severe VHD; management of patients with atrial fibrillation (AF) and failed rhythm control therapy who require interventional or surgical AF ablation [3]; and the indication and timing of surgery in patients with complicated endocarditis [2]. As timing may be crucial in acute settings, it is essential that urgent/​emergent diagnostic or therapeutic decisions, as well as specialists to be contacted, are coordinated in advance as much as possible, with predefined and clear communication channels to minimize delays. In these settings, it is helpful to define, in a written institutional heart team protocol, simple decision pathways based on actionable steps, as well as local feasibility and expertise considerations to streamline the process of care, including common ‘real-​world’ scenarios.

Considerations for optimal interaction Interaction between components defines heart teams. It is therefore essential to discuss requisites for balanced relationships between members, detail their structure, and reflect on strategies for optimal interaction. First, a written institutional protocol is a preliminary step in this regard and, as recommended by current guidelines, should be produced [1]‌. The local protocol should be agreed upon designated representatives of each component and include clear decisional pathways (especially for urgent or emergent situations) based, whenever possible, on relevant guidelines and scientific evidence, clear instructions indicating criteria for selecting patients that should be presented on heart team round-​tables, feasibility considerations, and local expertise. The protocol should be regularly revised, as new evidence emerges or local facilities/​expertise evolve and indicate how often planned meetings should be convened. It should also indicate the modality of unplanned meetings when rapid decision-​making is required. According to current guidelines, institutional protocols should also be established in institutions without on-​site cardiac surgery where cardiology departments should team up with a referral cardiac surgery unit [1]. Second, the responsibilities and area of expertise of each component should be clearly outlined in the local protocol. While team-​based decisions should be informed by, and do not rely solely on, scores [1]‌, the use of validated risk scores, such as the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) scores, the Society of Thoracic Surgeons (STS) scores, and EuroScore II, has potential advantages and may help delineate an explicit risk assessment [15, 16]. Actionable (i.e. which provide a risk/​benefit stratification algorithm to inform decision-​making on the preferable therapeutic option) scores should be favoured. A limitation is inclusion of relevant comorbidities (such as advanced dementia or frailty) that are currently not part of most scores. These should be reported in writing and considered for the final decision-​making. Last, but not least, the management of disagreements among members should be addressed. In general, different opinions should be viewed as an opportunity, not as a barrier, for decision-​ making. Concerns and observations by any component should be adequately discussed, analysed, and documented. As a general rule, the team component with the highest expertise in the area of disagreement should take the final decision. For example, in case of disagreement on the assessment of surgical risk, such as low predicted risk based on score, but perceived higher risk based on other comorbidities, the opinion of the cardiac anaesthesiologist and surgeon should weighed relatively more than that of the clinical cardiologist or interventional cardiologist. If after extensive discussion, major disagreements on patient management persist, these should be transparently communicated to the patient—​ideally together and by the entire team. Eventually, transparent communication is necessary to inform and share decision-​making with the patient in non-​urgent settings.

Heart teams in patients with complex coronary artery disease requiring revascularization

Heart teams in patients with complex coronary artery disease requiring revascularization The concept of the heart team was first proposed by the Task Force of ESC/​EACTS 2010 Myocardial Revascularization Guidelines and subsequently developed for patients with complex CAD to jointly decide the optimal mode of revascularization, i.e. surgical or percutaneous [17]. In this section, we provide practical guidance to implement the heart team for these patients and specifically discuss indications, patient communication strategies, and specific considerations on decision-​making regarding the optimal mode of revascularization (see E Figure 4.1).

Indications Multidisciplinary decision-​making is not required in all patients undergoing coronary revascularization but should be considered in patients with complex and stable CAD (elective patients) or stabilized non-​ST elevation acute coronary syndrome (NSTE-​ ACS) [1, 18]. This latter group includes patients admitted for ACS, but without evidence of recurrent myocardial ischaemia (symptoms or dynamic ST changes on the ECG), as well as haemodynamic (AHF or cardiogenic shock) and/​or electrical instability (cardiac arrest or sustained ventricular arrhythmias) [1, 19]. A separate setting (urgent or emergent indications) is composed by patients with unstable ACS, including ST elevation acute coronary syndrome (STE-​ACS), or patients experiencing mechanical complications. While heart teams should ideally take place in all stable patients with complex CAD, there may be situations—​very elderly patients or those with reduced life expectancy, advanced dementia, and other substantial comorbidities—​that are unfavourable for

General practitioner (Interventional) cardiologist

Intensivist Heart team Family Geriatrician

Patient

Imaging specialist

Anaesthesiologist

Cardiac surgeon Other specialist

Figure 4.1  Composition of the heart team to decide on myocardial

revascularization in patients with complex CAD. Green box: comprises the core members of the heart team. Yellow box: represents facultative members to be consulted for heart team meetings.

surgery (and/​or PCI) and may not require formal heart team meetings. These factors should be jointly discussed by heart team member representatives and listed in the written institutional protocol to minimize inappropriate heart team meetings and possible treatment delays.

Non-​urgent (elective) indications (patients with stable CAD or stabilized NSTE-​ACS) A heart team is usually recommended for elective patients with complex CAD. Complex CAD involves at least one of three anatomical settings: (1) significant involvement of the proximal left anterior descending (LAD) artery (≥50% of luminal diameter narrowing, as assessed visually by coronary angiography in the ‘worst view’ angiographic projection); (2)  significant distal left main stenosis; and (3)  three-​vessel disease. In the last two settings, calculation of the SYNTAX score is recommended and should be routinely performed [1]‌.

Urgent or emergent indications In an urgent or emergent situation, such as unstable NSTE-​ACS (or ACS patients with persistent ST elevation) and complex CAD, a culprit-​lesion PCI is generally indicated. In patients with residual multivessel CAD who may benefit from a surgical completion of revascularization (e.g. residual involvement of the proximal LAD or significant left main stenosis), heart team discussion should occur after clinical stabilization, also considering hybrid revascularization. Uncommon, but clinically important, scenarios include mechanical complications of AMI. In these situations, urgent CABG with concomitant surgical correction should be generally considered. To streamline decision-​making processes, it is advisable to include in the written institutional protocol predefined decisional steps, as a formal heart team meeting may delay lifesaving care. Specifically, all ACS patients presenting with cardiogenic shock, a new (or presumably new) loud systolic murmur, or flash pulmonary oedema should routinely undergo emergency echocardiography to diagnose a possible mechanical complication while awaiting coronary angiography [20, 21]. In these situations, heart team discussion is important to optimize the timing for surgery, rather than to discuss therapeutic options. In some very high-​risk patients with post-​infarct ventricular septal defect (VSD), multidisciplinary discussion may include the option of haemodynamic stabilization (by ECMO or axial left ventricular–​aorta pumps) or percutaneous VSD closure. In an urgent or emergent situation of a conscious patient, communication should be kept as simple as possible and only verbal consent should be considered.

Patient communication strategies In elective patients, communication about the possibility—​and mode—​of myocardial revascularization should start when first consenting for coronary angiography. This is the first important opportunity to illustrate therapeutic options that include medical therapy and myocardial revascularization, with discussion of the

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The heart  t eam

pros and cons of percutaneous and surgical revascularization. If the patient, after adequate consent, expresses a clear preference for one of the options, this should be reported in writing in the clinical chart and considered for decision-​making at the time of angiography. Deciding on the mode of coronary revascularization at the time of coronary angiography in elective patients (i.e. stable CAD or stabilized NSTE-​ACS) with complex CAD is generally discouraged. For the same reason, ad hoc PCI in these patients should be generally avoided. The proportion of patients who refuse one type of revascularization might be influenced by the way this is communicated. For this reason, patients who refuse CABG or PCI might be monitored and reported for quality purposes (see E Table 4.1). To optimize and share decision-​making on the mode of coronary revascularization, it is advisable that the heart team reaches a consensus on the recommended mode of revascularization before discussing with the patient. Providing separate opinions has the potential to generate biased perception and confusion (especially in challenging cases or when conflicting evidence is present) and may compromise patient trust and optimal decision-​making.

Roles and responsibilities of team components The main responsibilities of the clinical cardiologist are to lead patient communication (both at the time of coronary angiography and subsequently after team decision), assess the clinical indications for revascularization (ischaemic threshold and consequences of ischaemia on quality of life, presence of myocardial viability) and potential concomitant indications for surgery (such as VHD), and define the clinical profile, including risk factors for CAD (such as diabetes), as well as relevant comorbidities, especially if not included in risk scores (such as advanced dementia), and medications compliance [such as contraindications to adequate dual antiplatelet therapy (DAPT)]. The main responsibilities of the interventional cardiologist are to quantify the anatomical complexity and functional severity of CAD, anticipate the completeness and complexity of percutaneous revascularization (including anticipated contrast medium volume), and describe the general procedural aspects (including number and type of stent, anticipated DAPT duration, and other

aspect such as indications for mechanical circulatory support in patients undergoing high-​risk PCI). The primary responsibility of the cardiac surgeon is to provide an opinion on feasibility, anticipate completeness and complexity of surgical revascularization, and describe the general procedural aspects. The main responsibility of the anaesthesiologist is to assess surgical risk in tandem with the cardiac surgeon and potential measures to reduce this risk.

Considerations on decision-​making and optimal mode of revascularization The rationale for revascularization is provided not only by the presence of severe coronary lesions, but also by an underlying viable myocardium. In patients with normal systolic function, it can be generally assumed that the ischaemic myocardium is viable and should be revascularized. Patients with systolic dysfunction, especially if severe, may need further testing. Markedly depressed left ventricular (LV) function in patients with ischaemic cardiomyopathy, but with preserved viability, may be reversed by revascularization [22, 23]. In this setting, advanced imaging, such as cardiac magnetic resonance imaging (MRI), single-​photon emission computerized tomography (SPECT), or echocardiography, may be very helpful. Cardiac MRI is nowadays the gold standard to assess myocardial scarring as evidence of non-​viable tissue. SPECT can estimate resting perfusion, stress-​induced ischaemia, scarring, and cardiac function.

Optimal use (and potential limitations) of scores of anatomical complexity The calculation of the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score is currently recommended in patients with complex CAD to quantify anatomical complexity [Class I, level of evidence (LoE) B][1]. The SYNTAX score is a comprehensive anatomical assessment of CAD complexity. In brief, each coronary lesion with ≥50% of luminal stenosis in vessels ≥1.5  mm is included on the basis of the modified American Heart Association (AHA) coronary tree segment classification and independently scored considering the presence of bifurcations/​trifurcations, ostial location, chronic occlusion, vessel tortuosity, calcification, length, and thrombus formation. The score of each lesion is added to obtain the patient’s

Table 4.1  Potential tools for heart team implementation in stable or stabilized patients with complex coronary artery disease Indicator

Reporting method Comments

1. Written institutional protocol

Presence: yes/​no

This should be an agreed representative of each component locally and include feasibility considerations

2. Anatomical assessment of coronary severity Proportion

SYNTAX score

3. Assessment of surgical risk

Proportion

STS score favoured over EuroScore II

4. Heart team discussion performed

Proportion

This should be written in the patient record and include, at a minimum, the clinical cardiologist, interventional cardiologist, and cardiac surgeon

Heart teams in patients with complex coronary artery disease requiring revascularization final SYNTAX Score, with higher scores indicative of increasingly complex coronary disease. After being derived from the SYNTAX trial, the score has been validated in different patient populations [24, 25]. There are, however, several independent observations of substantial interindividual variability in calculating the SYNTAX score [26–​28]. The scoring of bifurcation and trifurcation lesions and the presence of small-​vessel disease remain the main source of inconsistency [26]. In one study, the interobserver variability of a group of interventional cardiologists with an average of 7.5  years of experience was poor and improved only slightly after core laboratory team revision. This may have important implications for the adoption of the SYNTAX score in clinical decision-​making  [26]. The residual SYNTAX score was developed to quantitatively assess the degree and complexity of residual stenoses, based on recalculating the SYNTAX score after PCI [29]. The intention of this index is to quantitatively assess the angiographic completeness of revascularization. High residual SYNTAX scores have been associated with worse outcomes in patients undergoing angiography-​guided PCI [30,  31]. Hence the anticipated completeness of revascularization by PCI or CABG should be considered and prioritized for final decision-​making (Class IIa, LoE B)  [1]‌. In addition, the functional significance of a lesion, based on fractional flow reserve (FFR) or instantaneous wave-​free ratio (iFR), is an important determinant of future adverse cardiac events in patients undergoing PCI [32–​34]. In conclusion, the calculation of the SYNTAX score should be performed by experienced operators and—​ ideally—​ independently confirmed by both the interventional cardiologist and the cardiac surgeon. Functional assessment of coronary lesions (invasive or non-​invasive) should be routinely considered to guide revascularization in stable patients in cases of lesions of intermediate-​grade stenosis (i.e. 50–​90% by visual assessment) or without documented ischaemia. If functional assessment is not (or cannot be) performed, the residual SYNTAX score can be helpful to verify if revascularization is anatomically complete (0.5 mm during chest pain New or presumably new bundle branch block Sustained ventricular tachycardia High-​degree atrioventricular block

Biomarkers

Elevated cTn

Score

GRACE risk score ≥140 HEART score ≥7

PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; ECG, electrocardiogram; GRACE, Global Registry of Acute Coronary Events; HEART, History, ECG, Age, Risk factors, and Troponin.

discharge from the ED, these patients need prolonged clinical observation following an accelerated diagnostic pathway, comprising serial ECG recordings and cardiac injury biomarker measurements obtained over 1–​3 hours to accurately diagnose (rule in) or exclude (rule out) an ACS. Most often, this is carried out in an observation unit in the ED or a dedicated chest pain unit (CPU), within or close to the ED [15]. A negative accelerated diagnostic evaluation allows early discharge, whereas patients with a diagnosis of AMI are admitted to an ECG monitoring unit and referred for early coronary angiography. Clinical risk stratification tools may help clinicians to integrate symptoms, ECG, and biomarker findings in risk stratification of chest pain patients. These tools have been incorporated in accelerated diagnostic pathways that facilitate fast triage and safe early discharge of low-​risk chest pain patients [16, 17]. The guidelines on NSTE-​ACS recommend the use of the TIMI (Thrombolysis In Myocardial Infarction) and GRACE risk stratification tools mainly to assess the prognosis of patients with ACS and to identify patients who may benefit from intensive antithrombotic therapy and an early invasive strategy [13, 18]. Both the TIMI and GRACE risk stratification tools were initially validated in patients already diagnosed with an ACS [19, 20]. In a validation study in chest pain patients presenting in the ED, a modified TIMI score correlated well with 30-​day clinical outcome but failed to optimally risk-​stratify the patients [21]. As patients with the lowest risk defined by a TIMI score of 0 had a 1.7% incidence of AEs, it was concluded that the TIMI risk score should not be used in isolation to guide which ED chest pain patients can be discharged safely. The ASPECT (ASia Pacific Evaluation of Chest pain Trial) and ADAPT (2-​Hour Accelerated Diagnostic protocol to Assess Patients with chest pain symptoms using contemporary Troponins as the only biomarker) trials combined a modified TIMI risk score with ECG findings and 0-​hour and 2-​hour contemporary cardiac

troponin (cTn) measurements [22, 23]. Between 10% and 20% of the patients presenting with chest pain in the ED were classified as low risk with >99% sensitivity and a negative predictive value (NPV) of almost 100%. In a randomized trial that compared the ADAPT protocol with a standard-​care pathway (cTn test on arrival at hospital, prolonged observation, and a second cTn test 6–​ 12 hours after onset of pain), use of the ADAPT pathway resulted in an almost doubling of the proportion of patients with chest pain discharged early [24]. In a retrospective analysis on the original ADAPT cohort, a modified ADAPT pathway using a TIMI score of 0 or 1 and a high-​sensitivity, instead of a contemporary non-​high-​sensitivity, cTn assay allowed to identify 40% of patients as low risk with >99% sensitivity and NPV. This was further corroborated in a prospectively studied APACE (Advantageous Predictors of Acute Coronary Syndromes Evaluation) cohort [25]. The TRUST (Triage Rule-​out Using high-​Sensitivity Troponin) accelerated diagnostic protocol (ADP) pathway based on a modified Goldman risk score, a non-​ischaemic ECG, and a single high-​sensitivity cTn (hs-​cTn) assay measured on presentation also allowed to classify 40% of the patients as low risk, similarly to ADAPT and APACE, with very high sensitivity and NPV [26]. The HEART score was specifically developed for unselected patients with chest pain presenting at the ED [27]. The HEART score (see E Figure 10.1) differs from the TIMI and other risk stratification tools, as it also includes clinical suspicion by the physician and the presence of multiple coronary risk factors in its calculation. Moreover, as it is mainly based on simple clinical parameters, it can be easily calculated at the bedside. The HEART score represents the patients’ risk of developing a major adverse cardiac event (MACE) within 6 weeks after initial presentation. The HEART score has been tested and validated in numerous studies performed in Europe [28–​30], the US [31, 32], and the Asia-​Pacific [27, 33]. Overall a HEART score of ≤3 allowed to identify 35–​46% of low-​risk patients with very high sensitivity and NPV [34]. Patients with HEART scores of ≥7 are a very high-​risk subgroup, with >50% of MACEs within 6 weeks [28], who therefore should be admitted immediately to an ICCU. The HEART score was initially validated for use in conjunction with contemporary cTn assays. The HEART score based on the results of hs-​cTn assays should therefore be used with caution, as the troponin-​related points may vary with the assay used. However, in two retrospective cohort studies in which hs-​cTn assays were used, application of the HEART score resulted in the identification of 31.6–​37.2% of low-​risk patients with a sensitivity of 93.7–​100% and an NPV of 98.3–​100%, results that are very similar to those observed in earlier validation studies [26, 29]. The North American Chest Pain Rule was 100% sensitive for a cardiac event within 30 days and classified 18% of patients as low risk who may be suitable for discharge [35]. The Vancouver Chest Pain Rule for detection of low-​risk patients is based on clinical assessment of the ECG, cardiac history, nitrate use, age, pain characteristics, and a single measurement of troponin at 2 hours after presentation. Using either contemporary or high-​ sensitivity troponin assays, the rule allows detecting

Diag n o st i c   t e st i n g 6-week MACE

HEART score

50

40

ECG

2 = significant ST-depression 1 = non-specific repolarization disturbance 0 = normal

30

Age

2 = ≥65 years 1 = ≥45 to ULN

Figure 10.6  The ESC 0-​hour/​3-​hour rule-​out and rule-​in algorithm of NSTE-​ACS using hs-​cTn assays [13]. ULN, upper limit of normal.

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C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t Acute chest pain: suspected NSTEMI

0-hour hs-cTn 0h hs-cTn lowB very or and lowA* no 0-1 hour ∆C

Other

0-hour hs-cTn highD or 0-1 hour ∆ +++E

Rule-out

Observe

Rule-in

Discharge Outpatient follow-up

ED or CPU hs-cTn 3 hours Echocardiography Functional imaging Coronary angiography (invasive or CCTA)

ICCU or CCU Coronary angiography (invasive)

Figure 10.7  The ESC 0-​hour/​1-​hour rule-​out and rule-​in algorithm using hs-​cTn assays in patients presenting with suspected NSTEMI to the ED. * If chest pain onset >3 hours. For three additional hs-​cTnI assays, a 0-​hour/​1-​hour algorithm has been derived and validated and the respective manuscripts are currently undergoing peer review.

exclusively on information provided by hs-​cTn blood concentrations on blood samples taken on admission and 1 hour later. The decision points derived and validated for each assay are assay-​specific [13, 82–​87]. The 0-​hour/​1-​hour ESC algorithm obviates the need for formal use of clinical scores and allows safe rule-​out of MI, even in patients with mild, non-​specific ECG abnormalities. The diagnostic algorithms using hs-​cTn assays have substantially improved the efficiency of triage of chest pain patients in the ED. The increased sensitivity of hs-​cTn assays abridges the troponin blind period early after onset of MI and allows marked shortening of the time interval to the second blood sample needed to demonstrate a significant rise of the biomarker. The 0-​hour/​1-​hour ESC algorithm is as effective as the 0-​hour/​3-​hour ESC in ruling in and ruling out AMI with a very high NPV [88]. Moreover, it allows to detect—​1 hour earlier—​ a greater number of patients eligible for early discharge than the previously widely used ADPs using contemporary cTn assays (ADAPT-​ADP) that included the additional calculation of a clinical low-​risk score (see E Figure 10.8). Institutional standard operational procedures for the diagnosis of acute chest pain based on the 0-​hour/​1-​hour ESC algorithm will therefore not only increase patients’ safety, but also markedly shorten the duration of stay in the ED, which may lead to important cost savings. The 0-​hour/​3-​hour and 0-​hour/​1-​hour ESC algorithms have inflexible rules for the timing of troponin resampling and cut-​ off levels for the diagnosis of MI that clinically is not always applicable. An international consortium has recently developed and validated a risk assessment tool that integrates hs-​cTn concentrations at ED presentation, the dynamic change in concentration during serial sampling, and the time between obtaining samples that allows, in a more flexible way, to determine the probability of MI and 30-​day outcomes [90].

Echocardiography Echocardiography should be routinely available in the ED or CPU, and performed by a trained staff [91]. It is not required where a non-​cardiac diagnosis is obvious or in whom the probability of an acute cardiovascular cause is considered very low. TTE is indicated in patients with acute chest pain and: (1) a diagnosis or a high clinical suspicion of an ACS; (2) haemodynamic instability; (3)  AHF; (4)  suspicion of acute aortic syndromes, myocarditis, or pericarditis; and (5) underlying cardiac disease such as aortic valve stenosis and hypertrophic cardiomyopathy. Although it is reasonable for individual risk stratification during the hospital stay, echocardiography is not recommended in haemodynamically stable, normotensive patients with suspected PE [92]. Transoesophageal echocardiography (TOE) may be indicated when TTE is non-​diagnostic. In cases of suspected aortic dissection, TOE is more sensitive than TTE [93]. Echocardiographic signs suggestive of myocardial ischaemia or necrosis include: (1) segmental wall motion abnormalities; (2)  impaired myocardial perfusion detected by contrast echocardiography; and (3)  reduced regional function using strain and strain rate imaging [91].

Chest  X-​ray A CXR is often performed in the evaluation of patients attending the ED. In one large study, a quarter of such patients showed significant findings:  cardiomegaly, pneumonia, and pulmonary oedema [94]. When there is a high clinical suspicion of acute life-​ threatening conditions other than an ACS (pericardial effusion, acute aortic dissection, PE, pneumothorax, or pneumonia), a CXR is indicated and should be available, preferably within 30 minutes.

Computerized tomography Coronary computerized tomography angiography (CCTA) has been proposed as a rapid and accurate diagnostic technique to

Diag n o st i c   t e st i n g HEART ≤3

Undetectable hs-cTn 100 100

98.1 98

100

ESC 0-hour/1-hour algorithm

ADAPT-ADP TIMI = 0 C cTn

ADAPT-ADP TIMI ≤1 hs-cTn

99.3 99.7

99.7 99.7

98.4 99.5

ESC 0-hour/3-hour algorithm 98.4 92.4

80 63.7

60 %

52 40

40 28

20

20

19

16

17.3

0 0

0

1

2

2

3

Decision based on blood samples obtained × hours after presentation to the ED Rule-in ACS

Low-risk or rule-out ACS

Sensitivity

Negative predictive value

Figure 10.8  Comparison of the performance in ruling in and ruling out AMI or identifying low-​risk chest pain patients with various risk stratification scores and/​or diagnostic pathways either using contemporary (C cTn) or hs-​cTn assays [16, 89]. The 0-​hour/​1-​hour ESC algorithm is very effective in ruling in and ruling-​out AMI with a very high NPV.

rule out obstructive CAD, given its very high NPV [95, 96]. Three multicentre studies have evaluated the feasibility, safety, and diagnostic accuracy of early CCTA, compared to usual care, in the triage of chest pain patients in the ED [97–​99]. A meta-​analysis showed that a diagnostic strategy using early CCTA is as safe as usual care of chest pain patients in the ED and results in a significant reduction of cost and length of hospital stay [100]. However, in a recent multicentre study that compared early CCTA with standard optimal care diagnostic protocols based on the use of hs-​cTn assays, early CCTA failed to identify more patients with significant CAD requiring coronary revascularization, shorten hospital stay, or allow for more direct discharge from the ED [101]. Selective use of CCTA may be considered in the 20% of chest pain patients in whom a diagnosis of NSTE-​ACS cannot be reliably ruled out or ruled in by the ECG and hs-​cTn diagnostic algorithms [13, 102]. Computerized tomography angiography (CTA) of the aorta plays a central role in the diagnosis, risk stratification, and management of acute aortic syndromes. In most patients with suspected acute aortic dissection, CTA is the preferred initial imaging modality [93]. Pulmonary CTA allows the detection of PE and adequate visualization of the pulmonary arteries down to at least the segmental level [103,  104]. Pulmonary CTA is the second-​line test in patients with suspected non-​high-​risk PE and an elevated D-​dimer level, whereas it is the first-​line test in patients with suspected

high-​risk PE, i.e. those presenting with shock or hypotension or those with a high clinical probability of PE. The high accuracy of CTA in the diagnosis of PE and acute aortic dissection and the utility of CCTA in excluding CAD have led to the development of a triple rule-​out scan protocol, allowing the simultaneous assessment of all three causes of acute chest pain with a single scan [105]. Even with modern scanners, which offer a wider coverage and a greater temporal resolution, this necessitates a longer scanning time and an increased contrast volume. In a recent registry, a triple rule-​out protocol was associated with a slightly higher yield of PE and acute aortic dissection than CCTA, specifically in patients presenting in the ED [103].

Ultrasonography (other than echocardiography) Ultrasonography (US) can help in the management of acute chest pain, in particular when evaluating possible non-​cardiac causes. Lung US is useful to detect pleural effusion or pneumothorax. The CXR may miss the diagnosis when the volume of fluid or air is small, while US has a higher sensitivity and specificity (>90%). Typical findings in pleural effusion are the ‘quad and sinusoid signs’, while the ‘seashore sign’ (lung sliding) and ‘stratosphere (barcode) sign’ suggest pneumothorax [104]. Lung US is also important in detecting B-​lines or ‘comets’, which indicate the amount of extravascular lung water and correlate with AHF that can be associated with acute ischaemic chest pain. When gastrointestinal

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C hest pain in  th e emergency depa rtm en t a n d the chest pa i n  u n i t

(GI) causes of chest pain are suspected (e.g. cholecystitis, biliary colic, pancreatitis), abdominal US is appropriate.

Further predischarge testing Exercise ECG or non-​invasive stress testing has been recommended in low-​risk patients as the final confirmatory test before safe discharge from the ED [18, 106]. Routine use of predischarge ischaemia testing may, however, lead to a longer length of stay in the ED or observation units, more downstream invasive angiography and revascularization procedures, more radiation exposure, and greater costs without any improvement in clinical outcome [107–​110]. Use of the HEART score may aid in identifying patients in whom predischarge testing should be considered [31,  32]. In the HEART pathway implementation trial, patients with a HEART score of ≤3 in whom an ACS was excluded by serial troponin testing could be safely discharged without further testing [111]. Based on these studies, it is proposed to limit predischarge exercise testing and cardiac imaging to patients with a HEART score of >3 (see E Figure 10.8).

Role of chest pain units CPUs are organizational short-​stay units with specific management protocols designed to facilitate and optimize the diagnosis of patients presenting with chest pain in whom the diagnosis is still uncertain after an initial clinical assessment and who are at too high risk to be discharged immediately from the ED. Clinical studies, mainly from the US and the UK, have demonstrated that CPUs manage their patients as effectively as inpatient admission, but in a shorter time and at a lower cost [112–​114]. In Germany, an almost complete network of 244 certified CPUs has been established [115]. In Europe, many hospitals have developed some elements of CPU care, although sometimes without establishing a formal CPU [116, 117]. Clinical observation in a certified CPU results in enhanced quality of care of chest pain patients—​adherence to guidelines is better [118] and clinical outcome of patients with ACS is improved [119]. Furthermore, admission to the CPU offers a favourable moment to instruct patients about a heart-​healthy lifestyle while they are undergoing a diagnostic evaluation to rule out myocardial ischaemia [120]. A recent position paper of the ESC-​ACVC describes the optimal organizational structure and the physical and technical requirements of a CPU either close to the ED or as an integral part of the ED (see E Box 10.2) [15]. Different requirements are suggested for standard or advanced CPUs. A standard CPU should be supervised by a cardiologist, which can be in co-​direction with an EP, and should be staffed by a specialist or fellow in training for internal or emergency medicine. The medical staff should be assisted by at least one certified emergency, CPU, or CCU nurse per four beds. A higher level of accreditation requires the permanent presence of a specialist in cardiology or emergency medicine, the

Box 10.2  Physical and technical requirements of a CPU ◆ Two to four monitoring beds ◆ One examination room ◆ One waiting room ◆ Continuous heart rhythm monitoring, preferably centralized ◆ Continuous non-​invasive blood pressure monitoring ◆ External defibrillator with transcutaneous pacing modality ◆ Non-​invasive ventilation equipment available 30 minutes despite treatment, consider admission to intensive care unit Respiratory rate >35/minute Oxygen saturation 40 years) Holosystolic mitral murmur Jugular venous distension Peripheral oedema

Figure 11.3  Use of signs to differentiate cardiac from pulmonary causes of acute dyspnoea. The less central the position of the box, the more helpful the sign.

pleural effusions, or alveolar oedema, suggest the presence of AHF (see E Figure 11.4) [28–​31]. It is important to note that up to 20% of patients with AHF may have no radiographic signs of congestion. On the other hand, bronchitis and pneumonia may mimic many of the radiographic findings of congestion. Therefore, all radiographic findings need to be co-​assessed to form an overall impression, which can then have moderate to high accuracy in the diagnosis of acute dyspnoea. Recently, lung US has emerged as an additional, or even alternative, imaging modality in patients presenting with acute dyspnoea [30]. Based on the interpretation of US artefacts, specific structure appearances, and their distribution, lung US allows for a rapid point-​of-​care evaluation of a number of conditions, including pulmonary oedema and consolidation, as well as pleural effusion and pneumothorax [30]. The ease of learning, Table 11.1  Sensitivity of findings on physical examination in the diagnosis of AHF Findings Third heart sound

Sensitivity (%) 5

Jugular venous distension

50

Lower extremity oedema

60

Rales

the relatively short examination duration, and the non-​invasive nature of this technique make it an attractive point-​of-​care tool. Quantification of B-​lines (vertical artefacts that result from an increase in interstitial density) seems useful in the diagnosis, monitoring, and risk assessment of patients with suspected AHF [30]. Moreover, pleural effusions can be detected rapidly by US and represent specific treatment targets by drainage.

60–​70

NPs, including B-​type natriuretic peptide (BNP), N-​terminal pro-​B type natriuretic peptide (NT-​proBNP), and mid-​regional pro-​ atrial natriuretic peptide (MR-​ proANP) are considered quantitative markers of haemodynamic cardiac stress and HF (see E Chapter 33). The clinical introduction of NPs constitutes the most important advance in the management of patients with acute dyspnoea in the last decades. BNP is a 32-​amino acid polypeptide that is co-​secreted with the inactive NT-​proBNP from the left and right cardiac ventricles, in response to ventricular volume expansion and pressure overload [19]. Recent data suggest that LV end-​ diastolic wall stress and wall stiffness may be the predominant triggers of BNP and NT-​ proBNP synthesis and release. NPs are released into blood in relation to disease severity and correspond to the New York Heart Association (NYHA) functional classification system. The NP level can be used to quantify the severity of heart failure, reflecting the combined haemodynamic consequences of systolic and diastolic LV dysfunction, as well as VHD and RV dysfunction [19]. The clinical importance of a specific disease marker is related to the overall importance of the disease or the biological signal it quantifies, the availability of alternative methods to reliably diagnose the disease and quantify disease severity, and, of course, the performance of the marker. NPs, as quantitative markers of cardiac stress and heart failure, owe their enormous clinical importance to the fact that heart failure is a major public health problem, the uncertainty in the clinical diagnosis and management of heart failure, and their excellent diagnostic and prognostic utility. Two important principles underlie the clinical use of NPs. First, the NP level is not a standalone test. It is always of greatest value when it complements the physician’s clinical skills, along with other available diagnostic tools e.g. estimated glomerular filtration rate (eGFR). Second, NP levels should be interpreted and used as continuous variables in order to make full use of the biological information provided by the measurement. NPs have consistently shown very high accuracy in the diagnosis of heart failure in patients presenting with acute dyspnoea to the ED. NP levels are very high in patients with dyspnoea due to heart failure, and low in patients with other causes of dyspnoea [11–​13, 17, 19, 21]. Numerous diagnostic studies including patients presenting with dyspnoea have validated NPs against a gold standard diagnosis of AHF and have shown convincingly that NPs have a very high diagnostic accuracy [11, 12, 17–​24]. The higher the NP level, the higher the probability that dyspnoea is caused by AHF. Overall, all clinically available NPs (BNP, NT-​proBNP, and rarely

Fro m sym p to m s to   diag n o si s Table 11.2  Common ECG abnormalities in heart failure Abnormality

Cause

Clinical implication

Sinus tachycardia

Decompensated heart failure, anaemia, fever, hyperthyroidism

Clinical assessment, laboratory investigation

Sinus bradycardia

β-​blockade, digoxin, ivabradine, antiarrhythmics, hypothyroidism, sick sinus syndrome

Evaluate drug therapy, laboratory investigation

Atrial tachycardia/​flutter/​fibrillation

Hyperthyroidism, infection, mitral valve diseases, decompensated heart failure, infarction

Slow AV conduction, medical conversion, electroversion, catheter ablation, anticoagulation

Ventricular arrhythmias

Ischaemia, infarction, cardiomyopathy, myocarditis, hypokalaemia, hypomagnesaemia, digitalis overdose

Laboratory investigation, exercise test, perfusion studies, coronary angiography, electrophysiology testing, ICD

Ischaemia/​infarction

CAD

Echocardiography, troponins, coronary angiography, revascularization

Q-​waves

Infarction, hypertrophic cardiomyopathy, LBBB, pre-​excitation

Echocardiography, coronary angiography, ICD

LV hypertrophy

Hypertension, aortic valve disease, hypertrophic cardiomyopathy

Echocardiography/​Doppler

Atrioventricular (AV) block

Infarction, drug toxicity, myocarditis, sarcoidosis, Lyme disease

Evaluate drug therapy, pacemaker, systemic disease

Microvoltage

Obesity, emphysema, pericardial effusion, amyloidosis

Echocardiography, CXR

QRS length >120 ms or LBBB morphology

Electrical and mechanical dyssynchrony

Echocardiography, cardiac resynchronization treatment (CRT) (CRT pacemaker, CRT defibrillator)

Reproduced from Dickstein K, Cohen-​Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) [published correction appears in Eur Heart J 2010 Apr;12(4):416. Dosage error in article text] [published correction appears in Eur Heart J 2010 Mar;31(5):624. Dosage error in article text]. Eur Heart J 2008;29(19):2388–​2442 doi:10.1093/​eurheartj/​ehn309 with permission from Oxford University Press.

MR-​proANP) seem to have similar accuracy in the diagnosis of AHF [19, 21]. The clinical impact of using the diagnostic and prognostic information provided by BNP or NT-​proBNP was demonstrated also in several randomized controlled studies [13, 22, 32–​34]. In the BASEL study, the BNP group showed a significant reduction in time to adequate therapy, admission rate, and time to discharge. Hence, if we diagnose the cause of dyspnoea earlier and with greater accuracy, we can initiate appropriate treatment earlier; patients would improve more rapidly and would be able to be discharged sooner from the hospital. These findings were confirmed by two additional randomized controlled studies [22, 33]. Thus, data from three large randomized controlled studies consistently demonstrated that the additional use of NPs improves medical and economic outcomes in patients with dyspnoea. Accordingly, the use of NPs is supported by a class I recommendation in current guidelines [1]‌. Easily applicable algorithms for the interpretation of NPs by applying specific cut-​off levels have been developed (see E Table 11.3). It is important to see that NPs are quantitative variables and should always be used in conjunction with other clinical information. As NPs are quantitative markers of heart failure, the use of cut-​off levels is only the second best approach. Yet, in the busy emergency room, NP decision limits can be helpful. In a patient

presenting with dyspnoea, BNP levels 400 pg/​mL have a very high specificity and PPV for AHF. Similar cut-​off values apply for NT-​proBNP (see E Table 11.3). In patients with NP levels above the upper cut-​off level, and therefore with substantial cardiac haemodynamic stress, we can be quite certain that AHF is the predominant cause of dyspnoea, and it is imperative to promptly initiate appropriate treatment such as nitrates, diuretics, and ACE-​Is. It is important to remember that NPs are also secreted from the right ventricle (RV). Therefore, severe PE with resulting RV stretch will also result in NP secretion and should always be included in the differential diagnosis of elevated NP levels. The vast majority of patients with acute dyspnoea will present with either low or high NP levels. However, about 25% of patients will present with NP levels in the grey zone. These patients need further clinical evaluation for a correct diagnosis. NT-​proBNP and BNP levels need to be adjusted in obese patients. In addition, BNP levels need to be adjusted in those with severe kidney disease but do not have to be adjusted for gender or age [19]. When using NT-​proBNP, the use of an age-​adjusted upper cut-​off level largely obviates the need for further adjustments for renal function [18]. For patients presenting with NP levels in the grey zone, other diagnostic tools, including CT scans and bedside echocardiography, have particular additional value.

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Ac u te dyspnoea in  th e emerg en cy  depa rtm en t Case report A 76-​year-​old male patient presented to the ED with acute dyspnoea over 24 hours. The patient reported a history of exercise-​ induced dyspnoea, but he emphasized that it was the first time he experienced dyspnoea at rest. His past medical history included CAD, persistent AF, and COPD. At presentation, the patient was tachypnoeic, with a body temperature of up to 38.5°C, a heart rate of 60 bpm, a blood pressure of 120/​80 mmHg, and an O2 saturation on room air of 94%. Clinical examination revealed prolonged expiration and wheezing and mild pre-​existing bilateral ankle oedema. Neither a third heart sound nor a heart murmur could be auscultated, while the jugular venous pressure (JVP) could not be reliably assessed. The ECG confirmed the already known AF without any other relevant changes, compared to the previous ECG. Initial assessment suggested an infective exacerbation of COPD, while measurement of BNP clearly identified AHF as the predominant cause of his acute dyspnoea. BNP concentration was substantially elevated at 1000 ng/​L. This value documents massively increased intracardiac filling pressures and thus makes a cardiac aetiology of acute respiratory distress very likely. In this case, AHF complicated an infection in a patient with known COPD. Loop diuretic therapy was initiated to relieve congestion and fluid overload, together with a prompt cardiological evaluation, including echocardiography, to select further management and identify the underlying structural heart disease. This case should show: 1. Fever and a systemic infection are not only common causes of exacerbated COPD, but also the most common triggers of AHF. 2. An obstructive auscultation finding (such as wheezing) is equally likely to be an expression of pulmonary congestion (in the sense of cardiac asthma) in patients with pre-​existing heart disease, and not only a sign of obstructive pulmonary disease. 3. BNP or NT-​proBNP play an important role in the diagnostic evaluation of patients with dyspnoea whenever HF is included in the differential diagnosis.

Echocardiography

Figure 11.4  Chest radiograph during various stages of AHF, showing

different radiographic findings and degrees of congestion. (A) Close-​up view of a posteroanterior radiograph revealing clearly visible bronchial walls (arrows) without blurring of the margins (no peribronchial cuffing). Hilar vessels (arrowheads) are sharply outlined (no hilar changes). Redistribution of flow is present. (B) Close-​up view of a posteroanterior radiograph from the same patient with increasing signs of congestion. Prominent thickening of bronchial walls (plain arrows), with partially indistinct outlines (peribronchial cuffing), as well as hilar enlargement, together with blurred vascular margins. Septal lines (tailed arrows) appear between indistinct vessels in the basal region. (C) Close-​up view of an anteroposterior radiograph obtained in the supine position. There is now complete loss of the bronchial interface (arrows, peribronchial cuffing). The density and size of the hila have further increased (arrowheads), and the margins of hilar vessels are indeterminable. Alveolar oedema is present (asterisks).

TTE with tissue Doppler imaging (TDI) should be performed immediately in all patients with acute dyspnoea and shock, and in those patients in whom the diagnosis remains uncertain after the initial work-​up (see E Chapter 18.2) [27]. In patients diagnosed with AHF, echocardiography is critical to determining the underlying structural heart disease. In most of these cases, echocardiography can be deferred safely, until dyspnoea has improved sufficiently to allow the patient to remain in the supine position for some time (usually on day 2 of hospitalization). Routine assessment includes determination of atrial and ventricular size, ventricular wall thickness, regional and global LV and RV function, including TDI, valvular structure and function, possible pericardial pathology, and mechanical complications of MI. About 50% of patients with AHF will be found to have heart failure with preserved LVEF; therefore, a detailed evaluation of LV diastolic function, including TDI, as well as global longitudinal strain (GLS), is critical. In addition, increased left atrial

Fro m sym p to m s to   diag n o si s Table 11.3  Cut-​off levels for NT-​proBNP and BNP in acute dyspnoea Cut-​off levels (ng/​L)* NT-​proBNP Age 75

Age 900

>1800

>400

Age 50–​75

Age >75

S4

Mainly S4

Rales

Present

Present

Peripheral oedema

Present

Rare

Cardiomegaly

Constant

Variable

Myocyte energy imbalance

Abnormal ECG

Constant

Variable

Relaxation can be defined as ‘the time period during which the myocardium loses its ability to generate force and shortens and returns to an unstressed length and force’ [5]‌. It corresponds to the dissociation of actin–​myosin cross-​bridges that begins during the early phase of LV ejection, before aortic valve closure [6]. Thus, diastolic dysfunction involves phenomena that occur not only during diastole, but also earlier in the cardiac cycle, at the time of calcium (Ca2+) uptake by the sarcoplasmic reticulum [7]. Since relaxation is an energy-​ consuming process, it is adversely affected by myocardial ischaemia. Ischaemia precludes optimal Ca2+ exchanges between the cytosol and the sarcoplasmic reticulum and is rapidly associated with impairment in LV relaxation [8]‌.

LVEF

Reduced

>40%

LV dilatation

Nearly constant

Absent

BNP/​NT-​proBNP

Markedly increased

May be only mildly increased

These authors showed that in diastolic heart failure patients, in contrast to normal subjects, isovolumic relaxation was incomplete at the time of Pmin. Thus, τ was prolonged and Pmin increased, resulting in a positive correlation between τ and Pmin. Incomplete relaxation accounted for 7 ± 1 mmHg of the measured increase in Pmin. Among these patients, LV compliance was also significantly altered, as supported by an increase in LV end-​diastolic pressure, despite a reduced LV end-​diastolic volume.

Contraction–​relaxation coupling As a consequence of the close relation between relaxation and contraction, LV relaxation is greatly affected by the lack of homogeneity in LV contraction. Both LV segmental coordination and atrioventricular (AV) synchronization are essential to guaranteeing efficient relaxation [9,  10]. The loss of atrial contraction associated with AF not only alters LV filling, but also results in a slowing of myocardial relaxation. Several other factors known to alter contractile function, including changes in afterload and use of inotropes, markedly affect relaxation. On the other hand, the effect of preload variations on relaxation is still a matter of debate. In a failing heart, an increase in afterload induces a delay in the onset of relaxation and an increase in the time constant of isovolumic relaxation [11].

Afterload reserve The afterload reserve is the ability of the normal LV to respond to afterload elevation without changes in LV end-​systolic volume and LV pressure decline [12]. Ventricles with altered contractile function consistently show a decreased afterload reserve [13–​15]. In such ventricles, even a small afterload elevation will markedly deteriorate LV relaxation parameters and increase LV systolic and diastolic volumes.

An alternative concept: end-​systolic volume dependency Chemla et al. proposed an alternative approach based on the suggestion that, at constant heart rate, relaxation might depend more

BNP, B-​type natriuretic peptide; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; NT-​proBNP, N-​terminal natriuretic peptide.

on LV end-​systolic volume than on afterload, namely LV systolic pressure [16]. Indeed, recoiling forces are generated when the LV contracts below its equilibrium volume (usually slightly higher than LV end-​systolic volume), and therefore recoiling forces act during early diastole. Thus, since a healthy heart is able to respond to increased afterload without any change in its LV end-​systolic volume, relaxation remains unaffected. On the contrary, in failing dilated ventricles, LV end-​systolic volume might exceed the equilibrium volume, which deprives the LV of recoiling forces and decreases the rate of isovolumic relaxation.

How to assess left ventricular diastolic function in clinical practice E Table 12.1 shows the major differences between systolic and diastolic dysfunction, in terms of symptoms, physical examination, ECG abnormalities, and radiographic findings. Diagnostic criteria for heart failure with preserved (HFpEF) or mid-​range (HFmrEF) ejection fraction are also proposed in E Box 12.1. Echocardiography plays a major role in the diagnosis of diastolic dysfunction. Specific findings are detailed elsewhere. NPs, either BNP or NT-​proBNP, have shown high sensitivity for the diagnosis of AHF. Normal values of NPs in patients presenting with suspected AHF make the diagnosis unlikely [17]. It is important to keep in mind that NPs may be unexpectedly low in some patients with preserved LV systolic function presenting with acute hypertensive (‘flash’) pulmonary oedema [18].

Left ventricular systolic dysfunction Pathophysiology LV systolic dysfunction refers to impaired ventricular contractility (inotropy). In HF with reduced left ventricular ejection fraction (HFrEF), loss of cardiac inotropy results in a decrease in

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Box 12.1  Diagnostic criteria of diastolic dysfunction in patients with HFpEF and HFmrEF

Criteria ◆ Presence of symptoms and signs of heart failure AND ◆ Normal or mid-​range LVEF (echocardiography) AND ◆ Elevated BNP or NT-​proBNP AND ◆ Objective evidence of underlying cardiac functional and structural alterations (echocardiography or CMR imaging) AND ◆ In case of uncertainty, a stress test or invasive measurement of elevated LV filling pressure may be needed to confirm the diagnosis (echocardiography or right heart catheterization in selected cases) BNP, B-​type natriuretic peptide; CMR, cardiac magnetic resonance imaging; HFpEF, heart failure with preserved left ventricular ejection fraction; HFmrEF, heart failure with mid-​range left ventricular ejection fraction; LVEF, left ventricular ejection fraction; NT-​proBNP, N-​terminal natriuretic peptide.

stroke volume and a compensatory rise in preload [often measured as ventricular end-​diastolic pressure or pulmonary capillary wedge pressure (PCWP)]. The rise in preload is considered compensatory, because it activates the Frank–​Starling mechanism to help maintain the stroke volume despite the loss of inotropy. If the preload did not rise, the decline in stroke volume would be even greater for a given loss of inotropy. Depending on the precipitating cause of heart failure, there will be LV hypertrophy, dilatation, or a combination of the two. (See also E Chapter 45.) Loss of intrinsic inotropy is associated with an increase in end-​ systolic volume. There is also an increase in end-​diastolic volume (compensatory increase in preload), but this increase is not as great as the increase in end-​systolic volume. Therefore, the net effect is a decrease in stroke volume. Because stroke volume decreases and end-​diastolic volume increases, there is a substantial reduction in ejection fraction (EF). The reason for preload rising as inotropy declines is related to the increased end-​systolic volume. Indeed, in the failing heart, at the beginning of diastole, there is already a ‘high’ end-​systolic volume. The venous return is added to this, leading to an increase in end-​diastolic volume and pressure. Thus, an important and deleterious consequence of systolic dysfunction is the rise in end-​ diastolic pressure. This can lead to pulmonary congestion and oedema. Another important determinant of LV systole is the interplay between the LV and the arterial (e.g. aortic) system, namely LV–​ aortic coupling, which is a key determinant of global cardiovascular performance [19, 20]. Sagawa et al. showed that during the ejection phase in a given P/​V loop, the end-​systolic volume points for different afterload conditions all fall along an approximately

ESPVR Increased afterload

150 LV pressure

118

100

c Stroke volume

50

0

b

d

Increased preload

a 0

ESV

50

EDV LV volume

100

Figure 12.2  Left ventricular pressure–​volume relationships. A cardiac cycle

is illustrated by the loop labelled ‘a’, ‘b’, ‘c’, and ‘d’. ESPVR, end-​systolic pressure–​ volume relationship; LV, left ventricular. Reproduced from Walley KR. Left ventricular function: time-​varying elastance and left ventricular aortic coupling. Critical Care (2016)20:270. Creative Commons Attribution 4.0 International License (http://​creativecommons.org/​licenses/​by/​4.0/​.

straight line—​ the end-​ systolic pressure–​ volume relationship (ESPVR) (see E Figure 12.2). The slope of this line is the time-​ varying elastance, defined as the change in pressure over time or ΔP/​ΔV (note that compliance is the inverse of elastance, expressed as ΔV/​ΔP). Ventricular systole is best defined by time-​varying elastance in [20–​21]. Consequently, if preload is increased (or decreased), so that end-​diastolic volume is increased (or decreased), the subsequent stroke volume is increased (or decreased) to the same extent, so that the end-​ systolic pressure–​ volume point still lies on the same ESPVR. Importantly, for energetically efficient systolic ejection, ventricular elastance is matched to aortic elastance. If ventricular elastance is less than arterial elastance, as in HFrEF, then energy is wasted as potential mechanical work. It is important to realize that AHF may or may not be followed by ventricular remodelling. Indeed, in the case of AHF resulting from a large anterior MI occurring in a previously healthy heart, a large portion of the anterior wall becomes functionally inactive within seconds and the rest of the ventricular myocardium is suddenly exposed to an increase in its haemodynamic load; it has to perform the work of the whole ventricle, including the ischaemic/​ infarcted area, under very unfavourable biological conditions called ‘biomechanical stress’. In this case, AHF simply results from acute dysfunction of the cardiac pump as a whole, with an associated hyperfunction of the remote area that tries to compensate for the loss of function of the ischaemic/​infarcted myocardial area. Another example of this situation of AHF with no previous cardiac remodelling is acute mitral regurgitation (MR) due to chordae rupture. In the case of AHF occurring as a decompensation of a chronically failing heart, cardiac myocytes have been remodelled through years of biomechanical stress resulting from the originating disease. In such a situation, the heart is obviously placed in an unfavourable situation when, being previously weakened by a long process of detrimental remodelling, it is unable to compensate for

Ca rdi o g e n i c   sh o c k the, often mild, insult at the origin of the acute decompensation (e.g. an episode of paroxysmal AF).

Clinical assessment The aetiology of LV dysfunction is diverse, but the leading cause is currently CAD. A previous history of MI makes the diagnosis of AHF more likely. Other causes of heart failure include long-​ standing hypertension and alcohol excess. A smaller proportion of patients have VHD. In these patients, symptoms and signs develop gradually, over days or weeks, and pulmonary and systemic congestion (jugular venous distension, pulmonary rales, and peripheral oedema) is usually present. They usually have a reduced LVEF. Despite high LV filling pressures, they may present with variable degrees of pulmonary congestion (clinical and/​or radiographic) and some may only have minimal pulmonary congestion. In Western Europe, the five most frequent causes of AHF are ischaemia, arrhythmia, infection, hypertension, and non-​ compliance with medication, and precipitating factors are independently associated with 90-​day mortality [22].

Investigations An ECG can provide very useful information. LV systolic dysfunction was found to be unlikely in a primary care population if there was no major abnormality on the ECG (sensitivity 9%, NPV 98%) [23]. Thus, in patients with breathlessness and a normal ECG, the clinical context needs to be carefully assessed and alternative causes might be considered first, although patients must be investigated further (e.g. with echocardiography) if heart failure is still thought to be the likely diagnosis. A chest radiograph may provide useful information. Cardiomegaly may be present—​ cardiothoracic ratio (CTR) >0.50. It may also show pulmonary congestion or another explanation for breathlessness. All patients in whom the diagnosis of heart failure cannot be excluded require an assessment of LV function. Patients in whom the diagnosis of heart failure is secure may also be considered for an assessment of LV function as an indicator of prognosis. Echocardiography is the most frequently used investigation but may not be possible for technical reasons, and alternative investigations may be necessary. AF also makes the assessment of LV function less reliable. Some patients may have had an alternative method to estimate LV function in secondary care, e.g. gated heart scan, LV angiography during coronary angiography.

Cardiogenic shock (See also E Chapter 47.) CS occurs when the heart is unable to deliver enough blood to maintain adequate tissue perfusion, and therefore oxygenation. It is one of the most challenging emergencies for the intensivist. The leading cause of CS is AMI, responsible for up to 80% of cases, with the remaining 20% of CS cases due to a broad range

of medical conditions [24]. CS mortality is extremely high and remains the most common cause of death in hospitalized patients with AMI [25, 26]. In this setting, CS usually results from an extensive acute infarction, although a smaller infarction in a patient with previously compromised LV function may also precipitate shock. CS can also be caused by mechanical complications of infarction such as acute MR, rupture of the interventricular septum or rupture of the free wall, or by a large RV infarction.

Pathophysiology CS pathophysiology is complex and has evolved over the past 20 years from a classic model based on the severe depression of myocardial contractility to a model that takes into account the derangements of the entire circulatory system [25]. In general, there is a profound depression of myocardial contractility, resulting in a potentially deleterious spiral of reduced cardiac output, low blood pressure, and further coronary ischaemia, followed by additional reductions in contractility. Indeed, myocardial perfusion, which depends on the pressure gradient between the coronary arteries and the LV and on the duration of diastole, is compromised by hypotension and tachycardia, exacerbating ischaemia. Increased ventricular diastolic pressures caused by pump failure further reduce CPP, and the additional wall stress elevates myocardial O2 requirements, further worsening ischaemia. This classic paradigm also includes compensatory systemic vasoconstriction, which has an additional adverse impact, resulting in increased afterload. This relatively simple pathological concept has been enriched by evidence demonstrating that CS can cause severe derangements in the entire circulatory system, with microcirculation involvement playing a major role. Additionally, SIRS develops in many patients with CS without evidence of sepsis and is associated with decreased SVR, impaired inotropy, and end-​organ damage [27, 28]. Endothelial and inducible nitric oxide (NO) synthase may play a major role in the production of high NO levels, along with peroxynitrite, which has a negative inotropic effect and is cardiotoxic. Other inflammatory mediators, such as interleukins (ILs) and tumour necrosis factor (TNF), can also contribute to systemic vasodilatation and have been associated with mortality in CS.

Clinical assessment The initial diagnosis of CS is based on the recognition of symptoms and signs of congestion and hypoperfusion (see E Table  12.2). Patients with shock are usually cyanotic and can have cool skin and mottled extremities. Cerebral hypoperfusion may cloud the sensorium. Pulses are rapid and faint and may be irregular in the presence of arrhythmias. Jugular venous distension and pulmonary rales are usually present, although their absence does not exclude the diagnosis. The precordial heave, resulting from LV dyskinesis, may be palpable. Heart sounds may be distant, and third or fourth heart sounds are usually present. A  systolic murmur of MR or VSD may be heard, but these complications may occur without an audible murmur. Documentation of

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Table 12.2  Clinical diagnosis of cardiogenic shock Persistent hypotension AND

SBP 90 mmHg

Symptoms and signs of elevated or normal filling pressures AND

Orthopnoea, paroxysmal nocturnal dyspnoea, pulmonary rales (bilateral), S3

Symptoms and signs of abnormal organ perfusion AND

Cold sweated extremities, oliguria, mental confusion, dizziness, narrow pulse pressure, urine output 2 mmol/​L

SBP, systolic blood pressure; S3, third heart sound.

myocardial dysfunction and exclusion of alternative causes of hypotension allow for the diagnosis of CS.

Investigations An ECG should be performed immediately. Other initial diagnostic tests should include a chest radiograph and measurement of ABGs, including blood lactate [29], electrolytes, full blood count, and cardiac biomarkers (see E Chapter 17). Echocardiography is an excellent tool for confirming the diagnosis of CS and for sorting through the differential diagnosis and should be performed as early as possible (see E Chapters 18.1 and 18.2). Invasive haemodynamic monitoring, usually with a PAC, can confirm the diagnosis of CS and exclude volume depletion and is also used to guide management and optimize therapy in refractory cases.

Right ventricular failure RV failure is a complex syndrome that results from many causes (see E Box 12.2). Its prevalence is difficult to estimate, but its predominant causes (i.e. LV dysfunction, PE, and AMI) are common. Pathophysiologic changes in right heart failure vary according to the underlying cause.

Pathophysiology RV mechanics and function are altered in the setting of either pressure or volume overload. Various mechanisms are involved, including decreased RV contractility, increased RV pressure, and increased RV volume (see E Figure 12.3) [30].

Right ventricular systolic impairment This condition occurs most often in cases of RV ischaemia and infarction. Usually, RV infarction is due to proximal occlusion of the right coronary artery (RCA). In this condition, the RV is unable to contract against a normal pulmonary artery pressure (PAP). Accordingly, RV ischaemia rapidly leads to RV dilatation, with a concomitant rise in RV diastolic pressure. Such elevation causes a shift of the interventricular septum towards an already

Box 12.2  Causes of right ventricular failure ◆ Acute left ventricular failure ◆ Right ventricular ischaemia/​infarction ◆ Acute pulmonary embolism ◆ Exacerbation of chronic lung disease and/​or hypoxia ◆ Acute lung injury or respiratory distress syndrome ◆ Sepsis ◆ Chronic pulmonary hypertension (groups 1–​5) ◆ Pericardial disease (tamponade) ◆ Arrhythmias (supraventricular or ventricular tachycardia) ◆ Congenital heart disease (e.g. atrial or ventricular septal defect, Ebstein’s anomaly) ◆ Valvulopathies (e.g. tricuspid valve regurgitation, pulmonary valve stenosis) ◆ Cardiomyopathies (e.g. arrhythmogenic right ventricular dysplasia, familial, idiopathic) ◆ Myocarditis or other inflammatory diseases ◆ Cardiac surgery (e.g. cardiac transplant or left ventricular assist device implantation) ◆ Haematological disorders (e.g. acute chest syndrome in sickle-​cell disease)

underfilled LV [31]. These changes in RV mechanics lead to a depressed right-​sided output, a decreased LV preload, and subsequently a reduced overall cardiac output [32].

Effect of an increase in right ventricular afterload As described previously, increased PAP alters both coronary perfusion and ventricular function of the RV. In a patient with pulmonary hypertension, the RV dilates to maintain the stroke volume, though the EF is reduced and peristaltic contraction is lost, causing an accelerated worsening in RV failure. The increased afterload also prolongs the isovolumic contraction phase and ejection time, and therefore the increased myocardial O2 consumption. In addition, RCA perfusion only occurs in diastole. Accordingly, in a patient with a further increase in PAP and a decrease in RCA perfusion, it is important to rapidly reduce the RV afterload to improve the O2 supply/​demand balance in the RV and maintain RV function. Of note, in patients with acute respiratory distress syndrome (ARDS), circulating vasoconstrictors, increased sympathetic tone, microvascular obstruction, and hypoxic vasoconstriction all increase RV afterload. In addition, mechanical ventilation also increases RV afterload.

Effect of an increase in right ventricular volume Volume overload is common during RV failure, and volume loading may further dilate the RV, increase tricuspid regurgitation (TR), and consequently worsen hepatic and renal congestion and RV failure. Accordingly, volume management is

Ri g ht ven tri cu l a r   fa i lure RV pressure overload

Tricuspid regurgitation Pulmonary regurgitation

RV dilatation

RV volume overload

↓ Contractility RV dysfunction

↑ Right atrial pressure ↑ Central venous pressure

↓ RV output

↑ RV wall tension

Arrhythmia, RV ischaemia, injury, inflammation

↑ Oxygen demand

↓ Coronary perfusion

Altered systolic or diastolic ventricular interdependence

↓ LV preload

Systemic congestion

↓ Cardiac output Hypotension Shock

Organ dysfunction or failure

Figure 12.3  Pathophysiology of acute right ventricular failure. LV, left ventricular; RV, right ventricular. Reproduced from Veli-​Pekka Harjola, Alexandre Mebazaa, Jelena Celutkien, Dominique Bettex, Hector Bueno, Ovidiu Chioncel et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and theWorking Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail (2016) 18, 226–​241 with permission from John Wiley and Sons.

a difficult, but important, task in the treatment of RV failure. Physiologically, volume loading may be useful in increasing preload, but in the large majority of patients with RV failure, this compensatory mechanism is potentially limited beyond a mean PAP of 30 mmHg [33], and therefore, caution is warranted when considering volume loading in any patient with suspected RV failure.

events occurs, self-​worsening RV dysfunction. This is unique to the RV and is rarely seen in isolated LV failure. A sudden increase, although modest, in RV afterload (inhaled NO withdrawal, for instance) on an ischaemic RV immediately dilates the ventricle, induces TR, and decreases cardiac output.

Consequences of systemic venous congestion

There is a high degree of ventricular interdependence due to the role of the interventricular septum in the contraction of both ventricles, which is pronounced because of the presence of the pericardium [34]. Indeed, increases in the end-​diastolic volume of the LV are transmitted to the RV by movement of the interventricular septum towards the right cavity, increasing the end-​diastolic pressure of the RV. Similarly, when the RV end-​ diastolic volume is increased, the interventricular septum shifts towards the left cavity during diastole due to restrictions imposed by the pericardium on the RV as the cavity volume increases. This leftward shift impairs the function of the LV due to the reduction in LV volume, decreasing both LV filling and compliance, manifested as increased LV muscle stiffness.

The liver and kidneys are tied in inextensible capsules. In the case of venous congestion, intraorgan pressure of the liver and kidneys rapidly increases, leading to lower organ perfusion pressure and higher sensitivity to ischaemia when cardiac output is reduced (see E Chapter 45). Congestion in liver sinusoids collapses the bile ducts, leading to cholestasis [35, 36]. Centrolobular necrosis occurs when a mechanism of reduced O2 supply is associated with passive venous congestion. This causes hypoxic hepatitis (formerly known as ‘shock liver’), characterized by intense hepatic cytolysis [37]. In kidneys, venous congestion in the Bowman’s capsule increases interstitial pressure which compresses the tubules, impairing the GFR (38–​40). This mechanism is thought to be the most predominant factor, leading to renal failure, rather than a low cardiac output, when RV failure is present.

The vicious cycle of auto-​aggravation

Assessment of right ventricular function

Compared to the LV, RV failure progresses quickly from compensated to end-​stage heart failure because of a vicious cycle of auto-​aggravation. Auto-​aggravation implies that after an initial injury (change in loading or pressure condition), a cascade of

The sensitivity of conventional chest radiography techniques in identifying changes in RV structure is limited by the unusual shape of the RV and the unpredictable manner in which it dilates (see E Chapter 17).

Ventricular interdependence

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Inferential diagnosis may be possible by the identification of other radiographic changes such as the state of the pulmonary circulation and the position of the heart in the chest. Changes in the LV may be apparent on a chest radiograph, resulting from the decreased LV preload as a consequence of RV failure. Liver congestion causes cholestasis with elevated alkaline phosphatase and direct bilirubin levels [35]. When associated with compromised O2 delivery to the liver, cytolytic hepatitis can occur, with increases in transaminases (up to 100-​fold the upper limit of normal) and total bilirubin [37]. This hypoxic hepatitis can lead to acute liver failure, with low prothrombin time (PT) and elevated lactate levels, sometimes misdiagnosed as viral or toxic hepatitis (whereas this level of cytolysis is unlikely in non-​ hypoxic causes). Echocardiography is an alternative, more accessible technique for the diagnosis of RV failure and for intermittent repetitive follow-​up of the dynamics of therapeutic responses (see E Chapters 18.1 and 18.2). Its advantage is that a qualitative conclusion can be reached instantaneously. When RV failure is secondary to an increase in afterload, the isovolaemic contraction phase and ejection time are prolonged and increases in PAP and flow are accelerated. Echocardiography also provides information about the mechanisms of RV failure such as pericardial effusion, with or without tamponade, tricuspid insufficiency, PEs, or RV ischaemia and the resulting acute cor pulmonale. Additionally, echocardiography enables the simultaneous evaluation of LV function, a possible component of the RV failure. Because of the geometry and location of the RV, the accuracy and necessity of determining the exact RV dimensions remain questionable and an experienced intensive care physician familiar with performing and evaluating echocardiography is essential. Although serial echocardiographic evaluations can be performed, in many cases, continuous information provided by the PAC may be valuable.

Vascular dysfunction An artery is not a cylindrical tube of constant diameter. In reality, an artery is a viscoelastic tube consisting of three layers (intima, media, and adventitia), with its diameter varying with a pulsating system. In addition, the arterial system will propagate pressure, flow, and diameter waves, generated by ejection from the ventricle, at a given velocity, which is largely determined by the elastic properties of the arterial wall. There are two kinds of vascular dysfunction. The first consists of an increase in arterial stiffness due to atherosclerosis, leading to a chronic increase in LV afterload and eventually to an impairment of organ perfusion. The second consists of a decrease in arterial resistance, leading to vasoplegia and low blood pressure. The latter is an acute phenomenon whose main cause is the systemic release of vasoactive substance. Severe sepsis and septic shock are the usual causes of vasoplegia, which can also be associated with AHF.

Pulmonary hypertension PH is defined as a resting mean pulmonary arterial pressure (mPAP) of >20  mmHg measured by right heart catheterization (RHC) [41]. PH is currently classified into five groups, based on the underlying aetiology, with the term pulmonary arterial hypertension (PAH) reserved for group 1 PH. PH secondary to left heart disease (PH-​LHD) can be seen in HFrEF, HFmrEF, and HFpEF; it is the most common form of PH and is classified as group 2 PH. Of note, PH-​LHD can be further sub-​classified into isolated post-​capillary PH and combined post-​and precapillary PH in which pulmonary vascular disease is superimposed with passive elevation of mPAP caused by elevation of LV filling pressures.

Pathophysiology In the majority of patients with PH-​LHD, the elevation in mPAP can be considered a manifestation of HF, with a normal pulmonary vascular response, though early remodelling of pulmonary arterioles and veins can still be present [42, 43]. Increased left heart filling pressures can also reduce pulmonary arterial compliance, promoting ‘stiff ’ pulmonary vasculature. This can lead to enhanced pulmonary wave reflections during systole and an elevated pulsatile load on the RV [42–​44]. Functional MR and loss of LA compliance are additional haemodynamic insults that can promote LA hypertension that transmits back to the pulmonary vasculature. The subset of patients with PH-​LHD with combined post-​and precapillary PH develop pulmonary vascular disease secondary to vasoconstriction and pathologic remodelling of the pulmonary vasculature, generating an elevation in mPAP that is ‘disproportionate’ to that generated by the transmission of increased left-​sided filling pressures alone. Chronic contraction of the right heart against this increased resistive afterload can ultimately lead to maladaptive hypertrophy, dilatation, and subsequent contractile failure [45].

Clinical assessment Patients with PH-​ LHD typically present with symptoms and signs of both left-​and right-​ sided heart failure. Differential diagnosis with other groups of PH and distinguishing between isolated post-​ capillary and combined post-​and precapillary PH-​LHD can be challenging. Initial investigations should be focused on establishing the diagnosis of PH-​LHD and its mechanisms. Echocardiography is nowadays the mainstay for the evaluation of patients with suspected PH-​LHD. RHC may be necessary in order to confirm the diagnosis and evaluate for the presence of precapillary PH.

Pericardial diseases The pericardium is a thin, double-​layered fibroblastic sac that surrounds the heart. It normally contains only a small amount of pericardial fluid. By virtue of their anatomic and functional

U se of pu l mona ry a rtery catheter i n  acu te hea rt   fa i lure interactions, medical conditions affecting the pericardium almost invariably will affect the heart and the cardiovascular system. Thus, whenever larger amounts of fluid accumulate (pericardial effusion) or changes in its elastic properties (pericardial constriction) occur, one of three major pericardial syndromes will develop:  pericardial tamponade, constrictive pericarditis, or effusive–​constrictive pericarditis.

Pathophysiology Pericardial tamponade is characterized by a sudden or progressive accumulation of fluid in the pericardial cavity that results in an increase in pericardial pressure and compression of cardiac vessels and chambers. The resulting compromise in venous return also leads to a reduction in end-​diastolic volumes. Once the pericardial pressure overcomes the diastolic pressures, expansion of the RV during diastole is limited by the rigid pericardium. This phenomenon generates a shift of the interventricular septum towards the already underfilled LV, further reducing LV compliance [46]. In constrictive pericarditis, a thickened and inelastic pericardium prevents transmission of the physiologic inspiratory decrease in intrathoracic pressure to the heart. The rigid pericardium also represents an obstacle to venous return and diastolic filling. As the severity of constriction increases, a progressive reduction in ventricular and stroke volumes is seen [47]. Effusive–​constrictive pericarditis is characterized by an underlying constrictive physiology with a coexisting pericardial effusion, often with cardiac tamponade. This usually results in a mixed haemodynamic picture with features of both constrictive pericarditis and cardiac tamponade.

Clinical assessment Differential diagnosis of pericardial syndromes can be challenging, especially when the patient presents with features of both effusion and constriction. Clinical examination is notable for symptoms and signs of elevated right heart pressures (e.g. increased JVP). Pulsus paradoxus (a drop of >10 mmHg in arterial pressure during inspiration) and Kussmaul’s sign (JVP increase during inspiration) can be present but are also unspecific findings. In constrictive pericarditis, a pericardial knock may be audible. Definite diagnosis is largely based on echocardiographic findings. Other investigations such as MRI and RHC may be necessary in selected cases.

Use of pulmonary artery catheter in acute heart failure The use of the PAC has been challenged over the last decade. Many RCTs failed to demonstrate an outcome benefit in patients having a therapeutic strategy based on PAC data [48]. Nonetheless, several factors may explain these findings, including the fact that in these trials, patients were highly

selected, with CS patients being clearly underrepresented [49–​ 51]. However, many physicians still consider the PAC as a useful monitoring device when indications are rationalized, team trained, and measurements, interpretations, and therapeutic actions correct [52]. Indeed, an increase in the use of the PAC in heart failure patients has been recently reported [53]. The PAC provides the physician with haemodynamic parameters (cardiac output; right atrial, pulmonary, and pulmonary artery occlusion pressures; and possibly RV volumes) and also with tissue perfusion variables (venous O2 saturation, O2 extraction, and venous CO2 pressure). These PAC-​derived parameters are briefly summarized in E Table 12.3.

Recommendations/​indications for heart failure According to the ESC guidelines [17] published in 2016, the PAC may be considered only in a subset of the most complex patients ‘who, despite pharmacological treatment present refractory symptoms (particularly with hypotension and hypoperfusion)’ (Class IIb, LoE C). Current American College of Cardiology Foundation (ACCF)/​ AHA heart failure guidelines recommend limiting the use of the PAC to patients with ‘respiratory distress or impaired systemic perfusion when clinical assessment is inadequate’ (Class  I, LoE C) and discourage its use in routine management of heart failure (Class III, LoE B) [54]. Experts have stated that direct measurement of haemodynamic parameters can be helpful in patients for whom physical examination is limited or discordant with symptoms. It may be particularly useful for determining the contribution of heart failure to a complex clinical picture such as sepsis, acute renal failure, or ACS in the setting of chronic heart failure. Another common setting where PAC insertion may be helpful is the evaluation of dyspnoea and elevated right heart pressures in patients with concomitant pulmonary and cardiac disease.

The particular case of right ventricular failure Recent data show that, in patients with PH, evaluations of PAP and cardiac output using echocardiography are inaccurate [55–​ 57]. In right heart failure, catheterization of the pulmonary artery is more invasive than echocardiography but is useful to evaluate RV function and to confirm the presence of RV failure in patients in ICU [58]. The PAC measures both mixed venous O2 saturation and intravascular pressures or pressure changes in the RV, as well as PAP and PCWP. Despite difficulties in the interpretation of mean intravascular pressure values, the tracings showing changes in pressure and flow enable the assessment of the impact of treatment on RV function. This cautious interpretation accounts for the almost constant reflux due to tricuspid insufficiency, which can be observed by central venous and right atrial pressure changes. Such regurgitation could be used as a hallmark for RV failure and as a marker for treatment efficacy. If a CVC or PAC is in place, haemodynamic parameters that can aid in the diagnosis of RV failure include an increase in right atrial pressure and a decrease in arterial blood pressure, cardiac output,

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Table 12.3  Pulmonary artery catheter-​derived measurements Method

Normal values

Clinical value

RAP

Direct

0–​7 mmHg

Measure of RV preload; evaluation of AHF, shock, and PH

RVP

Direct

Systolic: 15–​25 mmHg; diastolic: 3–​12 mmHg

Evaluation of AHF, shock, and PH

PAP

Direct

Systolic: 15–​28 mmHg; diastolic: 5–​16 mmHg; mean: 4–​12 mmHg

Evaluation of AHF, shock, and PH

PAOP

Direct

10–​22 mmHg; mean: 16 mmHg

Obtained after inflating the distal balloon of the PAC; it reflects LAP and LVEDP; evaluation of AHF and shock

CO/​CI

Direct: thermodilution (intermittent or continuous)

2.8–​4.2 L/​minute/​m2

Gold standard tool for measuring cardiac output; evaluation of AHF, shock, and PH

PAPi

Indirect: PAPi: PAPS–PAPD /PVC

>0.9

Marker of severe RV dysfunction

SvO2

Direct: intermittent or continuous

60–​80%

Measures the balance between O2 delivery and consumption (directly related to O2 extraction ratio; OER = VO2/​DO2); evaluation of shock

SVR/​SVRI

Indirect: SVR = 80 × (MAP –​ CVP)/​CO

900–​1400 dyn·s/​cm5

PVR/​PVRI

Indirect: PVR = 80 × (mean PAP –​PAOP)/​CO

5

150–​250 dyn·s/​cm 2

Measure of LV afterload; evaluation of shock Measure of RV afterload; evaluation of PH

SV/​SVI

Indirect: SVI = CI/​heart rate

30–​65 (mL/​m /​beat)

Variation in SV/​SVI can be used to assess fluid responsiveness

CPO/​CPOI

Indirect: CPO = (MAP · CO)/451

>0.6 W

Prognostic value in CS

DO2

Indirect: DO2 = CI × 13.4 × haemoglobin concentration × arterial O2 saturation

Approximately 1000 mL/​minute

Assessment of tissue perfusion; evaluation of shock

VO2

Indirect: VO2 = CI × 13.4 × haemoglobin concentration × (arterial O2 saturation –​ venous O2 saturation)

Approximately 250 mL/​minute

Assessment of tissue perfusion; evaluation of shock

AHF, acute heart failure; CO/​CI, cardiac output and CO index; CPO/​CPOI, cardiac power output and CPO index; CS, cardiogenic shock; DO2, oxygen delivery; LAP, left atrial pressure; LV, left ventricular; LVEDP, left ventricular end-​diastolic pressure; MAP, mean arterial pressure; O2, oxygen; OER, oxygen extraction ratio; PAC, pulmonary artery catheter; PAOP, pulmonary artery occlusion pressure; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PVR/​PVRI, pulmonary vascular resistance and PVR index; RAP, right atrial pressure; RV, right ventricular; RVP, right ventricular pressure; SvO2, mixed venous oxygen saturation; SVR/​SVRI, systemic vascular resistance and SVR index; SV/​SVI, stroke volume and SV index; VO2, oxygen uptake.

and mixed venous O2 saturation (see E Figure 12.4), despite usually preserved PAP and PCWP. For difficult cases, a technique often cited in the literature for the diagnosis of RV failure involves the administration of 250 mL of crystalloids or colloids over 10 minutes [59]. If the patient is suffering from RV failure, all of the above haemodynamic parameters would worsen, including a

Conclusion

• Analgesia, sedation • Myorelaxation • Mechanical ventilation • Hypothermia

• Shivering • Pain, stress • Hyperthermia

• Right-to-left shunt • Hypoxaemia

SvO2 = SaO2 -

• Myocardial ischaemia • Hypovolaemia • Tamponade • Massive pulmonary embolism

VO2 CO . Hb . OP

• Fever • High (2,3-DPG) • Acidosis • Hypercapnia

• Bleeding • Haemodilution

Figure 12.4  Main factors influencing mixed venous O2 saturation. OP, oxyphoric power of haemoglobin.

dramatic increase in right atrial pressure, with no change in cardiac output. This test should not be used in patients who are in acute RV failure, as there is a risk of severe aggravation of tricuspid insufficiency and organ congestion after volume loading.

Understanding the pathophysiological principles of the multiple medical conditions that can affect the cardiovascular system is imperative in the acute and critical care settings. Indeed, prompt identification of the underlying mechanisms will lead to an appropriate therapeutic strategy.

Personal perspective This chapter illustrates the importance of prompt identification of the pathophysiological mechanisms related to medical conditions affecting the cardiovascular system and the challenge of maintaining an appropriate balance between the need for invasive and non-​invasive investigations.

REFERENCES

Further reading Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med 2004;351:1097–​1105. Harjola VP, Mebazaa A, Čelutkienė J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016;18:226–​41. Harjola VP, Parissis J, Brunner-​La Rocca HP, et  al. Comprehensive in-​ hospital monitoring in acute heart failure:  applications for clinical practice and future directions for research. A  statement from the Acute Heart Failure Committee of the Heart Failure Association

(HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail 2018;20:1081–​99. Sanfilippo F, Scolletta S, Morelli A, Vieillard-​Baron A. Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care. Ann Intensive Care 2018;8:100. van Diepen S, Katz JN, Albert NM, et al. Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation 2017;136:e232–​68. Walley KR. Left ventricular function:  time-​varying elastance and left ventricular aortic coupling. Crit Care 2016;20:270.

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45. Fayyaz AU, Edwards WD, Maleszewski JJ, et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 2018;137:1796. 46. Adler Y, Charron P, Imazio M, et  al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases:  The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-​ Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921. 47. Welch TD. Constrictive pericarditis:  diagnosis, management and clinical outcomes. Heart 2018;104:725. 48. Shah MR, Hasselblad V, Stevenson LW, et  al. Impact of the pulmonary artery catheter in critically ill patients: meta-​analysis of randomized clinical trials. JAMA 2005;294:1664–​70. 49. Rhodes A, Cusack RJ, Newman PJ, Grounds RM, Bennett ED. A randomised, controlled trial of the pulmonary artery catheter in critically ill patients. Intensive Care Med 2002;28:256–​64. 50. Richard C, Anguel N, Deye N, et  al.; French Pulmonary Artery Catheter Study Group. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome. JAMA 2003;290:2713–​20. 51. Harvey S, Harrison DA, Singer M, et al.; PAC-​Man study collaboration. Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-​Man): a randomised controlled trial. Lancet 2005;366:472–​7. 52. Sionis A, Rivas-​Lasarte M, Mebazaa A, et al. Current use and impact on 30-​day mortality of pulmonary artery catheter in cardiogenic shock patients: Results From the CardShock Study. J Intensive Care Med 2019 Feb 7:885066619828959. doi: 10.1177/​0885066619828959. [Epub ahead of print]. 53. Pandey A, Khera R, Kumar N, Golwala H, Girotra S, Fonarow GC. Use of pulmonary artery catheterization in us patients with heart failure, 2001–​2012. JAMA Intern Med 2016;176:129–​32. 54. Yancy CW, Jessup M, Bozkurt B, et  al. 2013 ACCF/​AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/​American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–​52. 55. Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009;179:615–​21. 56. Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest 2011;139:988–​93. 57. Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-​analysis. Heart Br Card Soc 2011;97:612–​22. 58. Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right ventricular failure—​from pathophysiology to new treatments. Intensive Care Med 2004;30:185–​96. 59. Zwissler B. [Acute right heart failure. Etiology, pathophysiology, diagnosis, therapy]. Anaesthesist 2000;49:788–​808.

CHAPTER 13

The respiratory system Antoine Vieillard-​Baron

Contents Summary  127 Introduction  127 Definitions—​physiological reminders  127 Blood gas exchange  127 Alveolar ventilation and dead space  128 Main causes of acute hypoxaemia  128 Airway pressures and respiratory mechanics  128 Heart–​lung interactions  129

What can and should be monitored at the bedside?  129 Conclusion  131 Personal perspective  132 Further reading  132 References  132

Summary The respiratory system is key to the management of patients with respiratory, as well as haemodynamic, compromise and should be monitored. The ventilator is more than just a machine that delivers gas; it is a true respiratory system monitoring device, allowing the measurement of airway pressures and intrinsic positive end-​expiratory pressure and the plotting of pressure/​volume curves. For effective and reliable monitoring, it is necessary to keep in mind the physiology such as the alveolar gas equation, heart–​lung interactions, the equation of movement, etc. Monitoring the respiratory system enables adaptation of not only respiratory management, but also haemodynamic management.

Introduction A textbook on intensive and acute cardiac care should describe most of the mechanisms responsible for haemodynamic compromise such as AHF with its many aetiologies [1]‌. However, the respiratory system status appears key to the management of such failure, first because many causes of heart failure lead to pulmonary congestion, and so to respiratory failure; second because changes in respiratory system properties may impact on the haemodynamics; and finally because mechanical ventilation, when required, may have beneficial, but also deleterious, effects on cardiac function [2]. Cardiologists and intensivists have to be fully conversant with heart–​lung interactions, with how their knowledge helps to understand changes in haemodynamics related to changes in ventilatory settings or respiratory mechanics, and with how monitoring of the respiratory system is usable at the bedside. (See also E Chapters 21, 22, 62, 63, and 64.)

Definitions—​physiological reminders Blood gas exchange Blood gas exchanges occur passively through the alveolar–​capillary membrane, according to the gradient in gas concentration between the capillary blood and the alveoli. This gradient is mediated, in part, by the equilibrium between O2 and CO2 in the alveoli, depending on the alveolar gas equation (see E Figure 13.1): PAO2 = PIO2 − 1.2 × PACO2

(where PAO2 is the alveolar pressure of O2, PACO2 the alveolar pressure of CO2, and PIO2 the inspired pressure of O2, calculated as FiO2 × (760 –​47) where FiO2 is the fraction

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Main causes of acute hypoxaemia

PIO2 PvO2 40 mmHg

PAO2

PvCO2 45 mmHg PA

PaO2 100 mmHg PaCO2 40 mmHg

O2

CO2

PV Q

RV

V/Q =1

LV

PAO2 = PIO2 – 1.2 PACO2

Figure 13.1  Schematic representation of blood gas exchange mechanisms. Oxygenation of blood depends on the alveolar gas equation and the V/​Q ratio, whereas decarboxylation depends on alveolar ventilation. PA, pulmonary artery; PaCO2, CO2 arterial pressure; PACO2, CO2 pressure in the alveoli; PaO2, O2 arterial pressure; PAO2, O2 pressure in the alveoli; PIO2, O2 inspired pressure; PV, pulmonary vein; PvCO2, CO2 venous pressure; PvO2, O2 venous pressure; LV, left ventricle; RV, right ventricle; V/​Q, ventilation/​ perfusion ratio.

of inspired O2, 760  mmHg is the atmospheric pressure, and 47 mmHg is the part of the inspired gas that is transformed into water.) Moreover, PACO2 is directly proportional to CO2 consumption and inversely proportional to alveolar ventilation. Differences between PAO2 and arterial pressure of O2 (PaO2) are, in part, explained by the ventilation/​perfusion (V/​Q) ratio. In a ‘perfect’ lung, i.e. a lung where V/​Q = 1, PaO2 is close to PAO2. Then, in room air, oxygenation directly depends on alveolar ventilation. A  decrease in alveolar ventilation will increase PACO2, and so decrease PAO2. Under O2, it is the FiO2 that mainly determines the level of oxygenation. This explains why lung function must be evaluated using the PaO2/​FiO2 ratio. A patient with a ‘perfect’ lung has a ratio close to 500 mmHg, whereas acute lung injury (ALI), and more recently ARDS [3]‌, is defined as a ratio below 300 mmHg.

Hypoxaemia may occur if there is a mismatch between ventilation and perfusion, with V/​Q 1) and the anatomical dead space (trachea, bronchi, etc.). Alveolar ventilation (L/​min) is thus the difference between minute ventilation (tidal volume VT × respiratory rate) and the physiological dead space and finally determines PaCO2. In healthy subjects, in the supine position, the anatomical dead space has been reported as between 100 and 120 mL, and the physiological dead space around 150 mL [4]‌. But dead space can also be expressed as a fraction of the tidal volume (VD/​VT).

Exp

0

PPL Insp

Insp

Exp

Insp

Exp

TPP

Insp

Exp

0

Figure 13.2  Airway pressures in spontaneous ventilation and in mechanical ventilation during inspiration (Insp) and expiration (Exp). PALV, alveolar pressure; PPL, pleural pressure; TPP, transpulmonary pressure.

W hat ca n a n d shou l d b e mon i tored at th e b e d si de ? during tidal ventilation in a mechanically ventilated patient and also sometimes during expiration, depending on the positive end-​ expiratory pressure (PEEP). Changes in PPL (ΔPPL) are related to changes in VT, according to the compliance of the chest wall (CCW): C CW = VT /∆PPL

PALV is nil at end-​expiration and at end-​inspiration in a spontaneously breathing patient (see E Figure 13.2). In a mechanically ventilated patient, airway pressure (PAIRWAY) depends first on PEEP, second on the resistive part of the pressure (Q × R), and finally on the static part of the pressure (VT/​CRS). It is expressed by the equation of movement: PAIRWAY = PEEP + (Q + R ) + VT /C RS

(where Q is the inspiratory flow, R the resistance to flow, and CRS the compliance of the respiratory system, i.e. lung + chest wall.) When the flow is nil, during a pause, PAIRWAY represents PALV. At end-​inspiration, this is the plateau pressure (PPLATEAU), which depends on VT and CRS. In normal subjects, PALV at end-​expiration is nil. It can become positive either if a ‘therapeutic’ PEEP is applied or if dynamic hyperinflation is occurring, leading to an intrinsic PEEP. Finally, TPP is the distending pressure of the lung, calculated as PALV –​ PPL. Changes in TPP (ΔTPP) are related to changes in VT, according to the compliance of the lung (CL): C L = VT /∆TPP

Any decrease in lung compliance will induce an increase in TPP for a given lung volume.

Heart–​lung interactions Briefly, any changes in respiratory mechanics, or passing from spontaneous ventilation to mechanical ventilation, will act on cardiac function by modifying the different airway pressures (see E Figure 13.2) [2]‌. An increase in PPL, due to a decrease in CCW, as in obese patients, or due to positive pressure ventilation (PPV), will decrease

systemic venous return (see E Figure 13.3) [6, 7]. This can explain the deleterious effect of PEEP in hypovolaemic patients or the beneficial effects of the same PEEP in a patient with cardio­ genic pulmonary oedema. What is true for therapeutic PEEP was also described for intrinsic PEEP. Some studies have suggested that a positive PPL will help a failed LV to act by decreasing its afterload [8, 9]. An increase in TPP, due to severe alteration in CL, will induce systolic overload of the RV [10]. This was especially described in patients ventilated for severe ARDS [11] (see E Chapter 64).

What can and should be monitored at the bedside? In general, monitoring of the respiratory system is limited in spontaneously breathing patients, whereas many tools are available in mechanically ventilated patients to evaluate the properties of the respiratory system. In the first situation, the main aim of monitoring will be to identify patients and situations requiring invasive or non-​invasive mechanical ventilation. In the second situation, the aims of monitoring will be to optimize respiratory settings (VT, respiratory rate, PEEP, etc.) to avoid excessive airway pressures, to limit the deleterious effect of PPV on cardiac function, and finally to optimize respiratory management. The first requirement of monitoring the respiratory system is the correct interpretation of clinical signs of respiratory failure. These include polypnoea, cyanosis, tachycardia, and intercostal, suprasternal, or supraclavicular recession. O2 saturation can be non-​invasively monitored by plethysmography (SpO2), but some differences have been reported between SpO2 and SaO2, and the signal is not always optimal when shock is associated. Physicians have to look for, in particular, signs suggesting hypercapnia, because they may require specific management such as application of non-​invasive mechanical ventilation. These include sweating, flapping tremor, and decrease in consciousness. Blood gas analysis will confirm the clinical evaluation (see E Chapter 16). In exacerbations of COPD, uncompensated respiratory acidosis will indicate the need for non-​invasive mechanical ventilation [12].

ZEEP

PEEP 5

SVC

Exp

Insp

Exp

Insp

Figure 13.3  TOE in a mechanically ventilated patient, at zero end-​expiratory pressure (ZEEP) and 5 cmH2O PEEP. Two-​dimensional view of the superior vena cava (SVC), associated with the time–​motion study, demonstrates collapse of the vessel during tidal ventilation in PEEP conditions, reflecting a decrease in systemic venous return. Exp, expiration; Insp, inspiration.

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FiO2 0.7

12/01/09 14:57

12/01/09 15:21

PEEP 5

ZEEP 70.0

7.46 41 64

7.50 38 101

13/01/09 15:24

13/01/09 16:20

pH PaCO2 PaO2

(b) FiO2 0.7

PEEP 5

pH PaCO2 PaO2

ZEEPTEL

7.44 41 108

7.41 45 57

Figure 13.4  CXR and blood gas analysis at ZEEP and PEEP (5 cmH2O) in a patient at day 1 (panel A) and at day 2 (panel B). At day 1, the CXR showed

unilateral injury of the lung. PEEP removal induced an increase in PaO2 and a decrease in PaCO2, reflecting overdistension of the lung related to PEEP. At day 2, lung injury was bilateral. PEEP injury induced a decrease in PaO2 and an increase in PaCO2, reflecting derecruitment of the lung.

Monitoring of blood gases, in accordance with the CXR, may also help to clarify the effect of PEEP in a patient mechanically ventilated for ALI, as illustrated in E Figure 13.4. Monitoring of PPLATEAU is crucial in a sedated mechanically ventilated patient (see E Figure 13.5) (see E Chapter 22). It is used as a surrogate for TPP but overestimates it [13]. TPP is not available in clinical practice, because PPL is difficult to record since it requires placement of a balloon in the oesophagus [14], while recent research suggested its feasibility and usefulness [15]. PPLATEAU has been reported to be strongly related to the risk of barotrauma (a) 60

and pneumothorax [16]. Strict limitation of PPLATEAU has been shown to save lives, especially in ARDS [17] and acute asthma [18]. However, a recent large multicentre international study reported that PPLATEAU was not very well monitored in ventilated patients, even with ARDS [19]. A PPLATEAU below 30 cmH2O, and much better if below 27  cmH2O, limits lung overdistension and PH and their effects on the RV [21]. However, respirators are not equipped with an alarm for PPLATEAU, but only for peak pressure, i.e. the pressure reached before the end-​inspiratory pause (see E Figure 13.5) (see E Chapter 22). As recalled previously (b) 60

Ppeak

Ppeak PPLATEAU

PPLATEAU Paw cmH2O

Paw cmH2O

4

8

12

16

20

4

8

12

16

20

Figure 13.5  Recording of airway pressure from the respirator trace in a patient ventilated with a respiratory rate of 15 cycles/​min (panel A) and 30 cycles/​min

(panel B). End-​expiratory occlusion (arrow) unmasked intrinsic PEEP at high respiratory rate, which caused an increase in airway peak pressure (Ppeak) and plateau pressure (PPLATEAU).

C on c lusi on (a) VT (litres) 1.2

(b) VT (litres) 1.2

(c) VT (litres) 1.2

0.8

0.8

0.8

0.4

0.4

0.4

0

0

10

20

0

0

10

20

0

0

10

20

Figure 13.6  Quasi-​static pressure/​volume loop of the respiratory system in three different mechanically ventilated patients. The loop was built by limiting the

flow to below 9 L/​min during inspiration and expiration to neglect the resistive part of the pressure. In patient (A), the compliance of the system was normal, as shown by the slope of the relationship during inspiration (dashed line). In patient (B), the compliance of the respiratory system was decreased, but the potential for lung recruitment was high, as suggested by the hysteresis between the inspiratory and the expiratory curves. In patient (C), the compliance was severely decreased and the potential for recruitment very low, as suggested by the absence of significant hysteresis between the two curves.

with the equation of movement, a peak pressure alarm may reflect: (1) an abrupt increase in intrinsic PEEP (does the patient have an expiratory flow limitation?); (2) an increase in flow resistance [is the endotracheal tube (ETT) partially occluded?]; and (3) a deterioration of lung mechanics (does the patient have pneumothorax? Does the patient have abrupt-​onset pulmonary oedema?). Intrinsic PEEP may be easily detected by performing an end-​expiratory pause, as shown in E Figure 13.5. Recording of expiratory CO2 is possible, especially in intubated patients, by sensors positioned between the proximal end of the ETT and the Y piece of the ventilator. Mean expiratory (PECO2) and end-​tidal (PetCO2) CO2 can thus be monitored, allowing calculation of the physiological dead space (VDphysiol/​VT = 1 –​  PECO2/​ PaCO2) and the alveolar dead space (VDalv/​VT = 1 –​ PetCO2/​PaCO2). A decrease in VD/​VT reflects improvement in respiratory mechanics and subsequently in the patient’s status. This is true in acute exacerbations of COPD or in acute asthma where a decrease in VD/​VT reflects a decrease in expiratory flow limitation, and also in ARDS where a decrease in VD/​VT mostly reflects a decrease in lung overdistension. It has been suggested that, in these patients, even a slight decrease in PaCO2 reflects functional lung recruitment induced by some procedures, such as prone positioning [21], and that this decrease [22] as the use of prone position [23] is associated with a better prognosis. The P/​V loop of the respiratory system has long been proposed as a means of evaluating respiratory mechanics [24]. Whereas the curve is linear during inspiration in patients without lung injury (see E Figure 13.6), it includes a lower and an upper inflection point in ARDS (see E Figure 13.6). The P/​V loop pattern has been proposed for assessing the ‘recruitability’ of the system [25, 26] (see E Figure 13.6). However, this loop is difficult to use at the bedside. Finally, a few words should be said about lung CT scanning. Although unavailable at the time at the bedside, many studies have demonstrated its utility in ARDS in assessing the ‘recruitability’ of the lung [27] and in evaluating the effect of PEEP in terms of lung

overdistension and recruitment [28]. A lung CT scan of a patient ventilated for severe ARDS is given as an example in E Figure 13.7 (see E Chapter  64). Whether lung US can non-​invasively give similar information remains to be confirmed [29, 30].

Conclusion The respiratory system is key to the management of patients with respiratory, and also haemodynamic, compromise. According to its properties, it may act differently on cardiac function. Because the most severely compromised patients in the ICCU are mechanically ventilated, it is mandatory for intensivists to understand fully that any change in ventilatory settings will also affect haemodynamics. It is clinically possible to monitor the respiratory system. The ventilator is more than just a machine that delivers gas; it is a true respiratory system monitoring device able to evaluate Ppeak, PPLATEAU, intrinsic PEEP, and expiratory flow limitation (see E Chapter 22).

Figure 13.7  Lung CT scan in a ventilated patient with severe ARDS related to extensive pneumonia.

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Personal perspective Because most ICCU patients are mechanically ventilated, respiratory management, and therefore respiratory monitoring, is critical. Respirators are too often considered as simple machines that deliver gas, whereas they can be used as a true monitoring device. A  serious effort has to be made to train intensivists better to understand how to monitor the respiratory system and why. Recent studies in severely compromised patients, such as those

with ARDS or acute asthma, show that a rigorous approach to ventilation can save lives. Such studies should be used to increase intensivists’ awareness of the importance of limiting PPLATEAU, avoiding intrinsic PEEP, and adapting respiratory settings to respiratory mechanics. In the future, new methods will be available at the bedside for all intensivists such as perhaps CT scanning and less ‘aggressive’ lung US.

Further reading Brochard L, Mancebo J, Wysocki M, et  al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995;333:817–​22. No authors listed. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301–​8. Scharf SM, Caldini P, Ingram RH. Cardiovascular effect of increasing airway pressure in the dog. Am J Physiol 1977; 232:35–​43.

The Task Force on Acute Heart Failure of the European Society of Cardiology. Guidelines on the diagnosis and treatment of acute heart failure. Eur Heart J 2005;26:1115–​40. Vieillard-​Baron A, Prin S, Chergui K, Page B, Beauchet A, Jardin F. Early patterns of static pressure-​volume loops in ARDS and their relations with PEEP-​induced recruitment. Intensive Care Med 2003;29:1929–​35. Whittenberger JL, McGregor M, Berglund E, Borst HG. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol 1960;15:878–​82.

References 1. The Task Force on Acute Heart Failure of the European Society of Cardiology. Guidelines on the diagnosis and treatment of acute heart failure. Eur Heart J 2005;26:1115–​40. 2. Scharf SM, Caldini P, Ingram RH. Cardiovascular effect of increasing airway pressure in the dog. Am J Physiol 1977;232:H35–​43. 3. ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526–​33. 4. Nunn JF. Respiratory dead space and distribution of the inspired gas. In:  Nunn JF. Applied Respiratory Physiology, first edition. Butterworth-​Heinemann: London; 1969. pp. 177–​94. 5. Jardin F, Gurdjian F, Desfonds P, Fouilladieu JL, Margairaz A. Hemodynamic factors influencing arterial hypoxemia in massive pulmonary embolism with circulatory failure. Circulation 1979;59:909–​12. 6. Guyton A, Lindsey A, Abernathy B, Richardson T. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol 1957;189:609–​15. 7. Vieillard-​Baron A, Augarde R, Prin S, et  al. Influence of superior vena caval zone condition on cyclic changes in right ventricular outflow during respiratory support. Anesthesiology 2001;95:1083–​8. 8. McGregor M. Pulsus paradoxus. N Engl J Med 1979;301:480–​2. 9. Buda AJ, Pinsky MR, Ingels NB Jr, et al. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979;301:453–​9. 10. Whittenberger JL, McGregor M, Berglund E, Borst HG. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol 1960;15:878–​82. 11. Jardin F, Brun-​Ney D, Cazaux P, Dubourg O, Hardy A, Bourdarias JP. Relation between transpulmonary pressure and right ventricular isovolumetric pressure change during respiratory support. Cathet Cardiovasc Diagn 1989;16:215–​20. 12. Brochard L, Mancebo J, Wysocki M, et  al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333:817–​22.

13. Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160–​6. 14. Milic-​Emili J, Mead J, Turner JM, Glauser EM. Improved technique for estimating pressure from esophageal balloons. J Appl Physiol 1964;19:207–​11. 15. Mauri T, Yoshida T, Bellani G, et al. Esophageal and transpulmonary pressure in the clinical setting: meaning, usefulness and perspectives. Intensive Care Med 2016;42:1360–​73. 16. Boussarsar M, Thierry G, Jaber S, Roudot-​Thoraval F, Lemaire F, Brochard L. Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome. Intensive Care Med 2002;28:406–​13. 17. Brower RG, Matthay MA, Morris A, Schoenfeld D, Taylor Thompson B, Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–​8. 18. Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984;129:385–​7. 19. Bellani G, Laffey JG, Pham T, et  al. LUNG SAFE investigators. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016;315:788–​800. 20. Jardin F, Vieillard-​ Baron A. Is there a safe plateau pressure in ARDS? The right heart only knows. Intensive Care Med 2007;33 444–​7. 21. Vieillard-​Baron A, Rabiller A, Chergui K, et al. Prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome. Intensive Care Med 2005;31:220–​6. 22. Gattinoni L, Vagginelli F, Carlesso E, et  al.; Prone-​Supine Group. Decrease in PaCO2 with prone position is predictive of improved

REFERENCES outcome in acute respiratory distress syndrome. Crit Care Med 2003;31:2727–​33. 23. Guerin C, Reignier J, Richard JC, et al.; Proseva study group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159–​68. 24. Matamis D, Lemaire F, Harf A, Brun-​Buisson C, Ansquer JC, Atlan G. Total respiratory pressure-​volume curves in the adult respiratory distress syndrome. Chest 1984;86:58–​66. 25. Demory D, Arnal JM, Wysocki M, et  al. Recruitability of the lung estimated by the pressure volume curve hysteresis in ARDS patients. Intensive Care Med 2008;34:2019–​25. 26. Vieillard-​Baron A, Prin S, Chergui K, Page B, Beauchet A, Jardin F. Early patterns of static pressure-​volume loops in ARDS and their relations with PEEP-​induced recruitment. Intensive Care Med 2003;29:1929–​35.

27. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775–​86. 28. Nieszkowska A, Lu Q, Viera S, Elman M, Fetita C, Rouby JJ. Incidence and regional distribution of lung overinflation during mechanical ventilation with positive end-​expiratory pressure. Crit Care Med 2004;32:1496–​503. 29. Arbelot C, Ferrari F, Bouhemad B, Rouby JJ. Lung ultrasound in acute respiratory distress syndrome and acute lung injury. Cur Opin Crit Care 2008;14:70–​4. 30. Bouhemad B, Brisson H, Le-​Guen M, et al. Bedside ultrasound assessment of positive end-​expiratory pressure-​induced lung recruitment. Am J Respir Crit Care Med 2011;183:341–​7.

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Neurological assessment of the acute cardiac care patient Mathieu van der Jagt, Jeroen JH Bunge, and Fabio S Taccone

Contents Summary  134 Introduction  134 General clinical neurological evaluation  135 Quick clinical neurological evaluation at the bedside  135 Level of consciousness  135 Cognition  136 Brainstem function  136 Motor function  137

Neurological phenotypes in acute cardiac care: diagnosis and acute management  137 Syncope  137 Delirium and encephalopathy  138 Stroke  138 Seizures and myoclonus  138 Coma  139 Post-​anoxic coma  139 Neurological complications in extracorporeal and cardiac assist devices  140 Neuromonitoring: who, when, and how?  140

Standard of care: neuromonitoring modalities  140 Electroencephalography  140 Somatosensory evoked potentials (SSEPs)  140 Imaging of the brain  141 Computerized tomography  141 Magnetic resonance imaging  141

Neuromonitoring modalities: what other options?  141 Monitoring cerebral perfusion and oxygenation  141 Near-​infrared spectroscopy  142 Case vignette  142 Brain ultrasound  142 Other modalities  142

Neuroprognostication  143

Clinical neurological examination  143 EEG  143

Summary Recognizing neurological conditions, as well as their initial diagnostic work-​up and first steps in management, should be part of the competence of doctors and nurses caring for these patients. In this chapter, we have aimed to convey the background and practical tips on the neurological clinical examination, as can be performed by non-​neurologists. Further, we have summarized the ancillary tests that are currently in use by most critical and acute care facilities caring for acute cardiac patients. The focus is on practical information that can be applied in everyday clinical practice, and this is based both on clinical practice experience by the authors and on scientific evidence, when available. We will provide a concise review of clinical knowledge and essential professional skills to facilitate the management of patients with neurological complications related to acute cardiac conditions within the setting of intensive and acute cardiovascular care. We will review clinical approaches to neurological assessment and review the most common phenotypes of neurological disorders in these patients, and their work-​up, diagnostic challenges, and prognosis.

Introduction It is vital to recognize neurological conditions in the acute cardiac patients, because some of these may be reversible upon prompt recognition, they may bear important prognostic implication, or they may be informative on the evolution of a cardiac condition or even point at an underlying diagnosis (e.g. endocarditis). This chapter aims to help readers

SSEP  144 CT  144 MRI  144 Biomarkers  144 Pupillometry  144

Conclusion  144 Personal perspective  145 References  145

G en er a l cl i n i ca l n eu rol o g i ca l eva luat i on acquire the knowledge needed to recognize and handle urgent neurological conditions in cardiac patients in the acute setting of an emergency room or cardiac care/​ICU. We will provide the ‘first steps’ in management, rather than being exhaustive, aimed for non-​neurologists. We will provide the reader with practical and, whenever possible, evidence-​based information that is applicable in everyday clinical practice in acute cardiac care. Neurological monitoring starts with clinical neurological assessment, which is—​in essence—​the best neurological monitor, since it aims to evaluate the actual function of the brain. It is important to recognize that all other (technical) neuromonitoring modalities generally monitor only a specific part or aspect of cerebral functioning and, as such, are more limited regarding the information they provide. Therefore, a key principle in neurological assessment of cardiac patients (which applies to all patients with neurological conditions) is that clinical examination should always be the first step of the assessment, with additional neuromonitoring modalities being used only for confirmation (e.g. of prognosis) or diagnostic evaluation (the reason for neurological worsening) or when clinical examination is impeded (e.g. when the patient is sedated).

General clinical neurological evaluation The first basic rule in neurological assessment of the acute cardiac patient is that neurological functioning should not be impeded at all, meaning that any (new) neurological impairment, be it consciousness, cognition, or motor functioning, and however subtle, requires prompt evaluation. This includes even mild impairments of attention or delirium. A second basic rule is that a brief global neurological examination will likely uncover most of the neurological conditions that can occur in acute cardiac patients.

Quick clinical neurological evaluation at the bedside (See E Figure 14.1.) A quick neurological evaluation is essential in every patient portraying any neurological deficit but may also be advised on a daily basis in every patient at high risk of neurological complications (e.g. endocarditis). Since a proportion of patients being

Consciousness: -arousal -awareness

Brainstem reflexes

Glasgow coma scale Delirium screening

Motor responses

Figure 14.1  Brief neurological evaluation.

managed in cardiac/​cardiothoracic critical care units (CCUs) will be sedated, daily ‘spontaneous awakening trials’ (SATs) are essential to facilitate regular neurological evaluations. It is important to note that current practices are moving away from routine sedation towards a state of being ‘comfortably awake’ [1]‌, acknowledging that circumstances can still call for targeted sedation, e.g. in the case of an agitated patient on ECLS. When sedation is indeed needed, short-​acting sedatives, rather than continuous IV benzodiazepines, are preferred. A  SAT entails daily stopping of all sedatives and, when the patient has no pain, all narcotics, with the aim to both evaluate the neurological function and facilitate spontaneous breathing trials (SBTs), which, combined with SATs, have been shown to improve ICU outcomes. SATs and SBTs are part of modern ICU management aimed at maximizing brain functioning during critical illness, instead of ‘putting the brain to sleep’. This modern approach is now the principle underlying the latest ABCDEF bundle (Assess, prevent, and manage pain; Both SATs and SBTs; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment) and the clinical practice guidelines for the Prevention and management of pain, Agitation/​sedation, Delirium, Immobility, and Sleep disruption (PADIS) in adult patients in the ICU [1].

Level of consciousness The Glasgow Coma Scale (GCS) should be considered a baseline competence of every physician and ICU nurse [2]‌. Newer tools, such as the Full Outline of UnResponsiveness (FOUR) score, have been adopted by some centres, but widespread use of such alternative tools has not surpassed that of the GCS. Although the initial use of the GCS was in traumatic brain injury patients to allow for structured follow-​up of consciousness over time, its use has become much more widespread, including all kinds of neurological conditions and other alterations of consciousness (e.g. metabolic encephalopathy). The GCS assesses arousal (reaction to stimulus) and also partly awareness (cognitive performance), which are the two components of consciousness. Arousal originates from the ascending reticular formation (ARF) in the dorsal regions of the brainstem (pons) and its ascending neuronal circuits to both thalami bilaterally. Awareness relates to the ‘contents’ of the conscious mind (originating from the cortex) [3]. Consequently, for intact consciousness, both need to be present. Well-​known examples of coma due to ARF or thalamic lesions are basilar artery thrombosis or compression of the brainstem, e.g. due to cerebellar haemorrhage. Examples of coma due to hemispheric and cortical disruption include post-​anoxic coma due to persistent vegetative state, or metabolic causes such as deep hypoglycaemia. The GCS (https://www.glasgowcomascale.org/) consists of three components—​ eyes (E), motor (M), and verbal (V)—​ and the score ranges from 3 (deep, unresponsive coma) to 15 (fully alert). Assessment of the GCS score always starts with calling the patient’s name out loud and, if no response follows, shaking the patient (without eliciting pain), followed finally by a pain stimulus. The painful stimulus can be one

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of several: pressing the supraorbital ridge where the supraorbital nerve exits in a small groove (medial orbital rim), pressing the nailbeds, and rubbing the sternum with the knuckles (not suitable for post-​cardiac surgery patients!). However, formally the supraorbital ridge stimulus should be used for the GCS-​M score. The other stimuli can be used to elicit arousal and evaluate the GCS-​E and V components. Further, regarding the GCS-​M: 2 (extension) means extension and endorotation/​pronation of the arms; 3 (abnormal flexion) means any flexing response in the elbow, with two of the following: concomitant extension or endorotation of the legs, flexion of fingers 2–​5 over the thumb, variable extension or endorotation of the arm, flexion in the wrist; 4 (flexion; withdrawal) means a flexing response in the elbow without the characteristics previously described under 3; 5 (localizing) means that the patient brings his hand towards the hand of the clinical investigator, above the level of the shoulders; and M6 (follows commands) means execution of commands by the clinician, which may be either a ‘thumbs up’ or making a fist/​squeezing the investigator’s hand or finger on request. Some patients may have a grasp reflex mimicking a squeeze, and to differentiate from purposeful behaviour in case of doubt, the command ‘let go of the finger’ can be added to confirm M6. Likewise, when eliciting a painful response through pressing the nailbed as an alternative to the supraorbital ridge, M5 can be scored when the patient crosses the midline towards the stimulus with the other arm (only reliable if no paralysis is present contralaterally). Importantly, although the M-​score component of the GCS is drafted as a continuum from 1 to 6, it should be acknowledged that M4 can be compatible with the persistent vegetative state, whereas a clear M5 will very often develop into an M6. Therefore, M4 may be regarded as a double-​edged score—​it may signify an intermediate score on the way to M5 and then probably M6, but it may also be a final situation, with M4 as a persisting maximum GCS-​M score, compatible with the vegetative state. However, in spite of the widespread use of the GCS, its application is certainly not without any flaws; for example, deafness, blindness, or non-​ cerebral neurological deficits (e.g. ICU-​acquired weakness) may falsely impede the GCS-​ M score and underestimate the GCS score as a measure of brain function. Especially in critically ill patients who have been in the ICU for more than a week, such ‘false negatives’ regarding GCS-​M may facilitate self-​f ulfilling prophecies regarding prognosis and may therefore be hazardous. Further, aphasia may impede even perfectly alert patients after a stroke from following commands and therefore may score M5 as a maximum, which does not mean that their consciousness is decreased because of decreased GCS. Also, the GCS does not include brainstem reflexes, which the FOUR score does, which may be regarded as a limitation. Finally, it is important to annotate the GCS score components in the medical file, when the interpretation is not straightforward (which often is the case), e.g. ‘M5, due to aphasia, and otherwise alert’ or ‘M1 with arms, due to cervical cord lesion, but M6 with eyelids, closing them on command’.

Cognition A good way to screen for acute changes in cognition is the routine use of validated bedside screening tools for delirium in acute and critically ill patients. These tools assess awareness, rather than arousal, for which the GCS is more suitable. These tools have been based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for delirium. Two of these tools have been recommended for the critical care setting in the latest PADIS guidelines [1]‌: the Confusion Assessment Method for the ICU (CAM-​ ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Explanations of their contents and use are readily available on excellent supporting websites (e.g. M https://​www.nice.org.uk/​guidance/​cg103 or M https://​www. icudelirium.org). Routine delirium testing in critically ill patients has an added value since it has been shown that hypoactive delirium often remains unrecognized, in spite of burdening the patient and adverse prognostic implication [4]. Furthermore, delirium portends a worse prognosis [5]. The CAM-​ICU involves a strict set of criteria and bedside cognitive tests and tests on attention that should be assessed in a strict order to decide whether the test is positive (indicating delirium) or not [6]‌. However, the consequence is, for example, that a patient may have delusions, but not be assessed as positive for delirium, since delusions and hallucinations are not part of the CAM-​ICU. In contrast, the ICDSC is a more graded test indicating whether more or less delirium symptoms are present, with ICDSC scores of 4 or more indicating delirium, scores of 1–​3 indicating ‘subsyndromal delirium’, and a score of 0 indicating no delirium [1]. Therefore, the ICDSC has a better resolution, rendering this screening tool more suitable for follow-​up over time and for subtle signs of delirium. For both, it is essential that they should be assessed ‘as is’, meaning that interpretations about the role of sedation for the delirium symptoms should not be included in the assessment. This can be understood because sedative drugs can contribute to delirium symptoms or even cause them, but on the other hand, sedation can also uncover underlying delirium. The so-​ called ‘sedation-​ related delirium’ will subside when sedatives are withdrawn, whereas ‘true delirium’ will persist [7]. Distinguishing these two forms of ‘delirium’ is important because of their prognostic implications—​sedation-​ related delirium does not increase mortality risk, in contrast to ‘true’ delirium. Especially in the acute cardiac and cardiovascular acutely and critically ill, screening for delirium, as the ‘canary in the coal mine’ (warning sign), is an essential part of general and neurological assessment in daily practice.

Brainstem function Brainstem dysfunction can uncover many clues with regard to underlying pathologies of the brain and has an important localizing value. Brainstem reflexes disappear when the reflex pathway from afferent to central/​nucleus and subsequently the efferent pathway back to the target organ (eye, face, etc.) has been damaged. Also, the brainstem reflexes as described below follow a

N eurol o gical ph enot ypes in  acu te ca rdiac ca re:  diag n o si s a n d acu te m a nag e m e n t rostro-​caudal sequence. Therefore, compression from the hemisphere towards the brainstem will damage the pupillary response first, thereafter the corneal reflex, etc., and this will be different when there is a pathologic condition lower in the brainstem. Pupillary reflexes:  isocore (same-​sized) pupillary response to light is normal. Absence of any response signifies bilateral impairment of both the optic (II) nerve (afferent), or its tract, and the oculomotor (III) nerve (efferent) and/​or its nucleus in the brainstem. Often, inexperienced operators document isocore, for responsive, large or very small pupils, but these may be normal variants. Any clear differences in size (anisocoria) between the two pupils should alert the clinician for pathology of the brainstem and impending neurological deterioration, independent from its cause, especially if this is accompanied by a decreased GCS score. Causes may be an expanding space-​occupying lesion, e.g. intracerebral haemorrhage (ICH) with oculomotor nerve compression, or a basilar artery thrombosis, with ischaemia of the brainstem, both of which would require immediate management. However, a perfectly alert patient with very mild anisocoria may just signify ‘physiological’ anisocoria. Commercially available pupillometers are becoming popular and are more sensitive, compared with the human eye, in the assessment of pupillary responses. Corneal reflexes:  similar to pupillary reflexes, but absence of corneal reflexes suggests an unfavourable outcome and indicates damage to the trigeminal (V) nerve, or the facial (VII) nerve, or one of their brainstem nuclei. As for abnormal pupillary reflexes, this may be caused, among others, by intracranial space-​occupying lesions, local ischaemia, or post-​anoxic brain damage. The corneal reflex is tested preferably by instillation of drops of water, rather than by eliciting the reflex using a cotton bud or gauze, since this has been shown to have a small risk of corneal abrasion. Other brainstem reflexes:  a ‘quickscan’ of the other brainstem reflexes involves assessment of eye movements in all directions (the patient is asked to follow his gaze left–​right and up–​down by moving an object, e.g. pencil—​divergence of the eyes will indicate partial muscular paresis of the eye through nerves III, trochlear (IV), abducens (VI); symmetric grimacing or laughing on request (facial motor functions by nerve VII); gag reflex or cough in unconscious patients [through manipulation of the ETT or suctioning through the tube—​glossopharyngeal (IX) and vagus (X) nerves]; sticking out the tongue [hypoglossal (XII) nerve XII]. Caloric and oculocephalic reflex testing is usually reserved for the specific setting of suspected brain death.

Motor function A quickscan of motor functions and their (a)symmetry is informative to detect hemiparesis and differentiate between a CNS and a peripheral nervous system problem which has important diagnostic relevance. Lesions leading to contralateral disability include hemispheric and brainstem lesions, whereas cerebellar and spinal cord lesions cause ipsilateral loss of function. Motor function that can be easily tested at the bedside includes:

◆ Strength: usually this is measured using the Medical Research Council (MRC) scale, ranging from 0 (no muscle contraction) to 5 (normal muscle strength). This can be tested against the strength of the investigator and may include at least flexion, extension at the elbow and wrist, and flexion/​extension at the hip, knee, and ankle. Asymmetry more often points to a CNS lesion, whereas symmetric paresis may point to a peripheral nervous system condition or spinal cord lesion. ◆ Coordination: ask the patient to point at your finger and at their own nose, back and forth. Another test is to ask the patient to put their heel on their knee and slide down their tibia. Ataxia will be evident when movements overshoot their targets, resulting in tremulous movements in an attempt to correct this. Abnormal coordination generally points at cerebellar pathology, although it can also point at peripheral nerve pathology. ◆ Muscle tone:  spasticity (subacutely after a CNS lesion) can be discerned from rigidity (basal ganglia disorders, meaning hypokinetic rigid syndromes, such as Parkinson’s disease, but also seen as a side effect of antipsychotic drugs such as haloperidol) or flaccid muscles (typical in the acute phase of a central lesion or in peripheral lesions). ◆ Tendon reflexes: reflexes at the biceps and knee are most easily elicited. Asymmetry points to a central lesion. This requires some practice to perform well and reliably. Brisk reflexes occur with central lesions, and low or absent reflexes with peripheral lesions. However, absent reflexes may be non-​pathologic. ◆ Skilfulness: usually tested with up-​speed alternating movements and comparing asymmetries between the left and right sides, e.g. supining/​pronating the palm of the hand (turning movement) as quickly as possible (or tapping with the foot)—​any asymmetry, however subtle, may point to a central lesion.

Neurological phenotypes in acute cardiac care: diagnosis and acute management Syncope Syncope is defined as a transient loss of consciousness (LOC) due to cerebral hypoperfusion, characterized by a rapid onset, a short duration, and a spontaneous, complete recovery. Main causes include reflex or orthostatic syncope or cardiac causes. The first steps in suspected syncope should include a detailed history (of current and previous episodes), physical examination, ECG, and assessing the need for further diagnostic evaluation thereafter. For further (cardiac) work-​up and risk stratification of syncope, we refer to the 2018 ESC guidelines on diagnosis and management of syncope [8]‌. Alternative diagnoses that have to be considered in the case of transient LOC are epilepsy or a psychogenic origin. Finally, rare causes include subclavian steal syndrome, vertebrobasilar transient ischaemic attack (TIA), or SAH. Important features that plea against (cardiac or reflex) syncope are: longer duration of LOC, gradual onset of decreased consciousness, and LOC accompanied

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by headache or neurological focal signs. Signs suggestive of epileptic seizures, rather than syncope, are: lack of a trigger, lack of anamnestic light-​headedness preceding LOC, duration of LOC of several minutes, tongue bite at the side of the tongue, no full alertness for 26.5 micromoles/​L) was independently associated with mortality [9]‌. Similarly, patients undergoing cardiac surgery showing a post-​operative increase in serum creatinine of >0.5 mg/​dL (>44.2 micromoles/​L), but also those with a decrease of >0.3 mg/​dL (>26.5 micromoles/​ L), have worse survival [10]. However, the evaluation of renal function by serial assessment of serum creatinine or urea demonstrates major limitations. For instance, it takes about 24 hours for the creatinine level to rise, even if both kidneys have ceased to function—​daily increase of about 0.9–​2.9 mg/​dL (79–​256 micromoles/​L). Moreover, as indicated when GFR falls, serum creatinine rises (see E Figure 15.1).

eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-​associated lipocalin; RBF, renal blood flow; RRT, renal replacement therapy.

Since GFR cannot easily be measured directly, endogenous creatinine clearance is used as a surrogate. Yet, a 50% reduction in GFR might keep the serum creatinine level within the normal range, despite doubling it (e.g. a baseline serum creatinine of 0.7 mg/​dL increases to 1.4 mg/​dL in response to a 50% fall in GFR). This calculation assumes a constant rate of creatinine production and sufficient time to reach a new steady state where the rates of production and elimination are identical. A number of alternative markers of renal function have been proposed, such as neutrophil gelatinase-​associated lipocalin (NGAL), KIM-​1, IL-​18, and cystatin C, but none are

1000 Serum creatinine (micromoles/L)

148

800 600 400 200 0

0

50 100 CreaCl (mL/min)

150

Figure 15.1  Relationship between creatinine clearance (CreaCl) and serum creatinine.

T h e   k i dn eys Table 15.1  Classification/​staging system for acute kidney injury Stagea

Serum creatinine criteria (changes within 48 hours)

Urine output criteria c

1

Increase ≥0.3 mg/​dL (≥26.5 micromoles/​L) or increase ≥1.5–​1.9-​fold from baseline

6 and 2–​3-​fold from baselinec

12 hours

b

3

c

Increase >3-​fold from baseline or ≥4.0 mg/​dL (≥354 micromoles/​L), with an acute increase of at least 0.5 mg/​dL (44 micromoles/​L)

125  mmHg, worsening renal function, defined by serum creatinine increase of ≥0.3 mg/​dL (27 micromoles/​L) or cystatin C increase of ≥0.3 mg/​L (22 nmol/​L) at day 2, occurs in about 15–​20% and is associated with an increased 180-​day all-​cause mortality [17] (see E Figure 15.2) [creatinine: hazard ratio (HR) 1.76, 95% CI 1.11–​2.82, P = 0.016; cystatin-​C: HR 2.10, 95% CI 1.38–​3.20, P = 0.0004). The role of worsening renal function as an independent determinant of outcomes in patients with AHF has, however, been questioned [18]. In a series with 599 consecutive patients with AHF, those patients with worsening renal function, but

0.20

5  mm) or calcified pericardium may be apparent but often is not. The ventricles are of normal size, whereas the atria are enlarged. Global LV and RV systolic functions are normal, but paradoxical septal motion is present. In clear-​cut cases, there is an inspiratory decrease in transmitral flow and an increase in transtricuspid flow, with opposite changes in expiration. Sometimes, however, this sign is blunted by massive diuretic therapy. The transmitral flow in a typical case is characterized by tall, short E waves, with short deceleration time (‘restrictive transmitral pattern’). (See also E Chapters 25 and 56.)

Traumatic cardiac and aortic injury A detailed discussion on traumatic cardiac and aortic injury is provided in E Chapter 60. A focus on echocardiography is provided in the online data supplement. Virtually all cardiac structures may be damaged by blunt trauma [16]. The ventricles may develop intramyocardial haematoma, myocardial necrosis, or frank rupture, leading to usually a lethal tamponade, if a free wall is affected, or else to a VSD. The RV free wall is most often affected due to its anterior localization in the chest. The atria may also rupture. Coronary vessels may be lacerated, leading to haematopericardium and tamponade. Valvular structures may also be damaged, including leaflets and the support apparatus, most prominently the papillary muscles or chordae. Tears of the pericardium, with or without other cardiac injury, may lead to herniation of other organs into the pericardial sac (e.g. intestinal herniation through an also ruptured diaphragm) or displacement of cardiac structures outside the pericardial sac. The thoracic aorta is affected, especially by deceleration trauma (e.g. traffic accidents or falls) (see also E Chapter  59). Traffic accidents typically cause aortic damage at the aortic isthmus, the junction of the aortic arch, and the descending aorta. Falls may lead to aortic damage at the level of the innominate artery. Damage to the aorta ranges from intramural haematoma to complete transection of the vessel. Echocardiography, and especially TOE, is very helpful after blunt chest trauma. In a study, more than half of 117 patients with blunt chest trauma showed clearly pathological findings on TOE, ranging from RV wall motion abnormalities to pericardial effusions; the ECG was often normal in these patients [16] (see E Table 18.1.3). Penetrating trauma of the heart or large Table 18.1.3  Echocardiographic signs of cardiovascular trauma

Figure 18.1.10  Large, circular pericardial effusion (arrows). Parasternal long-​axis  view.

◆ Pericardial effusion ◆ Wall motion abnormalities ◆ Rupture of valve leaflets or papillary muscles, with signs of acute regurgitation (especially in aortic or mitral valve damage) ◆ LV or RV FWR ◆ IMH of the aorta ◆ Aortic dissection ◆ Aortic rupture/​periaortic haematoma

Aorti c em e rg e n c i e s vessels is typically rapidly deadly, precluding echocardiographic examination.

Pulmonary embolism A dilated and hypokinetic RV is a typical echocardiographic finding in severe PE. Additionally, there is a variable increase in RV systolic pressure, as estimated by measuring the peak tricuspid regurgitant velocity (see E Figure 18.1.11). This is done by measuring the peak tricuspid regurgitant velocity using continuous-​wave Doppler, calculating the peak pressure difference between the RV and the right atrium from the Bernoulli equation (Δp = 4 × v2) and adding an estimate of the mean right atrial pressure, e.g. 10  mmHg (for more detail on right atrial pressure estimation, see E Heart failure, p. 206). Note, however, that in the acutely failing RV associated with fulminant PE, this pressure may be deceptively normal or only minimally elevated. Very high peak pulmonary pressures (e.g. >80  mmHg) cannot be generated by a previously normally loaded RV and do not occur in response to an acute embolism, unless there is previous PH. A  shift of the ventricular septum to the left, flattening the cross-​section of the LV into a ‘D’ shape, instead of the normal circular shape, in short-​axis views and paradoxical septal motion are important signs of acute RV pressure overload. TR is invariably present, and the inferior vena cava may be distended and lack inspiratory collapse. Thrombi may sometimes be seen directly in the pulmonary artery imaged in the parasternal or subcostal view. If TOE is performed, the right pulmonary artery can also be evaluated quite well and thrombotic material may be seen there. Acute pressure increase in the right atrium leads to a shift in position of the atrial septum to the left side and may create continuous right-​to-​left shunt through a patent foramen ovale. In the presence of severe PE, paradoxical embolism of thrombotic material through a patent foramen ovale is a recognized and devastating complication. On the other hand, small PEs are not detectable on echocardiography. The role of

echocardiography therefore is not in the definitive exclusion of a (small) PE, but in the assessment of whether a haemodynamically significant embolism has taken place and whether RV compromise warrants thrombolytic therapy. Echocardiographic differentiation of chronic and acute pulmonary pressure elevation is difficult. RV hypertrophy, with an end-​diastolic free wall thickness of >5  mm, supports chronic PH but does not exclude an additional acute pressure increase. Several signs that have been described as relatively specific (but not sensitive) for acute PE are: ◆ McConnell’s sign: a hypokinetic RV free wall, together with a hyperkinetic or normokinetic RV apex. ◆ The transpulmonary pulsed-​ wave Doppler flow profile that may show shortened acceleration time (53 kPa. A PaO2/​FiO2 of 30%. Patients with respiratory failure will often require partial or full ventilatory support to achieve correction of hypoxaemia, hypercapnia, and exhaustion. In addition, mechanical ventilation can achieve airway protection, decrease O2 consumption by reducing respiratory muscle work, and facilitate safe patient transfer and investigations (e.g. CT scan or coronary angiography). Effective positive pressure mechanical ventilation can be provided either invasively (through an ETT) or non-​ invasively (through an interface—​most commonly a face mask or helmet), either as continuous airway pressure alone (i.e. without additional inspiratory support—​CPAP) or with additional inspiratory pressure support (non-​invasive ‘ventilation’—​NIV) if work of breathing is elevated or there is hypercapnia [24–​26].

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The most common indications for acute non-​invasive respiratory support are: ◆ Acidotic hypercapnic ventilatory failure due to COPD exacerbations (NIV). ◆ ACPO (CPAP or NIV). ◆ Immunocompromised patients with mild to moderate acute respiratory failure (NIV). ◆ Mild ARDS (NIV in ICU). ◆ Ventilatory failure in obesity/​obstructive sleep apnoea (OSA) (CPAP or NIV). Absolute contraindications to non-​invasive respiratory support are: ◆ Immediate need for intubation. ◆ Severe haemodynamic instability. ◆ Extensive facial trauma or upper airway obstruction. ◆ Life-​threatening hypoxaemia. ◆ Severe bulbar weakness. The delivery of acute NIV is a complex intervention and can improve survival, unless it delays intubation and institution of invasive mechanical ventilation. Therefore, prompt recognition of NIV failure is essential for timely intubation. The criteria for NIV failure are: ◆ No improvement in pH at 4–​6 hours (approximately 25% of cases). ◆ Physiological deterioration. ◆ pH 8–​9 kPa; PaO2/​FiO2 >20–​26.6  kPa 6. Stable haemodynamics; no or minimal vasopressor support 7. No uncorrected metabolic abnormalities 8. Fluid balance optimized 9. Consider measuring NT-​proBNP for patients with LV dysfunction—​this may guide fluid management 10.  Tympanic temperature between 36°C and 38°C 1 1. No relevant electrolyte disorder and haemoglobin level 70–​80  g/​L

Weaning indices should be evaluated before the SBT, which functions as a diagnostic test to determine the probability of successful extubation. Integrative weaning indices evaluate more than one aspect of respiratory function. Although few of the weaning indices are predictive per se, the following indices should be routinely measured in clinical practice. The weaning index criteria can be particularly useful in situations in which the decision to liberate from mechanical ventilation is problematic (see E Table 22.5). Table 22.5  Weaning indices that predict successful ventilator discontinuation Indices

Cut-​off value

Ref

AUC

RSBI = f/​VT

6 days * These patients may benefit from ‘prophylactic’ NIV immediately post-​ extubation if SBT is successful.

RE F E RE N C E S approximated by an SBT without assistance or tube compensation. Therefore, a low-​PS SBT may underestimate the risk of extubation failure, especially if the prevalence of extubation failure is high (e.g. in patients under prolonged mechanical ventilation or having ICU-​acquired polyneuromyopathy), while low PS (5–​7 cmH2O) may be used in patients at low risk of failure. ATC can be added if the internal diameter of the ETT is ≤7 mm [91]. Similarly, maintaining PEEP during the SBT may increase the rate of extubation failures, as PEEP may mask worsening in LV function. Eliciting the patient’s subjective impression about the ability to breathe unassisted at the end of the weaning test has been shown to improve the predictive value of the weaning test [96]. SBT should not be performed more than once a day to prevent fatigue.

Conclusion During assisted mechanical ventilation, patient and ventilator interaction needs to be monitored. Asynchronies are prevalent and, if frequent, can affect important patient-​centred outcomes, including mortality. A systematic approach to detection of common abnormalities in flow and pressure waveforms can allow the clinician to diagnose and correct asynchronies. Holistic management of sedation, sleep, and ventilator settings is required to harmonize interaction with the ventilator and aid liberation from mechanical ventilation. Newer modes of ventilation (e.g. PAV+ based on analysis of respiratory mechanics, and NAVA based on neural respiratory output) that are designed to detect inspiratory muscle activity may improve synchrony and support the breath in proportion to the patient’s efforts.

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17. Reske AW, Costa EL, Reske AP, et al. Bedside estimation of nonaerated lung tissue using blood gas analysis. Crit Care Med 2013;41:732–​43. 18. Kallet RH, Zhuo H, Liu KD, et al. The association between physiologic dead-​ space fraction and mortality in subjects with ARDS enrolled in a prospective multi-​center clinical trial. Respir Care 2014;59:1611–​18. 19. Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary dead-​space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:1281–​6. 20. Mekontso-​Dessap A, Castelain V, Anguel N, et al. Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients. Intensive Care Med 2002;28:272–​7. 21. Lamia B, Monnet X, Teboul JL. Meaning of arterio-​venous PCO2 difference in circulatory shock. Minerva Anestesiol 2006;72:597–​604. 22. Gattinoni L, Pesenti A, Matthay M. Understanding blood gas analysis. Intensive Care Med 2018;44:91–​3. 23. Alessandri F, Pugliese F, Ranieri VM. The role of rescue therapies in the treatment of severe ARDS. Respir Care 2018;63:92–​101. 24. Frat JP, Joly F, Thille AW. Noninvasive ventilation versus oxygen therapy in patients with acute respiratory failure. Curr Opin Anaesthesiol 2019;32:150–​5. 25. Chiumello D, Brioni M. Severe hypoxemia: which strategy to choose. Crit Care 2016;20:132. 26. Bellani G, Laffey JG, Pham T, et  al. Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE Study. Am J Respir Crit Care Med 2017;195:67–​77. 27. Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 2019;5:18. 28. Tonetti T, Vasques F, Rapetti F, et al. Driving pressure and mechanical power: new targets for VILI prevention. Ann Transl Med 2017;5:286. 29. Slutsky AS, Ranieri VM. Ventilator-​induced lung injury. N Engl J Med 2013;369:2126–​36. 30. Nieman GF, Satalin J, Andrews P, et  al. Personalizing mechanical ventilation according to physiologic parameters to stabilize alveoli and minimize ventilator induced lung injury (VILI). Intensive Care Med Exp 2017;5:8. 31. Katira BH. Ventilator-​induced lung injury:  classic and novel concepts. Respir Care 2019;64:629–​37. 32. Gattinoni L, Tonetti T, Quintel M. Regional physiology of ARDS. Crit Care 2017;21(Suppl 3):312.

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33. Gattinoni L, Marini JJ, Collino F, et al. The future of mechanical ventilation: lessons from the present and the past. Crit Care 2017;21:183. 34. Curley GF, Laffey JG, Zhang H, et al. Biotrauma and ventilator-​induced lung injury: clinical implications. Chest 2016;150:1109–​17. 35. Cruz FF, Ball L, Rocco PRM, et  al. Ventilator-​induced lung injury during controlled ventilation in patients with acute respiratory distress syndrome:  less is probably better. Expert Rev Respir Med 2018;12:403–​14. 36. Cressoni M, Chiumello D, Algieri I, et  al. Opening pressures and atelectrauma in acute respiratory distress syndrome. Intensive Care Med 2017;43:603–​11. 37. Amato MB, Meade MO, Slutsky AS, et  al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747–​55. 38. Gattinoni L, Carlesso E, Cadringher P, et al. Physical and biological triggers of ventilator-​induced lung injury and its prevention. Eur Respir J 2003;47(Supplement 47):15s–​25s. 39. Gattinoni L, Carlesso E, Caironi P. Stress and strain within the lung. Curr Opin Crit Care 2012;18:42–​7. 40. Gattinoni L, Tonetti T, Cressoni M, et  al. Ventilator-​related causes of lung injury:  the mechanical power. Intensive Care Med 2016;42:1567–​75. 41. Gattinoni L, Carlesso E, Cressoni M. Selecting the ‘right’ positive end-​expiratory pressure level. Curr Opin Crit Care 2015;21:50–​7. 42. Brower RG, Lanken PN, MacIntyre N, et  al. Higher versus lower positive end-​expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327–​36. 43. Pintado MC, de Pablo R, Trascasa M, et al. Individualized PEEP setting in subjects with ARDS:  a randomized controlled pilot study. Respir Care 2013;58:1416–​23. 44. de Matos GF, Stanzani F, Passos RH, et  al. How large is the lung recruitability in early acute respiratory distress syndrome:  a prospective case series of patients monitored by computed tomography. Crit Care 2012;16:R4. 45. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-​ ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347–​54. 46. Gattinoni L, Carlesso E, Brazzi L, et  al. Friday night ventilation:  a safety starting tool kit for mechanically ventilated patients. Minerva Anestesiol 2014;80:1046–​57. 47. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775–​86. 48. Gattinoni L, Caironi P, Valenza F, et al. The role of CT-​scan studies for the diagnosis and therapy of acute respiratory distress syndrome. Clin Chest Med 2006;27:559–​70; abstract vii. 49. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159–​68. 50. Henderson AC, Sa RC, Theilmann RJ, et  al. The gravitational distribution of ventilation-​perfusion ratio is more uniform in prone than supine posture in the normal human lung. J Appl Physiol (1985) 2013;115:313–​24. 51. Johnson NJ, Luks AM, Glenny RW. Gas exchange in the prone posture. Respir Care 2017;62:1097–​110. 52. Kallet RH. A comprehensive review of prone position in ARDS. Respir Care 2015;60:1660–​87. 53. Mentzelopoulos SD, Roussos C, Zakynthinos SG. Prone position reduces lung stress and strain in severe acute respiratory distress syndrome. Eur Respir J 2005;25:534–​44. 54. Munshi L, Del Sorbo L, Adhikari NKJ, et al. Prone position for acute respiratory distress syndrome. A  systematic review and meta-​analysis. Ann Am Thorac Soc 2017;14(Supplement 4):S280–​8.

55. Pelosi P, Caironi P, Taccone P, et al. Pathophysiology of prone positioning in the healthy lung and in ALI/​ARDS. Minerva Anestesiol 2001;67:238–​47. 56. Pelosi P, Tubiolo D, Mascheroni D, et al. Effects of the prone position on respiratory mechanics and gas exchange during acute lung injury. Am J Respir Crit Care Med 1998;157:387–​93. 57. Scholten EL, Beitler JR, Prisk GK, et  al. Treatment of ARDS with prone positioning. Chest 2017;151:215–​24. 58. Sud S, Friedrich JO, Adhikari NK, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-​ analysis. CMAJ 2014;186:E381–​90. 59. Taccone P, Pesenti A, Latini R, et  al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA 2009;302:1977–​84. 60. Brodie D, Slutsky AS, Combes A. Extracorporeal life support for adults with respiratory failure and related indications:  a review. JAMA 2019;322:557–​68. 61. Parekh M, Abrams D, Brodie D, et  al. Extracorporeal membrane oxygenation for ARDS: optimization of lung protective ventilation. Respir Care 2018;63:1180–​8. 62. Bartlett RH. Physiology of gas exchange during ECMO for respiratory failure. J Intensive Care Med 2017;32:243–​8. 63. Fan E, Gattinoni L, Combes A, et  al. Venovenous extracorporeal membrane oxygenation for acute respiratory failure:  a clinical review from an international group of experts. Intensive Care Med 2016;42:712–​24. 64. Combes A, Fanelli V, Pham T, et al. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Med 2019;45:592–​600. 65. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018;378:1965–​75. 66. Ma B, Bates JH. Modeling the complex dynamics of derecruitment in the lung. Ann Biomed Eng 2010;38:3466–​77. 67. Magder S. Fluid status and fluid responsiveness. Curr Opin Crit Care 2010;16:289–​96. 68. Magder S. Heart–​ lung interaction in spontaneous breathing subjects: the basics. Ann Transl Med 2018;6:348. 69. Pinsky MR. Heart lung interactions during mechanical ventilation. Curr Opin Crit Care 2012;18:256–​60. 70. Pinsky MR. Cardiopulmonary interactions:  physiologic basis and clinical applications. Ann Am Thorac Soc 2018;15(Suppl 1):S45–​8. 71. Buda AJ, Pinsky MR, Ingels NB, Jr, et al. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979;301:453–​9. 72. Lemaire F, Teboul JL, Cinotti L, et  al. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology 1988;69:171–​9. 73. Rasanen J, Vaisanen IT, Heikkila J, et  al. Acute myocardial infarction complicated by left ventricular dysfunction and respiratory failure. The effects of continuous positive airway pressure. Chest 1985;87:158–​62. 74. Mekontso Dessap A, Roche-​ Campo F, Kouatchet A, et  al. Natriuretic peptide-​ driven fluid management during ventilator weaning: a randomized controlled trial. Am J Respir Crit Care Med 2012;186:1256–​63. 75. Georgopoulos D, Xirouchaki N, Tzanakis N, et al. Driving pressure during assisted mechanical ventilation:  Is it controlled by patient brain? Respir Physiol Neurobiol 2016;228:69–​75. 76. Kondili E, Prinianakis G, Georgopoulos D. Patient–​ventilator interaction. Br J Anaesth 2003;91:106–​19.

RE F E RE N C E S 77. Tobin MJ, Jubran A, Laghi F. Patient–​ventilator interaction. Am J Respir Crit Care Med 2001;163:1059–​63. 78. Pierson DJ. Patient–​ ventilator interaction. Respir Care 2011;56: 214–​28. 79. Nava S, Ceriana P. Patient–​ventilator interaction during noninvasive positive pressure ventilation. Respir Care Clin N Am 2005;11:281–​93. 80. Nava S, Bruschi C, Fracchia C, et al. Patient–​ventilator interaction and inspiratory effort during pressure support ventilation in patients with different pathologies. Eur Respir J 1997;10:177–​83. 81. Jolliet P, Tassaux D. Clinical review: patient–​ventilator interaction in chronic obstructive pulmonary disease. Crit Care 2006;10:236. 82. Hess DR. Patient–​ventilator interaction during noninvasive ventilation. Respir Care 2011;56:153–​65; discussion 155–​157. 83. de Wit M. Monitoring of patient–​ventilator interaction at the bedside. Respir Care 2011;56:61–​72. 84. Branson RD. Patient–​ventilator interaction: the last 40 years. Respir Care 2011;56:15–​24. 85. Georgopoulos D. Ineffective efforts during mechanical ventilation:  the brain wants, the machine declines. Intensive Care Med 2012;38:738–​40. 86. Georgopoulos D, Prinianakis G, Kondili E. Bedside waveforms interpretation as a tool to identify patient-​ventilator asynchronies. Intensive Care Med 2006;32:34–​47. 87. Akoumianaki E, Lyazidi A, Rey N, et al. Mechanical ventilation-​induced reverse-​triggered breaths: a frequently unrecognized form of neuromechanical coupling. Chest 2013;143:927–​38. 88. Murias G, de Haro C, Blanch L. Does this ventilated patient have asynchronies? Recognizing reverse triggering and entrainment at the bedside. Intensive Care Med 2016;42:1058–​61. 89. Akoumianaki E, Maggiore SM, Valenza F, et  al. The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med 2014;189:520–​31. 90. Lucangelo U, Bernabe F, Blanch L. Respiratory mechanics derived from signals in the ventilator circuit. Respir Care 2005;50:55–​65; discussion  65–​7. 91. Girard TD, Alhazzani W, Kress JP, et  al. An official American Thoracic Society/​ American College of Chest Physicians Clinical Practice Guideline:  liberation from mechanical ventilation in critically ill adults. Rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. Am J Respir Crit Care Med 2017;195:120–​33.

92. Thille AW, Richard JC, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med 2013;187: 1294–​302. 93. Perren A, Brochard L. Managing the apparent and hidden difficulties of weaning from mechanical ventilation. Intensive Care Med 2013;39:1885–​95. 94. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371:126–​34. 95. Schonhofer B. [Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously]. Pneumologie 1997;51:599–​600. 96. Perren A, Previsdomini M, Llamas M, et al. Patients’ prediction of extubation success. Intensive Care Med 2010;36:2045–​52. 97. Esteban A, Frutos F, Tobin MJ, et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med 1995;332:345–​50. 98. Ely EW, Baker AM, Dunagan DP, et  al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996;335:1864–​9. 99. Straus C, Louis B, Isabey D, et al. Contribution of the endotracheal tube and the upper airway to breathing workload. Am J Respir Crit Care Med 1998;157:23–​30. 100. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991;324:1445–​50. 101. Capdevila XJ, Perrigault PF, Perey PJ, et al. Occlusion pressure and its ratio to maximum inspiratory pressure are useful predictors for successful extubation following T-​piece weaning trial. Chest 1995;108:482–​9. 102. Nemer SN, Barbas CS, Caldeira JB, et al. Evaluation of maximal inspiratory pressure, tracheal airway occlusion pressure, and its ratio in the weaning outcome. J Crit Care 2009;24:441–​6. 103. Sassoon CS, Mahutte CK. Airway occlusion pressure and breathing pattern as predictors of weaning outcome. Am Rev Respir Dis 1993;148(4 Pt 1):860–​6. 104. Nemer SN, Barbas CS, Caldeira JB, et al. A new integrative weaning index of discontinuation from mechanical ventilation. Crit Care 2009;13:R152.

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CHAPTER 23

Temporary pacing Bulent Gorenek

Summary Contents Summary  306 Introduction  306 Indications  306

Acute coronary syndrome patients  307 Patients undergoing percutaneous coronary intervention  307 Sinus node dysfunction  308 Prevention, diagnosis, and termination of tachycardias  308

Methods of temporary pacing  308 Transvenous (endocardial) pacing  308 Modes of pacing  308 Single-​chamber pacing  308 Dual-​chamber pacing  308

Parts of transvenous (endocardial) pacing  309 Electrode catheters (leads)  309 The external generator  309 Implantation procedure  309 Complications  310 Complications related to venous access  310 Complications related to electrode catheters  310 Complications related to the electrical performance of the pacemaker  310 External (transcutaneous) pacing  310 Transoesophageal pacing  311 Biventricular pacing  311

Conclusion  311 Personal perspective  311 Further reading  312 References  312

Temporary cardiac pacing by electrical stimulation of the heart is indicated as a short-​term treatment of life-​threatening bradyarrhythmias or tachyarrhythmias. It can be used temporarily until the arrhythmias resolve or as a bridge to permanent pacing. Symptomatic bradycardias needing temporary pacing may occur in AMI, during percutaneous coronary intervention, and in patients with sinus node dysfunction. Temporary pacing can also be useful for terminating or suppressing some types of supraventricular and ventricular arrhythmias. Single-​chamber, dual-​chamber, or biventricular pacing modes can be used. In haemodynamically compromised patients, dual-​chamber pacing is preferred. Ideally, this procedure is performed under fluoroscopy, but electrode catheters can also be inserted without fluoroscopy, with ECG and/​or pressure monitoring. Several methods of temporary pacing are available: transvenous, external, and transoesophageal pacing. Transvenous pacing is the most commonly used technique. Although this method is safe and easy, some complications related to venous access or caused by the inserted electrode catheters or by an electrical dysfunction of the pacing device may occur, either during or after the implantation.

Introduction The contribution of the ICCU to the reduction in mortality from acute cardiovascular events over the past 30 years has been well documented. Many patients with acute CVDs hospitalized in the ICCU are at high risk of developing advanced degrees of conduction block or cardiac arrest that may necessitate temporary pacing, which is therefore considered to be a necessary skill for every cardiologist. Temporary pacing was first accomplished transcutaneously by Zoll in 1952 [1]‌and transvenously by Furman in 1958 [2]. Pacing techniques have since been refined, and new pacing modalities have been developed. The goal of temporary cardiac pacing in the ICCU is to restore effective cardiac depolarization and myocardial contraction, resulting in the delivery of adequate cardiac output. This chapter reviews the indications and methods of temporary pacing in the ICCU.

Indications The indications for temporary pacing are less certain than those for permanent pacing. Indeed, there is no clear consensus on many of the indications for temporary pacing,

In di c at i on s with most recommendations coming from clinical experience, rather than from clinical trials. As recommended in the 2013 ESC guidelines on cardiac pacing and CRT, the following issues are relevant as guidance for clinical practice  [3]‌: ◆ Temporary transvenous pacing shall not be used routinely and only as a last resort when chronotropic drugs are insufficient. ◆ Positive chronotropic drug infusion (e.g. isoproterenol, adrenaline, etc.) may be preferred for a limited time, unless there is a contraindication. ◆ Temporary transvenous pacing should be limited to cases of high-​degree AV block without escape rhythm, life-​threatening bradyarrhythmias, such as those that occur during interventional procedures (e.g. PCI), or rarely in acute settings such as AMI, drug toxicity, or concomitant systemic infection. ◆ If the indications for permanent pacing are established, every effort should be made to implant a permanent pacemaker as soon as possible. ◆ In general, temporary cardiac pacing should not be considered for asymptomatic patients who have a stable rhythm (like first-​ degree AV block or Mobitz 2 or stable escape rhythm). Although the mentioned rhythms are stable for most patients, there are exceptions. If there is doubt, having transcutaneous pacing ready for use in emergencies may be reasonable for daily practice.

Acute coronary syndrome patients Bradyarrhythmias are particularly well-​ recognized complications of AMI. Bradyarrhythmias, including AV block and sinus bradycardia, occur most frequently with an inferior MI. Complete AV block occurs in approximately 20% of patients with an acute RV infarction. Infranodal conduction disturbances with wide-​ complex ventricular escape rhythms occur most frequently in large anterior MI and portend a very poor prognosis. Sinus bradycardia is common in the first hours, especially in inferior infarction. It is estimated that approximately 20% of patients with an AMI develop an AV block [4–​6], which can be induced either by ischaemia or necrosis of the conduction system or by an autonomic imbalance. Patients with a peri-​infarction AV block have higher in-​hospital and late mortality than those with preserved AV conduction. The increased mortality is related to the extensive myocardial damage that is required to develop a heart block, rather than to the heart block itself. Management of patients with conduction disturbances after an MI depends, in part, on the location of the infarct. A high-​degree AV block that is associated with an inferior wall MI is located above the His bundle in 90% of patients [7, 8]. As a result, a third-​ degree AV block often results in only modest and usually transient bradycardia, with escape rhythm rates above 40 bpm. However, a high-​degree AV block that is associated with an anterior MI is more often located below the AV node [7]‌, is usually symptomatic, and has been associated with a higher mortality rate. Reperfusion strategies with thrombolysis and angioplasty have reduced the need for permanent pacing, since there is less

myocardial damage and a greater chance that the bradycardia and conduction abnormalities will resolve. There may, however, be a need for temporary pacing. Temporary pacing is necessary for patients with symptomatic bradycardias but should also be considered for those at high risk of developing a third-​degree AV block as a consequence of an ACS, particularly AMI. Patients with a third-​degree AV block and a wide QRS complex escape rhythm require a temporary pacemaker, even though symptoms are absent. The same is true of new-​onset type 2 second-​degree AV block. Temporary pacing is also indicated in trifascicular block. However, there is no common consensus for the use of temporary pacing in patients with bifascicular block, which carries a 15–​31% risk of progression to a second-​or third-​ degree AV block in AMI [9, 10]. A first-​degree AV block requires no treatment. A  new LBBB usually is associated with extensive anterior infarction, with a high likelihood for developing a complete AV block and pump failure. Preventive placement of a temporary pacing electrode may be warranted. Temporary pacing may also need to be considered if the patient with AMI experiences episodes of asystole or develops VT or VF in response to bradycardia. Bradycardia-​induced sustained ventricular arrhythmias can be prevented by rapid pacing in AMI patients. One example is torsades de pointes (TdP) that are associated with a long QT interval. Atrial or ventricular pacing at higher rates can prevent the initiation of TdP by shortening the QT interval and preventing ventricular ectopic beats that might initiate the tachycardia. While pacing has not been shown to increase long-​term survival, it may still be indicated in symptomatic bradyarrhythmias that are associated with AMI. In the current ESC guidelines for the management of AMI in patients presenting with ST-​segment elevation, temporary pacing is indicated in cases of failure to respond to atropine, sinus bradycardia associated with hypotension, AV block II (Mobitz 2), or AV block III with bradycardia that causes hypotension or heart failure [11].

Patients undergoing percutaneous coronary intervention New conduction defects occur in approximately 1% of patients who undergo PCI [12]. RBBBs are the most common conduction disturbances in these patients, and this is followed by first-​degree AV blocks. Although these defects almost always disappear without treatment before the time of hospital discharge, they occasionally require the elimination of drugs that depress cardiac activity [13]. Conduction disturbances are more common in AMI patients undergoing primary PCI. In a study published a few years ago, 6.3% of AMI patients developed a third-​degree AV block. In 86.3% of these cases, the block occurred before or during PCI. And in 94.5% of the patients, resolution of the block occurred in the catheterization laboratory [14]. Pacing is rarely required during PCI. Among interventional cardiologists, there is no consensus regarding the need for temporary pacemaker placement during PCI. When a third-​degree

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AV block develops, atropine (though rarely helpful in the setting of inadequate escape and deterioration) should be given. Coughing may help support the circulation and maintain consciousness while a temporary pacing catheter is inserted. Although there is no consensus, prophylactic lead insertion can be performed before intervention in some high-​risk patients undergoing PCI for the RCA or circumflex artery. However, it is not indicated in total occlusion patients.

Sinus node dysfunction In sinus node dysfunction, when signs or symptoms of haemodynamic compromise exist, temporary pacing may be necessary if IV atropine administration fails to stabilize the patient. Patients with compromised sinus node function may develop sinus nodal depression following drug therapy with antiarrhythmic drugs in the ICCU. Therapy with these agents can be carried out with greater safety if a temporary pacemaker is inserted to prevent drug-​induced bradycardia and circulatory decompensation; permanent pacing is frequently required, and its early use in selected patients can avoid the need for the additional invasive procedure of temporary pacing [15]. In a tachycardia–​bradycardia syndrome, there is often an oscillation between rapid rates that are due to AF and slow rates that are caused by sinus bradycardia. The slow sinus rates can result in AF as an escape arrhythmia; maintenance of a faster heart rate with pacing may prevent this.

Prevention, diagnosis, and termination of tachycardias Temporary pacemakers can be used for the prevention of pause-​ dependent VTs, which may occur in some patients with long QT syndrome, with the use of antiarrhythmic drugs, and also in AMI. In the current ESC guidelines for the management of AMI in patients presenting with ST-​segment elevation, temporary pacing is indicated in cases of failure to respond to atropine in patients with polymorphic VT [11]. Pacing may also be used for the differential diagnosis of tachycardias. In patients with wide-​complex tachycardia, an atrial recording may differentiate between VT and supraventricular tachycardia (SVT) with aberrancy. The atrial recording may be either transvenous or transoesophageal. Anti-​ tachycardia or overdrive pacing may be helpful for acute management of patients with frequent recurrent episodes, particularly when drug therapy is ineffective. Although this method is not effective in converting AF to sinus rhythm, many supraventricular re-​entrant tachycardias can be terminated by pacing techniques if the pathway is susceptible to penetration by exogenous electrical stimuli, a phenomenon known as ‘entrainment’ [16–​18]. Re-​entrant arrhythmias that can be interrupted following entrainment include sinus node re-​ entrant tachycardia, AV nodal re-​entrant tachycardia (AVNRT), atrial tachycardia (AT), atrial flutter, and AV re-​entrant tachycardia (AVRT) [15, 19–​23]. Re-​entrant monomorphic VT can also be ended by anti-​tachycardia pacing. However, VT rates that exceed 200 bpm

might be more likely to be accelerated by anti-​tachycardia pacing and subsequently deteriorate into VF. There are no known contraindications to the use of temporary pacing as a therapeutic or prophylactic modality. Nevertheless, certain relative contraindications may exist in any given patient. Among others, application of asynchronous pacing, in competition with an intrinsic rhythm, may provoke arrhythmias in electrically unstable individuals.

Methods of temporary pacing For most other patients, a rate of 60–​70 bpm will likely be adequate. If the patient is pacemaker-​dependent, the pacemaker can be turned to the least sensitive value. Methods of temporary pacing include transvenous (endocardial) pacing, external (transcutaneous) pacing, and transoesophageal pacing.

Transvenous (endocardial) pacing Although transvenous pacing is the most reliable pacing method available, its effective use requires an invasive procedure, as well as an experienced operator [23, 24].

Modes of pacing A number of pacing modes are available for temporary use; pacing can be single-​chamber (atrial or ventricular) or dual-​chamber. Single-​chamber pacing In single-​chamber temporary pacing, only one electrode catheter is placed into a chamber of the heart. Most often, it is placed into a ventricle, but on certain other occasions, an atrium is used. Ventricular pacing (VVI) is the most commonly used pacing mode in the ICCU. The advantages of ventricular pacing include the requirement for only a single electrode catheter and the ability to protect the patient from dangerous bradycardias. As for the technical aspect of implantation, it is a relatively simple procedure, as just a single lead needs to be implanted. The procedure time is shorter. Complication rates are lower, as only a single needlestick is needed to get venous access. However, ventricular pacing cannot maintain AV synchrony and a lack of AV synchrony can result in ‘pacemaker syndrome’, which can be defined as loss of AV synchrony, retrograde ventriculoatrial conduction, and absence of a rate response to physiological needs. Atrial pacing is appropriate for patients with sinus node dysfunction who have an intact AV nodal function or for termination of some SVTs. Dual-​chamber pacing Temporary dual-​chamber pacing may be useful for patients who require AV sequential pacing for haemodynamic benefit, for instance, during AMI, particularly when associated with haemodynamic instability. It can be used to assess the benefit of AV synchrony when permanent pacing is contemplated. In dual-​chamber pacing, electrode catheters are placed in two chambers of the heart. One paces the atrium, and the other paces the ventricle. This approach more closely matches the natural

M ethod s of tem p ora ry   pac i n g pacing of the heart, and this type of pacing can coordinate function between the atria and the ventricles. This was demonstrated by Murphy and colleagues in 1992; temporary ventricular pacing at 80 bpm was found to be no better than spontaneous bradycardia, whereas dual-​chamber pacing resulted in improved cardiac output and blood pressure and falls in the pulmonary wedge pressure and right atrial pressure [25]. This would suggest that the majority of temporary pacing should be AV synchronous in the presence of normal sinus node activity; however, despite these findings, the more complex procedure associated with temporary transvenous dual-​chamber pacing has led to the continued routine use of ventricular pacing in the temporary setting [26].

sensing, ventricular pacing on demand), or DDD (dual-​chamber sensing and pacing on demand). Generators either can be small enough to allow the patient to be ambulant or require to be placed at the bedside. Batteries must be checked at least daily and the generator sited, so that it cannot fall and exert traction on the pacing electrode catheter. Spare batteries should be kept available at all times. It is recommended that new batteries be used with each patient. Low battery condition is usually signalled by a flashing red light during sensing or pacing. When this occurs, the batteries should be replaced without delay. Some generators may also offer high-​rate pacing to allow overdrive pacing of tachyarrhythmias [26].

Parts of transvenous (endocardial) pacing

Implantation can be done at the bedside in the ICCU or in a specially equipped room that is near the ICCU. The equipment needed for implantation includes an introducer sheath, an electrode catheter, and an external generator. An ECG machine and a cardiac monitor should also be available. Once all the equipment has been assembled, the patient is prepped in the usual sterile fashion. A wide area should be cleaned, and the patient should be generously draped to ensure that all the equipment remains in a sterile field [30]. Venous access may be achieved via the internal jugular, external jugular, subclavian, antecubital, or femoral veins. However, the best access site for temporary pacing leads is via the left subclavian vein or the right internal jugular vein. On the other hand, the choice of a venous access site may depend on the physician’s preference and experience and on the urgency of the clinical situation. The subclavian route should be avoided following FL or in the presence of antithrombin therapy. If a permanent pacemaker is anticipated, the left subclavian site should generally be preserved and a different site should be used for temporary pacing. The right internal jugular and left subclavian veins may be accessed quickly in an emergency, and they may afford direct passage of the pacing catheter to the RV apex without requiring fluoroscopic imaging [24]. If fluoroscopy is available, a semi-​rigid pacing lead can be used. The lead is advanced until it reaches the right atrium. The preferred location for pacing in the RV is usually the apex. If fluoroscopy is not available, ECG can be used to guide lead placement. In such cases, it is recommended to use a balloon-​tipped catheter. When the catheter enters the right atrium, the A wave becomes larger than the V wave. And when the catheter enters the RV, the A wave becomes smaller than the V wave. The chamber must be paced at 10 bpm above the patient’s rate, and then the amplitude of the voltage delivered is slowly turned down until capture is lost. Capture is depolarization and resultant contraction of the atria or ventricles in response to a pacemaker stimulus. The threshold is the minimum voltage needed for capturing the chamber paced. Ideally, the ventricular capture threshold should be lower than 1 mA. The output should be set at 3–​5 times the capture threshold [24]. Sensing is the ability of the pacemaker to sense an intrinsic electrical signal, which depends upon the amplitude, slew rate,

A transvenous pacemaker system has two parts:  the electrode catheters (leads) and the external generator. Electrode catheters (leads) The tip of a bipolar temporary pacing electrode catheter has a distal tip electrode and a proximal ring electrode. As cathodal pacing has a lower threshold, it is customary to give a negative polarity to the tip and a positive polarity to the ring electrode. The proximal connectors of the electrode catheter are connected to an external pacemaker. Temporary pacing electrode catheters are classified as flexible, semi-​floating, or non-​floating catheters. The latter group carries a higher risk of cardiac perforation, and thus they are generally used only under fluoroscopic guidance where their stiffness yields the benefit of easier manipulation [27]. In emergency situations, a semi-​floating catheter, with or without a balloon tip, is used most commonly [27–​29]. In patients who are experiencing cardiac arrest, inflating the balloon carries no benefit; this is because there is no forward flow of blood to guide an inflated balloon through the venous system into the right side of the heart [30]. Most manufacturers misguidedly pack their temporary ventricular electrodes with a near 90° bend fashioned at the tip, often with a stiff former to keep this shape. This does not aid placement of the electrode. Ideally, there should be a 20–​30° curve at the tip, and it may be necessary to straighten some of the bend out of the electrode before insertion [31]. The external generator The external pacing generator is used to deliver the electrical current through the pacing catheter. The various available generators share the same basic features; these allow adjustment of the pacing output, pacing rate, pacing mode, and sensitivity to the intrinsic activity. Dual-​chamber generators will allow a greater flexibility in pacing mode and will enable the adjustment of AV delay and refractory periods [26]. Several types of external generators are available which permit single-​and dual-​ chamber pacing. The single-​ chamber units function in a VVI or AAI mode if demand pacing is used or in a VOO or AOO mode when fixed rate pacing is preferred; the dual-​chamber modes are DOO (fixed rate), DVI (dual-​chamber

Implantation procedure

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and frequency of the signal. The sensing threshold should also be measured if an intrinsic ventricular activity is present. Following positioning of either or both of the electrode catheters, they must be secured to the skin to prevent displacement by movement or traction [26].

Complications Transvenous cardiac pacing may be associated with a number of different complications, which occur in over 20% of patients [32]. These complications not only are restricted to the implantation per se, but also involve securing the position of the implanted lead, the change of capture threshold, malfunction, faulty programming, or battery depletion of the external pacemaker; it also includes those complications related to the patient who may extract the pacing lead accidentally. Furthermore, longer use of temporary transvenous pacing may restrict the patient to being bedridden, with accompanying risks of infection and thromboembolic events [8]‌. After lead placement, a chest radiograph should be obtained to establish the position of the lead, to evaluate for any evidence of pneumothorax. And in addition, an ECG should be recorded to determine the electrocardiographic appearance of the QRS complex. The following sections review the complications related to venous access, electrode catheters, and the electrical performance of the device. Complications related to venous access Venous access-​ related complications include pneumothorax, haemothorax, and air embolism. The risk of pneumothorax is related to the experience of the implanter and the number and difficulty of subclavian punctures. Pneumothorax is often small, asymptomatic, and noted incidentally on follow-​up CXR. However, tension pneumothorax should always be part of the differential diagnosis when hypotension or PEA ensues during an implantation. Haemothorax results from trauma to the great vessels [33]. Special care with regard to catheter insertion and manipulation should be taken in order to prevent air embolism, especially in patients with coexisting pulmonary disease, in whom coughing may increase the likelihood of venous air embolism. Massive air embolism, which is very rare, is potentially fatal and should be recognized and treated promptly. Complications related to electrode catheters Electrode catheter-​ related complications include perforation, dislodgement, diaphragmatic stimulation, malposition [34], and catheter-​induced arrhythmias. Perforation, which is very rare, can involve the great vessels, the right atrium, or the RV. It usually occurs without serious sequelae. However, a most devastating manifestation is cardiac tamponade, which requires prompt diagnosis and pericardiocentesis. An initial suspicion should be evaluated by fluoroscopy of the heart border, which is an immediately available diagnostic method. Confirmation of the diagnosis is obtained by emergent bedside echocardiography. Electrode catheter dislodgement takes place in 2–​5% of implants, usually in the first 24–​48 hours post-​implantation. Intermittent undersensing or loss of capture on post-​implantation telemetry should prompt

consideration of this complication. Definitive correction needs electrode catheter repositioning or replacement. Diaphragmatic stimulation results from phrenic nerve stimulation. Screening for this complication by pacing at maximum output is a requisite part of correct implantation procedure. Malposition is diagnosed by unacceptable implant pacing, sensing, or defibrillation thresholds. The presence of an atrial or ventricular septal defect can allow the passage of an electrode catheter to the left heart, which is one of the most common causes of malposition. Passage into the left heart is more common with ventricular electrode catheters [33]. The operator must be alert to the resultant paced ECG QRS complex morphology. If a right bundle is involved, a left-​sided ventricular lead position should be excluded. Various arrhythmias, including VT and VF, may also occur in some patients as an electrode catheter-​related complication which requires repositioning of the electrode catheter. Rarely, such arrhythmias (when they are frequent) do not allow the electrode catheter to be placed [33]. Complications related to the electrical performance of the pacemaker Some complications may be related to the electrical performance of the pacemaker electrode catheter and generator (see E Boxes 23.1, 23.2, and 23.3). If pacing suddenly fails, the connections to the external generator, generator batteries, and the possibility of oversensing must be checked. If pacing spikes can be seen, but no capture occurs, the output should be increased and consideration should be given to repositioning or replacing the electrode [26].

External (transcutaneous) pacing Transcutaneous (or external) pacing is a temporary means of pacing a patient’s heart during a medical emergency. It is accomplished by delivering pulses of electric current through the patient’s chest, which stimulates the heart to contract. During transcutaneous pacing, pads are placed on the patient’s chest, either in the anterior/​lateral position or in the anterior/​posterior position. The anterior/​posterior position is preferred, as it minimizes transthoracic electrical impedance. Chest wall electrodes with a high impedance interface are required for external pacing. Although these can be used during an asystolic cardiac arrest,

Box 23.1  Causes of loss of capture* ◆ Perforation ◆ Electrode catheter dislodgement ◆ Electrode catheter fracture ◆ Generator malfunction or battery depletion ◆ Generator lead connection problems ◆ Poor endocardial contact ◆ Local myocardial necrosis or inflammation ◆ Hypoxia acidosis ◆ Electrolyte disturbances

* Depolarization and resultant contraction of the atria or ventricles in response to a pacemaker stimulus.

Per s ona l  pe r spe c t i v e Box 23.2  Causes of undersensing* ◆ Perforation ◆ Inadequate cardiac signal ◆ Exit block ◆ Electrode catheter dislodgement ◆ Electrode catheter fracture ◆ Generator malfunction or battery depletion ◆ Local myocardial necrosis or inflammation

* Failure of the pacemaker circuitry to sense intrinsic P or R waves.

there is little evidence that external pacing is successful in this setting. In addition to synchronized transcutaneous pacing offered by newer cardiac monitors/​defibrillators, there is also an option for asynchronous pacing. Another possible indication is its use as a standby therapy for patients at high risk of developing symptomatic bradycardia. The available external pacemaker systems are suitable for providing standby pacing in AMI, especially for those not requiring immediate pacing and only at moderate risk of progression to an AV block. These do not entail the difficulty in application and risk of complications of IV systems. External pacing technology is also well suited to patients receiving thrombolytic therapy, as it reduces the need for vascular interventions. This method can also be used to terminate some sustained tachycardias. Single and multiple beat pacing stimulations have been described as a useful treatment for these arrhythmias. Despite some advantages, external pacing is not a preferred pacing technique for many physicians. In addition to causing significant discomfort, sedation or a state of unconsciousness is required to use this approach effectively for more than backup or emergency pacing. Reliability limits its use, and it is often difficult to determine if there is adequate ventricular capture. The task force members of the 2013 ESC guidelines on cardiac pacing and CRT warn that external pacing provided by patches and an external defibrillator does not provide reliable ventricular stimulation and therefore should only be used under strict haemodynamic and ECG monitoring, when no other option is available. As soon as possible, an alternative action should be undertaken such as administration of chronotropic drugs or temporary or permanent pacing [8]‌.

Box 23.3  Causes of oversensing* ◆ Myopotentials ◆ Electromagnetic interference ◆ Extrasystoles ◆ Electrode catheter dislodgement ◆ Electrode catheter fracture ◆ Generator malfunction

* The sensing of events other than P or R waves by the pacemaker circuitry.

Transoesophageal pacing Transoesophageal pacing is useful in selected patients in the ICCU to diagnose and treat arrhythmias. It is feasible because of the proximity between the oesophagus and the posterior aspect of the atria. In this technique, a transoesophageal pacemaker catheter can be used for atrial pacing and/​or recording. Depending on the type of catheter used, it can be inserted through the mouth or the nose. This approach is effective to convert SVTs such as atrial flutter. It results in immediate restoration of the sinus rhythm in 15–​50% of patients with atrial flutter. Oesophageal ventricular pacing has also been well described. However, the use of transoesophageal pacing is not common in daily practice, as the catheter is uncomfortable to place, pacing is usually unreliable, and pain is common because it requires a high current for capture.

Biventricular pacing Temporary biventricular pacing, which is rarely indicated, may improve cardiac performance in patients with major intraventricular conduction block and severe heart failure that is related to LV dysfunction [35]. CRT with biventricular pacing reduces heart failure symptoms and improves survival in patients with advanced heart failure, reduced LV systolic function, and mechanical dyssynchrony. A transvenous pacing catheter, placed in a coronary vein via the coronary sinus, may improve heart failure symptoms in these patients. It was demonstrated that this mode of pacing may provide short-​term benefits to selected patients in CS [36]. Moreover, responses to this therapy may also help to determine the benefit of permanent biventricular pacing. However, clinical experience on the use of temporary biventricular pacing is limited, and this method does not change the mortality rate within the ICCU.

Conclusion ICCU patients have an increased risk of new-​ onset cardiac conduction abnormalities. Temporary pacing is a potentially lifesaving intervention, used primarily to correct profound bradycardia in these patients. Any patient with acute haemodynamic compromise that is caused by bradycardia or episodes of asystole should be considered for temporary cardiac pacing in the ICCU. However, because of high complication rates, temporary transvenous pacing should not be used routinely and only as a last resort when chronotropic drugs are insufficient.

Personal perspective Although the techniques of cardiac pacing have been developed since 1958, there are still some problems with temporary pacing. For instance, the complication rates remain high. In the future, we believe that easier, less complicated, and faster electrode catheter placement methods will be

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developed. Non-​invasive pacing methods will become more comfortable and more effective. Furthermore, physiological pacing modes will be commonly preferred over ventricular

pacing, and the use of temporary biventricular pacing will be a routine therapeutic approach in the ICCU in selected patients with severely reduced LV function.

Further reading Brignole M, Auricchio A, Baron-​Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy:  the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–​329. Echt DS, Cowan MW, Riley RE, Brisken AF. Feasibility and safety of a novel technology for pacing without leads. Heart Rhythm 2006;3:1202–​6. Fitzpatrick A, Sutton R. A guide to temporary pacing. BMJ 1992;304:365–​9. Gammage MD. Temporary cardiac pacing. Heart 2000;83:715–​20. Ganz LI. Temporary cardiac pacing. Cardiac Electrophysiology Review 1999;2:389–​92. Gorenek B, Blomström Lundqvist C, Brugada Terradellas J, et al.; European Heart Rhythm Association; Acute Cardiovascular Care Association; European Association of Percutaneous Cardiovascular Interventions. Cardiac Arrhythmias in Acute Coronary Syndromes: Position Paper

From the Joint EHRA, ACCA, and EAPCI Task Force. Europace 2014;16:1655–​73. Hamad MA, van Gelder BM, Bracke FA, van Zundert AA, van Straten AH. Acute hemodynamic effects of cardiac resynchronisation therapy in patients with poor left ventricular function during cardiac surgery. J Card Surg 2009;24:585–​90. Harrigan RA, Chan TC, Moonblatt S, Vilke GM, Ufberg JW. Temporary transvenous pacemaker placement in the emergency department. J Emerg Med 2007;32:105–​11. Lee KL, Tse HF, Echt DS, Lau CP. Temporary leadless pacing in heart failure patients with ultrasound-​ mediated stimulation energy and effects on the acoustic window. Heart Rhythm 2009;6:742–​8. Silver MD, N Goldschlager. Temporary transvenous cardiac pacing in the critical care setting. Chest 1988;93;607–​13. Steg PG, James SK, Atar D, et  al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-​segment elevation. Eur Heart J 2012;33:2569–​619.

References 1. Zoll PM. Resuscitation of the heart in ventricular standstill by external electrical stimulation. N Engl J Med 1952;247:768–​71. 2. Furman S, Robinson G. The use of an intracardiac pacemaker in the correction of total heart block. Surg Forum 1958;9:245–​8. 3. Brignole M, Auricchio A, Baron-​Esquivias G, et al.; ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, et al.; Document Reviewers, Kirchhof P, Blomstrom-​ Lundqvist C, Badano LP, et  al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–​329. 4. Levine SA, Miller H, Penton GB. Some clinical features of complete heart block. Circulation 1956;13:801–​24. 5. Hejtmancik MR, Herrmann GR, Shields AH, Wright JC. A clinical study of complete heart block. Am Heart J 1956;52:369–​76. 6. Rowe JC, White PD. Complete heart block: a follow-​up study. Ann Intern Med 1958;49:260–​70. 7. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003;348:933–​40. 8. Feigl D. Early and late atrioventricular block in acute inferior myocardial infarction. J Am Coll Cardiol 1984;4:35–​8. 9. Hindman MC, Wagner GS, JaRo M, et al. The clinical significance of bundle branch block complicating acute myocardial infarction. Indications for temporary and permanent pacemaker insertion. Circulation 1978;58:689–​99. 10. DeGuzman M, Rahimtoola SH. What is the role of pacemakers in patients with coronary artery disease and conduction abnormalities? Cardiovasc Clin 1983;13:191–​207. 11. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-​segment elevation. Eur Heart J 2012;33:2569–​619.

12. Bredlau CE, Roubin GS, Leimgruber PP, Douglas JS Jr, King SB 3rd, Gruentzig AR. In-​hospital mortality in patients undergoing elective coronary angioplasty. Circulation 1985;72:1044–​52. 13. Ellis SG. Elective coronary angioplasty:  technique and complications. In:  Topol EJ (editor). Textbook of Interventional Cardiology. WB Saunders Company: Philadelphia, PA; 1994. p. 186. 14. Giglioli C, Margheri M, Valente S, et  al. Timing, setting and incidence of cardiovascular complications in patients with acute myocardial infarction submitted to primary percutaneous coronary intervention. Can J Cardiol 2006;22:1047–​52. 15. Silver MD, Goldschlager N. Temporary transvenous cardiac pacing in the critical care setting. Chest 1988;93;607–​13. 16. Obel IWP, Millar RNS. Temporary transvenous atrial pacing for the control of supraventricular tachycardia in the coronary care unit. Crit Care Med 1983;11:313–​16. 17. Okumura K, Henthorn RW, Epstein AE, Plumb VJ, Waldo AL. Further observations on transient entrainment:  importance of pacing site and properties of the components of the reentry circuit. Circulation 1985;72:1293–​307. 18. Landymore RW, Kinley CE, Gardner M. Encircling endocardial resection with complete removal of endocardial scar without intraoperative mapping for the ablation of drug-​resistant ventricular tachycardia. Thorac Cardiovasc Surg 1985;89:18–​24. 19. Alpert MA, Flaker CC. Arrhythmias associated with sinus node dysfunction. JAMA 1983;250:2160–​6. 20. Brugada P, Waldo A, Wellens HJJ. Transient entrainment and interruption of paroxysmal AV nodal tachycardia. J Am Coll Cardiol 1984;3:537. 21. Waldo AL, MacLean WAH, Karp RB, Kouchoukos NT, James TN. Entrainment and interruption of atrial flutter with atrial pacing. Studies in man following open heart surgery. Circulation 1977;56:737–​45.

RE F E RE N C E S 22. Waldo AL, Plumb VJ, Arciniegas JG, et  al. Transient entrainment and interruption of the atrioventricular bypass pathway type of paroxysmal atrial tachycardia; a model for understanding and identifying reentrant arrhythmias. Circulation 1983;67: 73–​83. 23. Francis GS, Williams SV, Achord JL, et  al. Clinical competence in insertion of a temporary transvenous ventricular pacemaker. A statement for physicians from the ACP/​ACC/​ATTA Task Force on Clinical Privileges in Cardiology. Circulation 1994;89:1913–​16. 24. Ganz LI. Temporary cardiac pacing. Cardiac Electrophysiol Rev 1999;2:389–​92. 25. Murphy P, Morton P, Murtagh JG, Scott M, O’Keeffe DB. Haemodynamic effects of different temporary pacing modes for the management of bradycardias complicating acute myocardial infarction. Pacing Clin Electrophysiol 1992;15:391–​6. 26. Gammage MD. Temporary cardiac pacing. Heart 2000;83:715–​20. 27. Jafri SM, Kruse JA. Temporary transvenous cardiac pacing. Crit Care Clin 1992;8:713–​25. 28. Wald DA. Therapeutic procedures in the emergency department patient with acute myocardial infarction. Emerg Med Clin North Am 2001;19:451–​67.

29. Bressman ES. Emergency cardiac pacing. In:  Robert JR, Hedge JR (editors). Clinical Procedures in Emergency Medicine, fourth edition. WB Saunders: Philadelphia, PA; 2004. pp. 283–​304. 30. Harrigan RA, Chan TC, Moonblatt S, Vilke GM, Ufberg JW. Temporary transvenous pacemaker placement in the Emergency Department. J Emerg Med 2007;32:105–​11. 31. Fitzpatrick A, Sutton R. A guide to temporary pacing. BMJ 1992;304:365–​9. 32. Hildick-​Smith, DJ, Petch, MC. Temporary pacing before permanent pacing should be avoided unless essential. BMJ 1998;317:79–​80. 33. Trohman RG, Kim MH, Pinski SL. Cardiac pacing: the state of the art. Lancet 2004;364:1701–​19. 34. Pavia S, Wilkoff B. The management of surgical complications of pacemaker and implantable cardioverter-​defibrillators. Curr Opin Cardiol 2001;16:66–​71. 35. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-​stage heart failure. J Am Coll Cardiol 1998;32:1825–​31. 36. Guo H, Hahn D, Olshansky B. Temporary biventricular pacing in a patient with subacute myocardial infarction, cardiogenic shock, and third-​degree atrioventricular block. Heart Rhythm 2005;2:112.

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CHAPTER 24

Ultrasound-​guided vascular access in intensive/​acute cardiac care Richard Paul

Contents Summary  314 Introduction  314 Reduced central venous cannulation complications with ultrasound  315 Arterial access  315 Indications for vascular access  315 Contraindications to vascular access  316 Equipment and operation  316 Probe type  316 Probe orientation  316 Type of images  316 Real-​time versus static imaging  317 Vessel identification  317 Anatomy  317 Doppler  317

Specific information for access via different routes  317 Internal jugular  317 Subclavian  318 Femoral  319 Arterial cannulation  319 Peripheral venous access  319

Training  320 Personal perspective  320 Further reading  320 References  320

Summary Vascular access is an essential requirement for the care of the critically ill cardiac patient, being necessary for drug and fluid delivery and for monitoring of a patient’s haemodynamic response to an instigated therapy. The most common vascular access procedures conducted in the acute cardiac care unit are central venous and peripheral venous access and arterial cannulation. Traditional landmark methods are associated with complication rates ranging from 18% to 40%, depending on the site of access. The use of ultrasound to guide venous and arterial access has been shown to reduce the incidence of complications, such as inadvertent arterial puncture and pneumothorax formation (venous) and posterior wall puncture (arterial), to reduce the time taken and number of attempts to place a catheter, and to reduce the incidence of complete failure to insert a vascular access device. Since 2002, international consensus groups have published recommendations that two-​dimensional ultrasound guidance should be the preferred method for elective and emergency internal jugular catheter insertion. This chapter explores the evidence for the use of ultrasound to guide vascular access across multiple sites of insertion and describes the basic equipment and techniques necessary for successful deployment.

Introduction Vascular access is vital for the care of the critically ill cardiac patient, with procedures including central venous, arterial, and peripheral venous cannulation. It is estimated that approximately 200 000 CVCs are inserted annually in the NHS in the UK [1]‌and >15 million devices sited per year in the US [2]. Historically, the preferred method to guide central venous cannula insertion was using anatomical landmarks; however, this depends upon the experience and skill of the operator, patient comorbidities (e.g. coagulopathy, obesity, previous surgery), the environment (e.g. resuscitation, mechanical ventilation), and crucially on the mistaken assumption that all patients share the same anatomy. Consequently, failure rates of 7–​26% have been reported in the literature [3–​5]. In the 1990s, multiple randomized clinical trials demonstrated the superiority of US-​guided vascular access over landmark techniques [6–​8]. These findings were supported by two meta-​analyses [9, 10]; however, with limited availability of equipment or formal training

I n di cati on s for  vas cul a r   ac c e s s and poor recognition of the benefits of using US, adoption was not immediately widespread [11–​13]. An analysis of cost-​ effectiveness estimated the economic cost of using US for central venous cannulation was 6, urgent pericardiocentesis is suggested (see Figure 25.4) [5]‌. In cases of pericardial effusion without haemodynamic compromise, pericardiocentesis may be considered for moderate to large effusions that are non-​responsive to medical therapy, when

tuberculous or purulent, or when neoplastic pericarditis is suspected (Class 1C)  [6]‌. Purulent pericarditis is a rare condition that should be managed aggressively, as it carries a high mortality rate if untreated. Purulent pericarditis commonly originates from severe infectious disease caused by Gram-​positive cocci (pneumonia and empyema), especially in immunocompromised patients [7]‌. Empirical systemic antibiotic therapy should be started promptly and complete surgical drainage performed, because a purulent effusion is often loculated and associated with dense adhesions. An alternative and less invasive method consists of percutaneous drainage associated with intrapericardial infusion of streptokinase. Fibrinolytic therapy can enhance the removal of material that would otherwise be too viscous or particulate to be removed by tube drainage [8]‌. This treatment should be considered before undertaking surgery. In cases of chronic (lasting >3  months) large pericardial effusions (>20  mm on echocardiography in diastole), optimal management is controversial. Some authors suggest that pericardiocentesis should be performed to avoid unexpected progression to tamponade [9]‌. However, the actual outcome of this clinical condition is poorly known. A recent large prospective study has demonstrated that the risk of cardiac tamponade is not as high as previously thought (2.2% per year) and the effusion spontaneously decreased in the majority of cases. In this setting, a careful follow-​up with clinical and echocardiographic examination every 3–​6 months could be the best way to approach pericardial effusion, with particular attention to the fact that cardiac tamponade may be precipitated if pericarditis occurs [10]. Pericardiocentesis for diagnostic purposes is not justified in the majority of cases of mild or moderate small effusions (45 mL/​kg/​hour identify very high-​volume haemofiltration (VHVHF) modalities. Intermittent procedures with brief, very high-​volume treatments at 100–​120 mL/​kg/​hour for 4–​8 hours, followed by conventional CVVH, are identified as pulse HVHF [19] QB >200 mL/​min; QEFF >35 mL/​kg/​hour

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CHAPTER 27  

Renal su pp ort  th erap y

clear that AKI in the ICU is a common syndrome and that acute kidney dysfunction can be the cause of further organ dysfunction (e.g. respiratory failure secondary to fluid accumulation). By contrast, the kidneys may be involved as distal organs in cases of acute heart failure (AHF) (e.g. congestive kidney injury due to sudden increase in CVP and/​or renal hypoperfusion in cases of cardiogenic shock (CS)). Mortality is clearly associated with organ dysfunction, reaching up to 50% when RRT is required [7]. Many patients admitted to the ICU require organ support (e.g. mechanical ventilation, RRT, intra-aortic balloon pump (IABP)), and in most of the cases, simultaneous assistance is required. In more complex clinical scenarios, extracorporeal support may be applied [e.g. veno-​venous (VV) or veno-​arterial (VA) extracorporeal membrane oxygenation (ECMO) or extracorporeal life support (ECLS) and RRT or extracorporeal CO2 removal and RRT]. All extracorporeal therapies that imply blood processing and manipulation with specific devices and techniques are now defined as extracorporeal organ support (ECOS) [8].

Historical notes The first continuous form of dialysis specifically dedicated to critically ill patients was the so-​called continuous arteriovenous haemofiltration (CAVH), first described by Peter Kramer in 1977 [9]‌. At that time, RRT in the intensive care setting was considered a last-​chance therapy for patients with MOF. In CAVH, the blood flow in the circuit was driven by a spontaneous arteriovenous pressure gradient (dependent on the MAP of the patient and the intrinsic resistance of the circuit), and spontaneous ultrafiltration (UF) occurred, depending on the transmembrane pressure (TMP) gradient (determined by the hydrostatic pressure drop inside the filter and the negative suction provided by the ultrafiltrate column from the patient level to the ground). CAVH enabled slow continuous fluid removal, maintaining steady solute concentrations and preventing peaks of toxic substances. CAVH, however, had serious limitations: (1) it required both arterial and venous accesses, at risk of high morbidity; (2) solute clearance was limited by low UF rates imposed by the relatively low blood flow in the circuit and by the low TMP gradient—​ this meant that the most haemodynamically unstable patients achieved the lowest clearances and developed early clotting of the circuit; (3) CAVH rarely exceeded 20 mL/​min of clearance, hardly sufficient to meet the needs of severely catabolic patients [10]. In order to overcome such technical limitations, new filters were designed with increased cross-​sectional area and inner hollow fibre diameter, a reduced unit length, and a lower resistance to blood flow. Another option explored in those days was the use of a second port in the filtrate compartment so that the countercurrent dialysate flow could be programmed in the newly conceived continuous arteriovenous haemodiafiltration (CAVHD) mode [10]. A significant step further was achieved when a peristaltic pump was added to the extracorporeal circuit, with subsequent hardware evolution. This made possible the use of double-​lumen catheters; the puncture of a single vein thus decreased the high

rate of complications due to the need of arterial cannulation. The driving force was no longer determined by the patient’s MAP but resulted from the mechanical action of the roller pumps [10]. The new continuous veno-​venous therapies required negative pressure measurements and an alarm in the arterial line before the pump, as well as positive pressure measurements and an alarm in the venous return line; a bubble trap had to be inserted before the blood was reinfused into the patient in order to prevent an air embolism (this was not necessary in CAVH where the circuit operated at positive pressure along the entire length of the system). Roller pumps with improved performance were conceived and allowed higher blood flows, producing higher filtration rates, and significantly increased solute clearance. For this reason, roller pumps were also applied to the dialysate or fluid replacement delivery section of the circuit, and external scales had to be frequently utilized to provide sufficiently accurate fluid balance during treatment. The benefits induced by the new technology were still counterbalanced by the gross inaccuracy of the systems and the limited integration between the extracorporeal circuit and the fluid balance devices [11]. The second-​generation machines were more accurate and reliable devices—​precursors of the current technology for RRT in CICUs. Modern RRT machines specifically dedicated to critically ill patients generally require 4–​5 roller pumps (blood, dialysate, reinfusion, UF/​effluent, accessory pump), 3–​4 scales, and pressure sensors (inlet, outlet, filter, and effluent) to monitor the entire circuit conditions. These machines allow a maximal flow rate of up to about 450 mL/​min for the blood pump and to about 8–​10 L/​hour for the dialysate/​replacement pumps; this also means that the effluent pump should be able to increase up to 20–​25 L/​hour [11]. The accuracy of roller blood pumps has been increased in order to warrant a wide flow rate range, keeping flow errors below 2%. New algorithms allow, in some models, to automatically update, hour by hour, the UF prescribed/​delivered gap and to correct it in the next hour, in order to reduce any prescription error. An interesting safety feature of third-​generation machines is the possibility of setting a limit of accepted UF errors (within a predetermined time frame), after which the session is automatically interrupted and the intervention of the operator required [12]; this feature seems important in the light of a possible lethal human mistake that might derive from a prolonged and uncontrolled overriding of UF error alarms.

Modes of renal replacement therapies and technical notes Extracorporeal blood purification achieved by CRRT should aim to approach that obtained by the native kidney. Blood driven through the semi-​permeable membrane is ‘purified’ in terms of water and solute removal. CRRT filters are a key feature of blood purification in critically ill patients. These filters are composed of groups of hollow fibres with different total surfaces (from 0.1 to over 2 m2) in order to meet the needs of differently sized patients. Polyacrylonitrile, polysulfone, and polymethyl-​ methacrylate membranes allow a high UF coefficient (over 20 mL/​ hour/​

Modes of rena l repl acem en t ther a pi es a n d techni c a l   n ot e s mmHg) and a high diffusive and convective performance. Such fibres have a generally high porosity (30–​50 A°), and there is no unequivocal evidence of the superiority of one membrane over another, provided their even biocompatibility that is determined by the change in blood factors induced by membrane/​blood contact.

Diffusion and convection A wide range of substances (water, urea, low-​and middle-​weight molecules) can be transported across RRT membranes, from the blood to the effluent side of the hollow fibres, by the mechanisms of diffusion (solutes) and convection (water and solutes) (see E Figure 27.1). During diffusion, the movement of solutes depends on their respective concentration on each side of the membrane; an osmotic shift of solutes from the compartment with the highest concentration to the compartment with the least concentration occurs. Other components of the semi-​permeable membrane deeply affect diffusion: dialysate flow (QD), thickness and surface, temperature, and diffusion coefficient. The dialytic solution flows through the filter countercurrent to the blood flow in order to maintain the highest solute gradient from the inlet to the outlet port. Diffusion is the solute transport method that is applied during continuous veno-​venous haemodialysis (CVVHD), although when a net UF flow rate is prescribed (e.g. 100 mL/​hour), convection is eventually applied (see E Figure 27.2) [13]. During convection, the solutes are transported across the semi-​permeable membrane, together with water; plasma water is ultrafiltered across the membrane in response to the TMP and solutes are carried with it, as long as the porosity of the membrane allows the molecules to be sieved from blood [12, 13]. The process of UF is governed by the UF flow (QUF), the membrane UF coefficient (KUF), and the TMP gradient generated by the pressures on both sides of the hollow fibre. As UF proceeds and plasma water and solutes are filtered from blood, the hydrostatic pressure within the filter is lost and oncotic pressure is gained, because blood concentrates and the haematocrit increases. The fraction of plasma water that is removed from blood during UF is called the filtration fraction; it should be kept in the range of 20–​25%,

Diffusion

in order to prevent excessive haemoconcentration within the filtering membrane and to avoid the critical point where the oncotic pressure is equal to the TMP, and a condition of filtration/​pressure equilibrium is reached. Finally, replacing plasma water with a substitution solution completes the haemofiltration (HF) process and returns to the patient’s purified blood. The replacement fluid can be administered after the filter, via a process called post-​dilution HF (QRPOST). Otherwise, the solution can be infused before the filter, in order to obtain pre-​dilution HF (QRPRE). While post-​dilution allows a urea clearance equivalent to therapy delivery, pre-​dilution, in spite of theoretical reduced solute clearances, allows a prolonged circuit lifespan by reducing haemoconcentration. Notably, among the molecules that are physically dragged towards the filter pores, albumin and proteins must be considered; since they cannot cross the membrane fibres, a protein layer deposit tends to progressively close fibre pores and to significantly limit solute transport [14]. A peculiar membrane capacity, defined as adsorption, has been shown to have a major role in higher-​molecular weight toxins [14]; however, it should be considered that membrane adsorptive capacity is generally saturated in the first treatment hours and it has only minor effects on mass separation processes with respect to diffusion and convection [15]. Convection is applied during slow continuous UF (SCUF) and continuous veno-​venous haemofiltration (CVVH) and in CVVHD only for the prescription of QUFNET (see E Figure 27.2). The application of both convection and diffusion configures continuous veno-​ venous haemodiafiltration (CVVHDF) (see E Figure 27.2). Typically, the molecular weight of solutes cleared during convective treatments is higher than during diffusion, due to physical transportation across the membrane occurring during HF that allows larger-​molecular weight solutes to be removed from blood. The difference between the volume of ultrafiltered plasma water and that of the reinfused substitution solution gives the QUFNET (or patient fluid removal), which is the fluid that is eventually removed from the patient for fluid balance control. QUFNET prescription is based on patient needs and can range from >1 L/​hour (pulmonary oedema in a patient with congestive heart failure and

Convection

Figure 27.1  Mechanisms of blood purification. Diffusion: the movement of solutes depends on their respective concentration on each side of the

membrane—​an osmotic shift of solutes from the compartment with the highest concentration to the compartment with the lowest concentration occurs. Convection: the solutes are transported across the semi-​permeable membrane, together with water; plasma water is ultrafiltered across the membrane, in response to the transmembrane pressure, and solutes are carried with it, as long as the porosity of the membrane allows the molecules to be sieved from blood.

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QPRE R in-flow

in-flow

P

out-flow QUF

P

CVVH

QPOST R out-flow QEFF

QB = 100–250 mL/min

QB = 100–250 mL/min

QUF = 5–15 mL/min

= 15–60 mL/min QPRE/POST R

CVVHD in-flow

P

QEFF

out-flow QD (in)

QPRE R in-flow

P QEFF

CVVHDF

QPOST R

out-flow QD (in)

QB = 100–250 mL/min

QB = 100–250 mL/min

QD (in) = 15–60 mL/min

= 7–30 mL/min QPRE/POST R QD (in) = 7–30 mL/min

Figure 27.2  Modalities applied when RRT is administered: slow continuous ultrafiltration (SCUF), continuous veno-​venous haemofiltration (CVVH), continuous veno-​venous haemodialysis (CVVHD), continuous veno-​ venous haemodiafiltration (CVVHDF). P, pump; QB, blood flow rate; QUF, ultrafiltration flow rate; QR, replacement (pre, pre-​filter; post, post-​filter); QD, dialysate flow rate.

diuretic resistance) to zero (sepsis with catabolic state increased creatinine levels and conserved diuresis).

Dose and prescription Renal replacement can be prescribed and administered according to a specific dose, as any other medical intervention. The RRT dose is a measure of the quantity of blood purified by ‘waste products and toxins’ during a certain time frame; this is the clearance (k). However, the RRT dose is generally synthetized as the measure of the clearance of a representative marker solute; urea and creatinine are generally used as reference solutes in order to measure renal replacement clearance for renal failure. It must be acknowledged that such marker solutes cannot, and do not, represent all the solutes that accumulate during AKI, because the kinetics and volume of distribution are different for each molecule. Despite this premise, the comprehension and application of the dialysis dose appear to increase the efficacy of RRT and finally its clinical utility [16]. The concept of the RRT dose is useful also for practical purposes; as it happens for antibiotics, vasopressors, anti-​inflammatory drugs, and mechanical ventilation, administration of an extracorporeal treatment for blood purification requires the operators to know exactly how and how much treatment should be prescribed and delivered [9]‌. During RRT, k depends on the circuit blood flow (QB), haemofiltration (QR) and/​or dialysis (QD) flow, the molecular weights of solutes, and the haemodialyser type and size. QB, as a variable in delivering the RRT dose, is mainly dependent on the vascular access and operational characteristics of utilized machines in the clinical setting. QR is strictly linked to QB, during convective techniques, by the filtration fraction. The filtration fraction does not limit QD, but, when the QD/​QB ratio exceeds 0.3, it can be estimated that the dialysate will not be completely saturated by blood-​diffusing solutes. As a rough estimate, we can consider that, during continuous slow efficiency treatments, the RRT dose is a direct expression of

QUF and/​or QD, depending on the membrane sieving coefficient (SC) of the cleared molecule. During continuous treatment, it is now suggested to deliver at least a urea clearance of 2 L/​hour, with clinical evidence that maybe 20–​35 mL/​kg/​hour might be the best prescription (i.e. about 2.8 L/​hour in a 70-​kg patient) (see E Table 27.1). A range as wide as 20–​35 mL/​kg/​hour is related to the concept of down-​time (periods of time when the machine treatment is stopped). Even if down-​time can be limited as much as possible when the CRRT operation is optimized, still it cannot be totally eliminated. This is the main reason why even if 25 mL/​ kg/​hour can be considered an acceptable dose, some degree of ‘over-​prescription’ can be suggested. New-​generation CRRT devices have recently been designed with the aim of improving therapy accuracy in dose delivery. These new systems are able to increase the dose delivery, if needed, in order to reach the prescribed dose over time [17]. Other authors suggest a prescription based on patient requirements, which are based on the urea generation rate and the catabolic state of the single patient. It has been shown, however, that, during continuous therapy, a clearance of 200 mL/​12 hours, but insufficient to prevent fluid accumulation), all factor into the decision of when to initiate RRT for those with AKI [41]. Data to support consideration of early RRT in these patients are unfortunately controversial and mainly provided by observational and prospective randomized studies [42–​45]. Three randomized trials have recently explored the question of timing for RRT initiation: the Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with Acute Kidney Injury (ELAIN) trial [43], the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial [44], and the Initiation of Dialysis Early Versus Delayed in the Intensive Care Unit (IDEAL-​ICU) trial [45]. Before the publication of the ongoing and much larger (>2800 patients) STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-​AKI) trial, the preliminary results of the available studies should be critically appraised. Huge differences in inclusion criteria, designs, and methodology make these three RCTs difficult to compare [46, 47]. Globally, taken collectively, the results of the three trials inform us that the decision to initiate RRT must be integrated in a larger clinical context and must account for other organ dysfunction, comorbidities, and the patient’s general trajectory. It is important to recognize that RRT initiation is not without risks of complications such as hypotension (and exacerbation of kidney injury), bleeding, dialysis catheter-​related complications, etc. The presence of one or more mitigating factors, such as rapidly worsening AKI and/​or the overall severity of illness, the presence of congestive heart failure, severe sepsis, and reduced renal reserve, would push to consider RRT in the earlier stages of AKI. Primary diagnoses associated with high catabolic rates (e.g. septic shock, major trauma, burn injury) or those likely to place considerable demand on kidney function (i.e. GI bleeding, rhabdomyolysis) should be identified in the context of a potential need for early initiation of RRT. Critically ill patients with ARDS (see also E Chapter  64) receiving lung-​protective ventilation may intentionally develop respiratory acidosis due to permissive hypercapnia [48]. Coexisting and/​or evolving AKI in these patients will significantly impair the capacity for kidney HCO3–​ regeneration to buffer systemic acidaemia. Earlier RRT may prove beneficial in these patients prior to the development of severe acidaemia, worsening ARDS, and/​or volume overload. On the other hand, ‘early’ RRT initiation has the potential to expose a large number of patients to this therapy who may have potentially spontaneously recovered kidney function. In light of this, many patients allocated to the delayed arm for RRT initiation in the three RCTs did not receive RRT. Therefore, in a not negligible number of patients, a ‘wait and see’ strategy

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may be the best way to avoid the potential complications related to RRT but obtain spontaneous recovery of kidney function. One of the most frequent indications for RRT is fluid accumulation, an independent predictor of mortality in ICU patients. A  positive fluid balance and overt clinical fluid overload, when refractory to medical therapy (i.e. diuretics), are also important circumstances where RRT initiation may prove beneficial. Other than fluid ‘overload’, in which the patient has obvious clinical signs of excess fluid (e.g. peripheral or pulmonary oedema, weight gain), usually in association with oliguria, we also recognize the concept of fluid ‘accumulation’. In the latter case, these clinical signs may not yet be readily apparent and the patient may have a urine output above the traditional definition of ‘oliguria’; however, this urine output is inadequate for keeping up with the patient’s daily intake, resulting in an increasingly positive fluid balance. In critically ill patients, fluid overload may be under-​recognized as an important contributor to morbidity and mortality [48]. Longer durations of mechanical ventilation, weaning failure, delayed tissue healing, and cardiopulmonary complications have all been associated with fluid overload [48]. Likewise, a positive fluid balance has been shown to be associated with higher mortality in critically ill adults and children [49]. RRT initiation should therefore be considered an important therapeutic measure for prevention (and not only for treatment) of refractory fluid overload.

When to stop In the specific setting of ‘weaning from RRT’, no good evidence exists at present and it is unlikely to be produced in the future. An interesting report from the BEST (Beginning and Ending Supportive Therapy) Kidney study group described current practice for the discontinuation of CRRT in a multinational setting, in order to identify variables associated with successful discontinuation and if the approach to discontinue CRRT may affect patient outcomes [50]. A total of 313 patients were weaned from CRRT for at least 7  days and classified as the ‘success’ group; 216 patients were classified as the ‘repeat RRT’ group. Multivariate logistic regression analysis for successful discontinuation of CRRT identified urine output (during 24 hours before stopping CRRT:  OR 1.078 per 100 mL/​day increase) and creatinine (OR 0.996 per mmol/​L increase) as significant predictors of successful cessation. The predictive ability of urine output was negatively affected by use of diuretics. As it always happens with observational studies, it is not possible to establish if the ‘repeat RRT’ population would have achieved a different outcome by waiting for a better creatinine level or urine output before stopping RRT. Risk factors for re-​dialysis were also analysed by the National Taiwan University Surgical ICU Acute Renal Failure Study Group [51]. In this study, RRT weaning of 94 post-​operative patients was considered successful when prolonged for at least 30 days (21%) and was correlated with Sequential Organ Failure Assessment (SOFA) score, age, dialysis duration, and again urine output. Interestingly, of the patients who remained ‘RRT-​free’ for 5 days after RRT discontinuation, more than two-​thirds remained RRT-​ free up to day 30.

As a general recommendation, before weaning from RRT, physicians should wait for an adequate urine output (without diuretic therapy) and optimized creatinine values (the additional effect of patient GFR and treatment clearance should lead to normal or subnormal creatinine values while on RRT). Once the renal function appears close to the baseline or ‘pre-​AKI’ level, it seems reasonable to interrupt the treatment without any specific weaning protocol. It is possible, on the other hand, that patients with signs of only partial renal recovery may benefit from more specific and prolonged weaning algorithms. Examples would be a decrease in the UF rate or the prescription of intermittent treatments where therapy was previously continuous. Future trials are needed to design, if possible, such protocols. Furthermore, the evaluation of new renal biomarkers (see also E Chapter 35) as prognostic factors is intriguing, in order to explore if they can predict when patients have recovered sufficient renal function to allow them to remain RRT-​free once RRT is stopped.

The cardiorenal syndromes A typical example of organ crosstalk is the cardiorenal syndromes (CRS); the general definition of CRS is ‘a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ’. The heart and kidneys are clearly linked in physiological and pathophysiological terms; both organs contribute together to the regulation of blood pressure, vascular tone, diuresis, natriuresis, and circulating volume homeostasis. Obviously, alteration of one of these functions, due to dysfunction of one of these organs, leads to considerable and lasting damage to the other, in a bidirectional vicious circle. Possible mechanisms of these elective affinities include an altered balance between NO and reactive oxygen species, systemic inflammation and apoptosis, activation of both the sympathetic nervous system and RAAS, and paracrine and systemic actions of various substances such as endothelin, prostaglandins, vasopressin, and natriuretic peptides [52]. To recognize and describe the complicated interactions between these organ systems, a classification of CRS into four subtypes has been proposed. (A brief summary on CRS is provided in Additional online material.)

Non-​pharmacological management of cardiorenal syndromes Each time the CRS ends up with severe dysfunction of the kidneys, extracorporeal renal support should be started and prescribed, according to the same indications as for critically ill patients [48]. For the purposes of this chapter, RRT in the context of acute decompensated heart failure (ADHF) patients will be described. In order to manage ADHF, the main target is to remove excess Na+ and water. A declining kidney function during CRS I (where acute cardiac failure, e.g. acute CS or ADHF, leads to AKI) is one of the strongest predictors of short-​and long-​ term adverse events (AEs), including readmission and mortality [53] (see also E Chapter  66). In this field, diuretics and

The ca rdi orena l   sy n dro m e s blood-​based extracorporeal UF are the main decongestive therapies. Peritoneal-​based UF has been used as well. Recent studies have shown that UF is a very effective method for removing excessive fluid from selected patient populations with ADHF. With this background (injured kidneys due to primary cardiac illness and pharmacologic management), SCUF was described many years ago in order to artificially remove plasma water and relieve cardiopulmonary symptoms, bypassing the need for intense diuresis [54]. In the case of a reno-​cardiac syndrome (ADHF secondary to acute or chronic renal failure), prescription of artificial fluid balance control and volume unloading for pulmonary oedema management to a dialytic session is a common approach applied by nephrologists [55]. On the other hand, SCUF is currently considered as a last-​chance therapy by the ESC guidelines algorithm for the management of ADHF in patients refractory to diuretic therapy [56]. Nevertheless, several randomized trials have been conducted, in order to verify if extracorporeal water removal might be beneficial with respect to diuretic therapy. The UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) Study showed that UF allowed to remove a greater amount of plasmatic water than furosemide [57]. Interestingly, however, more patients in the UF than in the diuretics arm experienced an increase in creatinine levels of 0.3 mg/​dL. Of note, the timing, dose, duration, and clinical target of UF remained to be investigated. By contrast, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-​ HF) trial showed that UF did not allow a significant difference in weight loss at 96 hours, and again it was associated with a significantly higher increase in creatinine levels [58]. CARRESS-​HF was a prospective RCT, sponsored by the National Heart, Lung, and Blood Institute and conducted at 22 centres. Patients with ADHF were eligible if there was evidence of persistent congestion, with an increase in serum creatinine (SCr) levels of 0.3 mg/​dL. Participants were randomly assigned to either UF (Aquadex System 100; CHF Solutions) or stepped pharmacologic therapy involving increasing doses of loop diuretics (with or without metolazone), vasodilators, and/​or inotropes, based on a treatment algorithm. The primary endpoint was a bivariate response, including changes in SCr levels and body weight 96 hours after randomization. The main finding of this study was that UF was inferior to diuretic therapy, with respect to the bivariate primary endpoint, primarily because of a significant increase in SCr levels in the UF group (an increase of 0.23 ± 0.70 mg/​dL for the UF group versus a decrease of 0.04 ± 0.53 mg/​dL for the pharmacologic therapy group; P = 0.002). There was no significant difference in weight loss at 96 hours between the two groups (5.7 ± 3.9 versus 5.5 ± 5.1 kg in the UF and pharmacologic therapy groups, respectively; P = 0.58). At 60-​day follow-​up, there were no significant differences in weight loss, mortality, or rate of hospitalization for heart failure between the two groups. Also, during the 60-​day follow-​up period, patients in the UF group had significantly higher rates of kidney failure, bleeding complications, and catheter-​related complications. Another recent small randomized

trial (Continuous Ultrafiltration for cOngestive heaRt failure, CUORE) showed that extracorporeal UF was associated with prolonged clinical stabilization and greater freedom from rehospitalization for AHF [59]. Given the apparently controversial results of these trials that are probably due to significantly different therapeutic algorithms, clinical targets, and the severity of included patients, it seems currently reasonable to reserve UF to the most severely ill patients with initial signs of diuretic resistance. Furthermore, pharmacologic and extracorporeal removal of water should not be seen as alternative approaches, but they could also be considered synergistic. Finally, institutional expertise with extracorporeal devices should always be taken into account, since it might have a significant impact on final outcomes. The large randomized study Aquapheresis versus Intravenous Diuretics and Hospitalizations for Heart Failure (AVOID-​HF) was designed to clarify the issue of UF therapy safety and effectiveness [60]. Whereas a stepped approach similar to that of the CARRESS-​HF trial was designed for the diuretic arm, the AVOID-​HF study also included a stepped UF prescription [61]. Initially planned to enrol >800 patients, the study was abruptly interrupted by the sponsor after the first 224 enrolments (essentially due to slow recruitment rate and budget issues) [62]. Although significantly underpowered, the recently published results appear, however, very interesting [63]. The first heart failure event in 90  days occurred in 25% of the adjustable ultrafiltration (AUF) patients and 35% of the adjustable loop diuretics (ALD) patients, and the time to the first event, the study primary endpoint, was longer in the former arm (62  days versus 34  days, although not statistically significant; P  =  0.106). Within 30  days after discharge, compared with the ALD group, patients in the AUF group had, per days at risk: fewer patients rehospitalized for heart failure (P = 0.034); fewer days in the hospital due to heart failure readmissions (P = 0.029); lower rehospitalization rates due to a cardiovascular event (P = 0.037); fewer rehospitalization days due to a cardiovascular event (P = 0.018); and fewer patients rehospitalized for a cardiovascular event (P = 0.042). Interestingly, this trial did not show any significant differences between creatinine values in the two arms, likely due to the UF stepped and gentler approach. Regrets remain for the unanswered questions of this ultimate important trial and clinicians may appraise that, likely, careful AUF application may be safe in terms of renal function, especially once technical aspects (i.e. vascular access-​related adverse events) can be optimized. As far as worsening of renal function during decongestion therapies is concerned, then it must be remarked that both loop diuretics and UF have been associated with increased creatinine levels. Extracorporeal water removal, however, has not been associated with neurohormonal activation and it should not activate tubuloglomerular feedback, as diuretics do [64]. Excessive intravascular depletion due to aggressive UF prescription or severely decreased GFR before UF starts might be considered as possible reasons for the described increase in creatinine levels [64]. Furthermore, regardless of whether decongestion is achieved by drugs or UF, a recent post

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hoc analysis of patients enrolled in the Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-​AHF) and CARRESS-​HF trials showed that only patients free from signs of orthoedema at discharge had lower 60-​day rates of death, rehospitalization, or unscheduled visits, compared with those having residual orthoedema [65]. The authors hypothesize that, despite congestion relief, therapies might be ineffective to definitively treat orthoedema during hospitalization. It might be speculated that tools, such as biomarkers, bioimpedance, echocardiography, and minimally invasive haemodynamic monitors, should also be implemented in order to improve patient care. As final bricks on the critical interpretation of extracorporeal UF for AHF management, two meta-​analyses have been lastly published with diametric opposite conclusions as far as the utility of UF on rehospitalization is concerned, compared to diuretics [66, 67]. This is only the ultimate confirmation of research equipoise in this field and the urgent need for a conclusive study.

Conclusion Renal support may be represented by a well-​established series of extracorporeal modalities for kidney rescue and substitution. In

recent years, RRT has evolved to the point that other organs can benefit from extracorporeal management of patient blood. Such evolution is continuing due to intense efforts that are currently ongoing on the mechanical support of critical patients and ADHF patients; in the near future, new diagnostic tools, clinical targets, and technical solutions will be proposed and validated in order to definitely affect and improve the outcomes of patients with AKI and MOF.

Personal perspective The history of artificial substitution of the failing kidney started about a century ago. One of the most important achievements of ‘modern’ RRT in critically ill patients is its evolution into ‘renal support therapy’—​optimal fine tuning and a combination of timing, dose, modality, anticoagulation, and interruption have led to an impressive variety of different receipts that allow not only to ultimately substitute end-​stage kidney failure, but also to support the kidney and many other failing organs, namely the heart, in their earliest dysfunctional states. The next steps will be to provide dedicated standardized recommendations for each kind of clinical condition (e.g. mild AKI, septic AKI, paediatric kidney injury, etc.).

Further reading Acute Dialysis Quality Initiative. Available from: M M http://​www.adqi.net. European Society of Cardiology. Clinical practice guidelines. Available from: M M http://​www.escardio.org/​guidelines.

Ronco C, Bellomo R, Kellum J. Critical Care Nephrology, second edition. Saunders Elseviers: Philadelphia, PA; 2008. Ronco C, Bellomo R, McCullough PA. Cardiorenal Syndromes in Critical Care. Karger: Basel; 2010.

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9. Kramer P, Wigger W, Rieger J, et al. Arterio-​venous hemofiltration: a new simple method for treatment of overhydrated patients resistant to diuretics. Klein Wschr 1977;55:1121–​2. 10. Ronco C, Polaschegg HD. History and development of continuous renal replacement therapy. In:  Ronco C, Bellomo R, Kellum J (editors). Critical Care Nephrology, second edition. Saunders Elsevier: Philadelphia, PA; 2009. pp. 1323–​5. 11. Ricci Z, Bonello M, Salvatori G, et al. Continuous renal replacement technology: from adaptive technology and early dedicated machines towards flexible multi-​ purpose machine platforms. Blood Purif 2004;22:269–​76. 12. Ronco C, Ricci Z, Bellomo R, Baldwin I, Kellum J. Management of fluid balance in CRRT:  a technical approach. Int J Artif Organs 2005;28:765–​76. 13. Ricci Z, Romagnoli S, Ronco C. Acute kidney injury: to dialyse or to filter? Nephrol Dial Transplant 2020;35:44–​6. 14. Ricci Z, Bellomo R, Ronco C. Renal replacement techniques:  descriptions, mechanisms, choices and controversies. In:  Ronco C, Bellomo R, Kellum J (editors). Critical Care Nephrology, second edition. Saunders Elsevier: Philadelphia, PA; 2009. pp. 1136–​40.

RE F E RE N C E S 15. Ricci Z, Ronco C, Bachetoni A, et  al. Solute removal during continuous renal replacement therapy in critically ill patients: convection versus diffusion. Crit Care 2006;10:R67. 16. Ricci Z, Bellomo R, Ronco C. Dose of dialysis in acute renal failure. Clin J Am Soc Nephrol 2006;1:380–​8. 17. Schläpfer P, Durovray J-​D, Plouhinec V, et  al. A first evaluation of OMNI®, a new device for continuous renal replacement therapy. Blood Purif 2017;43:11–​17. 18. Edrees F, Li T, Vijayan A. Prolonged intermittent renal replacement therapy. Adv Chronic Kidney Dis 2016;23:195–​202. 19. Villa G, Neri M, Bellomo R, et al. Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications. Crit Care 2016;20:283. 20. Bellomo R, Lipcsey M, Calzavacca P, et al.; RENAL Study Investigators and ANZICS Clinical Trials Group. Early acid–​base and blood pressure effects of continuous renal replacement therapy intensity in patients with metabolic acidosis. Intensive Care Med 2013;39:429–​36. 21. Tandukar S, Palevsky PM. Continuous renal replacement therapy: who, when, why, and how. Chest 2019;155:626–​38. 22. Clark WR, Mueller BA, Kraus MA, Macias WL. Renal replacement quantification in acute renal failure. Nephrol Dial Transplant 1998;13(suppl 6):86–​90. 23. Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–​637. 24. Vinsonneau C, Camus C, Combes A, et al.; Hemodiafe Study Group. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-​ organ dysfunction syndrome: a multicentre randomised trial. Lancet 2006;29:379–​85. 25. Guerin C, Girard R, Selli JM, Ayzac L. Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units:  results from a multicenter prospective epidemiological survey. Intensive Care Med 2002;28:1411–​18. 26. Uehlinger DE, Jakob SM, Ferrari P, et al. Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 2005;20:1630–​7. 27. Schwenger V, Weigand MA, Hoffmann O, et  al. Sustained low efficiency dialysis using a single-​pass batch system in acute kidney injury—​a randomized interventional trial:  the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts. Crit Care 2012;16:R140. 28. Schillinger F, Schillinger D, Montagnac R, Milcent T. Post catheterisation vein stenosis in haemodialysis:  comparative angiographic study of 50 subclavian and 50 internal jugular accesses. Nephrol Dial Transplant 1991;6:722–​4. 29. Parienti JJ, Mégarbane B, Fischer M-​O, et al. Catheter dysfunction and dialysis performance according to vascular access among 736 critically ill adults requiring renal replacement therapy: a randomized controlled study. Crit Care Med 2010;38:1118–​25. 30. Bellomo R, Mårtensson J, Lo S, et  al. Femoral access and delivery of continuous renal replacement therapy dose. Blood Purif 2016;41:11–​17. 31. Parienti JJ, Thirion M, Mégarbane B, et al. Femoral vs jugular venous catheterization and risk of nosocomial events in adults requiring acute renal replacement therapy:  a randomized controlled trial. JAMA 2008;299:2413–​22. 32. Naka T, Egi M, Bellomo R, Baldwin I, Fealy N, Wan L. Resistance of vascular access catheters for continuous renal replacement therapy: an ex vivo evaluation. Int J Artif Organs 2008;31:905–​9.

33. Tal MG. Comparison of recirculation percentage of the palindrome catheter and standard hemodialysis catheters in a swine model. J Vasc Interv Radiol 2005;16:1237–​40. 34. KDIGO:  Kidney Disease Improving Global Outcomes (KDIGO):  Acute Kidney Injury Work Group (2012). Kidney Int 2012;2:19–​36. 35. Tan HK, Baldwin I, Bellomo R. Continuous veno-​ venous hemofiltration without anticoagulation in high-​ risk patients. Intensive Care Med 2000;26:1652–​7. 36. Gainza FJ, Quintanilla N, Pijoan JI, Delgado S, Urbizu JM, Lampreabe I. Role of prostacyclin (epoprostenol) as anticoagulant in continuous renal replacement therapies:  efficacy, security and cost analysis. J Nephrol 2006;19:648–​55. 37. Mariano F, Morselli M, Bergamo D, et  al. Blood and ultrafiltrate dosage of citrate as a useful and routine tool during continuous venovenous haemodiafiltration in septic shock patients. Nephrol Dial Transplant 2011;26:3882–​8. 38. Lanckohr C, Hahnenkamp K, Boschin M. Continuous renal replacement therapy with regional citrate anticoagulation:  do we really know the details? Curr Opin Anaesthesiol 2013;26:428–​37. 39. Bagshaw SM, Wald R. Renal replacement therapy:  when to start. Contrib Nephrol 2011;174:232–​41. 40. Kellum JA, Lameire N; the KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury:  a KDIGO summary (Part 1). Crit Care 2013;17:204. 41. Cruz DN, Ricci Z, Bagshaw SM, Piccinni P, Gibney N, Ronco C. Renal replacement therapy in adult critically ill patients:  when to begin and when to stop. Contrib Nephrol 2010;165:263–​73. 42. Himmelfarb J, Joannidis M, Molitoris B, et  al. Evaluation and initial management of acute kidney injury. Clin J Am Soc Nephrol 2008;3:962–​7. 43. Zarbock A, Kellum JA, Schmidt C, et  al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury:  the ELAIN randomized clinical trial. JAMA 2016;315:2190–​9. 44. Gaudry S, Hajage D, Schortgen F, et  al. Initiation strategies for renal-​replacement therapy in the intensive care unit. N Engl J Med 2016;375:122–​33. 45. Barbar SD, Clere-​Jehl R, Bourredjem A, et  al. Timing of renal-​replacement therapy in patients with acute kidney injury and sepsis. N Engl J Med 2018;379:1431–​42. 46. Romagnoli S, Ricci Z. When to start a renal replacement therapy in acute kidney injury (AKI) patients: many irons in the fire. Ann Transl Med 2016;4:355. 47. Schneider AG, Romagnoli S. Renal replacement therapy:  time to give up on early initiation? Perhaps. Anaesth Crit Care Pain Med 2018;37:507–​8. 48. Bagshaw SM, Cruz DN, Gibney RT, Ronco C. A proposed algorithm for initiation of renal replacement therapy in adult critically ill patients. Crit Care 2009;13:317. 49. Sutherland SM, Zappitelli M, Alexander SR, et  al. Fluid overload and mortality in children receiving continuous renal replacement therapy:  the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis 2010;55:316–​25. 50. Uchino S, Bellomo R, Morimatsu H, et  al. Discontinuation of continuous renal replacement therapy:  a post hoc analysis of a prospective multicenter observational study. Crit Care Med 2009; 37:2576–​82. 51. Wu VC, Ko WJ, Chang HW, et  al. Risk factors of early redialysis after weaning from postoperative acute renal replacement therapy. Intensive Care Med 2008;34:101–​8.

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52. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med 2008;34:957–​62. 53. Freda BJ, Slawsky M, Mallidi J, Braden GL. Decongestive treatment of acute decompensated heart failure:  cardiorenal implications of ultrafiltration and diuretics. Am J Kidney Dis 2011;58:1005–​17. 54. Nalesso F, Garzotto F, Ronco C. Technical aspects of extracorporeal ultrafiltration:  mechanisms, monitoring and dedicated technology. Contrib Nephrol 2010;164:199–​208. 55. Ronco C, Haapio M, House A, et  al. Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527–​39. 56. McMurray JJ, Adamopoulos S, Anker SD, et  al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012;33:1787–​847. 57. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–​83. 58. Bart B, Goldsmith SR, Lee KL, et  al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–​304. 59. Marenzi G, Muratori M, Cosentino ER, et  al. Continuous ultrafiltration for congestive heart failure:  the CUORE trial. J Card Fail 2014;20:9–​17. 60. Krishnamoorthy A, Felker GM. Fluid removal in acute heart failure: diuretics versus devices. Curr Opin Crit Care 2014;20:478–​83.

61. Costanzo MR, Negoianu D, Fonarow GC, et al. Rationale and design of the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-​HF) trial. Am Heart J 2015;170:471–​82. 62. Mark DB, O’Connor CM. When business and science clash, how can we avoid harming patients?: the case of AVOID-​HF. JACC Heart Fail 2016;4:106–​8. 63. Costanzo MR, Negoianu D, Jaski BE, et  al. Aquapheresis versus intravenous diuretics and hospitalizations for heart failure. JACC Heart Fail 2016;4:95–​105. 64. Goldsmith SR, Bart B, Burnett J. Decongestive therapy and renal function in acute heart failure: time for a new approach? Circ Heart Fail 2014;7:531–​5. 65. Lala A, McNulty SE, Mentz RJ, et al. Relief and recurrence of congestion during and after hospitalization for acute heart failure. Circ Heart Fail 2015;8:741–​8. 66. Kabach M, Alkhawam H, Shah S, et al. Ultrafiltration versus intravenous loop diuretics in patients with acute decompensated heart failure: a meta-​analysis of clinical trials. Acta Cardiol 2017;72:132–​41. 67. Kwok CS, Wong CW, Rushton CA, et al. Ultrafiltration for acute decompensated cardiac failure: a systematic review and meta-​analysis. Int J Cardiol 2017;228:122–​8.

ADDITIONAL ONLINE MATERIAL For additional multimedia materials, please visit the online version of the book (M M oxfordmedicine.com/ESCIACC3e).

CHAPTER 28

Percutaneous (short-​term) mechanical circulatory support Holger Thiele and Pascal Vranckx Contents Summary   351 Introduction  351 General considerations  352 Design, performance requirements, and safety issues  352 Peripheral vascular disease  352 Thromboembolism and bleeding  352 Valvular heart disease  353 Right-​sided heart failure  353

Percutaneous devices for short-​term percutaneous mechanical support  353 Intra-​aortic balloon pumping  353

Advanced mechanical circulatory support  354 Intracardiac axial flow pumps: the Impella platform/​the HeartMate PHP  354 The Impella  354 HeartMate PHP  355 Centrifugal pumps  355 Extracorporeal membrane oxygenation/​extracorporeal cardiac life support  355 Percutaneous left atrial to femoral artery left ventricular support device (short-​term, centrifugal): TandemHeart™  356 The PulseCath iVAC 2L®  356 Right ventricular support  356 The Impella RP  356 Centrifugal blood pumps  356

Summary Percutaneous mechanical circulatory support can be used to resuscitate patients as a stabilizing measure for angiography and prompt revascularization, or to buy time until more definite measures can be taken. In addition, there is experimental evidence that ventricular unloading of the left ventricle can significantly reduce infarct size. Different systems for mechanical circulatory support are available to the medical community. Treatment options for mechanical circulatory support must be tailored to each patient in order to maximize the potential benefits and minimize the risk of detrimental effects. Intra-​aortic balloon pumping is still the most widely used mechanical circulatory support therapy. The relative ease and speed with which this device can be applied have led to its widespread use as a first-​line intervention among critically unstable patients at a time where evidence for the introduction of new devices was not as rigorously required as today. Where more haemodynamic support is required, an immediate triage to a more advanced percutaneous (short-​term) mechanical circulatory support may be warranted. Despite their extensive use, the utility of mechanical circulatory support devices in acute heart failure syndromes and cardiogenic shock remains uncertain. This chapter concentrates on the application of mechanical circulatory support relevant to the interventional cardiologist and cardiac intensive care physician.

Conclusion  357 References  357

Introduction CAD has emerged as the dominant aetiologic factor in acute heart failure syndromes (AHFS) and CS (see also E Chapters  40 and 42). Invasive management of the complex cardiac patient with advanced (decompensated) heart failure, CS, and/​or potential haemodynamic compromise during and after PCI has become the remit of specialty myocardial intervention centres. Such centres provide state-​of the art facilities for PCI, including experienced senior operators and critical care physicians who are available 24 hours per day, 7 days per week, with immediate access to cardiac surgery and mechanical circulatory support (MCS) systems. There are two primary indications for (short-​term)  MCS:

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◆ To resuscitate patients:  to ensure end-​organ perfusion in the event of failure of the heart to meet the metabolic demands of the body (see E Chapters 11 and 42), to buy time until definitive intervention(s), and to reverse the underlying pathology, and hence potentially to improve survival [1–​3]. ◆ As a stabilizing measure for angiography and (prompt) revascularization:  to withstand transient derangements in organ perfusion and cardiac function and to allow the original cardiac function to resume post-​procedure or immediately thereafter (~72 hours) [4]‌. Moreover, there is experimental evidence that unloading of the LV can significantly reduce infarct size and influence myocardial remodelling after an MI. Mechanical offloading of the myocardium during ischaemia and reperfusion has been shown to reduce LV pressure work and myocardial O2 consumption. A reduction in the infarct size has been related to the degree of pressure unloading of the LV [5]‌.

General considerations Design, performance requirements, and safety issues The IABP is a historically old support device that has been used in the management of patients suffering from the complications of acute CVD. The relative ease and speed with which this device can be applied to patients with a rapidly deteriorating haemodynamic picture have led to its use as a mainstay intervention among critically unstable patients despite the lack of sufficient evidence. The IABP acts on the concept of counter-​pulsation resulting in pressure unloading of the LV. The main limitations of the IABP include the lack of active cardiac support, the need for accurate synchronization with the cardiac cycle, the requirement of a certain level of LV function, and the limit of active support provided. In comparison to controls in randomized trials, the IABP did not have additional beneficial haemodynamic or metabolic effects with respect to cardiac output, SVR, arterial lactate, and also doses of catecholamines. Therefore, in many patients with severe depression of cardiac function and/​or persistent (tachy-​) arrhythmias, haemodynamic support and LV unloading derived from medical therapy, including IABPs, may be insufficient to maintain end-​organ tissue perfusion. In these circumstances, escalation to more advanced percutaneous (or implanted) (see E Chapter 44) MCS modalities may be warranted. The aims of advanced MCS include increasing myocardial O2 supply and improving O2 delivery to dependent organ systems, thereby preventing multiple organ dysfunction and subsequent death. A minimal flow rate of 70 mL/​kg body weight per minute (representing a cardiac index of at least 2.5 L/​m2) is generally required to provide adequate organ perfusion. This flow is the sum of percutaneous MCS output and residual cardiac pump function. A number of devices exist, the choice of which depends upon the underlying pathology, the expertise of the institution, and the required level of support. The main considerations when

choosing portable MCS include patient safety, deliverable flow rate, durability, device and cannula size, and ease of handling. The safety of the patient is the pre-​eminent concern, with the main considerations outlined in the following sections and potential contraindications listed in E Table 28.1. In addition, several other considerations exist, applicable to all types of MCS.

Peripheral vascular disease In patients with established CAD, potential peripheral artery disease should be a concern [7–​9]. The requirement for large-​bore cannulation of the femoral circulation is an important limitation of most portable MCS therapies. To make percutaneous insertion feasible, the diameters of cannulae are generally downsized to a maximum of approximately 10F. However, since the MCS device flow is limited by the size of the arterial cannula, in CS, larger cannula sizes (13–​17F) are required to achieve adequate organ perfusion. Strategies aimed at reducing femoral artery access site complications, such as use of pre-​insertion abdominal and iliofemoral angiography and vascular US to guide femoral access (see E Chapter 22), have been introduced and implemented in practice [10]. In cases of emergency in patients with severe atherosclerotic disease, angioplasty [percutaneous transluminal angioplasty (PTA)] of the femoral artery or direct surgical cut-​down may be performed. Ultimately, in patients on ECLS systems, a prophylactic distal perfusion catheter may be placed antegrade into the superficial femoral artery [11].

Thromboembolism and bleeding The occurrence of thromboembolic events depends on a number of factors, including the type of device, the duration of support, and the location and number of cannulation sites [12, 13]. Numerous physical factors must also be considered, including mechanical trauma, blood temperature, and blood flow. Embolization may occur during device insertion, function, and removal [14]. The rate of thromboembolic events is relatively low with a heparin anticoagulation regimen. Heparin therapy remains the mainstay

Table 28.1  Complications during IABP use (Benchmark Registry) Severe access site-​related bleeding

1.4%

Vascular injury

0.7%

Major limb injury

0.5%

Amputation

0.1%

Bowel, renal, and spinal cord infarcts

0.1%

Infection

0.1%

Stroke

0.1%

Venous thrombosis

0.1%

Death

0.05%

Reproduced from Cohen M, Urban P, Christenson JT, et al. Intra-​aortic balloon counterpulsation in US and non-​US centres: results of the Benchmark Registry. Eur Heart J. 2003;24(19):1763–​1770. doi:10.1016/​j.ehj.2003.07.002 with permission from Oxford University Press.

Percu taneou s devic es for  short- ter m percu ta n eou s m echa n i c a l   supp ort of anticoagulation during MCS and is monitored using ACT and/​ or activated partial prothrombin time (aPTT) and/​or heparin level. An ACT of 160–​200 seconds is usually recommended [15]. There is no evidence of benefit of additional antiplatelet therapy in MCS. Regional anticoagulation (within the device) may reduce systemic anticoagulation and the risk of bleeding, although systemic anticoagulation is the norm.

Valvular heart disease Abnormalities of the cardiac valves have important consequences in patients being considered for MCS, depending on the device selection and site of cannulation. In cases where LV assistance is initiated with LA to aortic cannulation, the presence of even mild to moderate aortic valve insufficiency may result in LV ballooning in the presence of significant LV dysfunction. Conversely, in cases of severe mitral valve stenosis and impairment in LV filling, LA to aortic cannulation may become the access route of choice (see E Chapter 55).

Right-​sided heart failure An adequate right heart function is required to maintain LV preload [16]. Acute RV failure occurs in multiple settings, including acute MI, fulminant myocarditis, ADHF, acute PE, decompensated PH, following cardiac transplant, and post-​ cardiotomy shock, and is a major determinant of survival [16]. Anatomic and physiologic determinants of RV function are distinct from those of LV function. The management of RV failure and CS should be tailored accordingly [16]. In patients who fail to respond to first-​line interventions and develop refractory CS secondary to RV failure, options for escalation of care are limited. However, in selected patients where it is felt that there is prospect for recovery and survival, temporary MCS devices may provide an attractive rescue option (see further sections) [16].

Percutaneous devices for short-​term percutaneous mechanical support This section focuses on devices and modalities of blood flow generation available. It is important to understand that the device never operates in a vacuum. Understanding the interaction of the patient–​device circuit is the cornerstone of proper monitoring, troubleshooting, and assessment of device performance.

Intra-​aortic balloon pumping The IABP is currently the most widely used of all portable devices for short-​term circulatory support. After publication of the IABP-​ SHOCK II trial in 2012, implantation rates declined [17, 18]. Its action is based on the concept of counter-​pulsation, with the assumption that reduction in end-​diastolic pressure improves LV function. Experimental studies suggest that counter-​ pulsation improves LV performance by favourably influencing myocardial O2 balance. It increases myocardial O2 supply by diastolic

Figure 28.1  Correct timing and pitfalls in the timing of inflation and

deflation of the IABP balloon. The balloon is inflated in diastole, concurrently with closure of the aortic valve, and is held in inflation until the onset of the next ventricular systole. The balloon is then rapidly deflated. Inflation of the balloon displaces blood in the aorta (by an amount equal to the volume of the balloon) towards the coronary tree, thereby increasing (augmenting) the coronary perfusion pressure (CPP) and blood flow. The collapse of the balloon creates a reduction in impedance of the LV ejection and decreased afterload, and consequently reduces LV work. With permission from Maquet Getinge Group.

augmentation of coronary perfusion and decreases myocardial O2 requirements through reduction of the afterload component of cardiac pressure work (see E Figure 28.1). However, in comparison to controls, there are no effects on cardiac output and no effect on cardiac power index, arterial lactate, or doses of catecholamines [17,  19]. Reduction of LV afterload may theoretically be helpful in patients with acute mitral valve insufficiency or VSD. The haemodynamic effects of the IABP are dependent on several factors (see E Box 28.1). IABP therapy consists of inflating and deflating a Durathane (Maquet, Fairfield, NJ, USA) balloon catheter in synchrony with the patient’s cardiac cycle. Different catheter sizes are currently available, allowing tailoring of the balloon size to patient length. The balloon catheter is commonly inserted through a femoral arteriotomy into the thoracic aorta. Accurate timing of the intra-​aortic balloon inflation and deflation is crucial. Timing errors typically produce characteristic pressure waveform changes that can be easily recognized (see E Figure 28.2). The pumping chamber, which is activated by helium, is usually synchronized with the heart by signals from the ECG or

Box 28.1  Conditions interfering with the haemodynamic effects of IABP ◆ Position of the balloon in the aorta ◆ Heart rate and rhythm ◆ Size and volume of the balloon ◆ Compliance of the aorta (aortic pressure/​volume relation)

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Figure 28.2  Proper positioning of the intra-​aortic balloon catheter in the descending aorta: balloon inflation/​deflation. Diagrammatic representation of IABP

inflation and deflation and its effects on blood flow, as timed by the cardiac cycle. (A) During diastole, the IABP is inflated, increasing the diastolic pressure, thus augmenting the flow not only into the coronary arteries, but also into the great vessels and the renal arteries. (B) During systole, the IABP is deflated, creating a void where the inflated balloon was thus increasing the forward flow into the aorta and to the periphery. With permission from Maquet Getinge Group.

the central aortic pressure transducer. Implementation of fibreoptic pressure signal transmission to a patient monitor results in faster signal acquisition and time to therapy. If paced, then pacing spikes can be used to detect cardiac cycle events. An internal trigger mode is available for asystolic arrested patients. Extreme tachycardia and cardiac arrhythmias may affect the efficiency of IABP. Pressure trigger is not recommended in patients with AF. Absolute contraindications for the IABP include severe aortic valve insufficiency and (acute) aortic dissection. The presence of an aortic aneurysm, severe iliofemoral vascular disease, and a history of aortic surgery are relative contraindications. Complications associated with the IABP are less common in the modern era. The IABP-​SHOCK II trial did not observe a higher rate of potentially device-​related complications in IABP-​treated patients in comparison to the control group. The indications and applications for the IABP have come a long way since the early days of counterpulsation. IABP counterpulsation does not improve outcomes in patients with MI and CS without mechanical complications, nor does it significantly limit infarct size in those with potentially large anterior MIs [17, 19–​21]. Therefore, the ESC guidelines do not recommend routine IABP use in patients with MI and CS [22,  23]. However, IABP counterpulsation can be used based on expert consensus, without data on outcome, in selected patients with haemodynamic instability/​CS due to mechanical complications (i.e. severe mitral insufficiency or VSD) [22]. Of note also, routine use of the IABP prior to high-​risk angioplasty did not reduce the primary endpoint, i.e. major cardiac and cerebrovascular events

(MACCE), a composite of death, AMI, cerebrovascular event, or further revascularization, at hospital discharge (capped at 28 days) [24]. The IABP is a typical example of a treatment based on a concept which subsequently in trials did not prove to change the outcome of patients.

Advanced mechanical circulatory support Although each device has its own characteristics, the available advanced short-​term MCS can be classified into two types: axial flow and centrifugal pumps. A  novel pulsatile circulatory support system with an extracorporeal membrane pump was recently introduced as a third type. Today, there are no comparative studies analysing any potential advantage of one MCS system over another. Moreover, published randomized trials have failed to demonstrate any outcome benefit for advanced MCS over the IABP in AHFS and CS [25–​28].

Intracardiac axial flow pumps: the Impella platform/​the HeartMate PHP The Impella The Impella (Abiomed, Danvers, MA, USA) is a catheter-​ mounted intravascular microaxial blood pump driven by an external electrical motor for short-​term use (Impella 5.5 up to 30 days in Europe). The Impella catheter delivers blood from the inlet area, which sits inside the LV, through the cannula, to the outlet opening in the ascending aorta. The device has a pigtail catheter at its tip to ensure a stable position in the LV and to prevent adherence to the myocardium. The axial flow pump systems

Percu taneou s devic es for  short- ter m percu ta n eou s m echa n i c a l   supp ort produce unloading of the LV and a reduction in LV wall stress [28]. The Impella Left comes in four versions. The Impella 2.5 (12F), Impella 5.0 (21F), Impella 5.5, and Impella CP (14F) catheters can be inserted percutaneously through the femoral (Impella 5.0 via femoral cut-​down only) or axillary artery and into the LV. The Impella LD is inserted directly through the ascending aorta and into the LV. The Impella 5.0 and Impella LD catheters have an electronic differential pressure sensor located at the proximal end of the 21F cannula that generates the placement signal, which is used by operators and the controller to monitor the position of the Impella cannula relative to the aortic valve. As with all axial pumps, its performance depends on the rotary speed (table) and the ‘pressure head’ (aortic pressure minus LV pressure, continuously monitored). Although the rotary speed is held constant (to the user selection), variation in the pressure head during the cardiac cycle results generally in a pulsatile flow pattern. Whether the additional mechanical support provided by the smaller Impella 2.5 or the Impella CP will be sufficient for patients with circulatory collapse still needs to be established [29–​35]. More promising in this regard is the Impella 5.0/​LD and the Impella 5.5, the latter capable of delivering a continuous flow of up to 6.0 L/​min [36–​38]. In a sheep infarction model, the Impella 5.0 was shown to reduce myocardial O2 demand and infarct size [5]‌. The Impella 5.0 is implanted most frequently via the subclavian artery, which allows for patient ambulation, although a minority of implants are accomplished through the femoral approach [36]. Limitations of axial support devices are related to the position across the aortic valve into the LV. The Impella is contraindicated for use in patients with mural thrombus in the LV, the presence of a mechanical aortic valve, aortic valve stenosis/​calcification (equivalent to an orifice area of 0.6 cm2 or less), moderate to severe aortic insufficiency (echocardiographic assessment graded as ≥2+), or cardiac tamponade. Because of the high rotation speed of the Impella, it can also provoke significant haemolysis mostly related to a suboptimal or an unstable position of the inlet in the LV or close to the aortic valve [39]. HeartMate PHP The HeartMate PHP (percutaneous heart pump) also is a catheter-​ based axial flow pump. The collapsible elastomeric catheter pump is inserted through a 14F sheath, deployed across the aortic valve, expanding to 24F and able to deliver up to 5 L/​min blood flow at modest operating speeds [40]. This unique design feature makes this device the lowest-​profile insertion cannula with the highest flow. For removal, the system can be collapsed to the initial 13F. Clinical experience with the device is limited to high-​risk PCI [41]. Clinical development of the HeartMate PHP is actually paused due to a small number of clinical events related to inappropriate pump stoppage during support in both the Shield II clinical trial and commercial uses.

Centrifugal pumps Centrifugal pumps operate in a fashion similar to that of some CPB pumps [42]. They typically consist of a cone-​shaped rotor contained within a plastic or metal housing. Blood flows into the pump at the apex of the cone and exits at the edge of the base.

Spinning of the rotor creates a centrifugal force that is imparted to the blood, generating a constant, non-​pulsatile flow. Femoral arterial access is provided by large-​bore arterial (ranging from 16F up to 19F) and venous cannulae (17–​21F). Bilateral femoral cannulation using smaller-​sized cannula may be an option in small patients. Limb ischaemia caused by femoral cannulation can be prevented by distal leg perfusion with a small catheter (5F) placed in the distal artery. Extracorporeal membrane oxygenation/​extracorporeal cardiac life support ECMO incorporates a centrifugal pump and an extracorporeal oxygenator. The percutaneous technique for the initiation of femoro-​femoral CPB support [percutaneous cardiopulmonary bypass support (PCBS)], using the Bard portable PCBS system, has been described as far back as 1990 [43]. Blood is aspirated by a centrifugal pump from the right atrium through a long 17–​21F bypass cannula in the femoral vein and is returned by means of a heat exchanger membrane oxygenator to a femoral artery cannula (16–​19F); flow rates of up to 6 L/​min may be obtained, providing near-​complete respiratory and circulatory support, independent of the intrinsic cardiac rhythm or ventricular function. The pump provides a continuous flow with the maintenance of a pulsatile arterial pressure, unless the circulation is completely supported by the CPB device. The ECMO can be configured according to the patient’s needs:  venous–​ venous ECMO for respiratory support and venous–​arterial ECMO for respiratory and haemodynamic support (in cases of LV, RV, or biventricular failure) [44–​46]. While venous–​arterial ECMO can support both respiration and circulation, optimal functioning of the system is preload-​dependent and may be hampered if hypovolaemia (e.g. severe bleeding) or tamponade is present. Frequent complications include lower extremity ischaemia (16.9%), stroke (5.9%), major bleeding (40.8%), and significant infection (30.4%) [13, 14,  47]. The increase in afterload with venous–​arterial ECMO may cause LV distension, especially when severely limited LV ejection or aortic valve insufficiency is present and may further increase LV and LA pressures [47, 48]. Failure to decompress the left heart under these circumstances can result in pulmonary oedema and upper body hypoxaemia, i.e. myocardial and cerebral ischaemia [48]. In these circumstances, non-​surgical venting can be obtained by atrial septostomy, a 7F pigtail catheter in the LV connected to the venous limb of the ECMO circuit, and insertion of an additional MCS device with LV unloading properties (i.e. Impella, IABP) [49–​54]. Again, the benefits and risks of venting mechanisms have not been studied extensively and are only theoretical. The initial experience with ECMO has been hampered by: the relatively complex system setup, necessitating a specialized team, including perfusionists; the high morbidity rate due to a high rate of associated complications; the need for extracorporeal circulation and a membrane oxygenator, with subsequent activation of cellular elements; and limited support time (usually synthesis

Amino acids

Liver Gluconeogenesis Glycogenolysis

VLDL

Glucose

Brain, heart, kidney Survival to next meal

1

Ketone bodies

2

(b) ?? Gastrointestinal tract ??

Sepsis Trauma

Adrenal glands

Pancreas

TNFα, IL-1 Adipose tissue lipolysis

VLDL

Amino acids Glutamine

? ?

Insulin

Glucagon

Cortisol + catecholamines Muscle protein Breakdown > synthesis

Amino acids

FFA ++ Glycerol Liver Gluconeogenesis Glycogenolysis

Immobilization Amino acids Glutamine

Acute phase proteins

Lactate Glucose ++ ? ?

Ketone bodies

Brain, heart, kidney, immune system, wound healing Survival

? ?

Figure 29.1  (A) Mobilization of endogenous nutrients during fasting. (1) Early phase: muscle protein (pink) serves hepatic gluconeogenesis (blue) or serves as

a regional energy source in, for example, the GI tract. (2) Later phase of fasting: lipolysis in adipose tissue fuels hepatic ketogenesis (black) and, to a small extent, gluconeogenesis. FFA, free fatty acids; VLDL, very low-​density lipoproteins. (B) Wasting in critical illness: massive mobilization of endogenous nutrients triggered by inflammation and immobilization, and largely independent of nutritional (in)adequacy. Amino acids (pink), released by muscle breakdown, are a substrate for hepatic gluconeogenesis, the production of acute phase proteins, gut metabolism, inflammation, and wound healing. FFA (black) are a direct energy source for muscle. Insulin resistance reduces glucose (blue) uptake in insulin-​dependent tissues. Incomplete oxidation of glucose results in a lactate flux back to the liver [29, 32]. VLDL, very low-​density lipoproteins; FFA, free fatty acids; TNFα, tumour necrosis factor α; IL-​1, interleukin-​1. Reproduced from ‘Impact of early parenteral nutrition on metabolism in critically ill patients’ MP Casaer, Acta Biomedica Lovaniensa 591, 2012, Thesis Dissertation with permission from Leuven University Press.

Autophagy activation might worsen load-​induced hypertrophic heart failure [36] (though results are conflicting [37]) but apparently preserves myocardial function in abdominal sepsis in murine experiments [38]. Cardiac failure reciprocally influences the nutritional status and induces tissue wasting, often referred to as cardiac cachexia [39].

RV failure is particularly associated with weight loss, and both combined are strong predictors of mortality and AEs [40]. The possible roles of a low cardiac output, venous and lymphatic congestion, and intestinal hypoxia have been described extensively [40]. Clinical features include fat malabsorption [41], losses of protein in paracentesis fluids, and a reduced oral nutrient intake,

Recent data on  nu tri ti on resea rch i n  acu te ( ca rdiac) cri ti c a l   i l l n e s s all leading to tissue wasting. Also, increased lipolysis due to increased BNP levels, among others, could play a role [40]. Whether EN or PN can reverse cardiac cachexia and improve survival remains to be shown [42, 43].

Nutrition and cardiac disease The importance of nutrition and lifestyle in patients with metabolic syndrome, CVD, or increased cardiovascular risks is well established. This has been covered in extensive guidelines by the ESC/​European Atherosclerosis Society, among others. The cornerstones are total energy intake adjusted to activity and body weight, reduced intake of fat (particularly saturated fat), consumption of vegetables and fruit, reduced alcohol intake, enhanced physical activity, and, of course, cessation of all tobacco product exposure [44, 45]. The evidence in favour of more specific nutritional interventions in patients with cardiac disease, however, has been challenged by some of the most recent RCTs [14, 15,  46]. The disappointing results with omega-​3 fatty acids (OFAs), despite earlier encouraging results, might be explained by an increased quality of medical care and prevention, widespread statin use over the last decades, a lower baseline of cardiovascular risk in participating countries, or a beneficial effect of the (olive) oil used in control patients [46]. In the VITAL-​RCT (N  =  25  871) randomizing patients to OFAs and vitamin D in a two-​by-​two factorial design, OFAs had no effect on the incidence of major cardiovascular complications. However, in 13 514 patients consuming 350 ng/​L (green) are shown separately, as derived from single, duplicate, and triplicate sampling, with each sample analysed singly, for estimating the homeostatic set points of the two serial results. Reproduced from Wu AH, Smith A, Wieczorek S, et al. Biological variation for N-​ terminal pro-​and B-​type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. Am J Cardiol 2003;92(5):628–​631. doi:10.1016/​s0002-​9149(03)00741-​0 with permission from Elsevier.

but there are very little data to substantiate it. There are robust data about BV, and it is, at a minimum, 25%, which supports the idea that much larger RCVs are necessary to be sure a change has occurred [70, 71]. Recently, Miller et  al. showed that either increases or decreases of 80% or greater were necessary to show associations with differences in outcome with BNP [72]. This may be why some trials using natriuretic peptides for titrating therapy have not been positive, as they have not induced sufficient increments in change [73]. For troponin, there are differences between men and women with all hs-​cTn assays [32] and there are some data indicating that it improves the detection of women with AMI [74]. The most recent Universal Definition of AMI endorses the use of sex-​specific thresholds [32]. There are no data suggesting that there are differences between racial or ethnic groups, but the majority worldwide have embraced values generated in the US and Europe, perhaps incorrectly.

Normal value issues Normal values should be established across different ethnic groups and by gender and age. The 99th percentile will increase with comorbidities and likely for that reason with age [75–​79]. For contemporary troponin assays, correction for age and sex is not necessary, but that will change at least for sex with high-​sensitivity assays [65, 76]. Since age-​related changes are related to comorbidities, the use of different cut-​off values would disadvantage individuals who lack comorbidities and is not recommended [32]. For BNP, differences with age and sex are clear [80, 81]. Recent data suggest differences are related to testosterone which suppresses values [82,  83]. Normal values rise with age [80,  84]. Women have higher values than men [81,  82]. Black patients have lower values [85]. Trial data suggest that separate values do not need to be established [83, 86] to diagnose heart failure. Most reports ignore these distinctions to generate simple paradigms [19, 84]. Some authors suggest that using age-​and gender-​ determined differences and correcting for BMI [85] would lead to greater accuracy. Substantially lower values are observed in obese individuals [86,  87]. BNP binds to the BNP clearance receptor and it was thought that perhaps fat provided more clearance receptors. It now appears that the majority of what is measured by both NT-​proBNP assays and BNP assays is actually proBNP [88] which binds to the clearance receptor. Subtle comorbidities, such as AF, even if not present at the time the patient presents, are associated with increased values [89] and renal dysfunction also increases values. This phenomenon is more marked for NT-​proBNP than for BNP, for unclear reasons. The renal clearance of both peptides is not different across a wide range of renal function [90] (see Figure 31.10). Nonetheless, higher cut-​off values to diagnose heart failure are needed for those with renal failure [91, 92]. For these reasons, the use of multiple cut-​off values, as opposed to a solitary value, seems prudent, as proposed for NT-​proBNP (see E Table 31.1) [93]. This consideration is important for CRP as well. There are differences in values, based on gender and ethnicity [94, 95]. Black

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Table 31.1  Optimal cut-​off values for NT-​proBNP from the Icon group Age strata

Optimal cut-​off point (pg/​mL)

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Accuracy (%)

450

97

93

76

99

95

900

90

82

82

88

85

1800

85

73

92

55

83

90

84

88

66

86

All 75 years (n = 519) Overall

Reproduced from Pascual-​Figal DA, Domingo M, Casas T, et al. Usefulness of clinical and NT-​proBNP monitoring for prognostic guidance in destabilized heart failure outpatients. Eur Heart J 2008;29(8):1011–​1018. doi:10.1093/​eurheartj/​ehn023 with permission from Oxford University Press.

individuals, especially black women, have higher values [95]. It is also clear that oestrogens raise CRP, as do inflammatory diseases [94]. Thus, if patients are ill at the time of sampling, a second sample must be taken when the patient has returned to health. If the individual is on oestrogens, one should expect higher values. Similarly, obesity and diabetes are associated with higher values, likely because they are associated with inflammation (see Figure 31.11).

Issues of interpretation Cardiac troponin There is a long list of reasons for cardiac injury, and one of the advances troponin has provided is an appreciation of these additional diseases that damage the heart [12]. The best way to differentiate acute elevations from chronic ones is by looking for a rising pattern of values. Even changing values have a broad differential diagnosis and could be due to inflammatory cytokines that damage the myocardium in patients who are septic or due to direct trauma, cardiac infections, such as myocarditis, or CAD. One exception to this rule is worth noting. If one is looking for small changes in values over short periods of time, one can miss significant changing patterns if one is not astute to the fact that the downslope (and thus falling patterns) manifests a much slower time course than increases on the upslope. In one study, up to 26% of all MIs presented in this manner [96]. Chronic elevations tend not to rise acutely [47]. The best understood paradigm for these chronic elevations are renal failure patients where elevations, especially of cTnT, are importantly prognostic and likely to be cardiac injury associated with renal dysfunction [97]. Even when baseline elevations are present, a changing pattern of values occurs during acute events [32]. Many patients with stable angina [98–​100] and many with heart failure have chronic troponin elevations, all of which are prognostically important [101]. They can also have intermittent acute elevations [101]. For troponin, one can determine the RCV, as indicated earlier. This should be defined by laboratories and reported as part of the results section of interpretation. If very high values of troponin are present, without a changing pattern, one should always consider an interfering substance [102]. Interfering substances cause

high values that do not change, until the interfering substance has gone. Thus, samples do not dilute linearly. Many interfering substances are due to antibody problems and can be unmasked with the use of additional blocking antibodies.

Natriuretic peptides Natriuretic peptides are also elevated in patients who are critically ill and those with volume increases, renal failure, Cushing’s disease, and/​or hyperaldosteronism [22]. Thus, one needs to interpret increases with close attention to the clinical context. One of the major differences between BNP and NT-​proNBP is in patients with renal failure. The aetiology for this is not understood, but increases in NT-​proBNP become very high in many patients with renal failure, with values that can be as high as 35 000 ng/​mL. These high values should not be a problem; the same principles in defining the change criteria apply—​the numbers are simply higher. It is not clear to this author whether or not natriuretic peptides can be used diagnostically in complicated, critically ill patients if the renal function is below 30 mL/​min, because the values are so high [103]. Recently, a new agent that inhibits the degradation pathways of many vasoactive peptides has been linked to an angiotensin receptor blocker (ARB) and has shown major improvements in heart failure events [104, 105]. The initial data suggest that BNP values may increase, while NT-​proBNP values decrease [105]. How this should influence how we interpret natriuretic peptide values has become more complex and controversial. Some thoughtful considerations were provided in a recent editorial [26].

C-​reactive protein Similar issues exist with CRP, having to do with concomitant illnesses and other inflammatory processes that confound values. In this instance, there are few options, because the CRP level needs to be taken early after presentation, before the acute response to necrosis occurs [31]. Thus, correction for concomitant disease may not be possible. If the value is elevated in the absence of these confounders and it is early after the onset of symptoms, it is likely that increases will persist and have long-​term prognostic significance [29]. From this perspective, the PROVE-​IT data [38], suggesting a CRP value at 4–​6 weeks post-​event, make good sense.

C ont emp orary issu es w i th the u se of acu te ca rdi ovas cu l a r  b i o m a rk e r s

Contemporary issues with the use of acute cardiovascular biomarkers Here, we will consider generic issues concerning the contemporary use of biomarkers.

Sensitivity and detection of new disease entities This issue has been common with cTn [13] and has posed a clinical challenge. All tests can have false positives, related to analytic issues [102]. Alternatively, it appears that additional disease entities cause most of these elevations. Malignancies are known to increase cTn values [106] and we now can monitor doxorubicin drug toxicity with troponins [107]. Furthermore, reducing elevations with ACE-​ Is prevents reductions in ventricular performance. It is likely that additional drug-​related and toxic aetiologies for cardiac damage will become clearer as we improve the sensitivities of our assays [108]. It is known, for example, that carbon monoxide poisoning causes troponin elevations acutely and that elevations are associated with an adverse prognosis [109]. Thus, rather than ignoring or impugning these elevations, clinicians need to explore the extent to which they open new pathophysiological opportunities. This was done by Assomull et al. [110] who investigated 60 patients with elevated troponins and ECG changes that appeared acute and who were thought to have AMI clinically. All of these individuals had ‘normal’ coronary angiograms but underwent CMR imaging. Diagnoses were elucidated in 65% of patients (see E Table 31.2). Some (11%) of these patients had a CMR signal suggestive of AMI and, in this circumstance, it is probably diagnostic. There are now several series showing exactly this, especially in women [111–​113]. This could occur because of the timing of the angiography, due to the presence of microvascular disease or endothelial dysfunction, and perhaps yet unappreciated pathophysiological determinants. Nonetheless, AMI with angiographically normal coronary arteries is not new [113] and myocardial infarction with non-​obstructed coronary arteries (MINOCA) is a real entity. In addition, 50% of the patients in Assomull et al.’s study had a CMR pattern suggestive

Table 31.2  CMR findings in 60 patients who presented with chest pain, elevated troponin values, and normal or near-​normal coronary arteries by angiography CMR findings

Number

%

Myocarditis

30

50

Acute

19

31.7

Non-​acute

11

18.3

MI

7

11.6

Takotsubo cardiomyopathy

1

1.7

Dilated cardiomyopathy

1

1.7

21

35.0

Normal CMR findings

Reproduced from Assomull RG, Lyne JC, Keenan N, et al. The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J 2007;28(10):1242–​1249. doi:10.1093/​ eurheartj/​ehm113 with permission from Oxford University Press.

of myocarditis, a relatively underdiagnosed, and probably unappreciated, disease. Indeed, CMR has unmasked a substantial number of cases of myocarditis previously not diagnosed [110, 114]. It had been previously reported that myocarditis could mimic AMI [115], but the frequency at which it occurred was unclear. As the troponin assay sensitivity improves still further [13], it is likely that we will find still more new examples of abnormal pathophysiology manifesting as cardiac injury. It is likely that the findings will be prognostically important. Some of this type of thinking may be facilitated by the designation of what has been termed ‘type 2 MI’ [32]. This is a circumstance where underlying coronary disease may be present but is stable until, in response to haemodynamic stress, increases in myocardial O2 consumption cause cardiac injury, marked by the release of troponin. Alternatively, it may be that toxic cytokines are predominantly responsible [13]. Irrespective of the aetiology, the complication of having cardiac injury associated with critical illness is associated with an adverse prognosis, both short-​and long-​term [116]. One of the dilemmas is that the appropriate therapeutic responses are not clear. Physicians need to think through the pathophysiology of the specific clinical entity involved to craft a therapeutic response. For example, in patients with sepsis, perhaps using the lowest possible dose of catecholamines for haemodynamic support might help. There are other possibilities as well. However, the purpose of this chapter is not to try to define the entire range of pathophysiological circumstances clinicians should consider, but rather to articulate concepts for the use of biomarkers. If one does that, it is very likely to improve the diagnostic yield from the use of these markers. Similar issues are likely to evolve with natriuretic peptides.

Issues of organ versus clinical specificity We would all like all of our markers to be totally specific, but this is not the case and is not likely ever to become so. Troponin comes the closest, but tissue specificity does not imply clinical specificity for the aetiology of elevations [12]. Thus, one needs to appreciate that troponin elevations, as well as those for natriuretic peptides and CRP, are likely to be observed commonly and that these biomarkers will unmask new, previously unknown, problems. Elevations of natriuretic peptides in the absence of heart failure likely represent an alternative pathophysiology such as anaemia or volume overload. Similarly, CRP elevations are often found in obese patients, and perhaps that is a risk factor for CAD.

Difficulties with legacies from the past Many clinicians learned about the use of CK-​MB and therefore have had difficulty giving up its use, despite the fact that there is no circumstance in which it provides additional information over and above troponin [34]. It may actually prevent clinicians from learning how to use cTn properly [34]. Some clinicians do not like using BNP, because they consider it as a substitute for clinical judgement. It should be synergistic with clinical judgement. For example, when patients have concurrent COPD and heart failure, it is difficult to determine which of the

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aetiologies might be responsible for the increasing shortness of breath. The use of BNP is remarkably efficacious in that circumstance. However, one can only use the data if one understands the analytic and pre-​analytic distinctions discussed. Similar caveats exist for CRP. The prognostic significance of CRP in the acute setting is fairly robust [117]. Using CRP to identify those patients who may receive a closer follow-​up and who then could/​should be evaluated, using the PROVE-​IT [38]-​suggested paradigm (see E Introduction, p. 387), makes sense. However, one cannot do that unless one learns the issues related to the measurement of CRP. Advocates often believe that it is essential to provide physicians with a simple paradigm, because they believe that clinicians will have difficulty if they have to learn too much about a marker. That is an insult to clinicians.

The future Troponin assays have become more sensitive. This increase will make an understanding of the analytical issues more essential for clinicians. For example, the minor differences between values seen with plasma and serum may become important [13]. There will also be differences in sex-​specific thresholds [15,  32]. It is now clear that there will be large numbers of elevations in many patients with CVD. For example, over 50% of patients with pacemakers will have such elevations, and after pacemaker implantation, an additional 30% or more will manifest elevations, some with a ‘rising’ pattern [75]. Whether the current treatment paradigms used in patients with ACS with elevations of contemporary troponin assays—​aggressive anticoagulation, antiplatelet agents, and an early invasive strategy—​are still appropriate with the new, more sensitive assays is unclear [118]. Additional markers in this area are unlikely to be necessary for AMI diagnosis. It is already clear that, when the 99th percentile cut-​off value is used, the so-​called ‘rapidly rising markers’ do not add to early diagnosis [119,  120] with contemporary or high-​sensitivity assays [121]. There are still some questions about additional markers for ruling out AMI. There is a recently reported trial evaluating copeptin for that use, in combination with a sensitive cTn assay [120], that suggests some benefit (CHOPIN), but data with hs-​cTn assays are less robust [121]. Time will tell. A marker that could help to identify those with ACS who are in need of urgent revascularization would be valuable [122]. Easy and novel protocols for the evaluation of

patients with chest discomfort will be developed [66]. They also will have pros and cons [69]. With natriuretic peptides, it is clear that the circulating form of BNP is proBNP [88]. Thus, heart failure itself is a failure of the synthesis and release of natriuretic peptides. This opens opportunities not only for therapeutic manipulations, but also for new markers such as corin, the protease responsible for cleaving proBNP into its active form [123]. In addition, multiple new analytes, such as mid-​range ANP, and an assay for proBNP are being developed [124,  125]. In addition, although natriuretic peptides predict mortality better than recurrent events such as AMI, there may be markers that are still better such as ST2 [126] and growth differentiation factor-​15 (GDF-​15) [127]. This paradigm may change with the use of neprilysin inhibitor agents [104,  105]. However, the basic principles governing the use of natriuretic peptide values should not be markedly changed by this advance [125]. New markers to assess inflammation are also present in large numbers. Finding a marker that would improve the specificity of CRP would be an advance, especially given recent evidence that treating inflammation reduces cardiac events, independent of any effects on LDL cholesterol [39, 128]. On the other hand, CRP amplifies the inflammatory signals from multiple inputs [129] and that may be why it has been so useful. Ultimately, combinations of markers will be employed, but this has not yet become a priority [130]. Thus, for now, the need is for clinicians to understand only one marker at a time, but to do that well.

Personal perspective There has been a lack of adequate education in this area, which leaves clinicians at the whim of lectures and special guideline documents that may sometimes represent bias, rather than facts. Clinicians should know some basic information about assays and how to think about them.

Acknowledgements Dr Jaffe is, or has been, a consultant to most of the major diagnostic companies who produce assays for cardiovascular biomarkers.

Further reading Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin Chem 2009;55:1303–​6. Apple FS, Parvin CA, Buechler KF, et  al. Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction. Clin Chem 2005;51:2198–​200.

Apple FS, Ranka L, Murakami MM. Determination of 19 cardiac troponin I  and T assay 99th percentile values from a common presumably healthy population. Clin Chem 2012;58:1574–​81. Bhatia S, Anstine C, Jaffe AS, et  al. Cardiac magnetic resonance in patients with elevated troponin and normal coronary angiography. Heart 2019;105:1231–​6.

RE F E RE N C E S Collinson PO, Heung YM, Gaze D, et al. Influence of population selection on the 99th percentile reference value for cardiac troponin assays. Clin Chem 2012;58:219–​25. Daniels LB, Laughlin GA, Clopton P, et  al. Minimally elevated cardiac troponin T and elevated N-​terminal pro-​B-​type natriuretic peptide predict mortality in older adults:  results from the Rancho Bernardo Study. J Am Coll Cardiol 2008;52:450–​9. Foo JYY, Wan Y, Schulz BL, et al. Circulating fragments of N-​terminal pro B-​type natriuretic peptide in plasma of heart failure patients. Clin Chem 2013;59:1523–​31. Jaffe AS. Chasing troponin. How low can you go if you can see the rise? J Am Coll Cardiol 2006;48:1763–​4. Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease—​the present and the future. J Am Coll Cardiol 2006;48:1–​11. Jaffe AS, Katus H. Acute coronary syndrome biomarkers—​the need for more adequate reporting. Circulation 2004;110:104–​6. Jaffe AS, Vasile VC, Ilone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle:  a noncardiac source of increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol 2011;58:1819–​24. Januzzi JL Jr, Chen-​ Tournoux AA, Christenson RH, et  al.; ICON-​ RELOADED Investigators. N-​terminal pro-​B-​type natriuretic peptide in the emergency department:  the ICON-​RELOADED Study. J Am Coll Cardiol 2018;71:1191–​200. Januzzi JL Jr, Peacock WF, Maisel AS, et  al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-​Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607–​13. Kavsak PA, MacRae AR, Yerna MJ, Jaffe AS. Analytic and clinical utility of a next generation, highly sensitive cardiac troponin I assay for early detection of myocardial injury. Clin Chem 2009;55:573–​7. Kempf T, von Haehling S, Peter T, et  al. Prognostic utility of growth differentiation factor-​15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054–​60. Khera A, McGuire DK, Murphy SA, et al. Race and gender differences in C-​reactive protein levels. J Am Coll Cardiol 2005;46:464–​9. Korley FK, Jaffe AS. Preparing the United States for high sensitivity cardiac troponin assays. J Am Coll Cardiol 2013;61:1753–​8. Mair J, Lindahl B, Giannitsis E, et  al.; the Biomarker Study Group of the European Society of Cardiology Acute Cardiovascular Care Association. Will sacubitril-​valsartan diminish the clinical utility of

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100. Omland T, Pfeffer MA, Solomon SD, et al. Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. J Am Coll Cardiol 2013;61:1240–​9. 101. Miller WL, Hartman KA, Burritt MF, et al. Serial biomarker measurements in ambulatory patients with chronic heart failure: the importance of change over time. Circulation 2007;116:249–​57. 102. Apple FS, Jesse RL, Newby LK, Wu AH, Christenson RH; National Academy of Clinical Biochemistry; IFCC Committee for Standardization of Markers of Cardiac Damage. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Circulation 2007;115:e352–​5. 103. Jaffe AS, Apple FS, Babuin L. Why we don’t know the answer may be more important than the specific question. Clin Chem 2004;50:1495–​7. 104. McMurray JJ, Packer M, Desai AS, et  al. Angiotensin/​neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–​1004. 105. Packer M, McMurray JJ, Desai AS, et  al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–​61. 106. Pavo N, Raderer M, Hülsmann M, et al. Cardiovascular biomarkers in patients with cancer and their association with all-​cause mortality. Heart 2015;101:1874–​80. 107. Cardinale D, Sandri MT, Colombo A, et  al. Prognostic value of troponin I  in cardiac risk stratification of cancer patients undergoing high-​dose chemotherapy. Circulation 2004;109:2749–​54. 108. Berridge BR, Pettit S, Walker DB, et al. A translational approach to detecting drug-​induced cardiac injury with cardiac troponins: consensus and recommendations from the Cardiac Troponins Biomarker Working Group of the Health and Environmental Sciences Institute. Am Heart J 2009;158:21–​9. 109. Henry CR, Satran D, Lindgren B, Adkinson C, Nicholson CI, Henry TD. Myocardial injury and long-​term mortality following moderate to severe carbon monoxide poisoning. JAMA 2006;295:398–​440. 110. Assomull RG, Lyne JC, Keenan N, et  al. The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J 2007;28:1242–​9. 111. Bhatia S, Anstine C, Jaffe AS, et al. Cardiac magnetic resonance in patients with elevated troponin and normal coronary angiography. Heart 2019;105:1231–​6. 112. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 2011;124:1414–​25. 113. Tamis-​Holland JE, Jneid H, Reynolds HR, et  al.; American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Quality of Care and Outcomes Research. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease:  a scientific statement from the American Heart Association. Circulation 2019;139:e891–​908. 114. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation 2004;109:1250–​8. 115. Franz WM, Remppis A, Kandolf R, Kubler W, Katus HA. Serum troponin T:  diagnostic marker for acute myocarditis. Clin Chem 1996;42:340–​1.

RE F E RE N C E S 116. Sandoval Y, Jaffe AS. Type 2 myocardial infarction. J Am Coll Cardiol 2019;73:1846–​60. 117. Kelly C, Weisz G, Maehara A, et al. CRP levels 180 days after PCI for ACS, but not earlier, predict late adverse cardiac events independent of plaque characteristics: the PROSPECT Study. J Am Coll Cardiol 2012;59:e335. 118. Katus HA, Giannitsis E, Jaffe AS, Thygesen K. Higher sensitivity troponin assays: quo vadis? Eur Heart J 2009;30:127–​8. 119. Kavsak PA, MacRae AR, Newman AM, et  al. Effects of contemporary troponin assay sensitivity on the utility of the early markers myoglobin and CKMB isoforms in evaluating patients with possible acute myocardial infarction. Clin Chim Acta 2007;380:213–​16. 120. Maisel A, Mueller C, Neath SX, et  al. Copeptin helps in the early detection of patients with acute myocardial infarction. Primary results of the CHOPIN Trial (Copeptin Helps in the Early Detection of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2013;62:150–​60. 121. Hillinger P, Twerenbold R, Jaeger C, et  al. Optimizing early rule-​ out strategies for acute myocardial infarction:  utility of 1-​hour copeptin. Clin Chem 2015;61:1466–​74. 122. Eisenberg PR, Kenzora J, Sobel BE, Ludbrook PA, Jaffe AS. Relation between ST segment shifts during ischemia and thrombin activity in patients with unstable angina. J Am Coll Cardiol 1991;18:893–​903. 123. Peleg A, Jaffe AS, Hasin Y. Enzyme-​linked immunoabsorbent assay for detection of human serine protease corin in blood. Clin Chim Acta 2009;409:85–​9. 124. Moertl D, Berger R, Struck J, et al. Comparison of midregional pro-​ atrial and B-​ type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular

systolic dysfunction, and prediction of death. J Am Coll Cardiol 2009;53:1783–​90. 125. Mair J, Lindahl B, Giannitsis E, et al.; the Biomarker Study Group of the European Society of Cardiology Acute Cardiovascular Care Association. Will sacubitril-​valsartan diminish the clinical utility of B-​type natriuretic peptide testing in acute cardiac care? Eur Heart J Acute Cardiovasc Care 2017;6:321–​8. 126. Januzzi JL Jr, Peacock WF, Maisel AS, et  al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-​Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607–​13. 127. Kempf T, von Haehling S, Peter T, et al. Prognostic utility of growth differentiation factor-​15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054–​60. 128. Ridker PM, Everett BM, Thuren T, et  al.; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–​31. 129. Tsimikas S, Willerson JT, Ridker PM. C-​reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006;47(8 Suppl):C19–​31. 130. Zethelius B, Berglund L, Sundstrom J, et  al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358:2107–​16.

ADDITIONAL ONLINE MATERIAL For additional multimedia materials, please visit the online version of the book (M M oxfordmedicine.com/ESCIACC3e).

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Biomarkers in acute coronary syndromes Jasper Boeddinghaus, Thomas Nestelberger, Raphael Twerenbold, and Christian Mueller

Contents Summary  400 Introduction: the role of biomarkers in acute coronary syndromes  400 High-​sensitivity cardiac troponin  401 Central laboratory versus point-​of-​care  403 Other biomarkers  403 Rapid ‘rule-​in’ and ‘rule-​out’ algorithms  404 Caveats of using rapid algorithms  404 Confounders of cardiac troponin concentration  405 Practical guidance on how to implement the ESC 0/​1-​hour algorithm  405 Avoiding misunderstandings: time to decision = time of blood draw + turnaround time  405 Personal perspective  406 References  407

Summary Biomarkers, particularly high-​sensitivity cardiac troponin T/​I (hs-​cTnT/​I), play a major role in the early diagnosis and risk stratification of patients presenting with symptoms suggestive of an acute coronary syndrome such as acute chest pain. As heart-​specific markers of cardiomyocyte injury, hs-​cTnT/​I complement clinical assessment and the 12-​lead electrocardiogram in the diagnosis of myocardial infarction, risk stratification for life-​threatening arrhythmias and death, and triage towards early revascularization. hs-​cTnT/​I allow the reliable measurement of cTnT/​I concentrations around the 99th percentile and in the normal range and increase the diagnostic accuracy for myocardial infarction at presentation. Absolute short-​term changes in hs-​cTnT/​I within 1 or 2 hours further increase the diagnostic accuracy for myocardial infarction. The European Society of Cardiology (ESC) hs-​cTnT/​I 0/​1-​hour algorithms are assay-​specific, early-​triage algorithms optimized for the early rule-​out and/​or rule-​ in of myocardial infarction. These algorithms triage patients towards rule-​out (about 60%), observe (about 25%), and rule-​in (about 15%). Triage towards rule-​out provides a very high sensitivity (99%) and negative predictive value (>99%) for the safe rule-​out of myocardial infarction, while triage towards rule-​in provides a high specificity (about 96%) and positive predictive value (about 75%) for myocardial infarction. Other biomarkers quantifying cardiomyocyte injury, e.g. CK-​MB, creatine kinase, lactate dehydrogenase, myosin-​binding protein C, or other pathophysiological processes involved in acute coronary syndromes, e.g. copeptin, B-​type natriuretic peptide (BNP), N-​terminal pro-​B-​type natriuretic peptide (NT-​proBNP), provide no or only very little incremental diagnostic value for myocardial infarction on top of the ESC hs-​cTnT/​I 0/​1-​hour algorithms. However, the latter provide incremental prognostic value for death and heart failure. Therefore, the use of BNP or NT-​proBNP as quantitative markers of haemodynamic stress and heart failure should be considered.

Introduction: the role of biomarkers in acute coronary syndromes The most important advance in biomarker testing in recent years was the clinical implementation of hs-​cTn assays. In contrast to conventional, less sensitive cTn assays, hs-​cTn assays have much higher analytical sensitivity and precision. This allows detecting smaller

Hi g h- sen si ti vi t y ca rdiac   t rop on i n amounts of myocardial necrosis and diagnosing an NSTEMI earlier and more accurately [1–​4], thereby at large overcoming the sensitivity deficit of conventional cTn assays at presentation. As a consequence, the ESC guidelines [3]‌recommend the implementation of hs-​cTn assays and their use in combination with a diagnostic strategy—​a 0/​1-​hour algorithm with a second sample already after 1 hour, and a 0/​2-​hour algorithm with a second sample after 2 hours. If the diagnosis is still uncertain or clinical suspicion for the presence of ACS is high, cTn testing at later time points is recommended. Furthermore, cTn concentrations should always be used in conjunction with the clinical presentation and history, as well as with the 12-​lead ECG. Alternatives to these algorithms, e.g. a 2-​hour accelerated diagnostic protocol with use of cTn concentrations, an instant rule-​ out strategy using a single hs-​cTn concentration with a cut-​off at the assay-​specific detection limit, a combination of low cTn or hs-​cTn concentrations together with low copeptin concentrations, or a strategy using cardiac myosin-​binding protein C

Low

(c-​MyC) concentrations, have been validated and some of them are clinically applied [5–​14]. Other biomarkers involved in different pathways, such as inflammation, activation of coagulation, myocyte necrosis, vascular damage, and haemodynamic stress, have been described. While they are less helpful for diagnosis, they may improve risk stratification and the selection of optimal treatment strategies. However, as cTn represents the standard of care in the diagnosis of NSTE-​ACS, E Chapter 33 mainly focuses on the clinical use of hs-​cTn assays.

High-​sensitivity cardiac troponin Biomarkers complement clinical assessment and the 12-​ lead ECG in the diagnosis, risk stratification, and treatment of patients with suspected NSTE-​ACS. Measurement of a biomarker of cardiomyocyte injury, preferably hs-​cTn, is mandatory in all patients with suspected NSTE-​ACS [3, 14–​19] (see E Figure 32.1).

Likelihood of myocardial infarction (MI)

High

I. Clinical setting Symptoms and vital signs

II. Electrocardiogram (ECG)

III. Troponin level at 0h Iv. Troponin change within 1h (or 2, 3h) Triage decision

Differential diagnosis

CPR/shock

ST depression (mild)

Normal ECG

–

–

Rule-out MI

Non-cardiac

ST depression (pronounced) –/+

+

–/+

+

Observe

Unstable angina

Other cardiac

ST elevation

++

+++

++

If any of the above, consider direct rule-in

Rule-in MI

NSTEMI

STEMI

Figure 32.1  The initial assessment is based on the integration of low likelihood and/​or high likelihood features derived from the clinical setting (i.e. symptoms and vital signs), 12-​lead ECG, and cardiac troponin level determined at presentation to the ED and serially thereafter. ‘Other cardiac’ includes, among others, myocarditis, Takotsubo cardiomyopathy, and congestive heart failure. ‘Non-​cardiac’ refers to thoracic diseases such as pneumonia and pneumothorax. Cardiac troponin and its changes in concentration during serial sampling should be interpreted as a quantitative marker—​the higher the 0-​hour level or the absolute change during serial sampling, the higher the likelihood for the presence of myocardial infarction. In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography should be performed/​interpreted by trained physicians immediately following a 12-​lead ECG. If the initial evaluation suggests aortic dissection or pulmonary embolism, D-​dimers and multi-​detector computerized tomography angiography are recommended according to dedicated algorithms [3, 20, 21, 73, 74]. CPR, cardiopulmonary resuscitation; ECG, electrocardiography; NSTEMI, non-​ST-​segment-​ elevation myocardial infarction; STEMI, ST-​segment-​elevation myocardial infarction.

Reproduced from Roffi M, Patrono C, Collet J-​P, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-​Segment Elevation of. Eur Heart J 2016 Jan 14;37(3):267–​315 with permission from Oxford University Press.

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cTn is a more sensitive and specific marker of cardiomyocyte injury than CK, its MB isoenzyme (CK-​MB), and myoglobin [3, 14–​ 21]. Troponin is a component of the contractile apparatus within skeletal and cardiac myocytes. Along with Ca2+ ions, troponin proteins regulate and facilitate the interaction between actin and myosin filaments, as part of the sliding filament mechanism of muscle contraction. cTn is a complex comprising three subunits: ◆ Troponin T attaches the troponin complex to the actin filament. ◆ Troponin C acts as the Ca2+ binding site. ◆ Troponin I  inhibits the interaction with myosin heads in the absence of sufficient Ca2+ ions. Troponin C is synthesized in skeletal and cardiac muscle. Troponin T and I  isoforms are highly specific and sensitive to cardiac myocytes and therefore are known as cTn. The detection of cTnT or cTnI in the bloodstream is therefore a highly specific marker for cardiomyocyte injury [22]. According to estimates from in vitro models, 92–​95% of cTn is attached to actin thin filaments in the cardiac sarcomere and the remaining 5–​8% is free in the myocyte cytoplasm [23]. Free, unbound cTn is thought to constitute the ‘early releasable troponin pool’ (ERTP) [24]. The concept of the ERTP helps when considering the various mechanisms of troponin release into the bloodstream. ERTP is thought

to be released immediately following myocyte injury and, assuming normal renal function, this would be cleared promptly. This is contrary to structurally bound cTn, which degrades over a period of hours to several days, causing a more stable and gradual troponin release. The plasma half-​life of cTn seems to be around 2 hours. Although the precise mechanism by which troponin is eliminated from the body remains unclear, it is hypothesized that troponin is cleared, at least in part, by the renal reticulo-​ endothelial system [25]. If the clinical presentation is compatible with myocardial ischaemia, then a dynamic elevation of cTn above the 99th percentile of healthy individuals indicates MI. In patients with MI, levels of cTn rise rapidly (i.e. usually within 1 hour if using hs-​cTn assays) after symptom onset and remain elevated for a variable period of time (usually several days) [3, 14–​21]. Advances in technology have led to a refinement in cTn assays and have improved the ability to detect and quantify cardiomyocyte injury [3, 14–​21, 26–​31]. Data from large multicentre studies have consistently shown that hs-​cTn assays increase diagnostic accuracy for MI at the time of presentation, as compared with conventional assays (see E Figure 32.2), especially in patients presenting early after CP onset, and allow for a more rapid ‘rule-​in’ and ‘rule-​out’ of MI [3, 14–​21, 26–​31] (see E Box 32.1).

Conventional assay micrograms/L

High-sensitivity assay × 1000

ng/L

100

0.100

Pathologic

Most POCT

Pathologic

50

0.030–0.040 CV of 10% Likely pathologic 0.010 Limit of detection Undetectable

402

???

99th percentile

10–20*

99th percentile

Likely normal Normal 1–5* Limit of detection

Figure 32.2  High-​sensitivity cardiac troponin (hs-​cTn) assays (right) are reported in ng/​L and provide identical information, as compared to conventional

assays (left, reported in micrograms/​L), if the concentration is substantially elevated, e.g. above 100 ng/​L. In contrast, only hs-​cTn allows a precise differentiation between ‘normal’ and mildly elevated. Therefore, hs-​cTn detects a relevant proportion of patients with previously undetectable cardiac troponin concentrations with the conventional assay who have hs-​cTn concentrations above the 99th percentile possibly related to acute myocardial infarction. * The limit of detection varies among the different hs-​cTn assays—​between 1 ng/​L and 5 ng/​L. Similarly, the 99th percentile varies among the different hs-​cTn assays—​between 10 ng/​L and 20 ng/​L for most of them [14–​17, 20, 21, 26–​28, 74].

Other  b i o m a rk e r s Box 32.1  Clinical implications of high-​sensitivity cardiac troponin assays Compared with standard cTn assays, high-​sensitivity assays: ◆ Have higher NPV for AMI. ◆ Reduce the ‘troponin-​blind’ interval, leading to earlier detection of AMI. ◆ Result in approximately 4% absolute and 20% relative increase in the detection of type 1 MI and a corresponding decrease in the diagnosis of UA. ◆ Are associated with a 2-​fold increase in the detection of type 2 MI. Levels of hs-​cTn should be interpreted as quantitative markers of cardiomyocyte damage (i.e. the higher the level, the greater the likelihood of MI): ◆ Elevations beyond 5-​fold the upper reference limit have high (>90%) PPV for acute type 1 MI. ◆ Elevations up to 3-​fold the upper reference limit have only limited (50–​60%) PPV for AMI and may be associated with a broad spectrum of conditions. ◆ It is common to detect circulating levels of cTn in healthy individuals. Rising and/​or falling cTn levels differentiate acute (as in MI) from chronic cardiomyocyte damage (the more pronounced the change, the higher the likelihood of AMI). AMI, acute myocardial infarction; cTn, cardiac troponin; MI, myocardial infarction; NPV, negative predictive value; PPV, positive predictive value; UA, unstable angina.

Central laboratory versus point-​of-​care The vast majority of cTn assays run on automated platforms in the central laboratory are sensitive (i.e. allow for detection of cTn in ~20–​50% of healthy individuals) or high-​sensitive (detection in ~50–​95% of healthy individuals) assays. hs-​cTn assays are recommended over less sensitive ones, as they provide higher diagnostic accuracy at identical low cost [3, 14–​21, 26–​31]. The majority of currently used point-​of-​care assays cannot be considered sensitive or high-​sensitivity assays [32]. Therefore, the obvious advantage of POCTs, namely a shorter turnaround time, is counterbalanced by lower sensitivity, lower diagnostic accuracy, and lower NPV. Overall, automated assays have been more thoroughly evaluated, as compared with POCTs, and seem to be preferable at this point in time [3, 14–​21, 26–​31). As these techniques continue to improve and performance characteristics are both assay-​and hospital-​dependent, it is important to re-​evaluate this preference once extensively validated high-​sensitivity point-​of-​care assays become clinically available [33]. In most patients with renal dysfunction, elevations in cTn should not be primarily attributed to impaired clearance and considered harmless, as cardiac conditions such as chronic coronary or hypertensive heart disease seem to be the most

Box 32.2  Conditions other than type 1 acute myocardial infarction associated with cardiomyocyte injury (= cardiac troponin elevation) ◆ Tachyarrhythmias ◆ Heart failure ◆ Hypertensive emergencies ◆ Critical illness (e.g. shock, sepsis, burns) ◆ Myocarditis* ◆ Takotsubo cardiomyopathy ◆ Structural heart disease (e.g. aortic stenosis) ◆ Aortic dissection ◆ Pulmonary embolism, pulmonary hypertension ◆ Renal dysfunction and associated cardiac disease ◆ Acute neurological event (e.g. stroke or subarachnoid haemorrhage) ◆ Cardiac contusion or cardiac procedures (CABG, PCI, ablation, pacing, cardioversion, or endomyocardial biopsy) ◆ Hypo-​and hyperthyroidism ◆ Infiltrative diseases (e.g. amyloidosis, haemochromatosis, sarcoidosis, scleroderma) ◆ Myocardial drug toxicity or poisoning (e.g. doxorubicin, 5-​fluorouracil, herceptin, snake venoms) ◆ Extreme endurance efforts ◆ Rhabdomyolysis and associated cardiac disease

CABG, coronary artery bypass surgery; PCI, percutaneous coronary intervention. Italics: most frequent conditions. * Includes myocardial extension of endocarditis or pericarditis.

important contributor to cTn elevation in this setting [30, 34]. Other life-​threatening conditions presenting with CP, such as aortic dissection and PE, may also result in elevated cTn concentrations and should be considered as differential diagnoses (see E Box 32.2).

Other biomarkers Among the multitude of additional biomarkers evaluated for the diagnosis of NSTE-​ACS, only CK-​MB, c-​MyC, and copeptin [5, 9, 35–​44] seem to have clinical relevance when used in combination with cTnT/​I. CK-​MB shows a more rapid decline after MI, as compared with cTn, and may provide added value for the timing of myocardial injury and the detection of early reinfarction [3]‌. c-​MyC is more abundant than cTn and may therefore provide clinical value as an alternative to, or in combination with, cTn [6]. Assessment of copeptin, the C-​terminal part of the vasopressin prohormone, may quantify the endogenous stress level in multiple medical conditions, including MI. As the level of endogenous stress appears to be invariably high at the onset of MI, the added value of copeptin to conventional (less sensitive) cTn assays is substantial [5, 37,  38]. Therefore, routine use of copeptin as an

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additional biomarker for early rule-​out of MI is recommended in the increasingly uncommon setting that hs-​cTn assays are not available. However, copeptin does not seem to have enough added value for institutions using one of the well-​validated hs-​cTn-​based rapid protocols in the early diagnosis of MI [9, 35, 36, 39–​44]. Other widely available laboratory variables, such as eGFR, glucose, and BNP, provide important incremental prognostic information and therefore help in risk stratification [45, 46].

Rapid ‘rule-​in’ and ‘rule-​out’ algorithms Due to the higher sensitivity and diagnostic accuracy for the detection of AMI at presentation, the time interval to the second cTn assessment can be shortened with the use of hs-​cTn assays. This seems to reduce substantially the delay to diagnosis, translating into shorter stays in the ED and lower costs [15, 47–​50]. It is recommended to use the ESC 0/​1-​hour algorithm or the 0/​2-​hour algorithm (see E Figure 32.3). These have been derived and well validated in large multicentre diagnostic studies using central adjudication of the final diagnosis for all currently available hs-​cTn assays [29, 30, 51–​55]. Optimal thresholds for rule-​out were selected to allow for a minimal sensitivity and NPV of 99%. Optimal thresholds for rule-​ in were selected to allow for a minimal PPV of 70%. The algorithms

Suspected NSTEMI

0h cTn: 1h

Very low* or

Low and no 1h∆

Other

High or 1h∆

Observe

Rule-in

*if CPO>3h Rule-out

3h cTN + echo Disposition: Imaging:

Discharge optional: Stress testing or CCTA or angiography or none

Ward Angiography or stress testing or CCTA or none

CCU Angiography and echo

Figure 32.3  ESC 0/​1-​hour rule-​out and rule-​in algorithm using hs-​cTn assays in haemodynamically stable patients presenting with suspected NSTEMI to the ED. ‘0h’ and ‘1h’ refer to the time from the first blood test. NSTEMI can be ruled out already at presentation if the hs-​cTn concentration is very low and if chest pain onset was >3 hours ago. NSTEMI can also be ruled out by the combination of low baseline levels and the lack of a relevant increase within 1 hour. Patients have a high likelihood for NSTEMI if the hs-​cTn concentration at presentation is at least moderately elevated or the hs-​cTn concentrations show a clear rise within the first hour [3, 14–​17, 20, 21, 26–​28, 74]. The same concept applies to the 0/​2-​hour algorithm. Cut-​off levels are assay-​specific. Cut-​off levels for other hs-​cTn assays are in development. * Only applicable if chest pain onset is >3 hours.

were developed in large derivation cohorts and then validated in large independent validation cohorts. As an alternative, the ESC 0/​3-​hour algorithm is recommended [3,  56]. However, three recent large diagnostic studies suggested that the ESC 0/​3-​hour algorithm seems to balance efficacy and safety less well than more rapid protocols using lower rule-​out concentrations, including the ESC 0/​1-​hour algorithm [57–​59]. The ESC 0/​1-​hour and 0/​2-​hour algorithms rely on two concepts. First, hs-​cTn is a continuous variable and the probability of MI increases with increasing hs-​cTn values [29, 30, 51–​53, 60, 61]. Second, early absolute changes of the levels within 1 or 2 hours can be used as surrogates for absolute changes over 3 or 6 hours and provide incremental diagnostic value to the cTn assessment at presentation [8, 29, 30, 51–​53, 55, 60, 61]. The cut-​off concentrations in the ESC 0/​1-​hour and 0/​2-​hour algorithms are assay-​specific (see E Table 32.1) [8, 29, 30, 51–​53, 55, 60, 61]. The NPV for MI in patients assigned ‘rule-​out’ exceeded 99% in several large validation cohorts [8, 29, 30, 51–​53, 55,  62]. Used in conjunction with clinical and ECG findings, the ESC 0/​1-​hour and 0/​2-​hour algorithms will allow the identification of appropriate candidates for early discharge and outpatient management. The PPV for MI in those patients meeting the ‘rule-​in’ criteria was about 75% [3, 51, 63, 64]. Most of the ‘rule-​in’ patients with diagnoses other than MI did have conditions that usually still require inpatient coronary angiography for an accurate diagnosis, including Takotsubo syndrome and myocarditis. Those algorithms should always be integrated with a detailed clinical assessment and a 12-​lead ECG, and repeat blood sampling is mandatory in cases of ongoing or recurrent CP. Patients who do not qualify for ‘rule-​out’ or ‘rule-​in’ represent a heterogenous group that usually require a third measurement of cTn at 3 hours and echocardiography as the next steps [65]. Coronary angiography should be considered in patients for whom there is a high degree of clinical suspicion of NSTE-​ACS (e.g. relevant increase in cTn from presentation to 3 hours), while in patients with low to intermediate likelihood for this condition, non-​ invasive imaging using stress testing (stress echocardiography), PET, myocardial perfusion scanning (MPS), or CMR or CT coronary angiography should be considered [47, 65]. No further diagnostic testing in the ED is indicated when alternative conditions, such as rapid ventricular rate response to AF or hypertensive emergency, have been identified.

Caveats of using rapid algorithms When using any algorithm, three main caveats apply:  (1) algorithms should only be used in conjunction with all available clinical information, including detailed assessment of CP characteristics and ECG; (2)  in patients presenting very early (e.g. within 1 hour from CP onset), an additional cTn level should be obtained at 3 hours, due to the time dependency of troponin release; (3)  as late increases in cTn have been described in

Avoi di n g m i su n der sta n di n g s Table 32.1  Optimal cut-​off levels 0/​1-​hour algorithm

Very low

Low

No 1 hour ∆

High

1 hour ∆

hs-​cTnT (Elecsys)

6000 patients has shown a significant reduction (17%) in early mortality with pre-​hospital, compared to in-​hospital, lysis initiation [49]. In a meta-​analysis of 22 trials, a much larger mortality reduction was found in patients treated within the first 2 hours than in those treated later [50]. These and more recent data support pre-​hospital initiation of fibrinolytic treatment if this reperfusion strategy is indicated [51]. The STREAM trial showed that pre-​hospital fibrinolysis followed by routine early angiography and PCI if indicated was associated with a similar outcome as transfer for primary PCI in STEMI patients presented within 3 hours after symptom onset who could not undergo primary PCI within 1 hour after FMC [33]. It is therefore recommended to initiate fibrinolytic therapy in the pre-​hospital setting.

Hazards of fibrinolysis Fibrinolytic therapy is associated with a small, but significant, excess of strokes, largely attributable to cerebral haemorrhage, appearing on the first days after treatment. Advanced age, lower weight, female gender, prior cerebrovascular disease, and hypertension on admission are significant predictors of ICH [52]. In the most recent STREAM trial, the initial excess in ICH (1% incidence) was reduced to 0.5% after protocol amendment to reduce the dose of tenecteplase by 50% in patients >75 years [33]. Major non-​cerebral bleeds can occur in 4–​13% of patients [33]. Contraindications to fibrinolytic therapy are shown in E Box 38.1.

Routine angiography after fibrinolytic therapy E Figure 38.3 shows treament strategies in patients undergoing fibrinolysis. If there is evidence of persistent occlusion, reocclusion, or reinfarction with recurrence of ST-​segment elevation after fibrinolysis, immediate angiography and rescue PCI are indicated. In this setting, re-​ administration of fibrinolysis has not been

Box 38.1  Contraindications for fibrinolysis

Absolute ◆ Previous ICH or stroke of unknown origin at any time ◆ Ischaemic stroke in the preceding 6 months ◆ Central nervous system neoplasms or arteriovenous malformation ◆ Recent major trauma/​surgery/​head injury (within the preceding month) ◆ Known bleeding disorder (excluding menses) ◆ Aortic dissection ◆ Non-​compressible punctures in the past 24 hours (e.g. liver biopsy, lumbar puncture)

Relative ◆ Transient ischaemic attack in the preceding 6 months ◆ Oral anticoagulant therapy ◆ Pregnancy or within 1 week postpartum ◆ Refractory hypertension (SBP >180 mmHg and/​or DBP >110 mmHg) ◆ Advanced liver disease ◆ Infective endocarditis ◆ Active peptic ulcer ◆ Prolonged or traumatic resuscitation

DBP, diastolic blood pressure; SBP, systolic blood pressure.

shown to be beneficial. Even if it is likely that fibrinolysis was successful, a strategy of routine early angiography is recommended if there are no contraindications. Several randomized trials and contemporary meta-​analyses [53] have shown that early routine angiography with subsequent PCI (if indicated) after fibrinolysis reduced the rates of reinfarction and recurrent ischaemia. Routine angiography should be performed 2–​24 hours after successful fibrinolysis.

Adjunctive anticoagulant and antiplatelet therapy Tenecteplase, enoxaparin, aspirin, and clopidogrel comprise the antithrombotic combination that has been most extensively studied as part of a fibrinolysis and early routine PCI strategy [33, 54]. Convincing evidence of the effectiveness of aspirin was demonstrated in the ISIS-​2 trial, in which the benefits of aspirin and streptokinase were additive—​with a first dose of 150–​300 mg (chewed) and a lower oral dose (75–​100 mg) daily thereafter. If oral ingestion is not possible, aspirin can be given IV (250–​ 500 mg). The benefit of clopidogrel added to aspirin in patients treated with fibrinolysis was demonstrated in the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) and Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trials [55,  56]. Accordingly, clopidogrel should be added to aspirin as an adjunct to lytic therapy in the acute phase. The recent

Speci fi c t y pes of i n fa rcti on a n d   sub g roup s Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis (TREAT) trial enrolled 3800 STEMI patients undergoing fibrinolysis and randomized them to clopidogrel or ticagrelor (both with loading dose) at a mean time of 11 hours after lytic therapy [57]. There were no differences in the rate of the combined outcome of cardiovascular mortality, MI, or stroke at 1 year. The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups [57]. Despite this trial being neutral, it provides strong evidence for the safety of using ticagrelor in patients who underwent fibrinolysis. There is no evidence that administration of GPIIb/​IIIa inhibitors improves myocardial perfusion or outcomes in patients treated with fibrinolysis [58], and a recent meta-​analysis showed that addition of GPIIb or GPIIIa inhibitors to fibrinolytic therapy increases the risk of major bleeding and should be discouraged [48]. Heparin has been extensively used during and after fibrinolysis. Heparin does not improve immediate clot lysis, but coronary patency evaluated in the hours or days following fibrinolytic therapy. Heparin infusion after fibrinolytic therapy may be discontinued after 24–​ 48 hours. Treatment with the low-​ molecular weight enoxaparin is associated with a significant reduction in the risk of death and reinfarction at 30 days, compared to a weight-​adjusted heparin dose [59]. This is, however, achieved at the cost of a significant increase in non-​cerebral bleeding complications. The net clinical benefit favours enoxaparin. When the dose is adjusted for age and renal function, this benefit was observed, regardless of the type of fibrinolytic agent and the age of the patient. Fondaparinux has been shown to be superior to placebo or heparin in preventing death and reinfarction, especially in patients receiving streptokinase [60].

Coronary bypass surgery in STEMI patients Emergent CABG should be considered for patients with a patent IRA, but with an unsuitable anatomy for PCI, and with either a large myocardial area at jeopardy or CS. In STEMI patients with failed PCI or coronary occlusion not amenable to PCI, emergent CABG is infrequently performed because the benefits of surgical revascularization in this setting are uncertain. In the absence of randomized data, optimal timing for non-​emergent CABG in stabilized post-​STEMI patients should be determined individually. A  review of California discharge data compared patients who underwent early (120 mmHg was associated with a significant reduction in infarct size measured by CMR at 5–​7 days and significantly higher LVEF at 6 months by CMR, compared with control treatment [66]. A subgroup analysis of the trial suggested that the sooner IV metoprolol was administered in the course of infarction, the smaller was the infarct size [67]. In the Early-​Beta blocker Administration before reperfusion primary PCI in patients with ST-​elevation Myocardial Infarction (EARLY-​BAMI) trial [68], early IV metoprolol administration did not show any benefit in reducing CMR-​based infarct size, but it reduced the rate of malignant ventricular arrhythmias. Based on the current available evidence, early administration of IV β-​blockers at the time of presentation should be considered in haemodynamically stable patients undergoing primary PCI. Oral β-​blockers should be initiated within 24 hours after STEMI.

Nitrates Routine use of nitrates in STEMI was of no benefit in a trial against placebo and is therefore not recommended [69]. IV nitrates may be useful during the acute phase in patients with hypertension or heart failure. E Figure 38.4 shows the most important therapies to be used in STEMI patients.

Specific types of infarction and subgroups Right ventricular infarction The recognition of RV infarction is important because it may manifest itself as CS, but the appropriate treatment strategy is quite different from that in shock due to severe LV dysfunction. RV infarction may be suspected by the specific, but insensitive, clinical triad of hypotension, clear lung fields, and raised JVP

487

CHAPTER 38  

ST- se g ment elevat ion myo ca rdia l  i n fa rcti on Strategy clock STEMI diagnosis

90 min

Cath lab

0

ECG Alert monitoring Cath lab & I B bypass ED I B

Aspirin loading1

Oxygen when sat 40%, no HF IIa B

LVEF >40%, no HF IIa A MRA (if LVEF ≤40% and HF) I B

Hospital discharge

6–12 weeks I year

Echo (LVEF) I C

b

Figure 38.4  ‘Do not forget’ interventions in STEMI patients undergoing a primary PCI strategy. Mostly prescribed interventions (Class I, green; Class IIa,

yellow) are presented, along with the expected timing of delivery. Solid lines represent recurrent (daily) intervention. Double-​arrowed dashed lines represent a time window in which the intervention can be delivered. 1 Aspirin loading dose: 150–​300 mg chewed or 75–​250 mg IV (in patients not already on an aspirin maintenance dose). 2 Prasugrel loading dose: 60 mg. Ticagrelor loading dose: 180 mg. If there are contraindications for prasugrel/​ticagrelor or these are not available, a loading dose of clopidogrel (600 mg) is indicated. 3 If the interventional cardiologist is not an expert in radial access, the femoral route is then preferred. 4 Enoxaparin or bivalirudin are alternatives to UFH (Class IIa A). 5 Aspirin maintenance dose: 75–​100 mg PO. 6 Prasugrel maintenance dose: 10 mg once daily. Ticagrelor maintenance dose: 90 mg twice daily. If there are contraindications for prasugrel/​ticagrelor or these are not available, clopidogrel maintenance (75 mg daily) is indicated. a 90 minutes represents the maximum target time to PCI-​mediated reperfusion. For patients presenting to a PCI-​centre, this target time is 60 minutes. b Prolongation of ticagrelor (60 mg twice daily), in addition to aspirin. ACE, angiotensin-​converting enzyme; DAPT, dual antiplatelet therapy; DES, drug-​eluting stent; ECG, electrocardiogram; echo, echocardiogram; ED, emergency department; HF, heart failure; IV, intravenous; IRA, infarct-​related artery; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation myocardial infarction; UFH, unfractionated heparin. Reproduced from Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-​Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Group ESCSD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-​segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-​segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39(2):119–​177 with permission from Oxford University Press.

Acu t e c omplicat i on s of ST- seg m en t el evati on m yo ca rdia l   i n fa rc t i on in a patient with inferior STEMI. ST-​segment elevation in V4R is very suggestive of the diagnosis. Echocardiography may confirm the diagnosis. When RV infarction can be implicated in hypotension or shock, it is important to maintain RV preload. It is desirable to avoid (if possible) vasodilator drugs such as opioids, nitrates, diuretics, and ACE-​Is/​ARBs. IV fluid loading is effective in many cases; initially, it should be administered rapidly. Revascularization should be performed as soon as possible, as it may result in rapid haemodynamic improvement [70].

Patients on chronic anticoagulation Management during STEMI Oral anticoagulation is a relative contraindication for fibrinolysis. Therefore, patients should be triaged for primary PCI strategy, regardless of the anticipated time to PCI-​mediated reperfusion. Patients should receive additional parenteral anticoagulation, regardless of the timing of the last dose of oral anticoagulant and INR. Loading of aspirin should be done as in all STEMI patients, and clopidogrel is the P2Y12 inhibitor of choice (it is not recommended to use prasugrel/​ ticagrelor). Ideally, a chronic anticoagulation regimen should not be stopped during admission. Gastric protection with a PPI is recommended.

Maintenance after STEMI While triple therapy (in the form of oral anticoagulation, aspirin, and clopidogrel) for 6 months has been the default strategy for these patients, recent evidence from the Open-​Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/​or Percutaneous Coronary Intervention (AUGUSTUS) trial [71] suggests that dual therapy in the form of P2Y12 inhibitor plus oral anticoagulation results in lower bleeding rates without an increase in ischaemic events. This trial enrolled 4600 patients with AF undergoing PCI (38% ACS) who were planning to take a P2Y12 inhibitor (>90% clopidogrel) to receive apixaban or a vitamin K antagonist (VKA) and to receive aspirin or matching placebo for 6 months (2 × 2 factorial design). Major or clinically relevant non-​major bleeding rates were significantly higher in the VKA group, compared to apixaban, and in patients receiving triple therapy, compared to those receiving dual therapy (i.e. no aspirin). Ischaemic events were not different among groups [71]. In general, non-​vitamin K new oral anticoagulants (NOACs), with the lowest effective tested dose for stroke prevention, are preferred over VKAs for any combination [41].

of myocardial dysfunction and possible complications such as MR and VSD. Patients with pulmonary congestion and SaO2 of 180 mmHg and/​or diastolic blood pressure >110 mmHg)

Central nervous system damage or neoplasms or arteriovenous malformation

Prolonged or traumatic resuscitation

Recent major surgery or trauma (including head trauma) within 4 weeks

Oral anticoagulant therapy

Non-​compressible punctures in past 24 hours (e.g. liver biopsy, lumbar puncture)

Infective endocarditis

Active internal bleeding

Pregnancy or within 1 week postpartum

Gastrointestinal bleeding within the past month

Active peptic ulcer

Known bleeding disorder

Advanced liver disease

Suspected aortic dissection

In the GUSTO-​III trial, which was designed as a superiority trial, 15 059 patients were randomized to double-​bolus reteplase given 30 minutes apart or to front-​loaded alteplase [19]. Mortality at 30 days was similar in both treatment arms (7.47% versus 7.24%, respectively), as was the incidence of haemorrhagic stroke or other major bleeding complications. Similar mortality rates were maintained for both treatment groups at 1-​year follow-​up [20].

In the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-​2) trial, 16 949 patients were randomized either to weight-​adjusted, single-​bolus TNK-​tPA or to standard front-​loaded alteplase [21]. Specifically designed as an equivalency trial, this study showed that TNK-​tPA and alteplase had equivalent 30-​day mortality rates (6.18% versus 6.15%, 90% CI 0.92–​1.10). Mortality rates remained similar at 1-​year follow-​up [22]. Although the rates of ICH were similar for TNK-​tPA (0.93%) and alteplase (0.94%), female patients, the elderly aged >75 years, and patients weighing 80%)

Tricuspid/​pulmonary atresia/​Fontan/​TCPC

PAC placement not possible

Intra-​/​extracardiac shunts

PAC unreliable

Chronic low CO state

Oesophageal Doppler unreliable (small aorta)

Multiple previous access, cutdowns, etc.

Expert in access required

Fontan, TCPC, tricuspid/​pulmonary atresia

Standard transvenous pacing is not possible. In an emergency, transcutaneous pacing may be required

ECG

Massive atrial enlargement and univentricular circulation

AT may be disguised as sinus tachycardia. High index of suspicion, comparison with previous ECGs; CSM/​adenosine/​pacemaker interrogation may be useful

INR

Cyanotic patients

If haematocrit >60, need citrate-​adjusted samples for accurate measurement

Circulating volume

Pulse oximetry

Cardiac output

Pacing

AT, atrial tachycardia; AV, atrioventricular; CO, cardiac output; CSM, carotid sinus massage; CVP, central venous pressure; INR, international normalized ratio; PA, pulmonary artery; PAC, pulmonary artery catheter; SpO2, oxygen saturations; TCPC, total cavopulmonary connection.

Cl i n i ca l  prese n tat i on s Table 58.4  Common acute presentations in patients with ACHD Diagnosis

Acute presentation

Comments

ASD

Atrial arrhythmia

May occur whether repaired or unrepaired Standard antiarrhythmic treatment recommended acutely Should be referred for further investigation/​intervention

LVF

Older patients may have significant LV disease

PH

May be disproportionate to the size of the shunt Expert assessment required to determine if should be closed, as PH may persist after closure

Endocarditis

On VSD, VSD patch, and/​or related anomaly (e.g. bicuspid aortic valve) Early liaison with multidisciplinary ACHD team recommended

Unrepaired: LV volume loading ± LVF

Assess if defect appropriate for repair

Unrepaired: left and right heart dilatation ± failure

May present with left heart volume loading if VSD present and/​or left AV valve regurgitation Degree of PH key Needs timely assessment by ACHD specialist

Unrepaired: Eisenmenger’s

Surgical repair contraindicated Standard Eisenmenger’s management Seek expert ACHD advice

Endocarditis

Diagnosis may be challenging, due to calcification related to previous repair—​expert echocardiography indicated Early liaison with multidisciplinary ACHD team recommended

AS

Angina/​dyspnoea/​syncope

Heralds rapidly worsening prognosis; refer for work-​up for urgent surgery Symptomatic ‘low-​gradient’ AS should be urgently referred for expert investigation

Sub-​AS

Angina/​dyspnoea/​syncope

May re-​present after previous successful intervention Early liaison with multidisciplinary ACHD team recommended

Coarctation

Uncontrolled upper body hypertension

VSD

AVSD

CVA

Association with berry aneurysm: urgent neurological investigation required

Marfan’s

Aortic dissection

Standard immediate management required Redissection can occur

RVOTO

Dyspnoea/​syncope

Higher degrees of obstruction usually better tolerated than left-​sided lesions Symptoms may be precipitated by development of arrhythmia

Endocarditis

Echocardiographic diagnosis may be challenging Early liaison with multidisciplinary ACHD team recommended

Tetralogy of Fallot

VF/​VT and aborted sudden cardiac death

Atrial and ventricular arrhythmias are common SCD reported in 1–​6% (VF/​VT) Standard emergency treatment and early liaison with ACHD specialist recommended regarding AICD and/​or ablation

PA + VSD

Haemoptysis

Usually due to rupture of collaterals or thrombus in a small pulmonary artery

Heart failure

Response to standard dilators and inotropic agents unpredictable May be precipitated by new arrhythmia; underlying cause should be sought and discussion with ACHD specialist recommended

Atrial tachyarrhythmias

Generally tolerated poorly (systemic RV), so early cardioversion recommended (see text) May precipitate rapid decline in systemic ventricular function

Sinus node dysfunction

Pacing specialist intervention in these patients

Systemic AV valve regurgitation

Associated with systemic ventricular failure Support with standard agents recommended IABP may not be helpful in younger patients (note: may also have small aortic diameter)

TGA + Rastelli

Syncope/​dyspnoea

Atrial and ventricular arrhythmias common Conduit stenosis may occur and be severe

TGA + arterial switch

Ventricular failure and arrhythmias

Generally relate to inadequate coronary perfusion (usually long-​standing), but coronary investigation is indicated and stenting/​surgery recommended for ongoing ischaemia Standard support recommended initially Early referral to ACHD specialist recommended

TGA + Mustard/​ Senning

(continued )

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CHAPTER 58  

C on genital h eart disease i n  a du lts

Table 58.4  Continued Diagnosis

Acute presentation

Comments

ccTGA

Syncope

AV block not uncommon Risk-​stratify for risk of sudden cardiac death

Heart failure

May be presentation in young adults with undiagnosed ccTGA Immediate standard therapy, and referral to ACHD specialist recommended

Hyperviscosity symptoms

Unusual if iron-​replete and with HCT 90  days) are used. The classification in time is important because complications occur more often and mortality is much higher in the acute and subacute phases of the disease [13]. In the first 2 weeks, rupture is the most frequent complication, whereas in the subacute phase, rapid aortic dilatation is important. This time-​based classification is also crucial because the dissected aorta loses its plasticity over a few months after the acute onset and treatment by endografting becomes less obvious in the chronic phase.

Traditional anatomical classifications Different types of dissections are distinguished on the basis of the location and extent of the dissection. Traditionally, two principal classifications (see E Figure 59.1) are used in clinical practice:  the DeBakey [14–​16] and the Stanford classification [17]. The DeBakey classification gives more information on the location and extent of the dissection, while the Stanford classification represents a more functional classification based on the principle that if the ascending aorta is involved, immediate surgery is mandatory. In these circumstances, the distal extent of the dissection has no influence on the decision to operate or not. It is important to notice that the location of the primary entry tear is unimportant in these traditionally used classifications. The classification of an IMH follows the same grouping. The traditionally used Stanford and DeBakey classifications were very helpful in the era when open surgery was the only choice. Actually the Penn and DISSECT classifications (see E Box 59.2) are valuable alternatives taking into consideration different factors and aspects of the dissection, focusing not only

Proximal

Distal

DeBakey

I

II

IIIa

IIIb

Stanford

A

A

B

B

Figure 59.1  Classification of acute aortic dissection, based on DeBakey

and Stanford. DeBakey classification: type I, involves the ascending aorta, arch, descending aorta, and abdominal aorta; type II, involves only the ascending aorta; type IIIa, involves the descending aorta; type IIIb, involves the descending aorta and abdominal aorta. Stanford classification: type A, involves the ascending aorta; type B, does not involve the ascending aorta. Reproduced from Salameh M, Ratchford E. Aortic dissection. Vasc Med 2016;21(3);276–​ 280 with permission from SAGE.

on the evolution of complications, but also on the endovascular therapeutic possibilities [19, 20]. At first glance, these new classifications might seem more complex, but they consider more elements that certainly were omitted in the old categories.

Incidence Because acute aortic dissection causes sudden death in a lot of patients, the incidence in the general population is difficult to estimate. An autopsy study has shown that up to 85% of acute aortic dissections were undiagnosed before death [21]. The incidence of aortic dissection is estimated at 2.5–​3.5 cases per 100 000 person-​years [22–​24]. The prevalence of acute type A aortic dissection in patients with OHCA is 7% [25]. A  lot of patients do not reach the hospital alive; pre-​hospital mortality is estimated to be almost 50% [26]. If deaths prior to hospital admission are included, the incidence of acute dissection is higher at 6/​100 000 person-​years (95% CI 4–​7) and it is estimated, based on projected evolution of age/​sex population structure, that the incidence may increase substantially over the next decades [27]. There have been circadian and seasonal variations described, with an incidence peaking in the morning during winter months [28,  29]. Type A dissection represents 60–​65% of acute aortic dissections, while type B represents only 35–​40%. Acute aortic dissection is twice as frequent in men than in women, and the mean age at presentation is 63 years for men and 67 years for women [30]. Patients with type A dissection tend to be younger than those with type B dissection. In patients with connective tissue disorders, aortic dissection tends to occur at a younger age, generally during the third or fourth decade of life. In these and younger patients, there is likely to be no history of hypertension, and type A dissection is more common.

807

808

CHAPTER 59  Aortic  emergencies

Box 59.2  Penn classification of complications in acute dissection and DISSECT classification

Penn classification ◆ Class A (uncomplicated): absence of branch vessel ischaemia or circulatory compromise ● Type 1: high risk of future complications ● Type 2: low risk of future complications ◆ Class B (complicated): branch vessel malperfusion with visceral, renal, lower extremity, and/​or spinal cord hypoperfusion ◆ Class C (complicated): circulatory compromise ● Type 1:  aortic rupture with haemorrhage outside the aortic wall, with/​without cardiac arrest, shock, and haemothorax ● Type 2: threatened aortic rupture typically heralded by refractory pain and/​or hypoperfusion ◆ Class BC (complicated): branch vessel malperfusion combined with circulatory compromise

DISSECT classification ◆ Duration ● Acute: 3 months ◆ Intimal tear (primary) location within aorta ● Ascending aorta

Risk factors and aetiology In many cases, histological analysis of a dissected aortic wall shows only changes corresponding to the age of the patient [31, 32]. This means that dissection may occur in an essentially normal aortic wall; however, several predisposing factors have been identified. Chronic or long-​term arterial hypertension is the factor most often associated with dissection and is found in 70% of cases [33]. The true incidence of hypertension in the acute stage can be blunted by haemodynamic shock. Most often, patients are not aware of the existing arterial hypertension. Acute arterial hypertension, such as that which occurs in weightlifters and cocaine or amphetamine users, but also in a large field of different situations in apparently healthy young subjects, also predisposes to acute aortic dissection [34, 35]. Another important predisposing factor is connective tissue disorders such as Marfan’s syndrome, in which a mutation in the fibrillin-​1 gene results in an abnormal media. Patients with Marfan’s syndrome (one per 5000 live births) generally develop aortic dilatation during the second to fourth decades of life, and 20–​40% of them experience aortic dissection [36, 37]. Ehlers–​Danlos, Loeys–​Dietz, Noonan’s, and Turner’s syndromes are other connective tissue disorders which predispose to aortic dissection relatively early in life [38–​41]. The frequently associated bicuspid aortic valve, moderate ascending aorta dilatation, and coarctation are also predisposing factors to aortic dissection [42,  43]. Familial aggregations of dissection without discerned biochemical or genetic abnormalities also exist [44]. During pregnancy, hypervolaemia and high cardiac output, combined with a

Aortic arch ● Descending aorta ● Abdominal aorta ● Unknown ◆ Size of aorta: based on maximum transaortic diameter measured by centre-​line analysis in millimetres at any level within the dissected segment ◆ Segmental extent of aortic involvement: ranging from the ascending aorta to the iliac vessels and everything in between ◆ Clinical complications ● Complicated: aortic valve involvement, tamponade, rupture, branch vessel malperfusion (anatomic and clinical), progression of aortic involvement, uncontrollable hypertension, rapid expansion (>10 mm in the first 2 weeks) ● Uncomplicated ◆ Thrombosis ●

● Patent aortic false lumen (evidence of flow or contrast); or ● Complete thrombosis of false lumen within the following segments (ascending aorta, aortic arch, descending aorta, abdomen); and ● Partial thrombosis within the following segments (ascending aorta, arch, descending aorta, abdomen)

changed hormonal state, contribute to an increased incidence of dissection [45]. Cardiac catheterization procedures, aortic cannulation, or cross-​clamping during cardiac surgery and placement of IABP are all situations carrying a low risk of provoking iatrogenic aortic traumatism that may lead to dissection. Vascular inflammation, such as occurring in certain autoimmune disorders like giant cell arteritis, polyarteritis nodosa, Takayasu’s arteritis, and Behçet’s disease, also may contribute to aortic dissection. Finally, closed blunt chest trauma or deceleration trauma (car accidents or fall from height) may rarely result in true aortic dissection.

Natural history and prognosis It is obvious that acute aortic dissection is the most lethal condition of the aorta. It is estimated that 40% of patients suffering from acute aortic dissection die immediately. For patients who survive after the onset of dissection and reach hospital alive, the risk of death remains high but varies in function of several factors. Hospital mortality is increased in older patients (≥70 years) and in patients who develop complications such as cardiac tamponade or severe hypotension with shock. Major organ malperfusion, such as cardiac ischaemia/​infarction, stroke, renal failure, and visceral or limb ischaemia, are other risk factors influencing survival negatively [46, 47]. In type A aortic dissection, the mortality rate is estimated to be 1–​2% per hour after the onset of acute symptoms [21, 48]. Data issued from the International Registry of Acute Aortic Dissection (IRAD) show that in type A  dissection, early surgical repair

Acu te aorti c  di s se c t i on decreases in-​hospital mortality by >50%, in comparison to medical treatment alone. At 14 days, repaired type A dissections have a mortality rate of 20% versus 49% for non-​repaired dissections [33]. From the same registry, uncomplicated type A dissections have a 17% in-​hospital mortality rate, in comparison to 31% for complicated dissections [49]. Acute type B dissection is less lethal than type A. Uncomplicated type B dissections, generally medically treated, have a relatively good prognosis, with a 14-​day mortality of 810 000 blunt trauma patients from the National Trauma Data Bank, the incidence of cardiac rupture was 0.05% [38]. Motor vehicle collision was the most common mechanism of injury (73%), followed by pedestrians struck by a car (16%) and falls from height (8%). The right cardiac chambers are most commonly injured, because of the more vulnerable location beneath the sternum and the relatively thin wall of the myocardium [39] (see E Figure 60.6). The low incidence of cardiac rupture in victims reaching hospital care is deceptive. The real incidence is much higher, but the vast majority of cases are declared dead at the scene and are transported to the coroner’s department or morgue. In a recent autopsy study of 304 deaths after traffic injuries in the County of Los Angeles, 20% had cardiac rupture; 85% of deaths occurred at the scene, and only 15% reached medical care [40]. Valvular or papillary muscle rupture may occur as a result of direct transmission of energy by the sternum or by increased pressure within the cardiac chambers. The most frequently injured valve is the aortic valve, followed by the mitral valve [38, 41, 42]. Some studies suggest that the valvular injuries are progressive and often require valve replacement [42]. Blunt coronary artery injury is found in 20  mmHg combined with pulmonary vascular resistance of ≥3 Wood units. While transthoracic echocardiography may provide clues on the presence of pulmonary hypertension, haemodynamic evaluation offers a more precise and comprehensive assessment. Pulmonary hypertension is heterogenous from a pathophysiological point of view, and the diversity is reflected in the haemodynamic definitions. The different haemodynamic forms of pulmonary hypertension can be found in multiple clinical conditions, which have been classified into five main groups and at least 26 subgroups. Each main clinical group shows specific pathological changes in the lung distal arteries, capillaries, and small veins. If we combine the haemodynamic and clinical heterogeneity, we understand the complexity of an accurate diagnosis in the individual patient, which is crucial for the prognostic assessment and treatment strategy. In addition, the concomitant presence of different haemodynamic and clinical mechanisms cannot be excluded in individual cases (e.g. in patients with congestive heart failure and associated lung diseases). The presence of pulmonary hypertension, as defined above, is always an ominous prognostic sign, even if the severity may differ according to the haemodynamic changes and underlying clinical condition. The therapeutic approach also is markedly different, according to the clinical group and symptomatic and haemodynamic severity. For these reasons, the four more frequent clinical groups are discussed individually, while the classifications are described in the Introduction section.

Introduction PH is a heterogenous haemodynamic and pathophysiological state that can be found in multiple clinical conditions which have been classified into five diagnostic groups with specific histological, clinical, and therapeutic features [1]‌. Recently, the clinical classification has been updated [2] (see E Box 62.1). Despite possible comparable elevations of pulmonary pressure in the different clinical groups, the underlying mechanisms, diagnostic approaches, and prognostic and therapeutic implications are completely different. Group 1, defined as pulmonary artery hypertension (PAH), includes rare conditions which share comparable clinical and haemodynamic pictures and virtually identical

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CHAPTER 62  P ulmonary h ypert ension

Box 62.1  Updated clinical classification of pulmonary hypertension [2]‌ 1 PAH 1.1 Idiopathic PAH 1.2 Heritable PAH 1.3 Drug-​and toxin-​induced PAH 1.4 PAH associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.5 PAH long-​term responders to calcium channel blockers 1.6 PAH with overt features of venous/​capillary (PVOD/​PCH) involvement 1.7 Persistent PH of the newborn syndrome 2 PH due to left heart disease 2.1 PH due to heart failure with preserved LVEF 2.2 PH due to heart failure with reduced LVEF 2.3 Valvular heart disease 2.4 Congenital/​acquired cardiovascular conditions leading to post-​capillary  PH

pathological changes in lung microcirculation. PAH comprises the idiopathic and familial forms and the forms associated with connective tissue diseases, congenital heart defects with systemic-​to-​pulmonary shunts, portal hypertension, and HIV infection. Treatment of more advanced stages (deteriorating WHO functional class  III or IV) requiring intensive care includes identification of precipitating conditions and appropriate use of diuretics, inotropic treatment, O2 therapy and ventilatory support, and specific PAH drug therapies (prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-​5 inhibitors). Intensive and acute care is also required in patients with lung infection and haemoptysis and in cases of elective surgery or during pregnancy, which should be avoided or terminated due to high mortality. Group 2 includes patients with PH due to left heart disease. In these cases, treatment is addressed to the underlying heart condition, and medications approved for PAH have not proven to be convincingly effective and may be detrimental [3]‌. Group 3 includes cases of PH associated with lung diseases, in which the use of PAH-​specific drugs is not recommended, on the basis of their minimal clinical efficacy and because they may impair pulmonary gas exchange. Group 4 comprises patients with chronic thromboembolic PH, for which the treatment of choice is pulmonary endarterectomy, and balloon pulmonary angioplasty (BPA) and/​or PAH-​specific drugs may be considered in non-​operable cases and/​or after suboptimal surgery. Group  5 includes heterogenous clinical conditions, in which PH is due to unclear and/​or multi-​factorial mechanisms.

3 PH due to lung diseases and/​or hypoxia 3.1 Obstructive lung disease 3.2 Restrictive lung disease 3.3  Other lung disease with mixed restrictive/​ obstructive pattern 3.4 Hypoxia without lung disease 3.5 Developmental lung disorders 4 PH due to pulmonary artery obstructions 4.1 Chronic thromboembolic PH 4.2 Other pulmonary artery obstructions 5 PH with unclear and/​or multi-​factorial mechanisms 5 .1 Haematological disorders 5.2 Systemic and metabolic disorders 5.3 Others 5.4 Complex congenital heart disease HIV, human immunodeficiency virus; LVEF, left ventricular ejection fraction; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary haemangiomatosis; PH, pulmonary hypertension; PVOD, pulmonary veno-​ occlusive disease.

Definitions and classifications Haemodynamic definitions According to the most recent PH guidelines, PH has been defined as an increase in mean PAP of ≥25 mmHg at rest, as assessed by RHC (see E Table 62.1) [1]‌. Recent re-​evaluation of available data have shown that normal mean PAP at rest is 14 ± 3 mmHg, with an upper limit of normal of approximately 20  mmHg. It has been proposed to define precapillary PH by the concomitant presence of mPAP >20 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and PVR ≥3 Woods unit (WU) (see ETable 62.1) [2], emphasizing the need for RHC, with mandatory measurement of cardiac output and accurate measurement of PAWP. The significance of mean PAP of between 21 and 24 mmHg has not been fully elucidated and patients presenting with PAP in this range need further evaluation in epidemiological studies. In addition, a change in the haemodynamic definition of PH does not imply treating these additional patients but highlights the importance of close monitoring in this population. Prospective trials are required to determine whether this PH population might benefit from specific management. The definition of PH on exercise as a mean PAP of >30 mmHg, as assessed by RHC, is not supported by published data and healthy individuals can reach much higher values [4]. Thus, no definition for PH on exercise, as assessed by RHC, can be provided at the present time. An important additional haemodynamic parameter which characterizes the definitions of PH is PAWP. In fact, according to various combinations of values of PAWP, PVR, and cardiac

Defi n i ti on s a n d  cl as si f i c at i on s Table 62.1  Haemodynamic definitions of pulmonary hypertension Definitions

Characteristics

Clinical group(s)

A: Haemodynamic definitions according to the most recent guidelines [1]‌ PH

Mean PAP ≥25 mmHg

All

Precapillary PH

Mean PAP ≥25 mmHg PAWP ≤15 mmHg

P AH PH due to lung diseases CTEPH PH with unclear and/​or multi-​factorial mechanisms

Post-​capillary PH

Mean PAP ≥25 mmHg PAWP >15 mmHg

PH due to left heart disease

IpcPH

DPG 3 WU

B: Haemodynamic definitions according to the Sixth World Symposium on Pulmonary Hypertension [2]‌ PH

Mean PAP >20 mmHg

All

Precapillary PH

Mean PAP >20 mmHg PAWP ≤15 mmHg

PAH PH due to lung diseases CTEPH PH with unclear and/​or multi-​factorial mechanisms

Post-​capillary PH

Mean PAP >20 mmHg PAWP >15 mmHg

PH due to left heart disease

IpcPH

PVR 3.4

Not required

High

B: Based on other echocardiographic pulmonary hypertension signs* (A) Ventricles

(B) Pulmonary artery

(C) Inferior vena cava and right atrium

Right ventricle:left ventricle basal diameter ratio >1.0

Right ventricular outflow Doppler acceleration time 21 mm, with decreased inspiratory collapse (2.2 m/​s

Right atrial area (end-​systole) >18 cm2

Pulmonary artery diameter >25 mm *

Echocardiographic signs from at least two different categories (A/​B/​C) from the list should be present to alter the level of echocardiographic probability of PH. Reproduced from Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/​ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37(1):67–​ 119. doi:10.1093/​eurheartj/​ehv317 with permission from Oxford University Press.

E Box 62.1). PAH includes different forms that share a similar clinical picture and virtually identical pathological changes of lung microcirculation. Comparative epidemiological data on the prevalence of the different groups of PH are not available. In a survey performed in an echocardiography laboratory [7]‌, the prevalence of PH (defined as pulmonary artery systolic pressure of >40 mmHg) among 4579 patients was 10.5%. Among the 483 cases with PH, 78.7% had left heart disease (group 2), 9.7% had lung diseases and hypoxaemia (group 3), 4.2% had PAH (group 1), and 0.6% had CTEPH (group 4), and in 6.8%, it was not possible to define the diagnosis [8].

Pulmonary arterial hypertension PAH represents the type of PH in which the most important advances in the understanding and treatment have been achieved in the past decade. It is also the group in which PH is the ‘core’ of the clinical problems and may be treated by specific drug therapy.

Pathology and pathophysiology PAH comprises apparently heterogenous conditions (see E Box 62.1) that share comparable clinical and haemodynamic pictures and virtually identical pathological changes of lung microcirculation. Pathological lesions affect the distal pulmonary arteries (70 mmHg.

Prevention of deep venous thrombosis and pulmonary embolism DVT and PE are feared complications in ICH patients. Only a few patients with ICH were included in trials evaluating different strategies of prevention. In the CLOTS trial [62], graduated compression stockings did not demonstrate any efficacy. However, only 232 ICH patients were included among 2518 stroke patients. The usefulness of heparin (UFH or LMWH) remains to be demonstrated in a setting where the haemorrhagic risk could easily counterbalance the benefit. In clinical practice, a low dose of SC heparin or LWMH can be considered after 24 hours [42]. The results of CLOTS 3 [43] showed that intermittent pneumatic compression is of interest.

Increased intracranial pressure ICP has a negative impact on vital and functional outcome. Invasive ICP monitoring has not been proven yet to be more efficient than clinical and radiological monitoring. All randomized studies to date have failed to demonstrate any efficacy on the outcome of ICH patients [63]. Methods for medical decompression of increased ICP may be useful to bridge the time to surgery, if the latter is planned. Corticosteroids are not recommended, and they should be avoided in the treatment of the acute phase

of ICH. Recommendations rely on a low level of evidence [42]. Medical treatment of elevated ICP includes glycerol, mannitol, hyper-​hydroxyethyl starch (HES), and short-​term hyperventilation (Class IV evidence). For example, mannitol (20%), in a dose of 0.75–​1 g/​kg, may be given as an IV bolus that is followed by 0.25–​0.5 g/​kg every 3–​6 hours, depending on the neurological status and fluid balance.

Haemostatic therapy Although very promising, to date, no haemostatic agents have proved their efficacy in the acute setting of ICH. The most recent candidate was recombinant factor VIIa. A phase III trial gathering 841 patients failed to demonstrate an improvement in outcome [64]. Other agents may be candidates such as ε-​aminocaproic acid. A careful analysis of current data suggests that a large randomized trial is necessary. Meanwhile, no haemostatic agent can be recommended in clinical practice.

Intracranial haemorrhage in patients treated with oral anticoagulants In the acute phase, every patient suffering from an ICH, with an INR >1.4, should be treated with IV vitamin K to reverse the effects of warfarin and with treatment to replace the clotting factors, regardless of the reason for the use of oral anticoagulant (i.e. including patients with mechanical heart valve) [42]. The aim of rapid reversal is to prevent secondary growth of the haematoma. European recommendations suggest using either prothrombin complex concentrate (PCC) or fresh frozen plasma, both of which are associated with IV vitamin K. Here is an example of the dosage for PCC (dosages are given in unit of FIX contained in PCC): 10–​20 U/​kg when INR 3.5, along with vitamin K 10 mg IV. Only a few case reports describe the use of recombinant FVIIa in this setting. To date, recombinant FVIIa should not be used routinely outside clinical trials.

Spec i f i c   i ssue s Until recently, there was no antidote for ICH occurring in patients treated with NOACs. This was a limitation of these drugs. However, it has been shown that idarucizumab completely reverses the anticoagulant effect of dabigatran within a few minutes [65], but the question of whether it improves outcome remains unanswered. Currently available agents have relatively short half-​ lives. Potential reversal strategies using FEIBA or other PCCs or recombinant activated factor VIIa might be considered. Fresh frozen plasma and vitamin K are not useful.

Intracranial haemorrhage in patients treated with antiplatelet drugs No specific strategy is recommended for patients bleeding while on antiplatelet drugs. Studies evaluating the efficacy of platelet infusion failed to demonstrate a benefit, or even showed that platelet transfusion is inferior to standard care [66]. Platelet transfusion cannot be recommended for this indication in clinical practice.

Thrombolytic therapies In ICH patients with intraventricular extension and obstruction of the third and fourth ventricles, some data suggest that the use of rtPA, injected directly in the ventricles, may improve functional outcome [67].

Surgery Infratentorial intracranial haemorrhage Clot evacuation should be considered if there is neurological dysfunction or radiological evidence of obliteration of CSF spaces infratentorially. The optimal timing has not been established, and there are no prospective RCTs of surgery in cerebellar haemorrhage. European recommendations state that ventricular drainage and evacuation of the cerebellar haematoma should be considered if haematomas are larger than 2–​3 cm in diameter or if hydrocephalus occurs, although advanced age and coma advocate against favourable outcomes [42]. Supratentorial intracranial haemorrhage The Surgical Trial in Spontaneous Intracerebral Haemorrhage (STICH) showed in 1033 patients that early surgery (within 24 hours) did not improve outcome, compared to medical management. Therefore, clinical observation and medical management are the first steps in the management of ICH patients. Pre-​specified subgroup analyses from STICH and a recent meta-​ analysis suggest that craniotomy could be considered in cases of deterioration in consciousness (from GCS score of 12 to 9 or lower) [68] or if the ICH is superficial (≤1 cm from the surface and does not reach the deep basal ganglia) [42, 68]. Deep-​seated haematomas do not benefit from craniotomy [68]. The STICH II trial [69] showed that early surgery does not increase the risk of death or disability at 6 months but might slightly increase survival in patients with spontaneous ICH and no intraventricular bleeding. Minimally invasive surgery with local thrombolysis may be an alternative [70].

Specific issues Stroke due to cerebral venous thrombosis Diagnosis Cerebral venous and sinus thrombosis (CVST) accounts for